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Background: Patients with chronic kidney disease (CKD) have considerable cardiovascular morbidity and mortality. Aortic stiffness is an independent predictor of cardiovascular risk and related to left ventricular remodeling and heart failure. Myocardial fibrosis is the pathophysiological hallmark of the failing heart.
Methods and results: An observational study of consecutive CKD patients (n = 276) undergoing comprehensive clinical cardiovascular magnetic resonance imaging. The relationship between aortic stiffness, myocardial fibrosis, left ventricular remodeling and the severity of chronic kidney disease was examined. Compared to age-gender matched controls with no known kidney disease (n = 242), CKD patients had considerably higher myocardial native T1 and central aortic PWV (p ≪ 0.001), as well as abnormal diastolic relaxation by E/e′ (mean) by echocardiography (p ≪ 0.01). A third of all patients had LGE, with similar proportions for the presence and the (ischaemic and non-ischaemic) pattern between the groups. PWV was strongly associated with and age, NT-proBNP and native T1 in both groups, but not with LGE presence or type; the associations were amplified in severe CKD stages. In multivariate analyses, PWV was independently associated with native T1 in both groups (p ≪ 0.01) with near two-fold increase in adjusted R2 in the presence of CKD (native T1 (10 ms) R2, B(95%CI) CKD vs. non-CKD 0.28, 0.2(0.15–0.25) vs. 0.18, 0.1(0.06–0.15), p ≪ 0.01).
Conclusions: Aortic stiffness and interstitial myocardial fibrosis are interrelated; this association is accelerated in the presence of CKD, but independent of LGE. Our findings reiterate the significant contribution of CKD-related factors to the pathophysiology of cardiovascular remodeling.
Partant des conditions de mise en place de l’une des dernières commissions d’historiens bilatérales en date – à savoir la commission germano-italienne en 2008 – et du constat de la nature à la fois ambigüe et excessive des attentes formulées à son encontre, cet ouvrage collectif dirigé par deux historiens du temps présent (l’Allemand Christoph Cornelißen et l’Italien Paolo Pezzino) place au cœur de la réflexion la figure de l’historien confronté à une demande d’expertise croissante dans le contexte de l’après guerre froide. Il examine les usages pratiques (voire politiques) des savoirs académiques historiques et leurs effets sur les standards de production de ces savoirs assurant la légitimité professionnelle et sociale des historiens. ...
Das hochwertig ausgestattete Buch vereint elf der im Jahre 2017 in Goslar gehaltenen Vorträge zum Jubiläum der tausendsten Wiederkehr des Geburtstages Heinrichs III. Der Rezensent beteiligte sich in dieser Reihe mit einem Beitrag, der wegen seiner umfangreichen Thematik ("Das salische Reich und Europa zur Zeit Kaiser Heinrichs III.") nicht in eine Kurzfassung gegossen werden konnte, was hier der Fairness halber bemerkt werden muss. ...
Introduction: Vacuolization is a frequently found morphological feature in acute myeloid leukemia (AML) blasts. Subcellular origin and biological function as well as prognostic impact are currently unknown. The aim of this study was to evaluate whether vacuolization correlates with clinically relevant AML features.
Materials & methods: Bone marrow smears of patients diagnosed with AML at the University Hospital Frankfurt between January 2011 and August 2013 were analyzed for blast vacuolization and correlated with clinically relevant AML features. Patients undergoing standard induction chemotherapy were further analyzed for molecular and cytogenetic features as well as treatment response and survival.
Results: 14 of 100 patients diagnosed with AML receiving standard induction chemotherapy had evidence of blast vacuolization. Positivity for vacuolization correlated with a CD15 positive immunophenotype and with a higher incidence of high-risk AML according to the European LeukemiaNet risk stratification. AML patients with blast vacuolization had a poor blast clearance after standard induction chemotherapy and poor survival.
Discussion: In conclusion, our findings demonstrate that vacuolization can easily be determined in myeloid leukemia blasts and may be a useful biomarker to predict AML risk groups as well as early treatment response rates and survival.
Masha Bruskina wurde im Jahr 1924 in Minsk als Jüdin geboren und genoss eine gute Bildung. Doch als sie gerade einmal 17 Jahren alt war, brach der Krieg über die Sowjetunion herein und es dauerte bloß sechs Tage, bis die deutschen Truppen die Stadt einnahmen. Bruskina war als überzeugte Kommunistin schon im jungen Alter Leiterin einer Pioniereinheit und doch gezwungen, im Minsker Ghetto zu leben. In dem Unwillen ihr Schicksal hinzunehmen, wechselte sie auf die sogenannte "arische Seite" und gab sich als Nichtjüdin aus: Sie färbte ihre Haare und nahm den Namen ihrer Mutter an. Bald darauf schloss sie sich dem im Untergrund operierenden Minsker Widerstand an und arbeite als Krankenschwester, um sowjetische Soldaten in einem Krankenhaus zu versorgen und ihnen bei der Flucht zu helfen. Sie schmuggelte zivile Kleidung und Medikamente, zudem eine Kamera, mit der sie gefälschte Ausweise herstellte. Waren die Soldaten wieder auf den Beinen, führten die anderen Widerständler sie durch die Wälder zur Partisanenbewegung. ...
The focus of this paper are space-improvements of programs, which are transformations that do not worsen the space requirement during evaluations. A realistic theoretical treatment must take garbage collection method into account. We investigate space improvements under the assumption of an optimal garbage collector. Such a garbage collector is not implementable, but there is an advantage: The investigations are independent of potential changes in an implementable garbage collector and our results show that the evaluation and other similar transformations are space-improvements.
