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Proportional determiner quantifiers in German allow interpretations that violate the conservativity universal of Keenan and Stavi (1986). I argue for an analysis that distinguishes between surface syntax and the logical form of sentences. I show that in surface syntax, German non-conservative quantifiers are determiners that form a constituent with a noun phrase and share case and agreement properties with the noun phrase. But I propose that at logical form the non-conservative determiners undergo an adverbialization movement and are interpreted by a mechanism that generalizes focus-a ected quantification of Herburger (2000). This result refines the understanding of conservativity as a constraint on interpretation.
The late physicist Carl Sagan, whom I quote in the first part of my title, skillfully phrased the common sense view on evidence in the mature sciences. In linguistics, however, evidence has become a controversial issue, especially so when it comes to the investigation of less well studied languages. In this paper, I argue that Sagan's principle should be applied to linguistics. The growing accessibility of a wide array of experimental techniques and computational tools to analyze such data makes it feasible to back up extraordinary claims with evidence from a variety of sources. At the same time, it is in many cases possible to agree on what constitutes an ordinary claim and focus the extra effort on extraordinary claims. For non-controversial claims no more than the minimum effort to establish the claim and properly document the evidence is necessary.
Irene Heim in unpublished work proposed a new syntax-semantics interface for propositional attitude reports based on an ontology without transworld individuals, but counterpart functions instead. We show that the approach can capture the 'de re'/'de dicto' distinction, but makes different predictions from accounts with transworld individuals. Specifically, the account uses a non-invertible counterpart functions: a single individual in an alternative world can be the counterpart of many individuals of the real world. The directionality of counterpart functions predicts that a 'de dicto' interpreted DP cannot be an argument of a 'de re' interpreted predicate. We show that the predicted restriction is corroborated by existing work on restrictions on 'de re' interpretation. The derivation of constraints on 'de re' interpretation argues empirically for the counterpart ontology and Heim’s implementation thereof.
During this study clumped isotope analysis of carbonates was established at the Goethe University of Frankfurt, Germany. Therefore, preparation protocols and analytical parameters were elaborated to obtain precise and accurate Δ47 data. Briefly, analyte CO2 was cleaned cryogenically using glass extraction lines to remove traces of water that enable re-equilibration of C–O bonds in the gases. Furthermore, analyte CO2 was passed through a gas chromatograph (GC) to clean it from contaminants that produce isobaric interferences with m/z 47. Initially, phosphoric acid digestions of carbonates was conducted at 25 °C in McCrea-type reaction vessels. Afterwards samples were reacted at 90 °C using a common acid bath. Mass spectrometric analyses were performed using a MAT 253 equipped with a dual inlet system. Δ47 values were directly projected to the absolute scale using CO2 gases equilibrated at distinct temperatures.
In cooperation with Stefano Bernasconi and his research group at ETH Zurich we studied the non-linearity that occurs for the measurement of m/z 47. This effect results from secondary electrons created by the m/z 44 beam. These electrons cause a negative background on the m/z 47 collector. A correction procedure was proposed that relies on the determination of the negative background on the m/z 47 Faraday cup. This approach might reduce time-consuming analyses of heated gases which were used so far to account for the observed non-linearity. However, the suggested correction of the negative background on the m/z 47 cup is only applicable if the slit width of the m/z 44 beam is significantly wider than that of the m/z 47 beam.
This thesis, furthermore, presents a comparison of the different phosphoric acid digestion techniques which are commonly used for carbonate clumped isotope analysis. For calcitic and aragonitic material digested at 25 °C in McCrea-type vessels we observed that the sample size has an effect on Δ47 data: higher mean Δ47 values and a larger scatter of data were received for samples <7 mg than for larger aliquots. For carbonate samples digested at 90 °C in a common acid bath no sample size effect was determined. We assume that secondary re-equilibration of CO2 with water preferentially occurs at 25 °C producing the observed differences. However, a sample size effect can be avoided if reaction temperature is increased to 90 °C.
