Refine
Year of publication
- 2011 (937) (remove)
Document Type
- Article (419)
- Part of Periodical (132)
- Book (109)
- Doctoral Thesis (82)
- Working Paper (68)
- Conference Proceeding (60)
- Part of a Book (39)
- Report (10)
- Review (10)
- Periodical (3)
Language
- English (937) (remove)
Keywords
- Dante Alighieri (20)
- Rezeption (20)
- Productive reception (18)
- new species (12)
- Englisch (11)
- Cape Verde Islands (9)
- Divina Commedia (9)
- Inferno (7)
- Intonation <Linguistik> (7)
- Interrogativsatz (6)
Institute
- Medizin (129)
- Physik (80)
- Biochemie und Chemie (62)
- Geowissenschaften (45)
- Biowissenschaften (44)
- Extern (44)
- Center for Financial Studies (CFS) (42)
- Frankfurt Institute for Advanced Studies (FIAS) (34)
- Institut für Ökologie, Evolution und Diversität (27)
- Wirtschaftswissenschaften (25)
The chitinase-like protein YKL-40 was found to be increased in patients with severe asthma and chronic obstructive pulmonary disease (COPD), two disease conditions featuring neutrophilic infiltrates. Based on these studies and a previous report indicating that neutrophils secrete YKL-40, we hypothesized that YKL-40 plays a key role in cystic fibrosis (CF) lung disease, a prototypic neutrophilic disease. The aim of this study was (i) to analyze YKL-40 levels in human and murine CF lung disease and (ii) to investigate whether YKL-40 single-nucleotide polymorphisms (SNPs) modulate CF lung disease severity. YKL-40 protein levels were quantified in serum and sputum supernatants from CF patients and control individuals. Levels of the murine homologue BRP-39 were analyzed in airway fluids from CF-like βENaC-Tg mice. YKL-40SNPs were analyzed in CF patients. YKL-40 levels were increased in sputum supernatants and in serum from CF patients compared to healthy control individuals. Within CF patients, YKL-40 levels were higher in sputum than in serum. BRP-39 levels were increased in airways fluids from βENaC-Tg mice compared to wild-type littermates. In both CF patients and βENaC-Tg mice, YKL-40/BRP-39 airway levels correlated with the severity of pulmonary obstruction. Two YKL-40 SNPs (rs871799 and rs880633) were found to modulate age-adjusted lung function in CF patients. YKL-40/BRP-39 levelsare increased in human and murine CF airway fluids, correlate with pulmonary function and modulate CF lung disease severity genetically. These findings suggest YKL-40 as a potential biomarker in CF lung disease.
Background
Cytochrome-P450 (CYP450) epoxygenases metabolise arachidonic acid (AA) into four different biologically active epoxyeicosatrienoic acid (EET) regioisomers. Three of the EETs (i.e., 8,9-, 11,12- and 14,15-EET) are rapidly hydrolysed by the enzyme soluble epoxide hydrolase (sEH). Here, we investigated the role of sEH in nociceptive processing during peripheral inflammation.
Results
In dorsal root ganglia (DRG), we found that sEH is expressed in medium and large diameter neurofilament 200-positive neurons. Isolated DRG-neurons from sEH-/- mice showed higher EET and lower DHET levels. Upon AA stimulation, the largest changes in EET levels occurred in culture media, indicating both that cell associated EET concentrations quickly reach saturation and EET-hydrolyzing activity mostly effects extracellular EET signaling. In vivo, DRGs from sEH-deficient mice exhibited elevated 8,9-, 11,12- and 14,15-EET-levels. Interestingly, EET levels did not increase at the site of zymosan-induced inflammation. Cellular imaging experiments revealed direct calcium flux responses to 8,9-EET in a subpopulation of nociceptors. In addition, 8,9-EET sensitized AITC-induced calcium increases in DRG neurons and AITC-induced calcitonin gene related peptide (CGRP) release from sciatic nerve axons, indicating that 8,9-EET sensitizes TRPA1-expressing neurons, which are known to contribute to mechanical hyperalgesia. Supporting this, sEH-/- mice showed increased nociceptive responses to mechanical stimulation during zymosan-induced inflammation and 8,9-EET injection reduced mechanical thresholds in naive mice.