Uni-Highlights Oktober 2019 : Einladungen zu ausgewählten Veranstaltungen der Goethe-Universität
(2019)
Facebook’s proposal to create a global digital currency, Libra, has generated a wide discussion about its potential benefits and drawbacks. This note contributes to this discussion and, first, characterizes similarities and dissimilarities of Libra’s building blocks with existing institutions. Second, the note discusses open questions about Libra which arise from this characterization and, third, potential future developments and their policy implications. A central issue is that Libra raises considerable questions about its role in and impact on the international monetary and financial system that should be addressed before policymakers and regulators give Libra the green light.
The identification of heat stress (HS)-resilient germplasm is important to ensure food security under less favorable environmental conditions. For that, germplasm with an altered activity of factors regulating the HS response is an important genetic tool for crop improvement. Heat shock binding protein (HSBP) is one of the main negative regulators of HS response, acting as a repressor of the activity of HS transcription factors. We identified a TILLING allele of Solanum lycopersicum (tomato) HSBP1. We examined the effects of the mutation on the functionality of the protein in tomato protoplasts, and compared the thermotolerance capacity of lines carrying the wild-type and mutant alleles of HSBP1. The methionine-to-isoleucine mutation in the central heptad repeats of HSBP1 leads to a partial loss of protein function, thereby reducing the inhibitory effect on Hsf activity. Mutant seedlings show enhanced basal thermotolerance, while mature plants exhibit increased resilience in repeated HS treatments, as shown by several physiological parameters. Importantly, plants that are homozygous for the wild-type or mutant HSBP1 alleles showed no significant differences under non-stressed conditions. Altogether, these results indicate that the identified mutant HSBP1 allele can be used as a genetic tool in breeding, aiming to improve the thermotolerance of tomato varieties.
leporello #1
(2019)
Function of p21 (Cip1/Waf1/CDKN1A) in migration and invasion of cancer and trophoblastic cells
(2019)
Tumor progression and pregnancy have several features in common. Tumor cells and placental trophoblasts share many signaling pathways involved in migration and invasion. Preeclampsia, associated with impaired differentiation and migration of trophoblastic cells, is an unpredictable and unpreventable disease leading to maternal and perinatal mortality and morbidity. Like in tumor cells, most pathways, in which p21 is involved, are deregulated in trophoblasts of preeclamptic placentas. The aim of the present study was to enlighten p21’s role in tumorigenic choriocarcinoma and trophoblastic cell lines. We show that knockdown of p21 induces defects in chromosome movement during mitosis, though hardly affecting proliferation and cell cycle distribution. Moreover, suppression of p21 compromises the migration and invasion capability of various trophoblastic and cancer cell lines mediated by, at least partially, a reduction of the extracellular signal-regulated kinase 3, identified using transcriptome-wide profiling, real-time PCR, and Western blot. Further analyses show that downregulation of p21 is associated with reduced matrix metalloproteinase 2 and tissue inhibitor of metalloproteinases 2. This work evinces that p21 is involved in chromosome movement during mitosis as well as in the motility and invasion capacity of trophoblastic and cancer cell lines.
Truffle fungi are well known for their enticing aromas partially emitted by microbes colonizing truffle fruiting bodies. The identity and diversity of these microbes remain poorly investigated, because few studies have determined truffle-associated bacterial communities while considering only a small number of fruiting bodies. Hence, the factors driving the assembly of truffle microbiomes are yet to be elucidated. Here we investigated the bacterial community structure of more than 50 fruiting bodies of the black truffle Tuber aestivum in one French and one Swiss orchard using 16S rRNA gene amplicon high-throughput sequencing. Bacterial communities from truffles collected in both orchards shared their main dominant taxa: while 60% of fruiting bodies were dominated by α-Proteobacteria, in some cases the β-Proteobacteria or the Sphingobacteriia classes were the most abundant, suggesting that specific factors (i.e., truffle maturation and soil properties) shape differently truffle-associated microbiomes. We further attempted to assess the influence in truffle microbiome variation of factors related to collection season, truffle mating type, degree of maturation, and location within the truffle orchards. These factors had differential effects between the two truffle orchards, with season being the strongest predictor of community variation in the French orchard, and spatial location in the Swiss one. Surprisingly, genotype and fruiting body maturation did not have a significant effect on microbial community composition. In summary, our results show, regardless of the geographical location considered, the existence of heterogeneous bacterial communities within T. aestivum fruiting bodies that are dominated by three bacterial classes. They also indicate that factors shaping microbial communities within truffle fruiting bodies differ across local conditions.
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.
Iodo(triphenyl)silane
(2019)
The molecular structure of the title compound, C18H15ISi, which crystallizes in the space group C2/c, does not exhibit any unusual features. Two weak C—H⋯π interactions may help to consolidate the packing. The present structure is not isostructural with the known Ph3SiX (X = F, Cl or Br) compounds.
This review summarizes studies of protection against singlet oxygen and radical damage by carotenoids. The main focus is on how substitutions of the carotenoid molecules determine high antioxidant activities such as singlet oxygen quenching and radical scavenging. Applied assays were carried out either in vitro in solvents or with liposomes, and in a few cases with living organisms. In the latter, protection by carotenoids especially of photosynthesis against light- and UV-stress is of major importance, but also heterotrophic organisms suffer from high light and UV exposure which can be alleviated by carotenoids. Carotenoids to be compared include C30, C40 and C50 molecules either acyclic, monocyclic or bicyclic with different substitutions including sugar and fatty acid moieties. Although some studies are difficult to compare, there is a tendency towards mono and bicyclic carotenoids with keto groups at C-4/C-4’ and the longest possible polyene structure functions to act best in singlet oxygen quenching and radical scavenging. Size of the carotenoid and lipophilic substituents such as fatty acids seem to be of minor importance for their activity but hydroxyl groups at an acyclic end and especially glycosylation of these hydroxyl groups enhance carotenoid activity.
