Refine
Year of publication
- 2009 (862) (remove)
Document Type
- Article (362)
- Book (118)
- Doctoral Thesis (116)
- Part of Periodical (89)
- Working Paper (80)
- Conference Proceeding (28)
- Report (21)
- Part of a Book (15)
- Preprint (12)
- Review (10)
Language
- English (862) (remove)
Keywords
- Deutschland (6)
- Haushalt (6)
- Lambda-Kalkül (6)
- Pragmatik (6)
- USA (6)
- new species (6)
- Bank (5)
- Optimalitätstheorie (5)
- China (4)
- Household Finance (4)
Institute
- Medizin (113)
- Biochemie und Chemie (112)
- Biowissenschaften (43)
- Physik (42)
- Geowissenschaften (41)
- Center for Financial Studies (CFS) (35)
- Frankfurt Institute for Advanced Studies (FIAS) (29)
- Informatik (21)
- Wirtschaftswissenschaften (21)
- E-Finance Lab e.V. (20)
Word formation in Distributed Morphology (see Arad 2005, Marantz 2001, Embick 2008): 1. Language has atomic, non-decomposable, elements = roots. 2. Roots combine with the functional vocabulary and build larger elements. 3. Roots are category neutral. They are then categorized by combining with category defining functional heads.
This paper investigates the class of Tree-Tuple MCTAG with Shared Nodes, TT-MCTAG for short, an extension of Tree Adjoining Grammars that has been proposed for natural language processing, in particular for dealing with discontinuities and word order variation in languages such as German. It has been shown that the universal recognition problem for this formalism is NP-hard, but so far it was not known whether the class of languages generated by TT-MCTAG is included in PTIME. We provide a positive answer to this question, using a new characterization of TT-MCTAG.
Various concurrency primitives had been added to functional programming languages in different ways. In Haskell such a primitive is a MVar, joins are described in JoCaml and AliceML uses futures to provide a concurrent behaviour. Despite these concurrency libraries seem to behave well, their equivalence between each other has not been proven yet. An expressive formal system is needed. In their paper "On proving the equivalence of concurrency primitives", Jan Schwinghammer, David Sabel, Joachim Niehren, and Manfred Schmidt-Schauß define a universal calculus for concurrency primitives known as the typed lambda calculus with futures. There, equivalence of processes had been proved. An encoding of simple one-place buffers had been worked out. This bachelor’s thesis is about encoding more complex concurrency abstractions in the lambda calculus with futures and proving correctness of its operational semantics. Given the new abstractions, we will discuss program equivalence between them. Finally, we present a library written in Haskell that exposes futures and our concurrency abstractions as a proof of concept.
We present a CYK and an Earley-style algorithm for parsing Range Concatenation Grammar (RCG), using the deductive parsing framework. The characteristic property of the Earley parser is that we use a technique of range boundary constraint propagation to compute the yields of non-terminals as late as possible. Experiments show that, compared to previous approaches, the constraint propagation helps to considerably decrease the number of items in the chart.
Multicomponent Tree Adjoining Grammars (MCTAGs) are a formalism that has been shown to be useful for many natural language applications. The definition of non-local MCTAG however is problematic since it refers to the process of the derivation itself: a simultaneity constraint must be respected concerning the way the members of the elementary tree sets are added. Looking only at the result of a derivation (i.e., the derived tree and the derivation tree), this simultaneity is no longer visible and therefore cannot be checked. I.e., this way of characterizing MCTAG does not allow to abstract away from the concrete order of derivation. In this paper, we propose an alternative definition of MCTAG that characterizes the trees in the tree language of an MCTAG via the properties of the derivation trees (in the underlying TAG) the MCTAG licences. We provide similar characterizations for various types of MCTAG. These characterizations give a better understanding of the formalisms, they allow a more systematic comparison of different types of MCTAG, and, furthermore, they can be exploited for parsing.
Background Chemoresistance acquisition may influence cancer cell biology. Here, bioinformatics analysis of gene expression data was used to identify chemoresistance-associated changes in neuroblastoma biology. Results Bioinformatics analysis of gene expression data revealed that expression of angiogenesis-associated genes significantly differs between chemosensitive and chemoresistant neuroblastoma cells. A subsequent systematic analysis of a panel of 14 chemosensitive and chemoresistant neuroblastoma cell lines in vitro and in animal experiments indicated a consistent shift to a more pro-angiogenic phenotype in chemoresistant neuroblastoma cells. The molecular mechanims underlying increased pro-angiogenic activity of neuroblastoma cells are individual and differ between the investigated chemoresistant cell lines. Treatment of animals carrying doxorubicin-resistant neuroblastoma xenografts with doxorubicin, a cytotoxic drug known to exert anti-angiogenic activity, resulted in decreased tumour vessel formation and growth indicating chemoresistance-associated enhanced pro-angiogenic activity to be relevant for tumour progression and to represent a potential therapeutic target. Conclusions A bioinformatics approach allowed to identify a relevant chemoresistance-associated shift in neuroblastoma cell biology. The chemoresistance-associated enhanced pro-angiogenic activity observed in neuroblastoma cells is relevant for tumour progression and represents a potential therapeutic target.
The study of the electromagnetic structure of hadrons plays an important role in understanding the nature of matter. In particular the emission of lepton pairs out of the hot and dense collision zone in heavy-ion reactions is a promising probe to investigate in-medium properties of hadrons and in general the properties of matter under such extreme conditions. The first experimental observation of an enhanced di-electron yield in the invariant-mass region 0:3 - 0:7 GeV/c2 in p+Be collisions at 4:9 GeV/u beam energy [2] was announced by the DLS collaboration [1]. Recent results of the HADES collaboration show a moderate enhancement above n Dalitz decay contributions for 12C+12C at 1 and 2 GeV/u [3, 4] confirming the DLS results. There are several theoretical explanations of this observation, most of them focusing on possible in-medium modifications of the properties of vector mesons. At low beam energies the question whether the observed excess is related to any in-medium effects remains open because of uncertainties in the description of elementary di-electron sources. In this work the di-electron production in p+p and d+p reactions at a kinetic beam energy of 1:25 GeV/u measured by the HADES spectrometer is discussed. At Ekin = 1:25 GeV/u, i.e. below the n meson production threshold in proton-proton reactions, the delta Dalitz decay is expected to be the most abundant source above the pi 0 Dalitz decay region. The observed large difference in di-electron production in p+p and d+p collisions suggests that di-electron production in the d+p system is dominated by the n+p interaction. In order to separate delta Dalitz decays and np bremsstrahlung the di-electron yield observed in p+p and n+p reactions, both measured at the same beam energy, has been compared. The main interest here is the investigation of iso-spin effects in baryonic resonance excitations and the off-shell production of vector mesons [5]. We indeed observe a large difference in di-electron production in p+p and n+p reactions. Results of these studies will be compared to recent calculations. We will also present our experimentally defined cocktail for heavy-ion data. At much higher beam energies experimental results of the CERES [6] and NA60 [7] collaborations also show an enhancement in the invariant mass region 0:3 - 0:7 GeV/c2, in principle similar to the situation in DLS. A strong excess of lepton pairs observed by recent high energy heavy-ion dilepton experiments hint to a strong influence of baryons, however no data exist at highly compressed baryonic matter, achievable in heavy-ion collisions from 8 - 45 GeV/u beam energy. These conditions would allow to study the expected restoration of chiral symmetry by measuring in-medium modifications of hadronic properties, an experimental program which is foreseen by the future CBM experiment at FAIR. The experimental challenge is to suppress the large physical background on the one hand and to provide a clean identification of electrons on the other hand. In this work, strategies to reduce the combinatorial background in electron pair measurements with the CBM detector are discussed. The main goal is to study the feasibility of effectively reducing combinatorial background with the currently foreseen experimental setup, which does not provide electron identification in front of the magnetic field.
This paper gives a brief overview of computation models for data stream processing, and it introduces a new model for multi-pass processing of multiple streams, the so-called mp2s-automata. Two algorithms for solving the set disjointness problem with these automata are presented. The main technical contribution of this paper is the proof of a lower bound on the size of memory and the number of heads that are required for solving the set disjointness problem with mp2s-automata.
TNFAIP3 (A20) is a tumor suppressor gene in Hodgkin lymphoma and primary mediastinal B cell lymphoma
(2009)
Proliferation and survival of Hodgkin and Reed/Sternberg (HRS) cells, the malignant cells of classical Hodgkin lymphoma (cHL), are dependent on constitutive activation of nuclear factor {kappa}B (NF-{kappa}B). NF-{kappa}B activation through various stimuli is negatively regulated by the zinc finger protein A20. To determine whether A20 contributes to the pathogenesis of cHL, we sequenced TNFAIP3, encoding A20, in HL cell lines and laser-microdissected HRS cells from cHL biopsies. We detected somatic mutations in 16 out of 36 cHLs (44%), including missense mutations in 2 out of 16 Epstein-Barr virus–positive (EBV+) cHLs and a missense mutation, nonsense mutations, and frameshift-causing insertions or deletions in 14 out of 20 EBV– cHLs. In most mutated cases, both TNFAIP3 alleles were inactivated, including frequent chromosomal deletions of TNFAIP3. Reconstitution of wild-type TNFAIP3 in A20-deficient cHL cell lines revealed a significant decrease in transcripts of selected NF-{kappa}B target genes and caused cytotoxicity. Extending the mutation analysis to primary mediastinal B cell lymphoma (PMBL), another lymphoma with constitutive NF-{kappa}B activity, revealed destructive mutations in 5 out of 14 PMBLs (36%). This report identifies TNFAIP3 (A20), a key regulator of NF-{kappa}B activity, as a novel tumor suppressor gene in cHL and PMBL. The significantly higher frequency of TNFAIP3 mutations in EBV– than EBV+ cHL suggests complementing functions of TNFAIP3 inactivation and EBV infection in cHL pathogenesis.
In the New-Keynesian model, optimal interest rate policy under uncertainty is formulated without reference to monetary aggregates as long as certain standard assumptions on the distributions of unobservables are satisfied. The model has been criticized for failing to explain common trends in money growth and inflation, and that therefore money should be used as a cross-check in policy formulation (see Lucas (2007)). We show that the New-Keynesian model can explain such trends if one allows for the possibility of persistent central bank misperceptions. Such misperceptions motivate the search for policies that include additional robustness checks. In earlier work, we proposed an interest rate rule that is near-optimal in normal times but includes a cross-check with monetary information. In case of unusual monetary trends, interest rates are adjusted. In this paper, we show in detail how to derive the appropriate magnitude of the interest rate adjustment following a significant cross-check with monetary information, when the New-Keynesian model is the central bank’s preferred model. The cross-check is shown to be effective in offsetting persistent deviations of inflation due to central bank misperceptions. Keywords: Monetary Policy, New-Keynesian Model, Money, Quantity Theory, European Central Bank, Policy Under Uncertainty
Despite the well-known importance of ribonucleic acids (RNA) in cell biology, it is astounding to realize the pace at which new fundamental functions of RNAs have been discovered. One of the fundamental reasons for the multitude of functions of RNA is the property of RNA to adopt different conformations or folds. The primary sequence of RNA, a linear polymer built from four different repetition units, can fold into alternate secondary structure motifs which in turn form alternate long-range interactions in complex tertiary structures. Ligands such as metal ions or small molecular weight metabolites and also proteins or peptides can bind to RNA and induce the changes in tertiary conformation. For example, in the cell, RNA participates in gene regulation in the form of riboswitches. Riboswitches are found in untranslated regions of messenger RNA (mRNA) and adopt alternate conformations depending on the presence or absence of specific metabolites. If a metabolite is present above a specific concentration, it induces a conformational change in the respective riboswitch by binding and thereby alters gene expression. Another example is the RNA thermometer which participates in the cell translational mechanism by a similar strategy. Translation initiation requires the binding of RNA thermometers to the ribosome. The ribosome binding region is located in the 5’ untranslated region of mRNA. At low temperatures this region is prevented from binding to the ribosome by forming basepairs. At higher temperatures, these basepairs dissociate allowing ribosome binding and subsequent translation. Therefore, the characterization and delineation of the kinetics and pathway of RNA folding is important to understand the function of RNA and is an important contribution to fundamentally understand RNA’s role in the cell. RNA conformational transitions occur over a wide range of timescales. Depending on the timescale, various biophysical techniques are used to study RNA conformational transitions. In these biophysical studies, achieving good structural and temporal resolution constitute frequently encountered challenges or limitations. For example, single molecule FRET spectroscopy provides high temporal resolution in the milliseconds at high sensitivity but lacks atomic resolution. Recent advances in the field of Nuclear Magnetic Resonance (NMR) spectroscopy have enabled the elucidation of tertiary folding events to be characterized with atomic resolution. This thesis involves the use of NMR spectroscopy to characterize the folding of RNA molecules. Kinetics experiments require rapid initiation of the kinetics followed by monitoring of the reaction. In this thesis, two different folding initiation techniques have been applied and coupled to the subsequent detection of RNA folding using NMR spectroscopy, namely, photocaging and rapid mixing. The method of photocaging is well established (Kuhn and Schwalbe, 2000) and builds on the following principle: A photolabile moiety is attached to a molecule that prevents a specific interaction. Upon irradiation of the molecule with the photolabile group using laser light at a specific wave length, at which the molecule of interest is not absorbing, the protecting group is released. In our group, together with the group of S. Pitsch, ETH Lausanne, we could "cage" RNA at its equilibrium state by a photolabile molecule (similar work has been carried out in the group of A. Heckel). Rapid and traceless release of the photolabile precursor compound by a laser pulse releases the RNA to fold into its native state; the build-up of the native state of the RNA is monitored by NMR signals that are uniquely characteristic for the native state of the RNA. By optically coupling a laser source to an NMR magnet, the above procedure can take place in situ and the kinetics recorded by NMR. Several different molecules can be caged: The photocage can be attached to RNA. Then, a modified photolabile nucleotide can be placed at strategic positions of a target RNA whose folding properties is to be studied. The photocage can also be attached to a ligand: if folding is dependent on ligand binding then the ligand can be modified to carry a photosensitive unit whose degradation allows binding to RNA. In this thesis, an alternative method for photocaging is introduced. Here, metal ions essential for folding of the RNA are photocaged using the photolabile chelating agent Dimethyl-nitrophen (DMN). Photolysis of DMNr releases the metal ion, thereby RNA folding is initiated. In the rapid-mixing technique, one of (several) components required for proper folding of the RNA is rapidly injected into an NMR sample in situ by the use of a pneumatic injection device. ...