In order to make carbonate Δ47 data obtained from acid digestions at 90 °C comparable to Δ47 data received from reactions at 25 °C the difference of the acid fractionation factores (Δ47*25-90) between both temperatures has to be known. For the determination of the Δ47*25-90 value we have considered Δ47 data made at 25 °C from samples >7 mg only. For calicte and aragonite we obtained differences in fractionation factores of 0.075‰ and 0.066‰, respectively. These Δ47*25-90 values are coincident with the theoretical prediction of 0.069‰ proposed for calcite (Guo et al., 2009).
Moreover, this dissertation comprises a calibration study of the clumped isotope thermometer based on various natural calcites that grew between 9 and 38 °C. The samples include a brachiopod shell, a bivalve shell, an eggshell of an ostrich and foraminifera tests which formed from distinct biomineralizing processes. Furthermore we included an authigenic carbonate crystallized from biological-induced precipitation. The following linear relationship between 1/T2 and Δ47 was determined (with Δ47 in ‰ and T in K):
Δ47 = 0.0327 (± 0.0026) x 106 / T2 + 0.3030 (± 0.0308) (R2 = 0.9915)
This equation differs from the pioneering Ghosh et al. (2006a) calibration. However, our regression line is statistically indistinguishable from that of Henkes et al. (2013) which is based on aragonitic mollusks and calcitic brachiopod shells. Both studies have in common that calibration data were, at first, directly referenced to the absolute scale. In addition, both datasets rely on similar digestion techniques. Furthermore, the two calibrations are conform with the theoretical prediction of Guo et al. (2009).
The calcite calibration of the clumped isotope paleothermometer received in this study was applied to Δ47 data measured for Silurian brachiopods shells from Gotland/Sweden. Prior to isotopic analysis the fossils were intensively investigated for their preservation state (CL, SEM, trace elements). The lowest T(Δ47) values of ca. 28 to 33 °C were estimated from ultrastructurally well-preserved regions of some shells. For these samples also the lowest δ18Ow values of Silurian seawater were determined. These estimates of ca. −1‰ confirm the assumption that the δ18O value of the Silurian ocean was buffered to (0 ± 1)‰.
Nevertheless, most studied shells were characterized by a patchwork of pristine and altered shell portions resulting in elevated T(Δ47) values which plot mostly between 40 and 60 °C. Our results indicate that the clumped isotopic composition of the shells were altered at low water-rock ratios, not affecting the δ18O values. Δ47 and δ18O data of associated diagenetic phases (sparitic and micritic phases of the inner fillings of the fossils) provide evidence that the sparitic cements grew during several diagenetic events which occurred at different temperatures in fluid-buffered systems. We, furthermore, conclude that the micritic phases lithified at a very early diagenetic stage with the δ18O values being most probably close to a Silurian seawater composition
Cultural heritage reconstructed - Compact Memory and the Frankfurt Digital Judaica Collection
(2014)
Compact Memory, the internet archive of German Jewish periodicals, provides free global internet access to the vast majority of German-Jewish newspapers and periodicals of the 19th and 20th century.
Jewish historical newspapers are the invaluable sources that supply direct and detailed information of the transformation process of Jewry and offer new insights into European Jewish history. The use of these historical sources however is extremely difficult, as complete sets of periodicals are very rarely to be found and they are scattered all over the world in different libraries and archives and in different physical formats (paper, microfilm).
Compact Memory contains the 110 most important Jewish German newspapers and periodicals in Central Europe in the period from 1806-1938, covering the complete range of religious, political, social, cultural and academic aspects of Jewish life. The texts are available partly as full-texts, processed by OCR, partly as graphic documents with corresponding index options. The database offers advanced search options, downloading and printing of articles. Thousands of essays of more than 10.000 individual contributors have been bibliographically indexed.
Compact Memory was established by the Judaica Division of the University Library Frankfurt am Main and in charge today in cooperation with the Aachen Chair of German-Jewish Literary History and the Cologne library Germania Judaica.
Compact Memory is one database within the Digital Collection Judaica which being part of Europeana and other digital portals offers resources for the reconstruction and representation of Jewish cultural heritage.