Hereditary Parkinson’s disease (PD) can be triggered by an autosomal dominant overdose of alpha-Synuclein (SNCA) as stressor or the autosomal recessive deficiency of PINK1 Serine/Threonine-phosphorylation activity as stress-response. We demonstrated the combination of PINK1-knockout with overexpression of SNCAA53T in double mutant (DM) mice to exacerbate locomotor deficits and to reduce lifespan. To survey posttranslational modifications of proteins underlying the pathology, brain hemispheres of old DM mice underwent quantitative label-free global proteomic mass spectrometry, focused on Ser/Thr-phosphorylations. As an exceptionally strong effect, we detected >300-fold reductions of phosphoThr1928 in MAP1B, a microtubule-associated protein, and a similar reduction of phosphoSer3781 in ANK2, an interactor of microtubules. MAP1B depletion is known to trigger perturbations of microtubular mitochondria trafficking, neurite extension, and synaptic function, so it was noteworthy that relevantly decreased phosphorylation was also detected for other microtubule and microfilament factors, namely MAP2S1801, MARK1S394, MAP1AT1794, KIF1AS1537, 4.1NS541, 4.1GS86, and ADD2S528. While the MAP1B heavy chain supports regeneration and growth cones, its light chain assists DAPK1-mediated autophagy. Interestingly, relevant phosphorylation decreases of DAPK2S299, VPS13DS2429, and VPS13CS2480 in the DM brain affected regulators of autophagy, which are implicated in PD. Overall, significant downregulations were enriched for PFAM C2 domains, other kinases, and synaptic transmission factors upon automated bioinformatics, while upregulations were not enriched for selective motifs or pathways. Validation experiments confirmed the change of LC3 processing as reflection of excessive autophagy in DM brain, and dependence of ANK2/MAP1B expression on PINK1 levels. Our new data provide independent confirmation in a mouse model with combined PARK1/PARK4/PARK6 pathology that MAP1B/ANK2 phosphorylation events are implicated in Parkinsonian neurodegeneration. These findings expand on previous observations in Drosophila melanogaster that the MAP1B ortholog futsch in the presynapse is a primary target of the PARK8 protein LRRK2, and on a report that MAP1B is a component of the pathological Lewy body aggregates in PD patient brains. Similarly, ANK2 gene locus variants are associated with the risk of PD, ANK2 interacts with PINK1/Parkin-target proteins such as MIRO1 or ATP1A2, and ANK2-derived peptides are potent inhibitors of autophagy.
The lipid status in patients with ulcerative colitis : Sphingolipids are disease-dependent regulated
(2019)
The factors that contribute to the development of ulcerative colitis (UC), are still not fully identified. Disruption of the colon barrier is one of the first events leading to invasion of bacteria and activation of the immune system. The colon barrier is strongly influenced by sphingolipids. Sphingolipids impact cell–cell contacts and function as second messengers. We collected blood and colon tissue samples from UC patients and healthy controls and investigated the sphingolipids and other lipids by LC-MS/MS or LC-QTOFMS. The expression of enzymes of the sphingolipid pathway were determined by RT-PCR and immunohistochemistry. In inflamed colon tissue, the de novo-synthesis of sphingolipids is reduced, whereas lactosylceramides are increased. Reduction of dihydroceramides was due to posttranslational inhibition rather than altered serine palmitoyl transferase or ceramide synthase expression in inflamed colon tissue. Furthermore, in human plasma from UC-patients, several sphinglipids change significantly in comparison to healthy controls. Beside sphingolipids free fatty acids, lysophosphatidylcholines and triglycerides changed significantly in the blood of colitis patients dependent on the disease severity. Our data indicate that detraction of the sphingolipid de novo synthesis in colon tissue might be an important trigger for UC. Several lipids changed significantly in the blood, which might be used as biomarkers for disease control; however, diet-related variabilities need to be considered.
From a global viewpoint, a lot of time is spent within the indoor air compartment of vehicles. A German study on mobility has revealed that, on average, people spend 45 minutes per day inside vehicles. In recent years the number of cars has increased to around 43 million vehicles in private households. This means that more than one car can be used in every household. The ratio has been growing, especially in eastern Germany and rural areas. "Overall and especially outside the cities, the car remains by far number one mode of transport, especially in terms of mileage". Therefore, numerous international studies have addressed different aspects of indoor air hygiene, in the past years. In this paper, meaningful original studies on car indoor air pollution, related to VOCs, COx, PMs, microbials, BFRs, OPFRs, cigarettes, electronic smoking devices, high molecular weight plasticizer, and NOx are summarized in the form of a review. This present review aimed to summarize recently published studies in this important field of environmental medicine and points to the need for further studies with special recommendations for optimizing the interior air hygiene.
Environmental niche modelling is an acclaimed method for estimating species’ present or future distributions. However, in marine environments the assembly of representative data from reliable and unbiased occurrences is challenging. Here, we aimed to model the environmental niche and distribution of marine, parasitic nematodes from the Pseudoterranova decipiens complex using the software Maxent. The distribution of these potentially zoonotic species is of interest, because they infect the muscle tissue of host species targeted by fisheries. To achieve the best possible model, we used two different approaches. The land distance (LD) model was based on abiotic data, whereas the definitive host distance (DHD) model included species-specific biotic data. To assess whether DHD is a suitable descriptor for Pseudoterranova spp., the niches of the parasites and their respective definitive hosts were analysed using ecospat. The performance of LD and DHD was compared based on the variables’ contribution to the model. The DHD-model clearly outperformed the LD-model. While the LD-model gave an estimate of the parasites’ niches, it only showed the potential distribution. The DHD-model produced an estimate of the species’ realised distribution and indicated that biotic variables can help to improve the modelling of data-poor, marine species.