"The whole is more than the sum of its parts." This idea has been brought forward by psychologists such as Max Wertheimer who formulated Gestalt laws that describe our perception. One law is that of collinearity: elements that correspond in their local orientation to their global axis of alignment form a collinear line, compared to a noncollinear line where local and global orientations are orthogonal. Psychophysical studies revealed a perceptual advantage for collinear over non-collinear stimulus context. It was suggested that this behavioral finding could be related to underlying neuronal mechanisms already in the primary visual cortex (V1). Studies have shown that neurons in V1 are linked according to a common fate: cells responding to collinearly aligned contours are predominantly interconnected by anisotropic long-range lateral connections. In the cat, the same holds true for visual interhemispheric connections. In the present study we aimed to test how the perceptual advantage of a collinear line is reflected in the anatomical properties within or between the two primary visual cortices. We applied two neurophysiological methods, electrode and optical recording, and reversibly deactivated the topographically corresponding contralateral region by cooling in eight anesthetized cats. In electrophysiology experiments our results revealed that influences by stimulus context significantly depend on a unit’s orientation preference. Vertical preferring units had on average a higher spike rate for collinear over non-collinear context. Horizontal preferring units showed the opposite result. Optical imaging experiments confirmed these findings for cortical areas assigned to vertical orientation preference. Further, when deactivating the contralateral region the spike rate for horizontal preferring units in the intact hemisphere significantly decreased in response to a collinear stimulus context. Most of the optical imaging experiments revealed a decrease in cortical activity in response to either stimulus context crossing the vertical midline. In conclusion, our results support the notion that modulating influences from stimulus context can be quite variable. We suggest that the kind of influence may depend on a cell’s orientation preference. The perceptual advantage of a collinear line as one of the Gestalt laws proposes is not uniformly represented in the activity of individual cells in V1. However, it is likely that the combined activity of many V1 neurons serves to activate neurons further up the processing stream which eventually leads to the perceptual phenomenon.
Photosystem (PS) I is a huge membrane protein complex which coordinates around 200 co-factors. Upon light excitation a charge separation at the PS I reaction centre is induced which leads to an electron transport across the thylakoid membrane and the generation of redox equivalents needed for several biochemical reactions, e.g. the synthesis of sugars. For higher plants and cyanobacteria the crystal structure of PS I complexes were resolved to resolutions of 4.4 Å and 2.5 Å. Furthermore, supramolecular structures of PS I of eukaryotic algae, mainly of the green line, were obtained recently. However, up to now, no structure of diatoms is available yet. Diatoms are key players in global primary production and derived from a secondary endosymbiosis event. Their chloroplasts are surrounded by four envelope membranes and their thylakoids are evenly arranged in bands of three, i.e. no separation in grana and stroma regions is apparent. In this thesis a protocol was developed to isolate a functional PS I complex of diatoms which can be used for structural analysis by transmissional electron microscopy (TEM). A photosystem I-fucoxanthin chlorophyll protein (PS I-FCP) complex was isolated from the pennate diatom Phaeodactylum tricornutum by ion exchange chromatography. Spectroscopic analysis proved that bound Fcp polypeptides function as a light-harvesting complex. An active light energy transfer from Fcp associated pigments, Chl c and fucoxanthin, towards the PS I core was proven by fluorescence spectroscopy. Oxidised minus reduced difference spectroscopy evidenced the activity of the PS I reaction centre P700 and yielded a chlorophyll a/P700 ratio of approximately 200:1. These data indicate that the isolated PS I-FCP complex exceeds the PS I cores from cyanobacteria and higher plants in the numbers of chlorophyll a molecules. Because of the strict conservation of PS I cores among organisms the additional 100 chlorophyll a molecules must either be coordinated by Fcps or function as linker molecules between the Fcp antenna and the PS I core as shown for the PS I-LHC I complex of higher plants. To tell something about the structural organisation, the PS I-FCP complex was compared with its cyanobacterial and higher plant counterparts. Whereas cyanobacterial PS I cores aggregate to trimers, usually without associated antennae, higher plant PS I is a monomer and binds additionally two LHC I heterodimers. BN-PAGE and gel filtration experiments showed that also diatoms contain PS I monomers associated with Fcps as light-harvesting antenna. First TEM studies evidenced these observations. Negatively stained PS I-FCP particles had an increased size compared to PS I cores of other organisms. No PS I trimers or higher oligomers have been found. The calculated diameter and shape of the particles correspond to PS I-LHC I particles obtained from green algae, which also comprise of a higher number of LHC I polypeptides compared to the higher plant x-ray structure. Additionally, the analysis of polypeptides indicates that the PS I associated Fcps differ from the free Fcp pool and also from Fcps of a PS II enriched fraction. The assumption that diatoms harbour just one Fcp antenna that serve both Photosystems equally seems to be wrong. To further study the association of Fcps with the two Photosystems, both complexes plus the free FCP complexes were isolated from the centric diatom Cyclotella meneghiniana. Because of the availability of antibodies directed against specific Fcp polypeptides of Cyclotella the PS I-FCP complex of Phaeodactylum could not be used. A trimeric FCP complex, FCPa, and a higher FCP oligomer, FCPb, have already been described for C. meneghiniana. The latter is assumed to be composed of only Fcp5, whereas the FCPa contains Fcp2 and Fcp6. Biochemical and spectroscopical evidences revealed a different subset of associated Fcp polypeptides within the isolated photosystem complexes. Whereas the PS II associated Fcp antenna resembles FCPa, at least three different Fcp polypeptides are associated with PS I. By re-solubilisation of the PS I complex and a further purification step Fcp polypeptides were partially removed from PS I and both fractions were analysed again by biochemical and spectroscopical means, as well as by HPLC. Thereby Fcp4 and a so far undescribed 17 kDa Fcp were found to be strongly coupled to PS I, whereas another Fcp, presumably Fcp5, is only loosely bound to the PS I core. Thus an association of FCPb and PS I is assumed.
Background: In this interdisciplinary project, the biological effects of heavy ions are compared to those of X-rays using tissue slice culture preparations from rodents and humans. Advantages of this biological model are the conservation of an organotypic environment and the independency from genetic immortalization strategies used to generate cell lines. Its open access allows easy treatment and observation via live-imaging microscopy. Materials and methods: Rat brains and human brain tumor tissue are cut into 300 micro m thick tissue slices. These slices are cultivated using a membrane-based culture system and kept in an incubator at 37°C until treatment. The slices are treated with X-rays at the radiation facility of the University Hospital in Frankfurt at doses of up to 40 Gy. The heavy ion irradiations were performed at the UNILAC facility at GSI with different ions of 11.4 A MeV and fluences ranging from 0.5–10 x 106 particles/cm². Using 3D-confocal microscopy, cell-death and immune cell activation of the irradiated slices are analyzed. Planning of the irradiation experiments is done with simulation programs developed at GSI and FIAS. Results: After receiving a single application of either X-rays or heavy ions, slices were kept in culture for up to 9d post irradiation. DNA damage was visualized using gamma H2AXstaining. Here, a dose-dependent increase and time-dependent decrease could clearly be observed for the X-ray irradiation. Slices irradiated with heavy ions showed less gamma H2AX-positive cells distributed evenly throughout the slice, even though particles were calculated to penetrate only 90–100 micro m into the slice. Conclusions: Single irradiations of brain tissue, even at high doses of 40 Gy, will result neither in tissue damage visible on a macroscopic level nor necrosis. This is in line with the view that the brain is highly radio-resistant. However, DNA damage can be detected very well in tissue slices using gamma H2AX-immuno staining. Thus, slice cultures are an excellent tool to study radiation-induced damage and repair mechanisms in living tissues.
This article discusses the divergent status of the two particles lé and lá in the grammar of Konkomba, a Gur language (Niger-Congo) of the Gurma subgroup. While previous studies claim that both particles are focus markers, this author argues that only the particle lá should be analyzed as a pure pragmatic device. Distributional studies suggest that the use of particle lé, on the other hand, is only required under specific focus conditions, and primarily represents a syntactic device.
The main tenet of the present paper is the thesis that nominalization – like other cases of derivational morphology – is an essentially lexical phenomenon with well defined syntactic (and semantic) conditions and consequences. More specifically, it will be argued that the relation between a verb and the noun derived from it is subject to both systematic and idiosyncratic conditions with respect to lexical as well as syntactic aspects.
Local interactions between particles of a collection causes all particles to reorganize in new positions. The purpose of this paper is to construct an energy-based model of self-organizing subgroups, which describes the behavior of singular local moves of a particle. The present paper extends the Hegselmann-Krause model on consensus dynamics, where agents simultaneously move to the barycenter of all agents in an epsilon neighborhood. The Energy-based model presented here is analyzed and simulated on finite metric space. AMS Subject Classifications:81T80; 93A30; 37M05; 68U20
Only a few Methyl-[11C]-l-methionine (MET) positron emission tomography (PET) studies have focused on children and young adults with brain neoplasm. Due to radiation exposure, long scan acquisition time, and the need for sedation in young children MET-PET studies should be restricted to this group of patients when a decision for further therapy is not possible from routine diagnostic procedures alone, e.g., structural imaging. We investigated the diagnostic accuracy of MET-PET for the differentiation between tumorous and non-tumorous lesions in this group of patients. Forty eight MET-PET scans from 39 patients aged from 2 to 21 years (mean 15 ± 5.0 years) were analyzed. The MET tumor-uptake relative to a corresponding control region was calculated. A receiver operating characteristic (ROC) was performed to determine the MET-uptake value that best distinguishes tumorous from non-tumorous brain lesions. A differentiation between tumorous (n = 39) and non-tumorous brain lesions (n = 9) was possible at a threshold of 1.48 of relative MET-uptake with a sensitivity of 83% and a specificity of 92%, respectively. A differentiation between high grade malignant lesions (mean MET-uptake = 2.00 ± 0.46) and low grade tumors (mean MET-uptake = 1.84 ± 0.31) was not possible. There was a significant difference in MET-uptake between the histologically homogeneous subgroups of astrocytoma WHO grade II and anaplastic astrocytoma WHO grade III (P = 0.02). MET-PET might be a useful tool to differentiate tumorous from non-tumorous lesions in children and young adults when a decision for further therapy is difficult or impossible from routine structural imaging procedures alone. Keywords Brain tumor - Children - PET - Methionine - Molecular imaging
L1-CAM (L1 cell-adhesion molecule), or more simply L1, plays an important role in the progression of human carcinoma. Overexpression promotes tumour-cell invasion and motility, growth in nude mice and tumour metastasis. It is feasible that L1-dependent signalling contributes to these effects. However, little is known about its mechanism in tumour cells. We reported previously that L1 is cleaved by ADAM (a disintegrin and metalloprotease) and that the cytoplasmic part is essential for L1 function. Here we analysed more closely the role of proteolytic cleavage in L1-mediated nuclear signalling. Using OVMz carcinoma cells and L1-transfected cells as a model, we found that ADAM10-mediated cleavage of L1 proceeds in lipid raft and non-raft domains. The cleavage product, L1-32, is further processed by PS (presenilin)/gamma-secretase to release L1-ICD, an L1 intracellular domain of 28 kDa. Overexpression of dominantnegative PS1 or use of a specific gamma-secretase inhibitor leads to an accumulation of L1-32. Fluorescence and biochemical analysis revealed a nuclear localization for L1-ICD. Moreover, inhibition of ADAM10 and/or gamma-secretase blocks nuclear translocation of L1-ICD and L1-dependent gene regulation. Overexpression of recombinant L1-ICD mediates gene regulation in a similar manner to full-length L1. Our results establish for the first time that regulated proteolytic processing by ADAM10 and PS/gamma-secretase is essential for the nuclear signalling of L1 in human carcinoma cell lines. Key words: a disintegrin and metalloprotease 10 (ADAM10), L1 cell-adhesion molecule (L1-CAM), nuclear translocation, presenilin (PS)/gamma-secretase activity, raft, signalling.
Introduction: Reliable predictive and prognostic markers for routine diagnostic purposes are needed for breast cancer patients treated with neoadjuvant chemotherapy. We evaluated protein biomarkers in a cohort of 116 participants of the GeparDuo study on anthracycline/taxane-based neoadjuvant chemotherapy for operable breast cancer to test for associations with pathological complete response (pCR) and disease-free survival (DFS). Particularly, we evaluated if interactions between hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) expression might lead to a different clinical behavior of HR+/HER2+ coexpressing and HR+/HER2- tumors and whether subgroups of triple negative tumors might be identified by the help of Ki67 labeling index, cytokeratin 5/6 (CK5/6), as well as cyclooxygenase-2 (COX-2), and Y-box binding protein 1 (YB-1) expression. Methods: Expression analysis was performed using immunohistochemistry and silver-enhanced in situ hybridization on tissue microarrays (TMAs) of pretherapeutic core biopsies. Results: pCR rates were significantly different between the biology-based tumor types (P = 0.044) with HR+/HER2+ and HR-/HER2- tumors having higher pCR rates than HR+/HER2-tumors. Ki67 labeling index, confirmed as significant predictor of pCR in the whole cohort (P = 0.001), identified HR-/HER- (triple negative) carcinomas with a higher chance for a pCR (P = 0.006). Biology-based tumor type (P = 0.046 for HR+/HER2+vs. HR+/HER2-), Ki67 labeling index (P = 0.028), and treatment arm (P = 0.036) were independent predictors of pCR in a multivariate model. DFS was different in the biology-based tumor types (P < 0.0001) with HR+/HER2- and HR+/HER2+ tumors having the best prognosis and HR-/HER2+ tumors showing the worst outcome. Biology-based tumor type was an independent prognostic factor for DFS in multivariate analysis (P < 0.001). Conclusions: Our data demonstrate that a biology-based breast cancer classification using estrogen receptor (ER), progesterone receptor (PgR), and HER2 bears independent predictive and prognostic potential. The HR+/HER2+ coexpressing carcinomas emerged as a group of tumors with a good response rate to neoadjuvant chemotherapy and a favorable prognosis. HR+/HER2- tumors had a good prognosis irrespective of a pCR, whereas patients with HR-/HER- and HR-/HER+ tumors, especially if they had not achieved a pCR, had an unfavorable prognosis and are in need of additional treatment options. Trial registration ClinicalTrials.gov identifier: NCT00793377
IL-18, a recently identified member of IL-1 family, is now recognized as an important regulator of innate and acquired immune responses. Therefore, the antitumor activities of IL-18 have been investigated. IL-18 has been shown to induce IFN-γ production by T, B, and NK cells, enhances NK cell activity, activates Fas ligandmediated apoptosis of the tumor cells, and improves the overall antitumor immunity. KG-1 cells were derived from a patient with acute myeloid leukemia (AML). IL-18 has been shown to induce IFN-γ production in those leukemic cells. TLR-3, in addition to its ability to recognize viral double stranded RNA, also can recognize the synthetic analogue poly(I:C) and induces type I IFN, inflammatory cytokine production, e.g TNF-α, and maturation of denderitic cells. In the present work the potential modulatory effect of PIC on IFN-γ and TNF-α production by KG-1 cells treated with IL-18 was investigated. Indeed, PIC strongly amplified the production of IFN-γ induced by IL-18 on mRNA and protein levels via NF-κB as well as p38 and JNK MAPK activation. Compared to IFN-γ, TNF-α showed different behaviour in KG-1 cells. On mRNA level I found only weak induction of TNF-α by IL-18 which was potentiated in the presence of PIC. Similarly, the release of TNF-α by IL-18 plus PIC required NF-κB as well as p38 and JNK MAPK activation. Furthermore, in the present work I found that TLR-3 is required for IFN-γ and TNF-α production. In addition, it is demonstrated by immunofluoresence that TLR-3 is localized in cytoplasm but not on the cell surface in KG-1 cells. Recently, it has been demonstrated that IFN-γ shows therapeutic potential as detected in AML blasts, specifically via inhibition of proliferation and induction of apoptosis. Thus our data could serve as a rationale for the clinical use of PIC and IL-18 in combination therapy. In search for new cytokines potentially modulated by the combination IL-18 plus PIC in KG-1 cells, cytokine antibody array analysis was performed. I found an upregulation of expected genes like IP-10 but most interestingly unexpected upregulation of PDGF-AA. Searching for detailed mechanisms of PDGF-AA induction, I found that neither p38 nor JNK is involved in PDGF-AA production but NF-κB is essential for the expression of PDGF-AA. Furthermore, I found that PDGF-AA is not able to increase the proliferation of KG-1 cells. PDGF and TGF-β are examples of signaling molecules which control the growth, survival, motility, and differentiation of cells. Therefore, the release of TGF-β by IL-18 plus PIC was monitored by ELISA. The level of TGF-β in cellular supernatants revealed that neither PIC nor IL-18 was able to significantly mediate release of TGF-β indicating that only PDGF-AA but not TGF-β is induced by PIC and IL-18 in KG-1 cells. To the best of our knowledge this is the first time that IL-18 or PIC is shown to induce the expression of PDGF-AA in KG-1 cells.