Conclusion
Our results show that the sEH can regulate mechanical hyperalgesia during inflammation by inactivating 8,9-EET, which sensitizes TRPA1-expressing nociceptors. Therefore we suggest that influencing the CYP450 pathway, which is actually highly considered to treat cardiovascular diseases, may cause pain side effects.
The present work comprises different projects within the scope of public health. In detail, they all aim at combating the high-burden diseases HIV/AIDS, malaria and tuberculosis more effectively. Since there was, and still is, no harmonization between the existing biowaiver guidelines, the biowaiver dissolution test conditions by WHO and FDA were compared against each other using drug products, which had already demonstrated BE to the comparator in vivo. Thereby it could be shown that the dissolution conditions proposed by the WHO are more appropriate for granting biowaivers than those of the FDA. Further, the applicability of the WHO dissolution test conditions was investigated using the APIs ethambutol, isoniazid and pyrazinamide (all BCS Class III) as model compounds. These investigations demonstrated that the concept of the biowaiver proved to work properly, i.e. leading to no false positive BE decision and an acceptable incidence of false negative BE decisions. In addition, four new biowaiver monographs were published addressing important APIs in the treatment of HIV/AIDS and malaria. Before these efforts, there were only a very few biowaiver monographs available for antiviral or antimalarial APIs, i.e. the database of biowaiver monographs has been clearly improved. The last part of the present work dealt with the extension of the biowaiver concept to related areas such as the WHO Prequalification of Medicines Programme. Investigations revealed that the biowaiver tools are generally eligible for prequalification of drug products containing ethambutol, isoniazid, pyrazinamide, or lamivudine to prove BE between an appropriate comparator and the test candidate. By contrast, some APIs are excluded from the biowaiver procedure. In conclusion, the implementation of the biowaiver tools for prequalification of biowaivable APIs is, along with BCS-based biowaiver approval of new generics, an important step towards making essential, high-quality drug products more cost-effective and, as a consequence, more accessible for a larger percentage of the population. In that way, the treatment conditions for those in need living in the developing countries can be improved enormously, so that those who are poor do not have to receive poor treatment. The quality standard of essential medicines will increase worldwide, thereby helping to combat the high-burden diseases better and, in turn, lead to an improvement of the global health status.
The current work investigated the association of trait anxiety and the neural efficiency of cognitive processing for affectively neutral (not threat-related) information. In a sample of 46 healthy volunteers, three fMRI experiments were conducted to test the prediction derived from attentional control theory (Eysenck et al., 2007) that high as compared to low trait-anxious individuals expend more neural effort on tasks requiring the top-down control of attention to reach a given level of performance. In a colour-word Stroop task requiring the inhibition of irrelevant stimulus information and associated responses as well as in a working-memorymanipulation task requiring the shifting of attention between items in working memory, trait anxiety (as measured with the State-Trait Anxiety Inventory; Spielberger et al., 1970) was positively associated with task-related increases in the activation of two adjacent regions in the right dorsolateral prefrontal cortex (DLPFC). The finding that along with a stronger activation of this brain region commonly implicated in top-down control processes, the high-anxious subjects showed equal (working memory manipulation) or worse (Stroop) performance when compared to low-anxious subjects, does support the assumption that processing is less efficient in the high anxious. However, in contrast to the predictions, trait anxiety did not show a significant association with task-related brain activation in a task-switching paradigm requiring shifting between task sets. It is discussed how different attentional control demands of the task may account for differences in the effects of trait anxiety on overt behavioural performance and underlying neural processes. In addition to DLPFC activation, trait anxiety modulated the functional connectivity of distributed regions involved in processing of the Stroop and the working-memory-manipulation task. It is discussed how the observed differences in regional DLPFC activation and network connectivity relate to each other. A possible interpretation suggests that activation increases in the DLPFC reflect an attempt to compensate for suboptimal connectivity by investing more effort in prefrontally supported control processes. Overall, the current work shows an association of trait anxiety with the neural efficiency of cognitive processing in affectively neutral tasks involving attentional control. Furthermore, it suggests that investigations of neural efficiency should take into account difference in functional integration in addition to regional activation.