Abiotic formation of n-alkane hydrocarbons has been postulated to occur within Earth's crust. Apparent evidence was primarily based on uncommon carbon and hydrogen isotope distribution patterns that set methane and its higher chain homologues apart from biotic isotopic compositions associated with microbial production and closed system thermal degradation of organic matter. Here, we present the first global investigation of the carbon and hydrogen isotopic compositions of n-alkanes in volcanic-hydrothermal fluids hosted by basaltic, andesitic, trachytic and rhyolitic rocks. We show that the bulk isotopic compositions of these gases follow trends that are characteristic of high temperature, open system degradation of organic matter. In sediment-free systems, organic matter is supplied by surface waters (seawater, meteoric water) circulating through the reservoir rocks. Our data set strongly implies that thermal degradation of organic matter is able to satisfy isotopic criteria previously classified as being indicative of abiogenesis. Further considering the ubiquitous presence of surface waters in Earth’s crust, abiotic hydrocarbon occurrences might have been significantly overestimated.
Der betongraue Bunker ist von Zwangsarbeitern der Nationalsozialisten im Zweiten Weltkrieg errichtet worden. Geplant war er als Luftschutzbunker für die Mitarbeiter und Kunden der Reichsbahn, damit sie sich im Ernstfall vom nah gelegenen Bahnhof, dem heutigen Bahnhof Friedrichstrasse, vor dem Bombenhagel retten konnten; bis zu 2.500 Menschen finden darin Platz. Nach dem Ende des Zweiten Weltkrieges wurde der Bunker sehr unterschiedlich genutzt: Zuerst diente er als Kriegsgefängnis der Roten Armee, danach als Lager für Textilien und anschließend für Südfrüchte, was ihm den Namen „Bananenbunker“ einbrachte. Nach dem Mauerfall ging das Gebäude in den Besitz des Bundes über und die Kultur Berlins zog ein: Erst in Form eines Techno-Clubs, in welchem auch Theaterstücke aufgeführt wurden, bis der Bund das Gebäude vorerst schloss. Der Werbeagentur-Inhaber Christian Boros erwarb zusammen mit seiner Frau Karen Boros den Bunker schließlich und baute ihn fünf Jahre lang um: Seit 2008 werden die Kunstwerke aus Boros’ privater Kunstsammlung präsentiert. ...
To prepare for an impending event of unknown temporal distribution, humans internally increase the perceived probability of event onset as time elapses. This effect is termed the hazard rate of events. We tested how the neural encoding of hazard rate changes by providing human participants with prior information on temporal event probability. We recorded behavioral and electroencephalographic (EEG) data while participants listened to continuously repeating five-tone sequences, composed of four standard tones followed by a non-target deviant tone, delivered at slow (1.6 Hz) or fast (4 Hz) rates. The task was to detect a rare target tone, which equiprobably appeared at either position two, three or four of the repeating sequence. In this design, potential target position acts as a proxy for elapsed time. For participants uninformed about the target’s distribution, elapsed time to uncertain target onset increased response speed, displaying a significant hazard rate effect at both slow and fast stimulus rates. However, only in fast sequences did prior information about the target’s temporal distribution interact with elapsed time, suppressing the hazard rate. Importantly, in the fast, uninformed condition pre-stimulus power synchronization in the beta band (Beta 1, 15–19 Hz) predicted the hazard rate of response times. Prior information suppressed pre-stimulus power synchronization in the same band, while still significantly predicting response times. We conclude that Beta 1 power does not simply encode the hazard rate, but—more generally—internal estimates of temporal event probability based upon contextual information.
Sulforaphane is a natural substance found in cruciferous vegetables such as broccoli or cabbage. There are promising results for a number of tumor entities regarding the potential anti-carcinogenic effects of sulforaphane. The experiments designed for this study were performed on prostate carcinoma cells. The aim was to investigate the influence of sulforaphane on the growth behaviour of prostate cancer cells.
Designed as an in-vitro-model, prostate carcinoma cell lines DU145 and PC3 were used in the study. The experiments can be roughly divided into two categories:
• Regulation of cell growth: After the growth inhibitory effect of sulforaphane has been confirmed (MTT test), the proliferation rate (BrdU assay) and apoptosis rate (apoptosis assay) of the cells were measured under the influence of sulforaphane. Studies on clonogenic growth completed this series of experiments.
• Regulation of the cell cycle: After determining the impact of sulforaphane on the phases of the cell cycle (cell cycle assay), the cell cycle-relevant proteins of the cyclin-CDK-axis, the CDK inhibitors p19 and p27 as well as the acetylated histones aH3 and aH4 were analysed (Western Blot).
An additional MTT test was performed to determine a possible induction of resistance by long-term sulforaphane exposure. In addition, the expression profile of CD44 subtypes v4, v5 and v7 under the influence of sulforaphane has been investigated by FACS analysis.
The growth and proliferation rate as well as the clonogenic growth of the prostate carcinoma cells were shown to be inhibited under the influence of sulforaphane in a concentration-dependent manner. Induction of apoptosis has not occurred. The treatment with sulforaphane resulted in a concentration-dependent G2/M arrest of the cell cycle. The level of expression of cyclins A and B and of CDKs 1 and 2 has increased due to sulforaphane exposure. The level of expression of pCDKs has decreased except for a slight increase in pCDK 2 in the DU145 cell line. The CDK inhibitors p19 and p27 were elevated, except for a reduction of p27 in the PC3 cell line. The level of expression of acetylated histones aH3 and aH4 has increased due to sulforaphane treatment. Indications for induction of resistance by long-term use of sulforaphane were not found. Treatment with sulforaphane resulted in an increased expression level of the CD44 subtypes v4, v5 and v7 in a concentration- and time-dependent manner.
The test results fit into the existing findings. The exact processes and relationships of the modes of action are not yet sufficiently understood. Nevertheless, it can be stated that sulforaphane can trigger anticarcinogenic mechanisms at the molecular level also in prostate cancer. Therefore, sulforaphane could eventually be used in clinical practice, whether prophylactically or therapeutically. Further studies, also in clinical settings on humans, are therefore necessary.