The subject of this thesis is the experimental investigation of the neutron-capture cross sections of the neutron-rich, short-lived boron isotopes 13B and 14B, as they are thought to influence the rapid neutron-capture process (r process) nucleosynthesis in a neutrino-driven wind scenario.
The 13;14B(n,g)14;15B reactions were studied in inverse kinematics via Coulomb dissociation at the LAND/R3B setup (Reactions with Relativistic Radioactive Beams). A radioactive beam of 14;15B was produced via in-flight fragmentation and directed onto a lead-target at about 500 AMeV. The neutron breakup of the projectile within the electromagnetic field of the target nucleus was investigated in a kinematically complete measurement. All outgoing reaction products were detected and analyzed in order to reconstruct the excitation energy.
The differential Coulomb dissociation cross sections as a function of the excitation energy were obtained and first experimental constraints on the photoabsorption and the neutron-capture cross sections were deduced. The results were compared to theoretical approximations of the cross sections in question. The Coulomb dissociation cross section of 15B into 14B(g.s.) + n was determined to be s(15B;14B(g:s:)+n) CD = 81(8stat)(10syst) mb ; while the Coulomb dissociation cross section of 14B into a neutron and 13B in its ground state was found to be s(14B;13B(g:s:)+n) CD = 281(25stat)(43syst) mb: Furthermore, new information on the nuclear structure of 14B were achieved, as the spectral shape of the differential Coulomb dissociation cross section indicates a halolike structure of the nucleus.
Additionally, the Coulomb dissociation of 11Be was investigated and compared to previous measurements in order to verify the present analysis. The corresponding Coulomb dissociation cross section of 11Be into 10Be(g.s.) + n was found to be 450(40stat)(54syst ) mb, which is in good agreement with the results of Palit et al.
Mapping is an important tool for the management of plant invasions. If landscapes are mapped in an appropriate way, results can help managers decide when and where to prioritize their efforts. We mapped vegetation with the aim of providing key information for managers on the extent, density and rates of spread of multiple invasive species across the landscape. Our case study focused on an area of Galapagos National Park that is faced with the challenge of managing multiple plant invasions. We used satellite imagery to produce a spatially explicit database of plant species densities in the canopy, finding that 92% of the humid highlands had some degree of invasion and 41% of the canopy was comprised of invasive plants. We also calculated the rate of spread of eight invasive species using known introduction dates, finding that species with the most limited dispersal ability had the slowest spread rates while those able to disperse long distances had a range of spread rates. Our results on spread rate fall at the lower end of the range of published spread rates of invasive plants. This is probably because most studies are based on the entire geographic extent, whereas our estimates took plant density into account. A spatial database of plant species densities, such as the one developed in our case study, can be used by managers to decide where to apply management actions and thereby help curtail the spread of current plant invasions. For example, it can be used to identify sites containing several invasive plant species, to find the density of a particular species across the landscape or to locate where native species make up the majority of the canopy. Similar databases could be developed elsewhere to help inform the management of multiple plant invasions over the landscape.
The deregulation of Polo-like kinase 1 is inversely linked to the prognosis of patients with diverse human tumors. Targeting Polo-like kinase 1 has been widely considered as one of the most promising strategies for molecular anticancer therapy. While the preclinical results are encouraging, the clinical outcomes are rather less inspiring by showing limited anticancer activity. It is thus of importance to identify molecules and mechanisms responsible for the sensitivity of Polo-like kinase 1 inhibition. We have recently shown that p21Cip1/CDKN1A is involved in the regulation of mitosis and its loss prolongs the mitotic duration accompanied by defects in chromosome segregation and cytokinesis in various tumor cells. In the present study, we demonstrate that p21 affects the efficacy of Polo-like kinase 1 inhibitors, especially Poloxin, a specific inhibitor of the unique Polo-box domain. Intriguingly, upon treatment with Polo-like kinase 1 inhibitors, p21 is increased in the cytoplasm, associated with anti-apoptosis, DNA repair and cell survival. By contrast, deficiency of p21 renders tumor cells more susceptible to Polo-like kinase 1 inhibition by showing a pronounced mitotic arrest, DNA damage and apoptosis. Furthermore, long-term treatment with Plk1 inhibitors induced fiercely the senescent state of tumor cells with functional p21. We suggest that the p21 status may be a useful biomarker for predicting the efficacy of Plk1 inhibition.