Experimental data shows that adult learners of an artificial language with a phonotactic restriction learned this restriction better when being trained on word types (e.g. when they were presented with 80 different words twice each) than when being trained on word tokens (e.g. when presented with 40 different words four times each) (Hamann & Ernestus submitted). These findings support Pierrehumbert’s (2003) observation that phonotactic co-occurrence restrictions are formed across lexical entries, since only lexical levels of representation can be sensitive to type frequencies.
We show that loanword adaptation can be understood entirely in terms of phonological and phonetic comprehension and production mechanisms in the first language. We provide explicit accounts of several loanword adaptation phenomena (in Korean) in terms of an Optimality-Theoretic grammar model with the same three levels of representation that are needed to describe L1 phonology: the underlying form, the phonological surface form, and the auditory-phonetic form. The model is bidirectional, i.e., the same constraints and rankings are used by the listener and by the speaker. These constraints and rankings are the same for L1 processing and loanword adaptation.
The present study argues that variation across listeners in the perception of a non-native contrast is due to two factors: the listener-specic weighting of auditory dimensions and the listener-specic construction of new segmental representations. The interaction of both factors is shown to take place in the perception grammar, which can be modelled within an OT framework. These points are illustrated with the acquisition of the Dutch three-member labiodental contrast [V v f] by German learners of Dutch, focussing on four types of learners from the perception study by Hamann and Sennema (2005a).
In this work we study the properties of quarkonium states in a quark-gluon plasma which, due to expansion and non-zero viscosity, exhibits a local anisotropy in momentum space. We determine the hard-loop resummed gluon propagator in an anisotropic QCD plasma in general linear gauges and define a potential between heavy quarks from the Fourier transform of its static limit. This potential which arises due to one-gluon exchange describes the force between a quark and anti-quark at short distances. It is closer to the vacuum potential as compared to the isotropic Debye screened potential which indicates the reduced screening in an anisotropic QCD plasma. In addition, angular dependence appears in the potential; we find that there is stronger attraction on distance scales on the order of the inverse Debye mass for quark pairs aligned along the direction of anisotropy than for transverse alignment. The potential at long distances, however, is non-perturbative and modeled as a QCD string which is screened at the same scale as the Coulomb field. At asymptotic separation the potential energy is non-zero and inversely proportional to the temperature. With a phenomenological potential model which incorporates the different behaviors at short and long distances, we solve the three-dimensional Schrödinger equation. Our numerical results show that quarkonium binding is stronger at non-vanishing viscosity and expansion rate, and that the anisotropy leads to polarization of the P-wave states. Furthermore, we determine viscosity corrections to the imaginary part of the heavyquark potential in the weak-coupling hard-loop approximation. The imaginary part is found to be smaller (in magnitude) than at vanishing viscosity. This implies a smaller decay width of quarkonium bound states in an anisotropic plasma.
Central America is one of the world’s most herpetological diverse areas in relation to its size. Nicaragua is the largest country in this region and separates Nuclear from Lower Central America. It is one of the least herpetological explored countries in Central America and few studies dealing with the herpetofauna of a potion or the entire country have been published. I here update the checklist of the Nicaraguan herpetofauna, present taxonomic revisions of some difficult species complexes, compare the similarities of the composition of the herpetofaunal communities in the major forest formations present in the country within a zoogeographical context, and identify those species with a greater vulnerability risk in Nicaragua. Taxonomy The herpetofauna of Nicaragua currently consists of 244 species representing 134 genera and 42 families with 78 amphibian species representing 35 genera and 15 families, and 166 reptile species representing 99 genera and 27 families, which includes six marine species. Sixteen species (12 amphibians and four reptiles) are endemic to the country. Of the 12 endemic amphibian species, three are here described. In addition, five genera (Anotheca, Cerrophidion, Duellmanohyla, Isthmohyla, and Rhinobothryum) and two species (Rhadinea godmani and Urotheca decipiens) are known to occur both north and south of Nicaragua although there are no voucher specimens of these taxa to confirm their presence in country. I complete a bibliographic research updating the nomenclature changes and provide a brief herpetological history of Nicaragua, a recompilation of all species described upon Nicaraguan material and their current synonymy, the first time each species was recorded from the country, and a list of all recognized subspecies occurring in Nicaragua. I discuss the taxonomic uncertainties among the Nicaraguan populations of amphibians and reptiles and take further detailed taxonomic revisions on selected Nicaraguan species groups from the genera Anolis, Bolitoglossa, and Craugastor along their known distributional range. I describe five new species of herpetofauna (three of which are based on Nicaraguan material), redescribe five species of Anolis (three of which occur in Nicaragua), and provide voucher specimens of five other species for the first time in Nicaragua. In detail: • I studied the pholidosis, morphometrics as well as hemipenis and dewlap morphology in Anolis wermuthi, an anole endemic to the highlands of northern Nicaragua. I examine patterns of geographic variation using discriminant function analysis and discuss the characters that vary both individually and among populations. The results indicate that A. wermuthi is a single species with several disjunct, slightly divergent populations. I provide a standardized description, illustrations of the everted hemipenis of an adult topotype, the male and female dewlap, and a distribution map. I also provide brief descriptions of the localities where this species occurs and some ecological notes. • I studied the pholidosis, morphometrics as well as hemipenis morphology in the Central American anole species Anolis humilis, A. quaggulus, and A. uniformis. The three taxa are distinct in hemipenis morphology. However, very little differentiation in pholidotic and morphometric characters is documented. I document interspecific variation in several characters but with overlap of the documented ranges. A discriminant function analysis based on five pholidotic characters yielded a scatter diagram that showed large overlap between the clusters of the three taxa. I provide head scalation illustrations, an identification key, a distribution map, and standardized descriptions of the commonly distributed in Nicaragua A. quaggulus as well as of the other two species. • I describe two new species of anoles (genus Anolis) from Panama formerly referred to as Anolis limifrons. The two new species, Anolis apletophallus and Anolis cryptolimifrons, differ from A. limifrons by having a large bilobed hemipenis (small and unilobed in A. limifrons). The new species differ from each other in male dewlap size and coloration. I provide illustrations of the head scalation, everted hemipenis, and dewlap, an identification key, a distribution map, and standardized descriptions of the commonly distributed in Nicaragua A. limifrons and the two new species described herein. • I describe two new species of salamanders of Bolitoglossa from southern Nicaragua. Bolitoglossa indio is known from Río Indio in the lowlands of the Río San Juan area and Bolitoglossa insularis from the premontane slopes of Volcán Maderas on Ometepe Island. The two new species are of unknown affinities but both differ from their congeners in coloration. Bolitoglossa indio is most similar to B. mexicana and B. odonnelli from which differ by having both broad dorsolateral pale brown stripes not clearly delimited in outline. Bolitoglossa insularis is most similar to B. mombachoensis and B. striatula from which differ by the absence of dark or light defined stripes on dorsum and venter. • I describe a new species of frog of the genus Craugastor from Río San Juan, Nicaragua. The new species, Craugastor chingopetaca, is assigned to the fitzingeri group and differs from most Central American species of that group by the absence of a midgular pale stripe. Within the fitzingeri group it is most similar to C. crassidigitus and C. talamancae from which it differs in several morphological characteristics such as more extensive webbing, retuse disk covers on some digits, and relative toe length. • I provide voucher specimens of Cochranella spinosa, Kinosternon angustipons, Mesaspis moreletii, Cnemidophorus lemniscatus and Adelphicos quadrivirgatum for the first time in Nicaragua. I include descriptions, illustrations, and brief ecological notes for the five new country records. Zoogeography Based on the concept of ecological formations proposed by HOLDRIDGE (1967), nine forest formations are found in Nicaragua. Of the total number of terrestrial species of herpetofauna found in Nicaragua, 131 species (55.0%) occur in Lowland Wet Forest, 21 of which (8.8%) are restricted to this forest formation, 168 species (70.6%) occur in Lowland Moist Forest, 15 of which (6.3%) are restricted to this forest formation, 84 species (35.3%) occur in Lowland Dry Forest, four of which (1.7%) are restricted to this forest formation, 47 species (19.7%) occur in Lowland Arid Forest, with no species restricted to this forest formation, 59 species (24.8%) occur in Premontane Wet Forest, three of which (1.3%) are restricted to this forest formation, 116 species (48.7%) occur in Premontane Moist Forest, 10 of which (4.2%) are restricted to this forest formation, 51 (21.4%) species occur in Premontane Dry Forest, with no species restricted to this forest formation, 13 species (5.5%) occur in Lower Montane Wet Forest, two of which (0.8%) are restricted to this forest formation, and 50 species (21.0%) occur Lower Montane Moist Forest, seven of which (2.9%) are restricted to this forest formation. The Coefficient of Biogeographic Resemblance algorithm show a distinct composition of the herpetofauna from the isolated highlands of northeastern Nicaragua, which is characterized by a high proportion of endemic species. Two other clusters are evident when analyzing the herpetofaunal similarities among Nicaragua, the Pacific versant and the central mountains and the Atlantic lowlands. In addition, the Pacific lowlands are characterized by a relatively homogeneous composition of the herpetofauna. In contrast, many species have their northern limit of distribution in the Atlantic lowlands with the ranges of most of these species ending in southern Nicaragua. The central mountains constitute the southern limit of distribution of several highland species. In general, there is a greater contribution of reptile than amphibian species to the total herpetofauna present in each forest formation. This unbalance is slightly higher in the dry than in the moist parts of the country. The similarities in the composition of the reptiles between the different forests formations seem to be relatively distinct on an elevation factor, whereas in amphibians similarities might be better explained in correlation with humidity. The total amount of amphibian and reptile species in Nicaragua has a Middle American Element dominance and varies between amphibians and reptiles, with and a greater South American Element influence in anurans and a greater Old Northern Element influence in reptiles. In general, there is a greater percentage of species with a South American Element in extreme southeastern Nicaragua with a decreasing tendency towards northern Nicaragua. Taking in account the geography and geologic history of Nicaragua as well as the known Central American dispersal routes, I identify species of probable occurrence in Nicaragua as well as those places with a greater potential to hold undescribed endemic species. Conservation In Nicaragua, no amphibian or reptile populations are entirely free from anthropogenic impact. I determine the endangerment level of all Nicaraguan amphibian and reptile species using the IUCN categorizations and the Environmental Vulnerability Scores. Seventy-six species (31.9%) of Nicaraguan amphibians and terrestrial reptiles have high vulnerability, 118 (49.6%) medium vulnerability, and 44 (18.5%) low vulnerability. Eighteen species (7.4% of the total herpetofauna) are unknown from protected areas, including 13 high vulnerability species (three are endemic), four medium vulnerability species, and one low vulnerability species. To preserve the future of Nicaragua’s amphibians and reptiles, every species should reside in at least one protected area, the protected areas must be guarded, and monitoring programs are needed to detect changes in amphibian and reptile populations, prioritizing highly vulnerable species.
Zusammenfassung Die Alzheimersche Krankheit (AD) ist mit 60% die am häufigsten auftretende Art der Demenz. Weltweit sind ca. 24 Mio. Menschen von der neurodegenerativen Krankheit betroffen, welche sich durch den Verlust der kognitiven Fähigkeiten auszeichnet. Es gibt zwei Ausprägungen der Demenz, zum einen die sporadische Verlaufsform, die bei Menschen in einem Alter ab 65 Jahren auftritt und zum anderen die familiäre Alzheimersche Krankheit (FAD), die schon weitaus jüngere Menschen betrifft und auf genetische Mutationen zurück zu führen ist. Beide Formen der Demenz zeigen den gleichen neuropathologische Phänotyp, der zur Ausbildung von extrazellulären Plaques und intrazellulären Neurofibrillen führt. Durch die Entstehung der Plaques und der Neurofibrillen werden die Verbindungen zwischen den einzelnen Neuronen verringert und die Neuronen sterben ab. Für das Auftreten der FAD sind Mutationen in den Genen des Amyloid Vorläufer Proteins (APP, Substrat) sowie der Aspartatprotease Einheit des γ-Sekretase Komplexes, Presenilin 1 (PS1) oder Presenilin 2 (PS2), verantwortlich. Die γ-Sekretase ist ein membranständiger Komplex bestehend aus den vier Untereinheiten PS1 oder PS2, Nicastrin (Nct), Aph-1 und Pen-2. Um ausreichende Informationen über den γ-Sekretase Komplex bezüglich seiner Interaktionsflächen, seines Katalysemechanismus und seiner Substraterkennung zu erhalten, wäre es hilfreich seine 3 Dimensionale Struktur aufzuklären, wozu große Mengen der sauberen und homogenen Proteine benötigt werden. Die Herstellung von ausreichenden Proteinmengen stellt derzeit aber einen Engpass für die strukturelle und funktionelle Charakterisierung des γ-Sekretase Komplexes in-vitro dar. Alzheimer’s disease (AD) is the most common cause of dementia, which affects 24 million people worldwide. It is a neurodegenerative disorder, which occurs either in its most common form in people over 65 years or in the rare early-onset familial AD (FAD). Responsible for the autosomal dominant FAD are mutations in the genes encoding for the β-amyloid precursor protein (APP) and the two homologues integral membrane proteins Presenilin 1 (PS1) and Presenilin 2 (PS2). The two PSs are major but alternative components of the intramembrane aspartyl protease γ-secretase. Further components are the membrane proteins Nicastrin (Nct), Aph-1 and Pen-2. Production of sufficient amounts of protein samples is still the major bottleneck for the detailed functional and structural in-vitro characterization of the γ-secretase complex. Due to toxicity, stability and targeting problems, the overproduction of MPs in conventional in-vivo systems often has only limited success. Therefore, efficient expression protocols using the cell-free (CF) system were established in this work. After optimization, I was able to produce up to milligram amounts of the single proteins PS1 and PS2, the cleavage products PS1-NTF and PS1-CTF, and Pen-2. The in-vitro produced γ-secretase subunits were further characterized, concerning their purity, secondary fold, thermal stability and homogeneity. Highest purities with over 90% after affinity chromatography could be achieved for PS1-CTF and Pen-2. Reconstitution of PS1, PS1-NTF, PS1-CTF and Pen-2 into E. coli liposomes results in a homogeneously distribution, which gives evidence for a structural folding. This was confirmed by CD spectroscopy of PS1-CTF and Pen-2. The thermal stability of Pen-2 shows a transition at 68°C, whereas PS1-CTF is stable up to 95°C. Both proteins show in addition homogeneous elution profiles investigated by analytical SEC and exhibit a monomeric (Pen-2) or dimeric (PS1-CTF) character analyzed by blue native PAGE. Different methods were performed to get evidence about the assembly of the complex, like pull-down experiments, immunoprecipitation, co-expression of radioactive labeled subunits and titration assays by liquid-state NMR. First hints for an interaction of the CF synthesized proteins could be observed by co-expression. Supplemental, Pen-2 and CTF could be purified in sufficient amounts and to apparent homogeneity that allow structural approaches by X-ray crystallography and liquid-state NMR spectroscopy. First conditions for protein crystals were achieved for Pen-2 and structural investigations of PS1-CTF by liquid-state NMR could be performed after optimization of the expression-, purification- and detergent conditions.