Nukleäre Rezeptoren sind ligandenaktivierte Transkriptionsfaktoren, die das pharmazeutische Interesse als Zielstrukturen für antientzündliche Wirkstoffe und andere Indikationen erwecken. Entzündungen werden durch Noxen physikalischer, chemischer oder mikrobiologischer Art hervorgerufen. Dabei reagiert das geschädigte Gewebe mit zahlreichen Vorgängen, die vaskuläre und zelluläre Reaktionen mit Immunantworten verknüpfen und nach der Wiederherstellung des ursprünglichen Zustands streben. Bei andauernder Wirkung können Entzündungen jedoch in einen schädlichen Prozess umschlagen, sodass in solchen Fällen eine therapeutische Intervention Notwendigkeit erlangt. Ziel dieser Arbeit war es deshalb, neue Liganden nukleärer Rezeptoren als Kandidaten für antientzündliche Wirkstoffe zu identifizieren.
Leber X Rezeptoren (LXRs) sind Zielstrukturen für entzündliche und neurodegenerative Erkrankungen mit antiphlogistischem Potenzial. Zur Identifikation neuer LXR-Liganden wurde eine Datenbank mit zugelassenen Wirkstoffen mithilfe einer selbstorganisierenden Karte (SOM) auf Interaktion mit LXR gescreent. Die Retinoid X Rezeptor (RXR)-Agonisten Alitretinoin (37) und Bexaroten (38) konnten in der anschließenden in vitro Charakterisierung als potente duale LXRalpha/LXRbeta-Partialagonisten mit moderater Aktivierungseffizienz bestätigt werden. Während 37 und 38 synthetische LXR-Vollagonisten partiell antagonisierten, führten sie mit dem endogenen Partialagonisten 22(R)-Hydroxycholesterol (4) zur additiven Aktivierung von LXR. Die Charakterisierung von Alitretinoin (37) und Bexaroten (38) als duale LXR/RXR-Agonisten liefert nicht nur eine weitere Erklärung für in klinischen Studien beobachtete Nebenwirkungen, sondern könnte auch den Startpunkt zur Entwicklung neuer antientzündlicher LXR- und dualer LXR/RXR-Liganden bieten.
Der Peroxisomen Proliferator-aktivierte Rezeptor (PPAR) gamma ist ein nukleärer Rezeptor, der neben der Steigerung der Insulinsensitivität auch antientzündliche Effekte aufweist. Auf Grundlage seiner Y-förmigen und fettsäuremimetischen Struktur konnte das Urikosurikum Lesinurad (47) als PPARgamma-Partialagonist in vitro charakterisiert werden. Im Gegensatz zu PPARgamma-Vollagonisten wie Pioglitazon (31) oder Rosiglitazon (32) induzierte 47 nicht die Differenzierung muriner 3T3-L1 Zellen in reife Adipozyten, aber erhöhte in der humanen Leberzellkarzinomzelllinie HepG2 die Expression von Genen, welche die Insulinsensitivität und den Fettsäureabbau steigern könnten. Folglich erwies sich Lesinurad (47), das bei der Pharmakotherapie von Gicht Anwendung findet, als selektiver PPARgamma-Modulator (sPPARgammaM) ohne adipogene Nebenwirkungen. Insbesondere Patienten mit Komorbiditäten wie Diabetes mellitus Typ 2 oder anderen Erkrankungen des metabolischen Syndroms könnten von einer Behandlung mit 47 profitieren. Inwiefern PPARgamma an der Auflösung von Entzündungen bei Gicht beteiligt ist, bleibt in zukünftigen Studien zu klären.
Synthetische RXR-Agonisten haben ein vielversprechendes Potenzial zur Behandlung entzündlicher neurodegenerativer Erkrankungen, das jedoch von nachteiligen Eigenschaften dieser Rexinoide beeinträchtigt wird. Durch ein pharmakophorbasiertes Screening einer fokussierten Substanzbibliothek aus Fettsäuremimetika konnte ein fortschrittliches RXR-Ligandgerüst identifiziert werden. Eine geeignete Synthesestrategie wurde etabliert und die Leitstrukturen durch systematisches Studium der Struktur-Wirkungsbeziehung (SAR) optimiert. In vitro Experimente wie Reportergenassays und die Quantifizierung der Zielgenexpression bestätigten die RXR-partialagonistische Aktivität der dabei entwickelten nanomolaren Verbindung 89. Mit seiner hohen Selektivität, gesteigerten wässrigen Löslichkeit sowie reduzierter Lipophilie und Toxizität könnte 89 die Probleme bisheriger synthetischer RXR-Agonisten überwinden. Seine Präferenz von RXRgamma hinsichtlich der Aktivierungseffizienz könnte richtungsweisend für die Entwicklung subtypselektiver Liganden sein.
Die nichtalkoholische Steatohepatitis (NASH) ist eine Leberentzündung, die aus einer Steatose hervorgehen kann und deren multifaktorielle Natur eine hohe therapeutische Effizienz erfordert. Diese könnte durch duale Modulation der nukleären Rezeptoren Farnesoid X Rezeptor (FXR) und PPARdelta mit antientzündlichen Eigenschaften und unterschiedlichem Wirkprinzip erreicht werden. Zur Validierung dieses Ansatzes mit synergistischem Potenzial sollten duale PPARdelta/FXR-Agonisten ausgehend von einer in früheren Studien des Arbeitskreises identifizierten Leitstruktur mit moderater Potenz entwickelt werden. Dazu wurde ein fünfstufiges Verfahren zur Synthese von Derivaten der Leitstruktur erarbeitet und die Derivate hinsichtlich ihrer Aktivität auf den Zielstrukturen in vitro evaluiert. In systematischen SAR-Studien wurden dabei Strukturmotive charakterisiert, welche die Wirksamkeit und Maximalaktivierung auf PPARdelta und FXR steigerten. Darüber hinaus konnten Modifikationen identifiziert werden, welche eine Selektivität über PPARalpha und PPARgamma gewährten. Die Kombination dieser vorteilhaften Gruppen und Substituenten könnte neue Wirkstoffkandidaten zur Behandlung von NASH hervorbringen.