Die wirtschaftlichen und rechtlichen Grenzen der Notenbanken oder die Zukunft der Zentralbanken waren zwei große Themen, die im vergangenen Jahr im Fokus des IMFS standen. Einen Überblick über alle Aktivitäten und Publikationen des IMFS im Jahr 2013 gibt der Jahresbericht 2013, der jetzt in der Download-Version erschienen ist. Der Jahresbericht umfasst 58 Seiten und ist nur auf Englisch erhältlich.
The transcription factor Tal1 is a critical activator or repressor of gene expression in hematopoiesis and leukaemia. The mechanism by which Tal1 differentially influences transcription of distinct genes is not fully understood. Here we show that Tal1 interacts with the peptidylarginine deiminase IV (PADI4). We demonstrate that PADI4 can act as an epigenetic coactivator through influencing H3R2me2a. At the Tal1/PADI4 target gene IL6ST the repressive H3R2me2a mark triggered by PRMT6 is counteracted by PADI4, which augments the active H3K4me3 mark and thus increases IL6ST expression. In contrast, at the CTCF promoter PADI4 acts as a repressor. We propose that the influence of PADI4 on IL6ST transcription plays a role in the control of IL6ST expression during lineage differentiation of hematopoietic stem/progenitor cells. These results open the possibility to pharmacologically influence Tal1 in leukaemia.
Predominant polarity in bipolar disorder and validation of the polarity index in a German sample
(2014)
Background: A large number of patients with bipolar disorder (BD) can be characterized by predominant polarity (PP), which has important implications for relapse prevention. Recently, Popovic et al. (EUR NEUROPSYCHOPHARM 22(5): 339¿346, 2012) proposed the Polarity Index (PI) as a helpful tool in the maintenance treatment of BD. As a numeric expression, it reflects the efficacy of drugs used in treatment of BD. In the present retrospective study, we aimed to validate this Index in a large and well characterized German bipolar sample.
Methods: We investigated 336 bipolar patients (BP) according to their PP and calculated the PI for each patient in order to prove if maintenance treatment differs according to their PP. Furthermore, we analysed whether PP is associated with demographic and clinical characteristics of BP.
Results: In our sample, 63.9% of patients fulfilled criteria of PP: 169 patients were classified as depressive predominant polarity (DPP), 46 patients as manic predominant polarity (MPP). The two groups differed significantly in their drug regime: Patients with DPP were more often medicated with lamotrigine and antidepressants, patients with MPP were more often treated with lithium, valproate, carbamazepine and first generation antipsychotics. However, patients with DPP and MPP did not differ significantly with respect to the PI, although they received evidence-based and guideline-driven treatment.
Conclusion: The reason for this negative finding might well be that for several drugs, which were used frequently, no PI value is available. Nevertheless we suggest PP as an important concept in the planning of BD maintenance treatment.
Experiments for p-process nucleosynthesis with special focus on the most abundant p nucleus 92Mo
(2014)
This thesis describes experimental investigations and astrophysical network calculations relevant for the nucleosynthesis of the p nuclei. These 35 proton-rich isotopes cannot be produced by neutron-capture reactions which is the general production mechanism for elements heavier than iron in the r and s processes. Therefore, other mechanisms like photo-disintegration reactions on heavy seed nuclei (γ process) or proton-capture reactions are taken into account.
The modelling of these processes relies on a hugh amount of reactions which mostly occur for unstable isotopes. This demands, in combination with the contribution of excited states to the stellar rate, the prediction of the rates by a suited theoretical approach: the Hauser-Feshbach statistical model. To improve the reliability of the predictions, systematic experimental investigations are performed within this work for the nuclear input to the calculations. The study of charged-particle optical model potentials using the activation approach for the investigation of (α,n) and (p,n) reactions is described as well as the investigation of (γ,n) reactions in a broad mass range of 140 ≤ A ≤ 210.