The mitsva reflects one of the most pivotal concepts of Judaism. It sanctifies those who answer its calling, and the Jew and Judaism is unique and “chosen” because of it. In this article we highlight the various ways the mitsvot and Halakha transform us and mold the Jewish personality: (a) by converting the “ought” into a “must”; (b) by transforming daily prosaic acts of man into sacred deeds; (c) by converting simple chronological, linear time into special moments of kedusha. The mitsva involves the total personality - “head, heart and hand” and makes the body equally important with the soul in the service of Hashem. Sanctification is accomplished both through deed and thought. The Torah wants the Jew to build an environment which strengthens his religious values and has designated Erets Yisrael as the most fitting place for kedusha.
We propose a variation of online paging in two-level memory systems where pages in the fast cache get modified and therefore have to be explicitly written back to the slow memory upon evictions. For increased performance, up to alpha arbitrary pages can be moved from the cache to the slow memory within a single joint eviction, whereas fetching pages from the slow memory is still performed on a one-by-one basis. The main objective in this new alpha-paging scenario is to bound the number of evictions. After providing experimental evidence that alpha-paging can adequately model flash-memory devices in the context of translation layers we turn to the theoretical connections between alpha-paging and standard paging. We give lower bounds for deterministic and randomized alpha-paging algorithms. For deterministic algorithms, we show that an adaptation of LRU is strongly competitive, while for the randomized case we show that by adapting the classical Mark algorithm we get an algorithm with a competitive ratio larger than the lower bound by a multiplicative factor of approximately 1.7.
Background Multidirectional interactions in social (or communication) networks can have a profound effect on mate choice behavior. For example, Poecilia mexicana males show weaker expression of mating preferences when being observed by an audience male. It was suggested that this behavior is an adaptation to reduce sperm competition risk, which arises because commonly preferred female phenotypes will receive attention also by surrounding males, and/or because the audience male can copy the focal male's mate choice. Do P. mexicana males indeed respond to perceived sperm competition risk? We gave males a choice between two females and repeated the tests under one of the following conditions: (1) during the 2nd part of the tests an empty transparent cylinder was presented (control); (2) an audience male inside the cylinder observed the focal male throughout the 2nd part, or (3) the audience male was presented only before the tests, but could not eavesdrop during the actual choice tests (non-specific sperm competition risk treatments); (4) the focal male could see a rival male sexually interacting with the previously preferred, or (5) with the non-preferred female before the 2nd part of the tests (specific sperm competition risk treatments). Results When comparing the strength of individual male preferences between the 1st and 2nd part of the tests (before and after presentation of an audience), male preferences declined slightly also during the control treatment (1). However, the decrease in strength of male preferences was more than two-fold stronger in audience treatment (2), i.e., with non-specific sperm competition risk including the possibility for visual eavesdropping by the audience male. No audience effect was found in treatments (3) and (5), but a weak effect was also seen when the focal male had seen the previously preferred female sexually interact with a rival male (treatment 4; specific sperm competition risk). Conclusions When comparing the two 'non-specific sperm competition risk' treatments (2 and 3), a very strong effect was found only when the audience male could actually observe the focal male during mate choice in treatment (2). This suggests that focal males indeed attempt to conceal their mating preferences in the visual presence of other males so as to avoid mate choice copying. When there is no potential for eavesdropping [treatment (3)], non-specific specific sperm competition risk seems to play a minor or no role. Congruent with studies on other poeciliid species, our results also show that P. mexicana males respond to perceived specific sperm competition risk, and tend to share their mating effort more equally among females when the resource value of their previously preferred mate decreases (after mating with a rival male). However, this effect is comparatively weak.
Background: Nitric oxide (NO) is an essential vasodilator. In vascular diseases, oxidative stress attenuates NO signaling by both chemical scavenging of free NO and oxidation and down-regulation of its major intracellular receptor, the alpha/beta heterodimeric heme-containing soluble guanylate cyclase (sGC). Oxidation can also induce loss of sGC's heme and responsiveness to NO.
Results: sGC activators such as BAY 58-2667 bind to oxidized/heme-free sGC and reactivate the enzyme to exert disease-specific vasodilation. Here we show that oxidation-induced down-regulation of sGC protein extends to isolated blood vessels. Mechanistically, degradation was triggered through sGC ubiquitination and proteasomal degradation. The heme-binding site ligand, BAY 58-2667, prevented sGC ubiquitination and stabilized both alpha and beta subunits.
Conclusion: Collectively, our data establish oxidation-ubiquitination of sGC as a modulator of NO/cGMP signaling and point to a new mechanism of action for sGC activating vasodilators by stabilizing their receptor, oxidized/heme-free sGC.
Poster presentation: Self-organized critical (SOC) systems are complex dynamical systems that may express cascades of events, called avalanches [1]. The SOC state was proposed to govern brain function, because of its activity fluctuations over many orders of magnitude, its sensitivity to small input and its long term stability [2,3]. In addition, the critical state is optimal for information storage and processing [4]. Both hallmark features of SOC systems, a power law distribution f(s) for the avalanche size s and a branching parameter (bp) of unity, were found for neuronal avalanches recorded in vitro [5]. However, recordings in vivo yielded contradictory results [6]. Electrophysiological recordings in vivo only cover a small fraction of the brain, while criticality analysis assumes that the complete system is sampled. We hypothesized that spatial subsampling might influence the observed avalanche statistics. In addition, SOC models can have different connectivity, but always show a power law for f(s) and bp = 1 when fully sampled. This may not be the case under subsampling, however. Here, we wanted to know whether a state change from awake to asleep could be modeled by changing the connectivity of a SOC model without leaving the critical state. We simulated a SOC model [1] and calculated f(s) and bp obtained from sampling only the activity of a set of 4 × 4 sites, representing the electrode positions in the cortex. We compared these results with results obtained from multielectrode recordings of local field potentials (LFP) in the cortex of behaving monkeys. We calculated f(s) and bp for the LFP activity recorded while the monkey was either awake or asleep and compared these results to results obtained from two subsampled SOC model with different connectivity. f(s) and bp were very similar for both the experiments and the subsampled SOC model, but in contrast to the fully sampled model, f(s) did not show a power law and bp was smaller than unity. With increasing the distance between the sampling sites, f(s) changed from "apparently supercritical" to "apparently subcritical" distributions in both the model and the LFP data. f(s) and bp calculated from LFP recorded during awake and asleep differed. These changes could be explained by altering the connectivity in the SOC model. Our results show that subsampling can prevent the observation of the characteristic power law and bp in SOC systems, and misclassifications of critical systems as sub- or supercritical are possible. In addition, a change in f(s) and bp for different states (awake/asleep) does not necessarily imply a change from criticality to sub- or supercriticality, but can also be explained by a change in the effective connectivity of the network without leaving the critical state.
Poster presentation: The brain is autonomously active and this self-sustained neural activity is in general modulated, but not driven, by the sensory input data stream [1,2]. Traditionally one has regarded this eigendynamics as resulting from inter-modular recurrent neural activity [3]. Understanding the basic modules for cognitive computation is, in this view, the primary focus of research and the overall neural dynamics would be determined by the the topology of the intermodular pathways. Here we examine an alternative point of view, asking whether certain aspects of the neural eigendynamics have a central functional role for overall cognitive computation [4,5]. Transiently stable neural activity is regularly observed on the cognitive time-scale of 80–100 ms, with indications that neural competition [6] plays an important role in the selection of the transiently stable neural ensembles [7], also denoted winning coalitions [8]. We report on a theory approach which implements these two principles, transient-state dynamics and neural competition, in terms of an associative neural network with clique encoding [9]. A cognitive system [10] with a non-trivial internal eigendynamics has two seemingly contrasting tasks to fulfill. The internal processes need to be regular and not chaotic on one side, but sensitive to the afferent sensory stimuli on the other side. We show, that these two contrasting demands can be reconciled within our approach based on competitive transient-state dynamics, when allowing the sensory stimuli to modulate the competition for the next winning coalition. By testing the system with the bars problem, we find an emerging cognitive capability. Only based on the two basic architectural principles, neural competition and transient-state dynamics, with no explicit algorithmic encoding, the system performs on its own a non-linear independent component analysis of input data stream. The system has rudimentary biological features. All learning is local Hebbian-style, unsupervised and online. It exhibits an ever-ongoing eigendynamics and at no time is the state or the value of synaptic strengths reset or the system restarted; there is no separation between training and performance. We believe that this kind of approach – cognitive computation with autonomously active neural networks – to be an emerging field, relevant both for system neuroscience and synthetic cognitive systems.
Poster presentation: How can two distant neural assemblies synchronize their firings at zero-lag even in the presence of non-negligible delays in the transfer of information between them? Neural synchronization stands today as one of the most promising mechanisms to counterbalance the huge anatomical and functional specialization of the different brain areas. However, and albeit more evidence is being accumulated in favor of its functional role as a binding mechanism of distributed neural responses, the physical and anatomical substrate for such a dynamic and precise synchrony, especially zero-lag even in the presence of non-negligible delays, remains unclear. Here we propose a simple network motif that naturally accounts for zero-lag synchronization of spiking assemblies of neurons for a wide range of temporal delays. We demonstrate that when two distant neural assemblies do not interact directly but relaying their dynamics via a third mediating single neuron or population and eventually achieve zero-lag coherent firing. Extensive numerical simulations of populations of Hodgkin-Huxley neurons interacting in such a network are analyzed. The results show that even with axonal delays as large as 15 ms the distant neural populations can synchronize their firings at zero-lag in a millisecond precision after the exchange of a few spikes. The role of noise and a distribution of axonal delays in the synchronized dynamics of the neural populations are also studied confirming the robustness of this sync mechanism. The proposed network module is densely embedded within the complex functional architecture of the brain and especially within the reciprocal thalamocortical interactions where the role of indirect pathways mimicking direct cortico-cortical fibers has been already suggested to facilitate trans-areal cortical communication. In summary the robust neural synchronization mechanism presented here arises as a consequence of the relay and redistribution of the dynamics performed by a mediating neuronal population. In opposition to previous works, neither inhibitory, gap junctions, nor complex networks need to be invoked to provide a stable mechanism of zero-phase correlated activity of neural populations in the presence of large conduction delays.
Poster presentation: The analysis of neuronal processes distributed across multiple cortical areas aims at the identification of interactions between signals recorded at different sites. Such interactions can be described by measuring the stability of phase angles in the case of oscillatory signals or other forms of signal dependencies for less regular signals. Before, however, any form of interaction can be analyzed at a given time and frequency, it is necessary to assess whether all potentially contributing signals are present. We have developed a new statistical procedure for the detection of coincident power in multiple simultaneously recorded analog signals, allowing the classification of events as 'non-accidental co-activation'. This method can effectively operate on single trials, each lasting only for a few seconds. Signals need to be transformed into time-frequency space, e.g. by applying a short-time Fourier transformation using a Gaussian window. The discrete wavelet transform (DWT) is used in order to weight the resulting power patterns according to their frequency. Subsequently, the weighted power patterns are binarized via applying a threshold. At this final stage, significant power coincidence is determined across all subgroups of channel combinations for individual frequencies by selecting the maximum ratio between observed and expected duration of co-activation as test statistic. The null hypothesis that the activity in each channel is independent from the activity in every other channel is simulated by independent, random rotation of the respective activity patterns. We applied this procedure to single trials of multiple simultaneously sampled local field potentials (LFPs) obtained from occipital, parietal, central and precentral areas of three macaque monkeys. Since their task was to use visual cues to perform a precise arm movement, co-activation of numerous cortical sites was expected. In a data set with 17 channels analyzed, up to 13 sites expressed simultaneous power in the range between 5 and 240 Hz. On average, more than 50% of active channels participated at least once in a significant power co-activation pattern (PCP). Because the significance of such PCPs can be evaluated at the level of single trials, we are confident that this procedure is useful to study single trial variability with sufficient accuracy that much of the behavioral variability can be explained by the dynamics of the underlying distributed neuronal processes.
Poster presentation: Background To test the importance of synchronous neuronal firing for information processing in the brain, one has to investigate if synchronous firing strength is correlated to the experimental subjects. This requires a tool that can compare the strength of the synchronous firing across different conditions, while at the same time it should correct for other features of neuronal firing such as spike rate modulation or the auto-structure of the spike trains that might co-occur with synchronous firing. Here we present the bi- and multivariate extension of previously developed method NeuroXidence [1,2], which allows for comparing the amount of synchronous firing between different conditions. ...
Poster presentation: Introduction The ability of neurons to emit different firing patterns is considered relevant for neuronal information processing. In dopaminergic neurons, prominent patterns include highly regular pacemakers with separate spikes and stereotyped intervals, processes with repetitive bursts and partial regularity, and irregular spike trains with nonstationary properties. In order to model and quantify these processes and the variability of their patterns with respect to pharmacological and cellular properties, we aim to describe the two dimensions of burstiness and regularity in a single model framework. Methods We present a stochastic spike train model in which the degree of burstiness and the regularity of the oscillation are described independently and with two simple parameters. In this model, a background oscillation with independent and normally distributed intervals gives rise to Poissonian spike packets with a Gaussian firing intensity. The variability of inter-burst intervals and the average number of spikes in each burst indicate regularity and burstiness, respectively. These parameters can be estimated by fitting the model to the autocorrelograms. This allows to assign every spike train a position in the two-dimensional space described by regularity and burstiness and thus, to investigate the dependence of the firing patterns on different experimental conditions. Finally, burst detection in single spike trains is possible within the model because the parameter estimates determine the appropriate bandwidth that should be used for burst identification. Results and Discussion We applied the model to a sample data set obtained from dopaminergic substantia nigra and ventral tegmental area neurons recorded extracellularly in vivo and studied differences between the firing activity of dopaminergic neurons in wildtype and K-ATP channel knock-out mice. The model is able to represent a variety of discharge patterns and to describe changes induced pharmacologically. It provides a simple and objective classification scheme for the observed spike trains into pacemaker, irregular and bursty processes. In addition to the simple classification, changes in the parameters can be studied quantitatively, also including the properties related to bursting behavior. Interestingly, the proposed algorithm for burst detection may be applicable also to spike trains with nonstationary firing rates if the remaining parameters are unaffected. Thus, the proposed model and its burst detection algorithm can be useful for the description and investigation of neuronal firing patterns and their variability with cellular and experimental conditions.