Insgesamt wurden in dieser Arbeit zahlreiche Wirkstoffe und Wirkstoffkandidaten erfolgreich als Liganden nukleärer Rezeptoren mit antientzündlichem Potenzial identifiziert. Alitretinoin (37) und Bexaroten (38) können als Leitstruktur zur Entwicklung neuer selektiver LXR- oder dualer LXR/RXR-Agonisten dienen. Die PPARgamma-partialagonistische Aktivität von Lesinurad (47) könnte einen Fortschritt in der Therapie von Gicht mit metabolischen Begleiterkrankungen bewirken. Zudem könnten im Zuge dieser Arbeit synthetisierte Serien von RXR- und dualen PPARdelta/FXR-Partialagonisten neue Therapieoptionen bei neurodegenerativen Erkrankungen oder NASH ermöglichen.
Human readers have the ability to infer knowledge from text, even if that particular information is not explicitly stated. In this thesis, we address the phenomena of text-level implicit information and outline novel automated methods for its recovery.
The main focus of this work is on two types of unexpressed content that arises between sentences (implicit discourse relations) and within sentences (implicit semantic roles).
Traditional approaches mostly rely on costly rich linguistic features, e.g., sentiment or frame-based lexicons, and require heuristics or manual feature engineering.
As an improvement, we propose a collection of generic resource-lean methods, implemented in the form of statistical background knowledge or by means of neural architectures.
Our models are largely language-independent and produce state-of-the-art performance, e.g., in the classification of Chinese implicit discourse relations, or the detection of locally covert predicative arguments in free texts.
In novel experiments, we quantitatively demonstrate that both types of implicit information are mutually dependent insofar as, for instance, some implicit roles directly correlate with implicit discourse relations of similar properties.
We show that implicit information processing further benefits downstream applications and demonstrate its applicability to the higher-level task of narrative story understanding.
In the conclusion of the dissertation, we argue for the need of implicit information processing in order to realize the goal of true natural language understanding.
Die wissenschaftliche Vernetzung, Betreuung und Unterstützung in der Promotionsphase steht im Zentrum dieser Forschungsarbeit, für die eine soziale Netzwerkanalyse (SNA) zur Karriereentwicklung in einem Bildungsforschungsprogramm in Deutschland durchgeführt wurde. Als Ausgangsproblem wird die schwierige Situation der unsicheren beruflichen Perspektiven Promovierter aufgegriffen.
Die Arbeit beschäftigt sich mit der Frage, wie Promovierende sowohl eine hohe fachliche Qualifikation erreichen, die für eine wissenschaftliche Karriere erforderlich ist, als auch eine gute Vernetzung in der wissenschaftlichen Gemeinschaft aufbauen können, um sich Chancen für die nächsten Karriereschritte zu eröffnen. Aus der Perspektive der Promovierten werden Chancen und Risiken der Vernetzung behandelt, um Überlegungen zu förderlichen und hinderlichen Aspekten der Betreuung und Unterstützung anzustellen.
Die Ergebnisse dieser Forschungsarbeit zeigen auf, welche Bedeutung soziale Netzwerke in der Berufsbiografie haben können und wie wissenschaftliches und soziales Kapital für die Karriere genutzt werden kann. Dazu richtet sich die erziehungswissenschaftliche Perspektive auf Prozesse des Wissenserwerbs und gemeinschaftlicher Lernprozesse, die zur Qualifizierung dienen und unterschiedliche Modelle von Betreuung umfassen. Im Verlauf der Promotionsphase und der weiteren wissenschaftlichen Karriere beginnen die Promovierenden auf der Wissensgrundlage ihres Studiums als Neulinge ihre erste umfangreiche empirische Forschungsarbeit. Sie werden durch die Mitarbeit im Projekt und ihre Beteiligung an Aktivitäten an die Arbeitsweisen in der Wissenschaft herangeführt. Von einer solchen eher randständigen Position aus erwerben sie Wissen, lernen hinzu, tauschen sich mit fortgeschrittenen WissenschaftlerInnen aus und sammeln eigene Erfahrungen. Nach einiger Zeit weiterer Qualifizierung und größerer Sichtbarkeit in der wissenschaftlichen Gemeinschaft können sie Positionen näher am Zentrum ihres Forschungsgebiets einnehmen, die auf ihren Kenntnissen und ihrer zunehmenden fachlichen und methodischen Expertise beruhen.
Neue Erkenntnisse über Betreuungsmodelle sind hilfreich, denn die Betreuung orientiert sich mal stark an dem klassischen Lehrer-Schüler-Modell (Individualbetreuung) oder an einer gemeinsamen Betreuung in einer Forschungsgruppe (Gruppenbetreuung). Die Untersuchung der Bedeutung von sozialem Kapital und situiertem Lernen in der Qualifikationsphase dient dazu, die Vernetzung von Promovierten in ihrer späteren akademischen Karriere zu analysieren.
Transposable elements (TEs) are replicating genetic elementst hat comprise up to 50% of mammalian genomes. A specific class of TEs are retrotransposons that proliferate by transcription into a RNA intermediate, followed by genomic reintegration into another locus (so called “copy & paste” mechanism). Due to the lack of removal mechanisms and very rare parallel insertions, the presence of TE insertions at ortholgous genomic loci in multiple taxa provides a virtually homoplasy free phylogenetic marker. So far, developing phylogenetically informative markers from TE insertions has been a tedious work of testing hundreds of putative candidate loci in a trial-and error approach with low success rate. Hence, phylogenetic studies using TE insertions were often limited to a few dozen markers.