"Finnegans Wake" has struck many of its exegetes as the epitome of the postmodern text. The oddity of James Joyce's last work has been and still is a provocation not only for literary criticism and theory but for every reader of the work. It provokes us to reflect on our preconceptions concerning such fundamental issues as reading, meaning and understanding. Due to this very quality, the work has been a fertile intellectual stimulus for an illustrious band of thinkers of the ―post-projects. Its singularity has provoked and facilitated the further development of theoretical frameworks beyond the confines of literary theory proper. This essay will trace the elaborate theoretical responses of Umberto Eco and Jacques Lacan to Joyce's grand literary arcanum. Eco's concept of the openness of modern works of art and Lacan's elaboration of his psychoanalytic concepts of the symptom and of the Borromean knot were inspired by their study of Joyce. As an extreme instance of literariness, Finnegans Wake thus constitutes an ideal opportunity to consider the scope and boundaries of the scholarly study of literary texts more generally.
Friedrich August Wolf posits in his "Prolegomena ad Homerum" that, from the time of the first transcription of Homer's epics around 700 BC to the time of the Alexandrian editions, the Iliad and Odyssey underwent repeated revisions by a multitude of poets and critics. According to Wolf, the "unified" works that we know are the products of emendations by Alexandrian critics who attempted to homogenize the style of the epics and to return them to their "original" form. This paper argues that Wolf's narration of the history of these texts relies on and produces aesthetic claims, not historical ones. Wolf determines the dates and origins of passages based on intuitive judgments of style for which he cannot provide linguistic or historical evidence. And his conclusions that the "Iliad" and "Odyssey" were not written by Homer, but rather by a history of emendations and revisions, enthrones his work — the work of philologists — in place of the literary genius Homer. Thus philology becomes for Wolf an aesthetic discipline that produces canonical and beautiful works of literature. This aesthetic task is essential for philology to fulfill its educational and political responsibilities.
This paper seeks to demonstrate the ways in which Bachmann's work constitutes a prime case for examining the scope and the boundaries of philological research. It does so by focusing on Bachmann‘s fragmentary and unfinished novel, "Das Buch Franza" [1965-1966], exploring the text and its author in an interdisciplinary light. Forming part of Bachmann's uncompleted "Todesarten"-Projekt, "Das Buch Franza" deals with the continuing legacy of fascism and its displaced forms in the post-war era. In its thematisation of the traumatic and necessarily belated after-effects of the Second World War and the Holocaust, Bachmann‘s text draws on various disciplines and discourses, namely geology, archaeology and psychoanalysis. I consider the ways in which the interdisciplinary ambitions of the text reflect Bachmann‘s struggle for a new form of representation, one that adequately mirrors the concerns of her society. Finally, drawing on Bachmann‘s own theoretical reflections on the field of literary study in her Frankfurt Lectures on poetics, I trace the ways in which the author's work repeatedly encourages us to adopt multiple disciplinary perspectives, as well as privileging literature with a utopian function that exceeds any generic or disciplinary boundaries.