Poster presentation: Coordinated neuronal activity across many neurons, i.e. synchronous or spatiotemporal pattern, had been believed to be a major component of neuronal activity. However, the discussion if coordinated activity really exists remained heated and controversial. A major uncertainty was that many analysis approaches either ignored the auto-structure of the spiking activity, assumed a very simplified model (poissonian firing), or changed the auto-structure by spike jittering. We studied whether a statistical inference that tests whether coordinated activity is occurring beyond chance can be made false if one ignores or changes the real auto-structure of recorded data. To this end, we investigated the distribution of coincident spikes in mutually independent spike-trains modeled as renewal processes. We considered Gamma processes with different shape parameters as well as renewal processes in which the ISI distribution is log-normal. For Gamma processes of integer order, we calculated the mean number of coincident spikes, as well as the Fano factor of the coincidences, analytically. We determined how these measures depend on the bin width and also investigated how they depend on the firing rate, and on rate difference between the neurons. We used Monte-Carlo simulations to estimate the whole distribution for these parameters and also for other values of gamma. Moreover, we considered the effect of dithering for both of these processes and saw that while dithering does not change the average number of coincidences, it does change the shape of the coincidence distribution. Our major findings are: 1) the width of the coincidence count distribution depends very critically and in a non-trivial way on the detailed properties of the inter-spike interval distribution, 2) the dependencies of the Fano factor on the coefficient of variation of the ISI distribution are complex and mostly non-monotonic. Moreover, the Fano factor depends on the very detailed properties of the individual point processes, and cannot be predicted by the CV alone. Hence, given a recorded data set, the estimated value of CV of the ISI distribution is not sufficient to predict the Fano factor of the coincidence count distribution, and 3) spike jittering, even if it is as small as a fraction of the expected ISI, can falsify the inference on coordinated firing. In most of the tested cases and especially for complex synchronous and spatiotemporal pattern across many neurons, spike jittering increased the likelihood of false positive finding very strongly. Last, we discuss a procedure [1] that considers the complete auto-structure of each individual spike-train for testing whether synchrony firing occurs at chance and therefore overcomes the danger of an increased level of false positives.
Poster presentation: An important challenge in neuroscience is understanding how networks of neurons go about processing information. Synapses are thought to play an essential role in cellular information processing however quantitative and mathematical models of the underlying physiologic processes that occur at synaptic active zones are lacking. We are generating mathematical models of synaptic vesicle dynamics at a well-characterized model synapse, the Drosophila larval neuromuscular junction. This synapse's simplicity, accessibility to various electrophysiological recording and imaging techniques, and the genetic malleability intrinsic to Drosophila system make it ideal for computational and mathematical studies. We have employed a reductionist approach and started by modeling single presynaptic boutons. Synaptic vesicles can be divided into different pools; however, a quantitative understanding of their dynamics at the Drosophila neuromuscular junction is lacking [4]. We performed biologically realistic simulations of high and low release probability boutons [3] using partial differential equations (PDE) taking into account not only the evolution in time but also the spatial structure in two dimensions (the extension to three dimensions will be implemented soon). PDEs are solved using UG, a program library for the calculation of multi-dimensional PDEs solved using a finite volume approach and implicit time stepping methods leading to extended linear equation systems be solvedwith multi-grid methods [3,4]. Numerical calculations are done on multi-processor computers for fast calculations using different parameters in order to asses the biological feasibility of different models. In preliminary simulations, we modeled vesicle dynamics as a diffusion process describing exocytosis as Neumann streams at synaptic active zones. The initial results obtained with these models are consistent with experimental data. However, this should be regarded as a work in progress. Further refinements will be implemented, including simulations using morphologically realistic geometries which were generated from confocal scans of the neuromuscular junction using NeuRA (a Neuron Reconstruction Algorithm). Other parameters such as glutamate diffusion and reuptake dynamics, as well as postsynaptic receptor kinetics will be incorporated as well.
Poster presentation: Characterizing neuronal encoding is essential for understanding information processing in the brain. Three methods are commonly used to characterize the relationship between neural spiking activity and the features of putative stimuli. These methods include: Wiener-Volterra kernel methods (WVK), the spike-triggered average (STA), and more recently, the point process generalized linear model (GLM). We compared the performance of these three approaches in estimating receptive field properties and orientation tuning of 251 V1 neurons recorded from 2 monkeys during a fixation period in response to a moving bar. The GLM consisted of two formulations of the conditional intensity function for a point process characterization of the spiking activity: one with a stimulus only component and one with the stimulus and spike history. We fit the GLMs by maximum likelihood using GLMfit in Matlab. Goodness-of-fit was assessed using cross-validation with Kolmogorov-Smirnov (KS) tests based on the time-rescaling theorem to evaluate the accuracy with which each model predicts the spiking activity of individual neurons and for each movement direction (4016 models in total, for 251 neurons and 16 different directions). The GLMs that considered spike history of up to 35 ms, accurately predicted neuronal spiking activity (95% confidence intervals for KS test) with a performance of 97.0% (3895/4016) for the training data, and 96.5% (3876/4016) for the test data. If spike history was not considered, performance dropped to 73,1% in the training and 71.3% in the testing data. In contrast, the WVF and the STA predicted spiking accurately for 24.2% and 44.5% of the test data examples respectively. The receptive field size estimates obtained from the GLM (with and without history), WVF and STA were comparable. Relative to the GLM orientation tuning was underestimated on average by a factor of 0.45 by the WVF and the STA. The main reason for using the STA and WVF approaches is their apparent simplicity. However, our analyses suggest that more accurate spike prediction as well as more credible estimates of receptive field size and orientation tuning can be computed easily using GLMs implemented in Matlab with standard functions such as GLMfit.
Poster presentation: Introduction Rhythmic synchronization of neural activity in the gamma-frequency range (30–100 Hz) was observed in many brain regions; see the review in [1]. The functional relevance of these oscillations remains to be clarified, a task that requires modeling of the relevant aspects of information processing. The temporal correlation hypothesis, reviewed in [2], proposes that the temporal correlation of neural units provides a means to group the neural units into so-called neural assemblies that are supposed to represent mental objects. Here, we approach the modeling of the temporal grouping of neural units from the perspective of oscillatory neural network systems based on phase model oscillators. Patterns are assumed to be stored in the network based on Hebbian memory and assemblies are identified with phase-locked subset of these patterns. Going beyond foregoing discussions, we demonstrate the combination of two recently discussed mechanisms, referred to as "acceleration" [3] and "pooling" [4]. The combination realizes in a complementary manner a competition for activity on a local scale, while providing a competition for coherence among different assemblies on a non-local scale. ...
Poster presentation: Introduction Adequate anesthesia is crucial to the success of surgical interventions and subsequent recovery. Neuroscientists, surgeons, and engineers have sought to understand the impact of anesthetics on the information processing in the brain and to properly assess the level of anesthesia in an non-invasive manner. Studies have indicated a more reliable depth of anesthesia (DOA) detection if multiple parameters are employed. Indeed, commercial DOA monitors (BIS, Narcotrend, M-Entropy and A-line ARX) use more than one feature extraction method. Here, we propose TESPAR (Time Encoded Signal Processing And Recognition) a time domain signal processing technique novel to EEG DOA assessment that could enhance existing monitoring devices. ...
Poster presentation: Functional connectivity of the brain describes the network of correlated activities of different brain areas. However, correlation does not imply causality and most synchronization measures do not distinguish causal and non-causal interactions among remote brain areas, i.e. determine the effective connectivity [1]. Identification of causal interactions in brain networks is fundamental to understanding the processing of information. Attempts at unveiling signs of functional or effective connectivity from non-invasive Magneto-/Electroencephalographic (M/EEG) recordings at the sensor level are hampered by volume conduction leading to correlated sensor signals without the presence of effective connectivity. Here, we make use of the transfer entropy (TE) concept to establish effective connectivity. The formalism of TE has been proposed as a rigorous quantification of the information flow among systems in interaction and is a natural generalization of mutual information [2]. In contrast to Granger causality, TE is a non-linear measure and not influenced by volume conduction. ...
Poster presentation: Our work deals with the self-organization [1] of a memory structure that includes multiple hierarchical levels with massive recurrent communication within and between them. Such structure has to provide a representational basis for the relevant objects to be stored and recalled in a rapid and efficient way. Assuming that the object patterns consist of many spatially distributed local features, a problem of parts-based learning is posed. We speculate on the neural mechanisms governing the process of the structure formation and demonstrate their functionality on the task of human face recognition. The model we propose is based on two consecutive layers of distributed cortical modules, which in turn contain subunits receiving common afferents and bounded by common lateral inhibition (Figure 1). In the initial state, the connectivity between and within the layers is homogeneous, all types of synapses – bottom-up, lateral and top-down – being plastic. During the iterative learning, the lower layer of the system is exposed to the Gabor filter banks extracted from local points on the face images. Facing an unsupervised learning problem, the system is able to develop synaptic structure capturing local features and their relations on the lower level, as well as the global identity of the person at the higher level of processing, improving gradually its recognition performance with learning time. ...
Poster presentation: Introduction We study the problem of object recognition invariant to transformations, such as translation, rotation and scale. A system is underdetermined if its degrees of freedom (number of possible transformations and potential objects) exceed the available information (image size). The regularization theory solves this problem by adding constraints [1]. It is unclear what constraints biological systems use. We suggest that rather than seeking constraints, an underdetermined system can make decisions based on available information by grouping its variables. We propose a dynamical system as a minimum system for invariant recognition to demonstrate this strategy. ...
Poster presentation: Introduction Dopaminergic neurons in the midbrain show a variety of firing patterns, ranging from very regular firing pacemaker cells to bursty and irregular neurons. The effects of different experimental conditions (like pharmacological treatment or genetical manipulations) on these neuronal discharge patterns may be subtle. Applying a stochastic model is a quantitative approach to reveal these changes. ...
NeuroXidence: reliable and efficient analysis of an excess or deficiency of joint-spike events
(2009)
Poster presentation: We present a non-parametric and computationally-efficient method named NeuroXidence (see http://www.NeuroXidence.com ) that detects coordinated firing within a group of two or more neurons and tests whether the observed level of coordinated firing is significantly different from that expected by chance. NeuroXidence [1] considers the full auto-structure of the data, including the changes in the rate responses and the history dependencies in the spiking activity. We demonstrate that NeuroXidence can identify epochs with significant spike synchronisation even if these coincide with strong and fast rate modulations. We also show, that the method accounts for trial-by-trial variability in the rate responses and their latencies, and that it can be applied to short data windows lasting only tens of milliseconds. Based on simulated data we compare the performance of NeuroXidence with the UE-method [2,3] and the cross-correlation analysis. An application of NeuroXidence to 42 single-units (SU) recorded in area 17 of an anesthetized cat revealed significant coincident events of high complexities, involving firing of up to 8 SUs simultaneously (5 ms window). The results were highly consistent with those obtained by traditional pair-wise measures based on cross-correlation: Neuronal synchrony was strongest in stimulation conditions in which the orientation of the sinusoidal grating matched the preferred orientation of most of the SUs included in the analysis, and was the weakest when the neurons were stimulated least optimally. Interestingly, events of higher complexities showed stronger stimulus-specific modulation than pair-wise interactions. The results suggest strong evidence for stimulus specific synchronous firing and, therefore, support the temporal coding hypothesis in visual cortex. ...
Poster presentation: Introduction We here focus on constructing a hierarchical neural system for position-invariant recognition, which is one of the most fundamental invariant recognition achieved in visual processing [1,2]. The invariant recognition have been hypothesized to be done by matching a sensory image of a particular object stimulated on the retina to the most suitable representation stored in memory of the higher visual cortical area. Here arises a general problem: In such a visual processing, the position of the object image on the retina must be initially uncertain. Furthermore, the retinal activities possessing sensory information are being far from the ones in the higher area with a loss of the sensory object information. Nevertheless, with such recognition ambiguity, the particular object can effortlessly and easily be recognized. Our aim in this work is an attempt to resolve such a general recognition problem. ...
Poster presentation: Introduction We here address the problem of integrating information about multiple objects and their positions on the visual scene. A primate visual system has little difficulty in rapidly achieving integration, given only a few objects. Unfortunately, computer vision still has great difficultly achieving comparable performance. It has been hypothesized that temporal binding or temporal separation could serve as a crucial mechanism to deal with information about objects and their positions in parallel to each other. Elaborating on this idea, we propose a neurally plausible mechanism for reaching local decision-making for "what" and "where" information to the global multi-object recognition. ...
We model the dynamics of ask and bid curves in a limit order book market using a dynamic semiparametric factor model. The shape of the curves is captured by a factor structure which is estimated nonparametrically. Corresponding factor loadings are assumed to follow multivariate dynamics and are modelled using a vector autoregressive model. Applying the framework to four stocks traded at the Australian Stock Exchange (ASX) in 2002, we show that the suggested model captures the spatial and temporal dependencies of the limit order book. Relating the shape of the curves to variables reflecting the current state of the market, we show that the recent liquidity demand has the strongest impact. In an extensive forecasting analysis we show that the model is successful in forecasting the liquidity supply over various time horizons during a trading day. Moreover, it is shown that the model’s forecasting power can be used to improve optimal order execution strategies.