Recently, genome sequencing of multiple species using reference-mapping allowed the identification of genome-scale datasets of TE insertions. and made the ad-hoc development of phylogenetic informative markers possible. However, genome scale TE detection methods have rarely been applied to non model organisms in which data availability and quality is comparably limited. In this thesis, I developed the TeddyPi pipeline (TE detection and discovery for phylogenetic inference), a software tool that made it possible to obtain reliable genome-scale TE insertion data from low-coverage genomes. This was achieved by integrating the data from multiple TE and structural variation callers as well as applying a stringent filtering pipeline to exclude low-quality insertion calls. Whole-genome sequencing datasets of bears (Ursidae) and baleen whales (Mysticeti) were used to apply TE based phylogenetic inference and evaluate the method in comparison to sequence-based phylogenomic analyses.
In the bear genomes, TeddyPi identified 150,513 high-quality transposable element (TE) insertions, which allowed me to reconstruct the evolutionary history of bears despite extensive phylogenetic conflict (Lammers et al., 2017). The large number of detected TE insertions made also detailed network analyses possible that visualize the phylogenetic conflict. Experimental polymerase chain reaction (PCR) assays validated up to 93 % of the computationally identified TE loci and demonstrated the high accuracy of the dataset underlying the phylogenetic analyses.
Second, I present the initial genome sequencing of six baleen whales and a detailed investigation of their evolutionary history using TE insertions and established sequence-based phylogenomic methods. The taxon sampling of baleen whales included iconic species like the blue whale (Balaneoptera musculus) or the humpback whale (Megaptera novaengliae) (Árnason et al., 2018). A sequence-based reconstruction of the baleen whale species tree solved the long-debated phylogenetic position of the gray whale (Echrichtius robustus) within rorquals (Balaneopteridae) for the first time with high statistical support. Furthermore, the genome data made it possible to identify large extent of phylogenetic conflict for divergences during the radiation of rorquals that occurred 7-10 million years ago (Ma).
The phylogenomic analyses of 91,589 TE insertions in the whale genomes confirmed the sequence-based topology (Lammers et al., 2019). The quantification of phylogenetic signals obtained from the TE insertions revealed a high degree of discordance for the divergence of the gray whale and rorquals. Despite the large genome-scale dataset, statistical tests showed only marginal support for a bifurcating divergence of gray whales and the rorqual species. The limited statistical support for a strictly bifurcating tree obtained from genome-scale datasets of thousands of markers demonstrates the importance for including phylogenetic networks for displaying evolutionary divergences.
In conclusion, this thesis shows that identification of TE insertions from whole-genome resequencing provides plentiful and accurate phylogenomic markers. For the application in non model organisms, I provide a easy-to-use software to integrate multiple datasets from TE and structural variation callers in order to obtain reliable and ascertainment-bias free datasets. Detecting genome-scale datasets of TE insertions in two case studies demonstrates the applicability of this marker system for phylogenetic reconstruction and inferring phylogenetic conflict.
Nominal modification in language production: Extraposition of prepositional phrases in german
(2019)
In my dissertation, I investigate the phenomenon of extraposition of PP out of NP in German in language production. Four production experiments, using the method of production of memory, and three experiments testing the acceptability of extraposition were conducted. In extraposition, a constituent is realized in a position to the right of what would be considered the canonical position. A special case is extraposition out of a nominal phrase (NP), in which a constituent is moved out of NP to the end of the utterance. The example in (1a) illustrates the canonical version, in which a prepositional phrase (PP) is adjacent to its head noun. In (1b) the PP is extraposed out of NP to the right edge of the sentence.
(1) a. Gestern hat eine Frau mit einer lauten, schrillen Stimme angerufen.
b. Gestern hat eine Frau angerufen mit einer lauten, schrillen Stimme.
There are two main aspects to consider: the length of the extraposed constituent (the PP), and the length of the intervening material. Experiment 1 investigated the influence of constituent length on extraposition. The hypothesis is that longer and more complex constituents are harder to produce and are therefore produced towards the end of the utterance. In the experiment, PPs of three different lengths (2-3, 5-6, 9-11 words) had to be reproduced in either adjacent or extraposed position. As to the length of the intervening material, the hypothesis is that sentences with more intervening material between head noun and extraposed PP will tend to be reproduced with the PP in adjacent position to the head noun. In order to test this hypothesis, the length of the intervening material (1, 2 and 4 words) was manipulated in Experiment 2. The same material was used in an acceptability experiment, using the method of magnitude estimation (Experiment 5).
Previous studies found that extraposition is preferred over verbal material only, thus Experiment 3 investigated the influence of different lengths of purely verbal intervening material. Experiment 4 was concerned with the differences between PP and RC extraposition in production.
Experiment 6 and 7 used Likert scales to assess the acceptability of extraposition. Experiment 6 investigated whether the acceptability of extraposition is influenced by the definiteness status of the NP out of which is extraposed and if a soft constraint for definiteness can be found for PP extraposition in German. Experiment 7 asked if the inner structure of the extraposed constituent (PP only vs. PP+RC) influences its acceptability. An extraposed PP that includes an RC should be "heavier" than a PP without an RC, since the number of phrasal nodes is higher. If indeed heavier constituents are realized at the end of an utterance, the acceptability of an extraposed PP that includes an RC should be higher than that of an extraposed PP without one.