However, there are also key reactions which are of special interest for the nucleosynthesis of individual p nuclei. An impressive example is the puzzle about the production of the most abundant p nucleus 92Mo. Within this work, the results of an experiment using high-resolution in-beam γ-spectroscopy for the study of the 90Zr(p,γ) reaction are summarized. In addition, the efforts to investigate the 91Nb(p,γ) reaction in standard kinematics by the production of target of the unstable isotope 91Nb to be used with the high-intensity proton-beam provided by the accelerator of FRANZ, Frankfurt, are discussed.
Finally, the influence of experimental results in astrophysical network calculations is discussed using post-processing nucleosynthesis methods for the γ process in type II supernovae.
The number of multilingual texts in the World Wide Web (WWW) is increasing dramatically and a multilingual economic zone like the European Union (EU) requires the availability of multilingual Natural Language Processing (NLP) tools. Due to a rapid development of NLP tools, many lexical, syntactic, semantic and other linguistic features have been used in different NLP applications. However, there are some situations where these features can not be used due the application type or unavailability of NLP resources for some of the languages. That is why an application that is intended to handle multilingual texts must have features that are not dependent on a particular language and specific linguistic tools. In this thesis, we will focus on two such applications: text readability and source and translation classification.
In this thesis, we provide 18 features that are not only suitable for both applications, but are also language and linguistic tools independent. In order to build a readability classifier, we use texts from three different languages: English, German and Bangla. Our proposed features achieve a classification accuracy that is comparable with a classifier using 40 linguistic features. The readability classifier achieves a classification F-score of 74.21% on the English Wikipedia corpus, an F-score of 75.47% on the English textbook corpus, an F-score of 86.46% on the Bangla textbook corpus and an F-score of 86.26% on the German GEO/GEOLino corpus.
We used more than two million sentence pairs from 21 European languages in order to build the source and translation classifier. The classifier using the same eighteen features achieves a classification accuracy of 86.63%. We also used the same features to build a classifier that classifies translated texts based on their origin. The classifier achieves classification accuracy of 75% for texts from 10 European languages. In this thesis, we also provide four different corpora, three for text readability analysis and one for corpus based translation studies.
Background: In this study, we examined patients who had non-progressive disease for at least 2 years after diagnosis of inoperable locoregional recurrent or metastatic breast cancer under continuous trastuzumab treatment. Our primary goal was to assess the long-term outcome of patients with durable response to trastuzumab.
Methods: 268 patients with HER2-positive inoperable locally recurrent or metastatic breast cancer and non-progressive disease for at least 2 years under trastuzumab treatment were documented retrospectively or prospectively in the HER-OS registry, an online documentation tool, between December 2006 and September 2010 by 71 German oncology centers. The study end point was time to tumor progression.
Results: Overall, 47.1% of patients (95% confidence interval (CI): 39.9–54.1%) remained in remission for more than 5 years, while the median time to progression was 4.5 years (95% CI: 4.0–6.6 years). Lower age (<50 years) and good performance status (ECOG 0) at time of trastuzumab treatment initiation as well as complete remission after initial trastuzumab treatment were associated with longer time to progression. Interruption of trastuzumab therapy correlated with shorter time to progression.
Conclusions: HER2-positive patients, who initially respond to palliative treatment with trastuzumab, can achieve a long-term tumor remission of several years.
Terrestrial climate and ecosystem evolution during ‘Greenhouse Earth’ phases of the early Paleogene remain incompletely known. Particularly, paleobotanical records from high southern latitudes are giving only limited insights into the Paleocene and early Eocene vegetation of the region. Hence, data from continuous well-calibrated sequences are required to make progress with the reconstruction of terrestrial climate and ecosystem dynamics from the southern latitudes during the early Paleogene.