A generic drug product (World Health Organization (WHO) terminology: multisource product) is usually marketed and manufactured after the expiry date of the innovator’s patent. Generic drugs are less expensive than the innovator products because generic manufacturers do not have to amortize the investment costs of research, development, marketing, and promotion. Multisource products must contain the same active pharmaceutical ingredients (APIs) as the original formulation and have to be shown to be interchangeable with the original formulation. Multisource products have to be shown bioequivalent to the innovator counterpart with respect to pharmacokinetic and pharmacodynamic properties. Multisource products are therefore identical in dose, strength, route of administration, safety, efficacy, and intended use. Bioequivalence can be demonstrated by in vitro dissolution, pharmacokinetic, pharmacodynamic or clinical studies. Since 2000, the U.S. Food and Drug Administration (FDA) allows the approval of certain multisource products solely on the basis of in vitro studies, i.e. by waiving in vivo studies in humans (“Biowaiver”), based on the Biopharmaceutics Classification Scheme (BCS). The BCS characterizes APIs by their solubility and permeability in the gastrointestinal tract (GIT). The different BCS Classes I-IV (Class I: high solubility, high permeability; Class II: low solubility, high permeability; Class III: high solubility, low permeability and Class IV: low solubility, low permeability) result from all possible combinations of high and low solubility with high and low permeability. Since the adoption of the BCS by the FDA in 1995, the BCS criteria have been under continuous development. In 2006, the WHO has released the most recent bioequivalence guidance including relaxed criteria for bioequivalence studies based on modified BCS criteria. According to this guidance, APIs belonging to the BCS classes I – and under defined conditions - II and III – are eligible for a biowaiver-based approval. The principal objective of this work was to characterize the first-line anti tuberculosis APIs, isoniazid, pyrazinamide, ethambutol dihydrochloride and rifampicin, according to their physicochemical, biopharmaceutical, pharmacokinetic and pharmacological properties and to classify them according to the BCS. Ethambutol dihydrochloride and isoniazid were classified as borderline BCS class I/III APIs. Pyrazinamide was classified as a BCS class III and rifampicin as a BCS class II API. Based on the BCS classification and the additional criteria defined in the WHO bioequivalence guidance, the possibility of biowaiver-based approval for immediate release (immediate release) solid oral dosage forms containing the first-line antituberculosis drugs was evaluated. A biowaiver-based approval with defined constraints was recommended for immediate release solid oral dosage forms containing isoniazid (interaction with reducing sugars), pyrazinamide and ethambutol dihydrochloride (relative narrow therapeutic index). Rifampicin was classified as a BCS class II API, and it was concluded that rifampicin containing solid oral immediate release drug products as well as Scale-Up and Post-Approval Changes (SUPAC) changes should not be approved by a biowaiver on the following basis: (i) its solubility and dissolution are highly variable due to polymorphism and instability, (ii) concomitant intake of food and antacids reduces its absorption and bioavailability, (iii) no in vitro predictive dissolution test has been found which correlates to in vivo absorption and (iv) several publications reporting cases of non-bioequivalent and bioinequivalent rifampicin products have been located in the literature. Thus, it is recommended that bioequivalence of rifampicin containing solid oral immediate release drug products should be established by in vivo pharmacokinetic studies in humans. This risk-benefit benefit assessment of a biowaiver-based approval was presented as a poster at the American Association of Pharmaceutical Scientists (AAPS) 2005 and subsequently published as “Biowaiver Monographs” in the Journal of Pharmaceutical Sciences. Based on the assessment of the dissolution properties of the antituberculosis drugs for a biowaiver approval, quality control dissolution methodologies for the International Pharmacopoeia (Pharm. Int.) were developed, presented at the WHO expert meeting and adopted in the Pharm. Int. (http://www.who.int/medicines/publications/pharmprep/OMS_TRS_948.pdf). Additionally, preliminary biowaiver recommendations were also developed for four firstline antimalarial drugs listed on the WHO Essential Medicines List (EML): Quinine, as both the hydrochloride and sulphate, and proguanil hydrochloride were classified as borderline BCS class I/III APIs. Since quinine is a narrow therapeutic index drug and many cases of non-bioequivalence have been reported in the literature, a biowaiverbased approval was not recommended. For solid oral immediate release dosage forms containing proguanil a biowaiver-based approval was recommended under the condition that they dissolve very rapidly. Primaquine phosphate was classified as a BCS class I API. Therefore, a biowaiver-based approval was recommended for immediate release solid oral dosage forms containing primaquine phosphate. Mefloquine hydrochloride was classified as a basic, BCS class IV/II API, making it ineligible for the biowaiver. Additionally, reports of non-bioequivalence and a narrow therapeutic index were found in the scientific literature. Consequently, bioequivalence of solid oral immediate release dosage forms containing mefloquine hydrochloride should be established by in vivo pharmacokinetic studies. The results for quinine hydrochloride and sulphate, proguanil hydrochloride, primaquine diphosphate and mefloquine hydrochloride were presented as a poster at the Pharmaceutical Sciences World Congress (PSWC) 2007 and published as a WHO Collaborating Center Report in June 2006. The aim of this project was to collect, evaluate, generate and publish relevant information for a biowaiver-based approval of essential medicines in order to provide a summary to local regulatory authorities. This information complements the selected list of essential medicines by providing information about the biopharmaceutical properties and pharmaceutical quality of solid oral immediate release dosage forms containing these APIs. The aim of the biowaiver project, inspired by the WHO and brought in life by the International Pharmaceutical Federation (FIP), is to enable access to essential medicines in standardized quality at an affordable price. In this work, a significant contribution to this aim in the form of four biowaiver monographs for the antituberculosis drugs and several reports on the antimalarials has been achieved.
Background: Microarray analysis still remains a powerful tool to identify new components of the transcriptosome and it has helped to increase the knowledge of targets triggered by stress conditions such as hypoxia and nitric oxide. However, analysis of transcriptional regulatory events remain elusive due to the contribution of altered mRNA stability to gene expression patterns, as well as changes in the half-life of mRNAs, which influence mRNA expression levels and their turn over rates. To circumvent these problems, we have focused on the analysis of newly transcribed (nascent) mRNAs by nuclear run on (NRO), followed by microarray analysis. Result: We identified 188 genes that were significantly regulated by hypoxia, 81 genes were affected by nitric oxide, and 292 genes were induced by the co-treatment of macrophages with both NO and hypoxia. Fourteen genes (Bnip3, Ddit4, Vegfa, Trib3, Atf3, Cdkn1a, Scd1, D4Ertd765e, Sesn2, Son, Nnt, Lst1, Hps6 and Fxyd5) were common to hypoxia and/or nitric oxide treatments, but with different levels of expression. We observed that 166 transcripts were regulated only when cells were co-treated with hypoxia and NO but not with either treatment alone, pointing to the importance of a crosstalk between hypoxia and NO. In addition, both array and proteomics data supported a consistent repression of hypoxia regulated targets by NO. Conclusion: By eliminating the interference of steady state mRNA in gene expression profiling, we increased the sensitivity of mRNA analysis and identified previously unknown hypoxia-induced targets. Gene analysis profiling corroborated the interplay between NO- and hypoxia-induced signalling.
Photo-initiated processes, like photo-excitation and -deexcitation, internal conversion, excitation energy transfer and electron transfer, are of importance in many areas of physics, chemistry and biology. For the understanding of such processes, detailed knowledge of excitation energies, potential energy surfaces and excited state properties of the involved molecules is an essential prerequisite. To obtain these informations, quantum chemical calculations are required. Several quantum chemical methods exist which allow for the calculation of excited states. Most of these methods are computationally costly what makes them only applicable to small molecules. However, many biological systems where photo-processes are of interest like light-harvesting complexes in photosynthesis or the reception of light in the human eye by rhodopsin are quite large. For large systems, however, only few theoretical methods remain applicable. The currently most widely used method is time-dependent density functional theory (TD-DFT), which can treat systems of up to 200–300 atoms with the excitation energies of some excited states exhibiting errors of less than 0.5 eV. Yet, TD-DFT has several drawbacks. The most severe failure of TD-DFT is the false description of charge transfer states which is particularly problematic in case of larger systems where it yields a multitude of artificially low-lying charge transfer states. But also Rydberg states and states with large double excitation character are not described correctly. Still, if these deficiencies are kept in mind during the interpretation of results, TD-DFT is a useful tool for the calculation of excited states. In my thesis, TD-DFT is applied in investigations of excitation energy and electron transfer processes in light-harvesting complexes. Since light-harvesting complexes, which consist of thousands of atoms, are by far too large to be calculated, model complexes for the processes of interest are constructed from available crystal structures. The model complexes are used to calculate potential energy curves along meaningful reaction coordinates. Artificial charge transfer states are corrected with the help of the so-called ∆DFT method. The resulting potential energy curves are then interpreted by comparison with experimental results. For the light-harvesting complex LH2 from purple bacteria the experimentally observed formation of carotenoid radical cations is studied. It is shown that the carotenoid radical cation is formed most likely via the optically forbidden S1 state of the carotenoid. In light-harvesting complex LHC-II of green plants the fast component of the so-called non-photochemical quenching (NPQ) is investigated. Two of several different hypotheses on the mechanism of NPQ, which have been proposed recently, are studied in detail. The first one suggests that NPQ proceeds via simple replacement of violaxanthin by zeaxanthin in the binding pocket in LHC-II. However, the calculated potential energy curves exhibit no difference between violaxanthin and zeaxanthin in the binding pocket. In combination with experimental results it is thus shown that simple replacement alone does not mediate NPQ in LHC-II. The second hypothesis proposes conformational changes of LHC-II that lead to quenching at the central lutein and chlorophyll molecules during NPQ. My TD-DFT calculations demonstrate that if this mechanism is operative, only the lutein 1 which is one of two central luteins present in LHC-II can take part in the quenching process. This is corroborated by recent experiments. Though several conclusions can be drawn from the investigations using TD-DFT, the interpretability of the results is limited due to the deficiencies of the method and of the models. To overcome the methodological deficiencies, more accurate methods have to be employed. Therefore, the so-called algebraic diagrammatic construction scheme (ADC) is implemented. ADC is a widely overlooked ab initio method for the calculation of excited states, which is based on propagator theory. Its theoretical derivation proceeds via perturbation expansion of the polarization propagator, which describes electronic excitations. This yields separate schemes for every order of perturbation theory. The second order scheme ADC(2), which is employed here, is the equivalent to the Møller-Plesset ground state method MP(2), but for excited states. It represents the computationally cheapest excited state method which can correctly describe doubly excited states, as well as Rydberg and charge transfer states. The quality of ADC(2) results is demonstrated in calculations on linear polyenes which serve as model systems for the larger carotenoid molecules. The calculations show that ADC(2) describes the three lowest excited states of polyenes sufficiently well, particularly the optically forbidden S1 state which is known to possess large double excitation character. Yet, the applicability of the method is limited compared to TD-DFT due to the much larger computational requirements. To facilitate the calculation of larger systems with ADC(2) a new variant of the method is developed and implemented. The variant employs the short-range behavior of electron correlation to reduce the computational effort. As a first step, the working equations of ADC(2) are transformed into a basis of local orbitals. In this basis negligible contributions of the equations which are due to electron correlation can be identified based on the distances of local orbitals. A so-called “bumping” scheme is implemented which removes the negligible parts during a calculation. This way, the computation times as well as the disk space requirements can be reduced. With the “bumping” scheme several new parameters are introduced that regulate the amount of “bumping” and thereby the speed and the accuracy of computations. To determine useful values for the parameters an evaluation is performed using the linear polyene octatetraene as test molecule. From the evaluation an optimal set of parameter values is obtained, so that the computation times become minimal, while the errors in the excitation energies due to the “bumping” do not exceed 0.15 eV. With further calculations on various molecules of different sizes it is tested if these parameter values are universal, i.e. if they can be used for all molecules. The test calculations show that the errors in the excitation energies are below 0.15 eV for all test systems. Additionally, no trend is visible for the errors that their magnitude might depend on the system. In contrast, the amount of disregarded contributions in the calculations increases drastically with growing system size. Thus, the local variant of ADC(2) can be used in future to reliably calculate excited states of systems which are not accessible with conventional ADC(2).
This paper explores the relationship between equity prices and the current account for 17 industrialized countries in the period 1980-2007. Based on a panel vector autoregression, I compare the effects of equity price shocks to those originating from monetary policy and exchange rates. While monetary policy shocks have a limited impact, shocks to equity prices have sizeable effects. The results suggest that equity prices impact on the current account through their effects on real activity and exchange rates. Furthermore, shocks to exchange rates play a key role as well. Keywords: current account fluctuations, equity prices, panel vector autoregression
The risk of deflation
(2009)
This paper was prepared for the meeting on Financial Regulation and Macroeconomic Stability: Key issues for the G20, organised by the CEPR and the Reinventing Bretton Woods Committee, London, 31 January 2009. Introduction: The onset of financial instability in August 2007, which quickly spread across the world, raises a number of questions for policy makers. First, what are the roots of the crisis? Many factors have been emphasized in the debate, including the opacity of complex financial products; the excessive confidence in ratings; weak risk management by financial institutions; massive reliance on wholesale funding; and the presumption that markets would always be liquid. Furthermore, poorly understood incentive effects – arising from the originate-to-distribute-model, remuneration policies and the period of low interest rates – are also widely seen as having played a role. Second, how can a repetition of the crisis can be avoided? Much attention is being focused on regulation and supervision of financial intermediaries. The G-20, at its summit in November 2008, noted that measures need to be taken in five areas: (i) financial market transparency and disclosure by firms need to be strengthened; (ii) regulation needs to be enhanced to ensure that all financial markets, products and participants are regulated or subject to oversight, as appropriate; (iii) the integrity of financial markets should be improved by bolstering investor and consumer protection, avoiding conflicts of interest, and by promoting information sharing; (iv) international cooperation among regulators must be enhanced; and (v) international financial institutions must be reformed to reflect changing economic weights in the world economy better in order to increase the legitimacy and effectiveness of these institutions. Third, how can the consequences for economic activity be minimized? Many of the adverse developments in financial markets – in particular the collapse of term interbank markets – reflect deeply entrenched perceptions of counterparty risk. Prompt and far-reaching action to support the financial system, in particular the infusion of equity capital in financial institutions to reduce counter-party risk and get credit to flow again, is essential in order to restore market functioning. A particular risk at present is that the rapid decline in inflation in many countries in recent months will turn into deflation with highly adverse real economic developments. This background paper considers how large the risk of deflation may be and discusses what policy can do to reduce it. It is organized as follows. Section 2 defines deflation and discusses downward nominal wage rigidities and the zero lower bound on interest rates. While these factors are frequently seen as two reasons why deflation can be associated with very poor economic outcomes, they should not be overemphasized. Section 3 looks at the current situation. Inflation expectations and forecasts in the subset of economies we look at (the euro area, the UK and the US) are positive, indicating that deflation is not expected. This does not imply that the current concerns of deflation are unwarranted, only that the public expects the central bank to be successful in avoiding deflation. The section also looks at the evolution of headline and “core” inflation, focusing on data from the US and the euro area. Section 4 reviews how monetary and fiscal policy can be conducted to ensure that deflation is avoided. Section 5 briefly discusses special issues arising in emerging market economies. Finally, Section 6 offers some conclusions. An Appendix discusses deflation episodes in the period 1882-1939.
This paper examines the sustainability of the currency board arrangements in Argentina and Hong Kong. We employ a Markov switching model with two regimes to infer the exchange rate pressure due to economic fundamentals and market expectations. The empirical results suggest that economic fundamentals and expectations are key determinants of a currency board’s sustainability. We also show that the government’s credibility played a more important role in Argentina than in Hong Kong. The trade surplus, real exchange rate and inflation rate were more important drivers of the sustainability of the Hong Kong currency board.
Over the last four decades the literature on bond rating changes and its effects on security prices increased significantly with almost all studies not controlling for the respective reason for those. We therefore investigate the impact of rating events on the stock and the credit default swap (CDS) market incorporating rating reviews and rating changes together with the reason mentioned by the rating agency. Our results for the general effects are in line with prior findings but conditioning on the respective reason shows that the markets’ anticipation of rating actions is largely driven by events due to changes in firms’ operating performance. Furthermore, we provide empirical evidence for the hypothesis in prior literature that a surprise downgrade does not necessarily have to be bad news for stockholders when wealth is transferred from bondholders, but negative rating actions are always bad news for bondholders. The results additionally reveal increasing rating announcement effects by declining credit quality of firms for both rating reviews and changes. JEL Classification: D82, G14, G20. Keywords: Credit Default Swaps, Credit Ratings, Credit Rating Reasons, Event Study.