Time-resolved spectroscopic analysis of fucoxanthin-chlorophyll proteins and isolated carotenoids
(2011)
The aim of this thesis was to elucidate the excitation energy transfer in the fucoxanthin-chlorophyll proteins (FCPs) isolated from the diatom Cyclotella meneghiniana in detail and to clarify the role of the different pigments contained. In a first step the excited state dynamics of the free pigments were studied by means of time-resolved absorption spectroscopy. The FCPs contain three different carotenoid species. Besides the main light-harvesting carotenoid fucoxanthin (fx) the xanthophyll cycle pigments diadinoxanthin (ddx) and diatoxanthin (dtx) are found in substoichiometric amounts. Fx is contained in an unusual carotenoid-to-chlorophyll ratio of about one. In case of ddx and dtx, changing the solvent polarity showed no significant effects on the absorption spectrum and the excited state dynamics were hardly influenced. In contrast, a solvent dependence is observed in the absorption spectrum and excited state dynamics of fx. The S1 lifetime depends strongly on the solvent polarity and an additional broad excited state absorption band red shifted compared to the S1 excited state absorption appears. The occurrence of the described features can be explained with an intramolecular charge transfer state, which is stabilized in a polar environment and appears only in carotenoids with a conjugated carbonyl group. Despite its rather short excited state lifetimes of less than 200 fs (S2) and 30-60 ps (S1), fx acts as a very efficient energy donor in the FCPs. The ultrafast energy transfer dynamics of the isolated proteins FCPa and FCPb were investigated in a comprehensive study using transient absorption in the visible and NIR spectral region complemented with polarized transient absorption spectroscopy. The excitation energy transfer was not influenced significantly by changing the light conditions during the growth, which yields an altered amount of ddx and dtx. It can be concluded that the contribution of the xanthophyll cycle pigments to the energy transfer is not significant. The altered oligomerization state results in a more efficient energy transfer for the trimeric FCPa, which is also reflected in different Chl a fluorescence quantum yields. Thus, an increased quenching in the higher oligomers of FCPb can be assumed. The observed dynamics change drastically for two different excitation wavelengths λ = 500 nm and λ = 550 nm, which both lead to the population of the S2 excited state of individual carotenoids, namely blue and red absorbing fx molecules. The differing absorption maxima result from distinct microenvironments within the protein. For FCPa an additional slow time constant of 25 ps was found after excitation at 500 nm. By means of polarized transient absorption spectroscopy applied to FCPa different transition dipole moments for the S1 and the ICT state of fx could be identified. Based on the presented studies a detailed model explaining the excitation energy transfer pathways could be developed. In agreement with the faster overall transfer rate which is also evident in the anisotropy data in case of 550 nm excitation, upon excitation at 500 nm one slow transfer channel is active. It can be attributed to a blue absorbing fx not strongly associated with a Chl a molecule. Most likely excitation energy transfer takes place between the S1/ICT states of two different fx molecules before the energy is transferred to Chl a. Additional transient absorption experiments with an improved time resolution were performed to investigate the oscillations observed. These coherent effects superimposed the kinetics of isolated carotenoids as well as FCPs within the first 500 fs. The oscillations showed a very unusual damping behavior and vanished already after two oscillation periods. In case of fx, the solvent environment as well as the excitation wavelengths had an influence on the oscillations. The frequencies of the oscillations were 70-100 cm^-1 for fx in solvents with varying polarity and 50-80 cm^-1 for the FCPs. These results could further confirm the assumption that the red absorbing fx molecules are located in a more polar environment within the protein compared to the blue absorbing fx. To clarify the origin of the oscillations in more detail, further experiments with a controlled chirp of the applied pulses and comparison between different carotenoids in various solvents are required. This approach promises to give further insight in the excited state dynamics and to answer the question whether dark states are involved. Right now, the coherent excitation of the strongly coupled excited states 1Bu+ (S2) and 1Bu- resulting in electronic quantum beats and the existence of an additional short lived excited state absorption (S2-SN2) in the visible spectral region are the most reasonable explanations for the occurrence of the coherent effects in the transient absorption spectra of carotenoids.
Capturing the zero: a new class of zero-augmented distributions and multiplicative error processes
(2011)
We propose a novel approach to model serially dependent positive-valued variables which realize a non-trivial proportion of zero outcomes. This is a typical phenomenon in financial time series observed at high frequencies, such as cumulated trading volumes. We introduce a flexible point-mass mixture distribution and develop a semiparametric specification test explicitly tailored for such distributions. Moreover, we propose a new type of multiplicative error model (MEM) based on a zero-augmented distribution, which incorporates an autoregressive binary choice component and thus captures the (potentially different) dynamics of both zero occurrences and of strictly positive realizations. Applying the proposed model to high-frequency cumulated trading volumes of both liquid and illiquid NYSE stocks, we show that the model captures the dynamic and distributional properties of the data well and is able to correctly predict future distributions.