In order to elucidate the terrestrial conditions from the high southern latitudes during the early Paleogene, terrestrial palynology was applied in the present study to two well-dated deep-marine sediment cores located at the Australo-Antarctic region: (i) IODP Site U1356 (Wilkes Land margin, East Antarctica) and (ii) ODP Site 1172 (East Tasman Plateau, southwest Pacific Ocean). The studied sequence from IODP Site U1356 comprises mid-shelfal sediments from the early to middle Eocene (53.9 – 46 million years ago [Ma]). For the ODP Site 1172, the studied succession is characterized by sediments deposited in shallow marine environments of the middle Paleocene to the early Eocene (60.7 – 54.2 Ma).
Based on the obtained pollen and spores (sporomorphs) results from the studied sequences of Site U1356 and Site 1172, this study aims to: (1) decipher the terrestrial climate conditions along the Australo-Antarctic region from the middle Paleocene to the middle Eocene; (2) evaluate the structure, diversity and compositional patterns of forests that throve in the Australo-Antarctic region during the early Paleogene; (3) understand the response of forests from the high southern latitudes to the climate dynamics from the early Paleogene; (4) establish a connection between the generated terrestrial palynomorph data and published Sea Surface Temperatures (SSTs) from the same cores.
To decipher the terrestrial climatic conditions on the Australo-Antarctic region, this study relies on the nearest living relative (NLR) concept that assumes that fossil taxa have similar climate requirements as their modern counterparts. This approach was applied to the sporomorph results of Site U1356 and Site 1172, following mainly the bioclimatic analysis. With regard to the structure and diversity patterns of the vegetation from the same region, the present study presents combined qualitative (i.e., reconstruction of the vegetation based mainly on the habitats of the known living relatives) and quantitative (i.e., application of ordination techniques, rarefaction and diversity indices) analyses of the fossil sporomorphs results.
The overall results from the paleoclimatic and vegetation reconstruction approaches applied in the present study, indicate that temperate and paratropical forests during the early Paleogene throve under different climatic conditions on the Wilkes Land margin and on Tasmania, at paleolatitudes of ∼70°S and ∼65°S, respectively.
Specifically, the sporomorph results from Site U1356, suggest that a highly diverse forest similar to present-day forests from New Caledonia was thriving on Antarctica during the early Eocene (53.9 – 51.9 Ma). These forests were characterized by the presence of termophilous taxa that are restricted today to tropical and subtropical settings, notably Bombacoideae, Strasburgeria, Beauprea, Spathiphyllum, Anacolosa and Lygodium. In combination with MBT/CBT paleotemperature results, they provide strong evidence for near-tropical warmth at least in the coastal lowlands along the Wilkes Land margin. The coeval presence of frost tolerant taxa such as Nothofagus, Araucariaceae and Podocarpaceae during the early Eocene on the same record suggests that paratropical forests were thriving along the Wilkes Land margin. Due to the presence of this kind of vegetation, it is possible to suggest that forests in this region were subject to a climatic gradient related to differences in elevation and/or the proximity to the coastline.
By the middle Eocene, the paratropical forests that characterized the vegetation of the early Eocene on the Wilkes Land margin were replaced by low diversity temperate forests dominated by Nothofagus, and similar to present-day cool-temperate forests from New Zealand. The dominance of these forests and the absence of thermophilous elements together with the lower temperatures suggested by the MBT/CBT and the sporomorph-based temperatures indicate consistently cooler conditions during this time interval.
With regard to the sporomorph results of Site 1172, this study suggests that three vegetation types were thriving on Tasmania from the middle Paleocene to the early Eocene under different climatic conditions. During the middle to late Paleocene, warm-temperate forests dominated by Podocarpaceae and Araucariaceae were the prevailing vegetation on Tasmania. The dominance of these forests was interrupted by the transient predominance of cool-temperate forests dominated by Nothofagus and Araucariaceae across the middle/late Paleocene transition interval (~59.5 to ~59.0 Ma). This cool-temperate forest was characterized by a lack of frost-sensitive elements (i.e., palms and cycads) indicating cooler conditions with harsher winters on Tasmania during this time interval. By the early Eocene, and linked with the Paleocene Eocene Thermal Maximum (PETM), Paleocene temperate forests dominated by gymnosperms were replaced by paratropical rainforests with the remarkable presence of the tropical mangrove palm Nypa during the PETM and the earliest Eocene. The overall results from Site U1356 and Site 1172, provide a new assessment of the terrestrial climatic conditions in the Australo-Antarctic region for validating climate models and understanding the response of high-latitude terrestrial ecosystems to the climate dynamics of the early Paleogene on southern latitudes.