The objective of this paper is to test the hypothesis that in particular financially constrained firms lease a higher share of their assets to mitigate problems of asymmetric information. The assumptions are tested under a GMM framework which simultaneously controls for endogeneity problems and firms’ fixed effects. We find that the share of total annual lease expenses attributable to either finance or operating leases is considerably higher for financially strained as well as for small and fast-growing firms – those likely to face higher agency-cost premiums on marginal financing. Furthermore, our results confirm the substitution of leasing and debt financing for lessee firms. However, we find no evidence that firms use leasing as an instrument to reduce their tax burdens. Keywords: Leasing; financial constraints; capital structure; asymmetric information.
This paper addresses the question whether close borrower-lender relationships, so called hausbank-relationships, facilitate the funding and beneficial development of SME. To this end, we derive a model which relates a firm's growth rate to its need for external funds and subsequently compute the firms that exceed their predicted growth rate. We then use this measure to identify specific characteristics that are associated with long- and short-term financing of firm growth, in particular the influence of relationship lending. We find that close ties with savings banks predict firms' access to external finance to fund growth. Moreover, the long-term liabilities of firms with hausbank-relationships almost double those with multiple relationships while the overall leverage is about the same. In turn, we find an strong empirical relationship between the provision of long-term funds and firm growth. Keywords: small business lending, credit access, public banks JEL Classifications: G21, D21
The purpose of this thesis was to investigate different aspects of the promotion of selfregulated learning in primary and secondary school education by focussing on its effectiveness, and on its assessment from different perspectives. Theoretically, the thesis is based on contemporary social-cognitive and constructivist theories of self-regulated learning. Two meta-analyses were conducted, an observation instrument was developed which was tested and employed in two observation studies, and a multi-method study was conducted to investigate different perspectives on the topic. Common to all studies is the evaluation of different aspects of the promotion of self-regulated learning among students. The results of this investigation are reported in four research articles (Studies 1-4), which have been accepted for publication (Study 1 and 2) or submitted to scientific peer reviewed journals (Study 3 and 4). The data are analyzed by applying a multi-method approach, using several sources of data (primary studies, self-reports, video data, interviews) and diverse methods (meta-analysis, observation analysis, survey analysis). The present data generally indicate that self-regulated learning can be enhanced both at primary and secondary school. The results of the first and the second study showed that primary and secondary school students partly benefit from different training characteristics. However, there were also common aspects of effective training characteristics that hold for both school levels. Moreover, the third study revealed that it was possible to develop an instrument to observe teachers’ promotion of self-regulated learning in a reliable way, which can be applied in several contexts. The results indicated that the stability of teachers’ promotion of selfregulated learning varies among the school subjects. Furthermore, the results showed that only little instruction of self-regulated learning takes place in primary and secondary school mathematics lessons. Yet, secondary school teachers showed more promotion of cognitive strategies than primary school teachers did, although the former included more constructivist characteristics in the learning environment. The observation studies produced a rich pool of data, serving as pilot studies for future studies with a larger sample sizes that are needed to further strengthen the results. As the fourth study indicated, teacher ratings differ significantly from video-based observations in perceiving their promotion of self-regulated learning. However, for some aspects they agree with their students’ perception. Finally, it was found that students’ perception on their teachers’ promotion of self-regulated learning had the highest impact on their self-regulation competence. In the future, it will be crucial to include the instruction of self-regulated learning from a theoretical and a practical perspective in the teacher training curriculum. Moreover, in future research the implementation of the promotion of self-regulated learning should be investigated, and in experimental settings different ways of supporting such an implementation should be examined. A close collaboration with teachers would be helpful to get deeper insights into teachers’ behaviour and attitudes. The promotion of self-regulated learning should start as early as in primary school as students are already able to learn it then and as it takes many years to develop it fully. In addition, when investigating teachers’ promotion of self-regulated learning, the school subject should be taken into account during assessment. Long-term measurements could acknowledge such a potential instability. Moreover, in further studies, observation data of a large sample of teachers should be gathered in order to get a representative overview of teachers’ promotion of self-regulated learning. Furthermore, research on the promotion of self-regulated learning should account for the impact of students’ perspectives referring on this.
In this thesis we report on the high pressure synthesis, crystal growth, structural characterisation and magnetic properties of the cubic vanadate pyrochlores A2V2O7 (with A = Y, Er and Dy). We have found that high pressure is requisite for the stabilization of the selected compounds. For this purpose, a multianvil high pressure apparatus was built in our laboratory and a new multianvil inset (i.e., a ceramic pressure medium and the interior parts) was developed. The multianvil press is based on a hydraulic press with a maximum force of 7.73 MN (corresponds to 788 tons), a Walker type module and a specially designed hydraulic and electric control. Pressure calibration of the multianvil setup was performed by high pressure fixed points (i.e. solid-solid transformation of Bi I-II (2.55 GPa) and Bi II-III (3.15 GPa)). A maximum pressure of 6 GPa was attained using hardened metal anvils (tungsten carbide) with truncation edge length (TEL) of 14 mm and a sample volume of ~ 70 mm3. Heating of the sample in our current multianvil setup (TEL = 14 mm) was achieved by resistive heating of a graphite furnace. Temperatures up to 1500 °C could be obtained at pressures up to 6 GPa. By systematic variation of the synthesis conditions (for instance the operation temperature or the choice of the crucible material) under high pressure and taking into account the well known ternary compounds, when accessing the phase diagram, the cubic vanadate pyrochlores A2V2O7 (with A = Y, Er and Dy) were synthesized successfully. It was found that the oxygen partial pressure is crucial for the formation of the desired pyrochlore phase. Gas-tight platinum crucibles were used as container material for the synthesis of the vanadate pyrochlores. We have investigated, that pressures of the order of 5.0 GPa and temperatures of approximately 1200 °C are necessary for the stabilization of the monophasic samples of the vanadate pyrochlores. Lu2V2O7 could be synthesized under ambient pressure conditions and is used in our studies for comparison purposes. A special graphite furnace was developed for the high pressure crystal growth of the vanadate pyrochlores. For the first time, A2V2O7 (with A = Y, Er and Dy) single crystals with a maximum size of 0.4 mm were grown by using the grain growth method at high pressure and high temperature conditions. The samples (i.e., powders and single crystals) were characterised by single crystal Xray diffraction, X-ray powder diffraction method, Laue method and scanning electron microscopy (SEM). Complementary to the X-ray diffraction methods, infrared absorsoption spectroscopy was used to distinguish between the fluorite and pyrochlore structure. It has been shown that all samples crystallize in a well-ordered cubic structure with the space group F d 3m. The vanadium (+4) content in the samples was determined by oxidative weight gain in air using a thermogravimetric (TG) balance. A structural phase transformation of cubic to tetragonal was observed by differential thermal analysis (DTA) in conjunction with high temperature diffractometry. The magnetic characterisation of the vanadate pyrochlores A2V2O7 (Y, Lu, Er and Dy) was performed by Katarina Removic-Langer in the laboratory of Prof. Dr. M. Lang. All materials studied are ferromagnetic. The ferromagnetic critical temperatures are between 70 and 73 K. In case of Er2V2O7 and Dy2V2O7 an additional increase in the magnetization was observed below 20 K. The increase in the magnetization below 20 K exhibited by Er2V2O7 and Dy2V2O7 originates from the interactions between the two magnetic sublattices (i.e., the rare earth- and the vanadium sublattice).
The objective of this paper is to test the hypothesis that in particular financially constrained firms lease a higher share of their assets to mitigate problems of asymmetric information. The assumptions are tested under a GMM framework which simultaneously controls for endogeneity problems and firms' fixed effects. We find that the share of total annual lease expenses attributable to either finance or operating leases is considerably higher for smaller firms with higher average interest rates and high-growth firms - those likely to face higher agency-cost premiums on marginal financing. Furthermore, our results confirm the substitution of leasing and debt financing for lessee firms. However, we find no evidence that firms use leasing as an instrument to reduce their tax burdens. Keywords: Leasing, financial constraints, asymmetric information, GMM JEL Classifications: D23, D92, C23
In the title compound, C27H20F6N2O2, the dihedral angles between the planes of the aromatic rings connected by the ether O atoms are 84.13 (8) and 75.06 (9)°. The crystal structure is stabilized by N-H...O and N-H...F hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.037; wR factor = 0.088; data-to-parameter ratio = 8.2.
In the title compound, C17H12F2N2OS, the planar thiazole ring (r.m.s. deviation = 0.012 Å) makes dihedral angles of 15.08 (9) and 81.81 (6)° with the 4-fluorophenyl and 2-fluorophenyl rings, respectively. The 2-fluorophenyl ring is disordered over two orientations with site-occupancy factors of 0.810 (3) and 0.190 (3). The structure contains intermolecular C-H...O hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; disorder in main residue; R factor = 0.034; wR factor = 0.082; data-to-parameter ratio = 16.1.
The title compound, C16H14N4, features an aromatic ring with two 2,2´-dicyanopropyl residues in positions 1 and 3, which are located above and below the ring plane. The two residues differ in their conformation with respect to the aromatic ring: whereas one of the Cmethyl-C-Cmethylene-Caromatic torsion angles is gauche [68.93 (12)°], the other one is fully staggered [177.63 (9)°]. The crystal structure is stabilized by C-H...N hydrogen-bonding interactions. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.037; wR factor = 0.101; data-to-parameter ratio = 15.0.
4-Chloro-N-m-tolylbenzamide
(2009)
In the title compound, C14H12ClNO, the dihedral angle between the two aromatic rings is 11.29 (15)°. The crystal packing is stabilized by N-H...O hydrogen bonds linking the molecules into chains running along the c axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.066; wR factor = 0.178; data-to-parameter ratio = 13.7.
6-(4-Nitrophenoxy)hexanol
(2009)
The title compound, C12H17NO4, features an almost planar molecule (r.m.s. deviation for all non-H atoms = 0.070 Å). All methylene C-C bonds adopt an antiperiplanar conformation. In the crystal structure the molecules lie in planes parallel to (1\overline{1}2) and the packing is stabilized by O-H...O hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.066; wR factor = 0.185; data-to-parameter ratio = 13.2.
In the title molecule, C13H16ClNO, the mean plane of the atoms in the -CONH- group forms a dihedral angle of 42.0 (4)° with the benzene ring plane. In the crystal structure, molecules are linked by intermolecular N-H...O hydrogen bonds, generating C(4) chains along [100]. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.030; wR factor = 0.069; data-to-parameter ratio = 18.2.
The structure of the title compound, C14H9Cl3N2OS, is composed of discrete molecules with bond lengths and angles quite typical for thiourea compounds of this class. The plane containing the thiocarbonyl and carbonyl groups subtends dihedral angles of 48.19 (3) and 87.51 (3)° with the planes formed by the 3-chloro and 2,6-dichlorophenyl rings, respectively; the dihedral angle between the two benzene ring planes is 45.32 (3)°. An intramolecular N-H...O hydrogen bond stabilizes the molecular conformation and the molecules form intermolecular N-H...S and N-H...O hydrogen bonds, generating a sheet along the alpha axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.037; wR factor = 0.094; data-to-parameter ratio = 25.5.
The title compound, C14H6Cl6N2OS·0.5CHCl3, crystallizes with four 1-(2,6-dichlorobenzoyl)-3- (2,3,5,6-tetrachlorophenyl)thiourea molecules and two trichloromethane molecules in the asymmetric unit. The thiourea molecules exist in the solid state in their thione forms with typical thiourea C-S and C-O bonds lengths, as well as shortened C-N bonds. The -NH-C(=S)-NH-C(=O)- plane is almost perpendicular to the benzene ring in each thiourea molecule. Intramolecular N-H...O hydrogen bonds stabilize the molecular conformation and intermolecular N-H...S hydrogen bonds stabilize the packing arrangement. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.051; wR factor = 0.147; data-to-parameter ratio = 23.2.
The title molecule, C16H15ClN2OS, exists in the solid state in its thione form with typical thiourea C-S and C-O bonds lengths, as well as shortened C-N bonds. An intramolecular N-H...O hydrogen bond stabilizes the molecular conformation and intermolecular N-H...S hydrogen bonds link the molecules into centrosymmetric dimers. The dihedral angle between the aromatic rings is 50.18 (5)°. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.032; wR factor = 0.085; data-to-parameter ratio = 15.3.
The asymmetric unit of the title compound, C14H8Cl4N2OS·0.5H2O, contains two independent molecules with different conformations with respect to the aromatic ring planes, and one water molecule. The bond lengths and angles are typical of thiourea compounds of this class. The molecule exists in the solid state in its thione form with typical thiourea C-S and C-O bonds lengths, as well as shortened C-N bonds. The dihedral angles between the two aromatic planes are 66.93 (8) and 60.44 (9)° in the two independent molecules. An intramolecular N-H...O hydrogen bond stabilizes the molecular conformation and the crystal packing is characterized by N-H...O, O-H...S and O-H...Cl hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.045; wR factor = 0.125; data-to-parameter ratio = 16.8.
The crystal structure of the title compound, C14H8Cl4N2OS, is composed of discrete molecules with bond lengths and angles quite typical for thiourea compounds of this class. The plane containing the central SONNCC atom set subtends a dihedral angle of 31.47 (3)° with the benzene ring. An intramolecular N-H...O hydrogen bond stabilizes the molecular conformation and the molecules form centrosymmetric dimers via intermolecular N-H...S hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.032; wR factor = 0.087; data-to-parameter ratio = 17.9.