Since combinatorial chemistry and high throughput screening have become a common technique in the drug discovery phase the number of compounds being considered has increased frequently. These structures are often characterized by high molecular weight, high lipophilicity and low solubility in aqueous and physiological media. Due to the generally poor bioavailability, new in vitro techniques were needed for screening of pharmacokinetic properties. An important parameter for these screening methods is the implementation at an early state of drug discovery phase, to find potential lead structures, before investment costs become significant. The established in vitro methods for the prediction of membrane interaction are not reliable especially for poorly soluble compounds. A new method that is fast and easy to use, requires only small amounts of NCE and which can provide more reliable predictions is needed. In this study, a new screening technique based on surface activity profiling for the prediction of oral drug absorption was evaluated with special emphasis on the predictability of biological membrane interaction of poorly soluble drug compounds. It was demonstrated that drug absorption through a bilayer membrane can be modeled by the orientation of compounds at the air/water interface. Thus amphilicity of a drug is generally related to both oral absorption and blood brain barrier penetration. In turn, amphiphilicity is influenced by the lipophilicity, size and charge distribution of a drug. Surface activity profiling was determined by analysis of surface pressure profiles using the Gibbs adsorption isotherm. The surface activity measurements were carried out using a multichannel tensiometer Delta 8, which was developed by Kibron to be utilized in conjugation high throughput screening in early drug discovery processes. For this study two test sets were analyzed, one for the prediction of gastrointestinal wall interaction and the second for the prediction of the penetration behavior at the blood brain barrier. Both test sets consist of drug compounds with a wide range of absorption properties and consist mainly of compounds with poor water solubility. Since the drugs characteristics varied, they were classified according to water solubility and surface activity and a sample preparation method for each group was established. For the prediction of oral drug absorption, three different methods were established to model the interaction of compound and gastrointestinal wall. For drug compounds with solubility above 1mmol/L the traditional shake-flask method enabled the determination of the amphiphilic properties of drug compounds in pure aqueous media. Compounds with solubility below 1mmol/L tend to not to exhibit any increase in surface activity. Thus surface tension measurements of compounds, which exhibited a limited surface activity due to poor aqueous solubility, were conducted from stock solutions prepared with various organic solvents. Mainly polar organic solvents were used. A mixture of DMSO and DMF resulted in the best combination of properties: the intensive solubility enhancing effect of DMF and the lower intrinsic surface activity of DMSO. The polar solvent ruptured the water clusters, so that highly lipophilic structures had a higher affinity to the solvent and higher concentrations could be obtained. For these compounds higher maximum surface pressure were generated than was possible in pure aqueous media. The surface pressure data were correlated with the fraction absorbed values in vivo. However it was found that poor water solubility is not the only limiting step to exhibiting any surface activity. Some compounds were showed no surface activity in either solvent system. Therefore a micelle vehicle method was established using short chain phospholipids to mimic the gastrointestinal wall. It could be concluded from the results, that non surface active drugs can interact with the phospholipids micelle vehicle in a way analogous to their interaction with the membrane bilayer. The relative critical micelle concentration was correlated with the fraction absorbed of this test set. A sample preparation schema based on the three types of drugs was established. This schema enabled us to predict the absorbance of slightly soluble and poorly soluble drugs with acceptable reliability for early compound screening. For the prediction of blood brain barrier penetration using surface activity profiling as analyzing method, a test set with very poorly soluble characteristics was chosen. The sample preparation method was based on a strictly aqueous approach using the ‘shake flask’ method. The surface tension measurements enabled correlation of the amphiphilic properties of the very poorly soluble drug compounds with BBB uptake. From the aqueous surface pressure profiles and the determination of physicochemical parameters, it was found that blood brain barrier is more likely when a drug provides a small cross-sectional area, As, at the interface. The cross-sectional area is the only parameter which is independent from the maximal concentration in aqueous media and it is particularly suitable for lower solubility compounds. In summary, it was shown that amphilicity is related to biological membrane interaction in the human body and that surface activity profiling with appropriate sample preparation can be used as a reliable screening tool for the prediction of oral drug absorption of poorly soluble drugs. Furthermore an in vitro screening method of blood-brain-barrier penetration was established.