The climatic conditions in the higher latitudes during the early Paleogene were further unravelled by comparing the obtained terrestrial and marine results. The integration of the obtained sporomorph data with previously published TEX86-based SSTs from Site 1172 documents that the vegetation dynamics were closely linked with the temperature evolution from the Australo-Antarctic region. Moreover, the comparison of TEX86-based SSTs and sporomorph-based climatic estimations from Site 1172 suggests a warm-season bias of both calibrations of TEX86 (i.e., TEX86Hand TEX86H), when this proxy is applied to high southern latitudes records of the early Paleogene.
In Reaktion auf zellulären Stress wie etwa Schädigungen der DNA oder die vermehrte Aktivität von Onkogenen aktivieren vorgeschaltete Signalkaskaden den Transkriptionsfaktor (TF) p53. Dieser kann über die Aktivierung der Expression von Zielgenen wiederum die Zellteilung stoppen, die Reparatur von DNA Schäden initiieren oder in schweren Fällen die Eliminierung der Zelle durch Apoptose einleiten. Ist p53 durch Mutationen deaktiviert, können sich entartete somatische Zellen vermehren und in der Folge Krebs entstehen.
In Wirbeltieren finden sich neben p53 mit p63 und p73 zwei weitere TFs, welche während der Evolution aus dem gleichen gemeinsamen Vorläufer durch Genduplikationen hervorgegangen sind. Die drei TFs sind modular aufgebaut und alle Isoformen verfügen jeweils minimal über eine DNA Bindungsdomäne (DBD) und eine Tetramerisierungsdomäne (TD). Werden die p53 ähnlichen TFs aktiviert, lagern sie sich über die TD vermittelt zu Tetrameren zusammen, wodurch ihre DBDs kooperativ an DNA Sequenzmotive binden können. Die DBD ist auch über große phylogenetische Abstände hinweg hoch konserviert, wodurch bereits gezeigt werden konnte, dass auch primitive vielzellige Tiere bereits Homologe dieser TF Familie besitzen. Im Vergleich zur DBD variiert die Proteinsequenz der TD deutlich stärker, was andeutet, dass deren Struktur im Laufe der Evolution erhebliche Veränderungen durchlaufen hat. Diese Veränderungen aufzuklären ist das übergeordnete Forschungsvorhaben zu dem diese Dissertationsschrift beiträgt.
Ciona intestinalis (C.int.) ist eine Spezies aus dem Unterstamm der Manteltiere. Diese sind die engsten lebenden Verwandten der Wirbeltiere und C.int. ist ein populärer Modelorganismus für die Erforschung der Embryonalentwicklung. Sein Genom kodiert für zwei p53 ähnliche TFs, welche mit p53/p73-a und p53/p73-b bezeichnet werden. Die Struktur ihrer TDs wurde im Rahmen der vorliegenden Arbeit mittels Kernspinresonanz (NMR) Spektroskopie untersucht.