The results of the production experiments show that sentences are mostly reproduced in their original linear sequence, which suggests that extraposed position seems to be just as canonical as adjacent position, especially when extraposition takes place over verbal material only. With regard to constituent length, in extraposed position long PPs are shortened less often, supporting the hypothesis that longer and more complex constituents tend to be produced at the end of the utterance. Recency effects were found for intervening material as participants dropped intervening material rather than change syntactic position of constituents. The length and type of the intervening material is important with respect to how much intervening material is acceptable. Verb clusters were not shortened in sentences with extraposed PPs, however, 1⁄3 of adverbs and 1⁄2 of PP adverbials including a lexical NP were shortened to „verb only“. Extraposed PPs are more often reproduced in adjacent position than adjacent PPs are reproduced in extraposed position. However, the position of RCs is more often changed from adjacent to extraposed than from extraposed to adjacent.
While producing extraposed PPs seems not to be any more difficult than producing adjacent ones, adjacent constituents are consistently rated higher than extraposed constituents in grammaticality judgment tasks. This is in line with findings of Konieczny (2000) on German RC extraposition. The number of phrasal nodes, as suggested by Rickford et al. (1995), did not have an influence on the acceptability of extraposition, while the length of the constituent, measured in words, seems to play a role. Definiteness had no effect on adjacent PPs, but when the PP was extraposed, sentences with an indefinite antecedent were rated higher than sentences with a definite antecedent. This suggests that there is a "soft constraint" for definiteness with regard to PP extraposition out of NP in German.
Buchbesprechungen
(2019)
Es werden folgende Publikation rezensiert: Daniel Barthélémy (Hrsg.): Pl@ntNet; Bunzel-Drüke et al.: Naturnahe Beweidung und Natura 2000; Martina D'Ascola: 50 sagenhafte Naturdenkmale in Hessen; Hessisches Landesamt für Naturschutz, Umwelt und Geologie: Guter Heinrich, Pfingst-Nelke, Färber-Scharte & Co. Hessische Verantwortungsarten – Teil 1.
Die von Wolfgang Ludwig hinterlassene Pflanzensammlung im Marburger Herbar wurde aufbereitet und dokumentiert. Vorgestellt werden Belege aus der in über 70 Jahren (1938–2010) entstandenen Sammlung, die für die hessische Flora bislang nicht bekannt waren sowie Belege zu inzwischen ausgestorbenen, sehr seltenen oder sonstigen bemerkenswerten Arten.
Das Naturschutzgebiet Kühkopf-Knoblochsaue mit 2 400 ha überflutbarer Aue eignet sich in dem potenziellen Wildreben-Verbreitungsgebiet in Deutschland (Oberrheingebiet zwischen Freiburg und Wiesbaden) aktuell bei weitem am besten zum Wiederaufbau überlebensfähiger, ausreichend heterozygoter Wildrebenbestände. Nach einer ersten Wiederansiedlung 2013 mit 65 Genotypen und 121 ausgebrachten wurzelnackten Pflanzen mit Draht-Verbissschutz wurden 2016 in einer zweiten Wiederansiedlungsmaßnahme 551 Wilde Weinreben (78 Genotypen) an 12 Standorten gepflanzt. Es handelte sich hierbei um zweijährige Topfpflanzen, die ohne Verbissschutz gepflanzt wurden. Ein Jahr nach der Pflanzung war eine durchschnittliche Überlebensrate von 69 % zu konstatieren. Die Überlebensraten variieren an den Standorten zwischen 55 und 87 %. 75 von Wildschweinen herausgewühlte Wilde Weinreben wurden wieder eingepflanzt; die Überlebensrate kann somit noch über 69 % steigen.
Bei einer Prüfung von 153 Gewässern in Frankfurt am Main wurden neben den heimischen Typha-Arten Typha angustifolia und T. latifolia Verwilderungen von Typha shuttleworthii und Pflanzungen von Typha laxmannii gefunden. Auch Typha ×glauca die Hybride zwischen Typha angustifolia und T. latifolia wurde mehrfach gefunden.
Im Rahmen der Kartierung der Gefäßpflanzenflora des Vor-, Hochund kammnahen Hintertaunus wurde im Jahre 2004 ein großer Bestand des für Deutschland bislang selten erwähnten Doronicum ×willdenowii entdeckt. Da sich die Art bis heute nicht nur gehalten, sondern vermehrt hat, besteht offensichtlich ein Trend zur lokalen Einbürgerung.
Im Jahr 2008 wurden im Hochtaunus zwei Vorkommen der für diesen Bereich in der Literatur bisher nicht erwähnten Süßdolde (Myrrhis odorata) entdeckt. Beide haben sich bis heute (2017) in dicht geschlossenen, einmal im Jahr gemähten Pflanzenbeständen gehalten. Die Art besitzt also offensichtlich das Potential zur Einbürgerung, wobei man angesichts der relativ geringen Bestandesgröße noch nicht von einem gesicherten Trend zur Einbürgerung sprechen darf. Beide Pflanzenbestände sind saumartig ausgebildet, wobei der Aspekt auch von typischen Saumarten bestimmt wird. Der für Saumgesellschaften auffallend hohe Anteil an Wiesenarten dürfte darauf zurückzuführen sein, dass beide Säume einmal im Jahr gemäht werden.
Um dem neuen Forschungsstand zu Luthers geistlichem Mentor im Augustinerorden endlich zum Durchbruch zu verhelfen, edieren Dohna und Wetzel u. a. Akten aus dem Häresie-Verfahren des Erzbischofs von Salzburg gegen den Augustiner Agricola. Staupitz, der ein Gutachten lieferte, hat sich keineswegs von der lutherischen Bewegung distanziert. Er blieb seiner frühreformatorischen Theologie treu und vermied eine Verurteilung. Agricola musste keineswegs fliehen, er wurde freigelassen. Während andernorts schon Scheiterhaufen brannten, hatten Reformkatholiken hier noch Platz in der abendländischen Kirche.
SAFE Newsletter : 2019, Q3
(2019)