This study focuses on structural features of a particular GPCR type, the family C GPCRs. Structure- and ligand-based approaches were adopted for prediction of novel mGluR5 binding ligand and their binding modes. The objectives of this study were: 1. An analysis of function and structural implication of amino acids in the TM region of family C GPCRs. 2. The prediction of the TM domain structure of mGluR5. 3. The discovery of novel selective allosteric modulators of mGluR5 by virtual screening. 4. The prediction of a ligand binding mode for the allosteric binding site in mGluR5. GPCRs are a super-family of structurally related proteins although their primary amino acid sequence can be diverse. Using sequence information a conservation analysis of family C GPCRs should be applied to reveal characteristic differences and similarities with respect function, folding and ligand binding. Using experimental data and conservation analysis the allosteric binding site of mGluR5 should be characterized regarding NAM and PAM and selective ligand binding. For further evaluation experimental knowledge about family A GPCRs as well as conservation between vertebrate rhodopsins was planned to be compared to results obtained for family C GPCRs (Section 4.1 Conservation analysis of family C GPCRs). Since no receptor structure is available for any family C GPCR, discussion of conserved sequence positions between family A and C GPCRs requires the prediction of a receptor structure for mGluR5 using a family A receptor as template. In order to predict the mGluR5 structure a sequence alignment to a GPCR template protein will have to be proposed and GPCR specific features considered in structure calculation (Section 4.1.4 Structure prediction of mGluR5). The obtained structure was intended to be involved in ligand binding mode prediction of newly discovered active molecules. For discovery of novel selective mGluR modulators several ligand-based virtual screening protocols were adapted and evaluated. Prediction models were derived for selection of possibly active molecules using a diverse collection of known mGluR binding ligands. For that purpose a data collection of known mGluR binding ligands should be established and this reference collection analyzed with respect to different ligand activity classes, NAM or PAM and selective modulators. The prediction of novel NAMs and PAMs using several combinations of 2D-, 3D-, pharmacophore or molecule shape encoding methods with machine learning techniques and similarity determining methods should be tested in a prospective manner (Section 4.2 Virtual screening for novel mGluR modulators). In collaboration with Merz Pharmaceuticals (Merz GmbH & Co. KGaA, Frankfurt am Main, Germany) the modulating effect of a few hundred molecules should be approved in a functional cell-based assay. With the objective to predict a binding mode of the discovered active molecules, molecule docking should be applied using the allosteric binding site of the modeled mGluR5 structure (Section 4.2.4 Modeling of binding modes). Predicted ligand binding modes are to be correlated to conservation profiles that had resulted from the sequence-based entropy analysis and information from mutation experiments, and shall be compared to known ligand binding poses from crystal structures of family A GPCRs.
The two aromatic rings in the title compound, C15H12Cl2N2O2S, enclose a dihedral angle of 37.49 (6)°. The molecule exists in the solid state in its thione form with typical thiourea C-S and C-O bonds lengths, as well as shortened C-N bonds. An intramolecular N-H...O hydrogen bond stabilizes the molecular conformation. In the crystal, molecules are connected by N-H...O and N-H...S hydrogen bonds, forming chains running along the alpha axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ (C–C) = 0.002 Å; disorder in main residue; R factor = 0.035; wR factor = 0.087; data-to-parameter ratio = 18.9.
The title compound, Cs2Mg(H2P2O7)2·2H2O, is isostructural with the related known isoformular phosphates. The crystal framework consists of corner-sharing MgO6 and H2P2O7 polyhedra, leading to tunnels parallel to the b-axis direction in which Cs+ ions are located. The H2P2O7 unit shows a bent eclipsed conformation. The Mg2+ ion lies on an inversion center. The water molecules form hydrogen bonds to O atoms of two different dihydrogenphosphate ions, which are further hydrogen bonded to symmetry-equivalent dihydrogenphosphate ions. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(P–O) = 0.006 Å; R factor = 0.048; wR factor = 0.125; data-to-parameter ratio = 12.3.
The crystal structure of the title compound, C15H17BrN2O4S, is stabilized by intermolecular N-H...O hydrogen bonds which link the molecules into centrosymmetric dimers. The dihedral angle subtended by the 4-bromophenyl group with the mean plane passing through the hydantoin unit is 83.29 (5)°. The cyclohexyl group adopts an ideal chair conformation with the methyl group in an equatorial position. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.030; wR factor = 0.070; data-to-parameter ratio = 16.8.
The five-membered ring of the title compound, C10H14NO, is almost planar [mean deviation from best plane = 0.006 (1) Å]. The N-O bond is in the plane of the five-membered ring. The molecule is positioned about a pseudo-mirror plane at y = 0.375. In the crystal, molecules are connected by intermolecular C-H...O contacts into layers parallel to (010). Key indicators: single-crystal X-ray study; T = 167 K; mean σ(C–C) = 0.002 Å; R factor = 0.062; wR factor = 0.157; data-to-parameter ratio = 27.3.
In the title compound, C15H17ClN2O4S, the atoms in the hydantoin ring are coplanar (r.m.s. deviation = 0.006 Å). The crystal structure is stabilized by intermolecular N-H...O hydrogen bonds which link the molecules into centrosymmetric dimers. The dihedral angle subtended by the 4-chlorophenyl group with the plane passing through the hydantoin unit is 82.98 (4)°. The cyclohexyl ring adopts an ideal chair conformation. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.030; wR factor = 0.081; data-to-parameter ratio = 15.0.
In the title Grignard reagent, [MgBr(C12H9)(C5H10O)2], the Mg centre adopts a distorted tetrahedral MgCO2Br arrangement. The dihedral angle between the two aromatic rings of the biphenyl residue is 44.00 (14)°. Each molecule incorporates one R- and one S-configured 2-methyltetrahydrofuran molecule. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.007 Å; R factor = 0.045; wR factor = 0.108; data-to-parameter ratio = 17.4.
The title compound, C17H18N2O6, crystallizes with two molecules in the asymmetric unit. In both molecules, one of the C-C bonds of the pentamethylene chain connecting the two aromatic rings is in a trans conformation and another displays a gauche conformation. The aromatic rings within each molecule are nearly coplanar [dihedral angles = 3.36 (9) and 4.50 (9)°] and the nitro groups are twisted slightly out of the planes of their attached rings [dihedral angles = 8.16 (3)/6.6 (2) and 4.9 (4)/3.8 (3)°]. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.003 Å; R factor = 0.040; wR factor = 0.101; data-to-parameter ratio = 13.5.
In the title compound, C16H16BrNO4, the dihedral between the planes of the aromatic rings is 7.74 (18)°. The amide group is tilted with respect to the bromo- and methoxy-substituted aromatic rings by 36.3 (8) and 35.2 (8)°, respectively. The meta-methoxy groups are essentially in-plane with the aromatic ring [dihedral angles CH3-O-C-C = -4.6 (4) and -2.5 (4)°]. The para-methoxy group is markedly displaced from the ring plane [dihedral angle CH3-O-C-C = -72.5 (4)°]. The crystal packing is stabilized by N-H...O hydrogen bonds linking the molecules into chains running along the b axis. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.004 Å; R factor = 0.033; wR factor = 0.076; data-to-parameter ratio = 14.6.
Adamantane-1-thioamide
(2009)
The title compound, C11H17NS, is an important intermediate for the synthesis of biologically active adamantlythiazolo-oxadiazoles. The adamantyl residue is disordered about a twofold rotation axis over two sites with site-occupation factors of 0.817 (3) and 0.183 (3). The crystal structure is stabilized by intermolecular N-H...S hydrogen-bonding interactions. Key indicators: single-crystal X-ray study; T = 173 K; mean &963;(C–C) = 0.002 Å; disorder in main residue; R factor = 0.038; wR factor = 0.103; data-to-parameter ratio = 12.3.
In the framework of this thesis the intense low energy ion beam transport was investigated. Especially, the beam transport in toroidal magnetic field configurations was discussed, as it may allow the accumulation of high intensive beams in the future. One of the specific tasks is to design an injection system that can be used for the proposed low energy accumulator ring. This thesis regarding beam transport investigations is related to the larger research fields, storage rings used in accelerator physics and non-neutral plasmas. The proposal of building a storage ring with longitudinal guiding magnetic fields was made. Due to natural transversal focussing in magnetic fields it is possible to accumulate very intense charged particle beams, a subject of interest within the physics community. A simulation code (TBT) was written to describe the particle motion in curved segments. Particle in Cell techniques were utilized to simulate a multi particle dynamics. This code allows the user to generate different particle distributions as input parameter. A possibility of reading an external data file was made available so that a measured distribution can be used to compare simulation results with measured ones. A second order cloud in cell method was used to calculate charge density and in turn to solve Poisson’s equation. The circular toroidal coordinate system was used. The drift motion and gyrating motion was proved to be consistent with analytical values. Further simulations were performed to study the self field effects on beam transport. The experiments with single toroidal segments find niche in the work. The experiments were performed to compare the simulation results and gain practical experience. The toroidal segment has similar dimensions (major axis R = 1:3 m, minor axis r = 0:1 m, arc angle 30°) as for a full scale ring design. The main difference lies in the magnetic field strength. The available segments can be operated at room temperature producing 0:6T on axis maximum magnetic field, while for the storage ring design this value is in the range of 5T. The preparatory experiments consisted of building and characterization of the ion source in a first step. Along with the momentum spectrometer and emittance scanner the beam properties were studied. Low mass ion beams He+ and mixed p, H2+, H3+ beams were analyzed. The proton beam consisting of a 48% H+ fraction was extracted regularly and used for further experiments. A moderate beam energy of 10 keV was chosen as operational energy for which 3.08 mA proton beam current was measured. In the second stage, beams were transported through a solenoid and the phase space distribution was measured as a function of the magnetic field for different beam energies. The phase-space as distributions measured in a first stage were simulated backward and then again forward transported through the solenoid. The simulated results were then compared with the measured distribution. The LINTRA transport program was used. The phase-space distribution was further simulated for transport experiments in a toroidal magnetic field. The experiments with a single toroidal segment give basic results necessary to compare the results between transport code (TBT) and measurements. The optical diagnostic provides measurements which can be well compared with the simulated results. A digital camera with a magnetic shield was used to record images in jpeg file format. A subroutine was written to analyze an image file to give the intensity distribution of a given image file. The integrated profile in vertical and horizontal direction was used to calculate the vertical drift and the beam size. The simulated values were in good agreement with the measured ones. The injection system needs most care. The transport program that was used to simulate the beam in the toroid was also used to design the injection system. The injection system with its special field configurations was designed to perform experiments with room temperature segments. The main point to tackle was to smoothly bring the charged particles generated outside the trap into the acceptance of the ring. The designed system consists of two sources, one representing a ring beam and the other one the injection beam. While simulations showed a clear way, how to inject the particle beam via a well positioned solenoid and in combination with a transverse electric field element causing an ExB drift into the main ring acceptance. After construction of these injection elements it will be very important to measure the robustness of such a system with respect to the beam stability- especially of the injection channel.
The title compound, C21H16N2O2, was derived from 1-(2-hydroxyphenyl)-3-(-methoxyphenyl)propane-1,3-dione. The molecular structure of the title compound is stabilized by an intramolecular O-H...N hydrogen bond. The dihedral angle between the hydroxyphenyl ring involved in this intramolecular hydrogen bond and the pyrazole ring is significantly smaller [10.07 (6)°] than the dihedral angle between the pyrazole and the other hydroxyphenyl ring [36.64 (5)°]. The benzene ring makes a dihedral angle of 54.95 (3)° with the pyrazole ring. The crystal packing is stabilized by O-H...O and O-H...N hydrogen bonds. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.039; wR factor = 0.101; data-to-parameter ratio = 16.2.
The title compound, C22H18N2O2, was derived from 1-(2-hydroxyphenyl)-3-(4-methoxyphenyl)propane-1,3-dione. The central pyrazole ring forms dihedral angles of 16.83 (5), 48.97 (4) and 51.68 (4)°, respectively, with the methoxyphenyl, phenyl and hydroxyphenyl rings. The crystal packing is stabilized by O-H...N hydrogen bonding. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.037; wR factor = 0.096; data-to-parameter ratio = 17.0.
The title compound, C25H22O5, was obtained by a dehydrogenative carbonylation reaction. It crystallizes with one half-molecule in the asymmetric unit. The molecules have crystallographic C2 symmetry and the two atoms of the carbonyl group are located on the rotation axis. The methoxy groups are coplanar with the benzene ring to which they are attached [C-C-O-C = 1.0 (6)°]. The two furan rings are inclined at 17.3 (3)° with respect to each other and the dihedral angle between the furan ring and the benzene ring is 75.83 (12)°. The crystal structure is stabilized by C-H...O hydrogen bonds. Key indicators: single-crystal X-ray study; T = 183 K; mean ( σ(C–C) = 0.006 Å; R factor = 0.081; wR factor = 0.195; data-to-parameter ratio = 13.4.
The title molecule, C14H9ClN2OS, exists in the solid state in its amide form with a typical C=O bond length, as well as shortened C-N bonds. The plane containing the HNCO atoms subtends dihedral angles of 12.3 (4) and 8.1 (3)° with the planes of the phenyl ring and benzothiazole group, respectively, whereas the dihedral angle between the planes of the phenyl ring and the benzothiazole group is 5.96 (6)°. In the crystal, molecules form intermolecular N-H...N hydrogen bonds, generating independent scissor-like R22(8) dimers. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.028; wR factor = 0.079; data-to-parameter ratio = 13.3.
In the molecule of the title compound, C14H16ClN3O, the benzene and pyrazole rings are oriented at a dihedral angle of 3.50 (3)°. In the crystal structure, intermolecular N-H...O hydrogen bonds link the molecules into chains. A [pi]-[pi] contact between the benzene and pyrazole rings [centroid-centroid distance = 3.820 (3) Å] may further stabilize the structure. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 Å; R factor = 0.031; wR factor = 0.086; data-to-parameter ratio = 14.1.
2-Chloro-5-nitroaniline
(2009)
The molecule of the title compound, C6H5ClN2O2, is close to being planar (rms deviation = 0.032 Å for all non-H atoms), with a maximum deviation of -0.107 (3) Å for an O atom. In the crystal structure, intermolecular N-H...O and N-H...N interactions link the molecules into a three-dimensional network. Key indicators: single-crystal X-ray study; T = 173 K; mean σ(C–C) = 0.002 A°; R factor = 0.023; wR factor = 0.061; data-to-parameter ratio = 11.8.
We report the case of a 62-year-old man with chronic pancreatitis who presented with increasing abdominal pain. Sonography, magnetic resonance imaging, contrast-enhanced computed tomography, and ultimately catheter angiography demonstrated a pancreatic pseudocyst that had eroded into the splenoportal venous confluence, mimicking an arterial aneurysm. The diagnostic was confirmed at the time of surgical treatment. This case demonstrates the use of imaging to diagnose complications of pancreatitis, and the difficulty of distinguishing an eroding pseudocyst from an arterial aneurysm.
Anaphylactic shock is a severe allergic reaction involving multiple organs including the bronchial and cardiovascular system. Most anaphylactic mediators, like platelet-activating factor (PAF), histamine, and others, act through G protein – coupled receptors, which are linked to the heterotrimeric G proteins Gq /G 11 , G12/G13 , and Gi . The role of downstream signaling pathways activated by anaphylactic mediators in defi ned organs during anaphylactic reactions is largely unknown. Using genetic mouse models that allow for the conditional abrogation of G q /G 11 - and G 12 /G 13 -mediated signaling pathways by inducible Cre/loxP-mediated mutagenesis in endothelial cells (ECs), we show that Gq /G11 -mediated signaling in ECs is required for the opening of the endothelial barrier and the stimulation of nitric oxide formation by various infl ammatory mediators as well as by local anaphylaxis. The systemic effects of anaphylactic mediators like histamine and PAF, but not of bacterial lipopolysaccharide (LPS), are blunted in mice with endothelial G alpha q/G alpha 11 deficiency. Mice with endothelium-specific G alpha q /G alpha 11 deficiency, but not with G alpha 12/G alpha 13 deficiency, are protected against the fatal consequences of passive and active systemic anaphylaxis. This identifies endothelial Gq/G11 -mediated signaling as a critical mediator of fatal systemic anaphylaxis and, hence, as a potential new target to prevent or treat anaphylactic reactions.