Die TD von menschlichem p53 (hp53) ist ein Dimer aus Dimeren. Jedes Monomer formt einen beta-Strang und eine alpha-Helix. Im primären Dimer lagern diese sich so zusammen, dass ein beta-Faltblatt entsteht und die alpha-Helices mit entgegen gesetzter Orientierung der Länge nach aneinander packen. Zwei dieser Dimer lagern sich dann so zum Tetramer zusammen, dass zwischen pol-ständigen beta-Faltblättern ein Bündel aus vier Helices entsteht. Dieses Motiv ist auch in den TDs der Ciona Proteine hochkonserviert und wird im Folgenden als Kern?TD bezeichnet. In den TDs von menschlichem p63 und p73 (hp63 und hp73) verfügt jedes Monomer an seinem C-terminus noch über eine zweite Helix. Die zweiten Helices eines jeden Dimers greifen wie Klammern um das jeweils andere primäre Dimer und stabilisieren so das Tetramer. Entscheidend für die stabile Anbindung an die Kern?TD ist dabei ein charakteristisches Tyrosin-Arginin (YR) Motiv in der zweiten Helix, welches sich auch in der Sequenz der TD von C.int. p53/p73-a wiederfindet. Analysen der Sekundärstruktur auf Basis von NMR Experimenten ergaben jedoch, dass die TD von C.int. p53/p73-a bei 25°C keine zweite Helix ausbildet. Mit Hilfe von chimären TD Peptiden, in denen Teile der Ciona Sequenz gegen die entsprechenden Abschnitte von hp73 ausgetauscht wurden, konnte gezeigt werden, dass die Kern TD von C.int. p53/p73-a fähig ist eine zweite Helix zu stabilisieren und hierfür neben dem YR Motiv auch der Sequenzabschnitt zwischen erster und zweiter Helix entscheidend ist. Stabilisierende Substitutionen in diesem Bereich bewirkten ebenso wie ein Absenken der Temperatur die Ausbildung einer zweiten Helix, welche jedoch im Gegensatz zu jener in hp73 nur transient faltet und auch nicht essentiell für die Bildung des Tetramers ist, wohl aber dessen Stabilität erhöht.
Spezifisch in der Entwicklungslinie von Ciona kam es dazu, dass eine, für eine entsprechende Vorläuferversion von C.int. p53/p73-a kodierende, mRNA spontan zurück in DNA übersetzt und ins Genom eingefügt wurde. Die durch diese Retrotransposition erzeugte neue Genkopie C.int. p53/p73-b muss demnach ursprünglich einmal für die gleiche Proteinsequenz kodiert haben, innerhalb der TD finden sich konservierte Reste jedoch nur im Bereich der Kern TD.
Von der TD von C.int. p53/p73-b wurde die molekulare Struktur in freier Lösung mittels NMR ermittelt. Diese zeigte, dass interessanterweise in der TD von C.int. p53/p73-b jedes Monomer am C-terminus eine stabil gefaltete, zweite Helix besitzt. Obwohl diese zweite Helix sich aus einer Sequenz faltet, die keinerlei Sequenzhomologie zu homologen Proteinen aus Wirbeltieren aufweist, lagert sie sich in einer Position auf die Kern TD, welche der in hp73 sehr nahe kommt. Da die primären Dimere der Kern TD aber anders als in hp63 und hp73 durch Salzbrücken miteinander verbunden sind, ist die zweite Helix jedoch nicht essentiell, um das Tetramer zu stabilisieren. Vermutlich kommt der zweiten Helix von C.int. p53/p73-b vielmehr u.a. die Aufgabe zu die Bildung von Heterotetrameren aus C.int. p53/p73-a und –b zu unterbinden.
Zusammengenommen zeigen die Ergebnisse, dass die Architektur der TD mit zweiter Helix bereits der Prototyp für die TDs aller p53 ähnlichen Proteine der Wirbel- und Manteltiere war und die als eine Art Klammer das Tetramer stabilisierende zweite Helix sich nicht erst während der Evolution der Wirbeltiere entwickelt hat.
Oscillations play a critical role in cognitive phenomena and have been observed in many brain regions. Experimental evidence indicates that classes of neurons exhibit properties that could promote oscillations, such as subthreshold resonance and electrical gap junctions. Typically, these two properties are studied separately but it is not clear which is the dominant determinant of global network rhythms. Our aim is to provide an analytical understanding of how these two effects destabilize the fluctuation-driven state, in which neurons fire irregularly, and lead to an emergence of global synchronous oscillations. Here we show how the oscillation frequency is shaped by single neuron resonance, electrical and chemical synapses.The presence of both gap junctions and subthreshold resonance are necessary for the emergence of oscillations. Our results are in agreement with several experimental observations such as network responses to oscillatory inputs and offer a much-needed conceptual link connecting a collection of disparate effects observed in networks.