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The 16O ( gamma ,p0) reaction has been studied with linearly polarized bremsstrahlung photons in and below the giant E1 resonance. The parity of the absorbed radiation was determined from the observed azimuthal asymmetry of the emitted protons. Combined with unpolarized measurements the polarized results determine the proton decay amplitudes of the M1 resonance at Ex=16.2 MeV in 16O. The shape of the unpolarized 16O ( gamma ,p3) angular distribution in the giant E1 resonance was derived from the measured analyzing power. NUCLEAR REACTIONS 16O( gamma ,p), E=15-25 MeV; measured analyzing power theta =90° linearly polarized bremsstrahlung; 16O dipole levels deduced pi ; 16.2 MeV 1+ resonance deduced p0 decay amplitudes; 16O GEDR deduced p3 angular distribution.
The parities of eleven J=1 levels in 208Pb were determined by nuclear resonance fluorescence scattering of linearly polarized photons. A new 1+ level at Ex=5.846 MeV with Gamma 02 / Gamma =1.2±0.4 eV was found. This level can probably be identified with the theoretically predicted isoscalar 1+ state in 208Pb. All other bound dipole states below 7 MeV with Gamma 02 / Gamma >1.5 eV have negative parity. The 1- assignment to the 4.842-MeV level is of special significance because of previous conflicting results about its parity.
Les recherches ethnologiques effectuées jusqu'à ce jour se sont concentrées principalement sur deux grands axes. Elles ont d'une part dressé un inventaire détaillé des forges et de leurs techniques dans les différents groupes ethniques de cette région. D'autre part, elles ont examiné l'histoire des migrations et de la sédentarisation des forgerons. Il serait intéressant de savoir si les résultats des recherches linguistiques concordent avec ceux des travaux d'ethnologie. Jusqu'ici, les recherches ont montré la mobilité des forgerons professionnels. Ces "travailleurs transfrontaliers" de la culture jouent le rôle de médiateurs et favorisent les échanges culturels à l'intérieur de chaque ethnie et entre les différentes ethnies. En raison de cette mobilité, l'inventaire et les produits des forges présentent souvent des caractères identiques, même sur des espaces géographiques de plus grande taille. Par contre, le vocabulaire est souvent influencé par des mots empruntés à d'autres langues. Ce phénomène constituera précisément un des éléments centraux dans la suite de nos recherches sur le thème des artisans.
Antibody library technology represents a powerful tool for the discovery and design of antibodies with high affinity and specificity for their targets. To extend the technique to the expression and selection of antibody libraries in an eukaryotic environment, we provide here a proof of concept that retroviruses can be engineered for the display and selection of variable single-chain fragment (scFv) libraries. A retroviral library displaying the repertoire obtained after a single round of selection of a human synthetic scFv phage display library on laminin was generated. For selection, antigen-bound virus was efficiently recovered by an overlay with cells permissive for infection. This approach allowed more than 10(3)-fold enrichment of antigen binders in a single selection cycle. After three selection cycles, several scFvs were recovered showing similar laminin-binding activities but improved expression levels in mammalian cells as compared with a laminin-specific scFv selected by the conventional phage display approach. Thus, translational problems that occur when phage-selected antibodies have to be transferred onto mammalian expression systems to exert their therapeutic potential can be avoided by the use of retroviral display libraries.
We performed a bioinformatical analysis of protein export elements (PEXEL) in the putative proteome of the malaria parasite Plasmodium falciparum. A protein family-specific conservation of physicochemical residue profiles was found for PEXEL-flanking sequence regions. We demonstrate that the family members can be clustered based on the flanking regions only and display characteristic hydrophobicity patterns. This raises the possibility that the flanking regions may contain additional information for a family-specific role of PEXEL. We further show that signal peptide cleavage results in a positional alignment of PEXEL from both proteins with, and without, a signal peptide.
While the adaptor SKAP-55 mediates LFA-1 adhesion on T-cells, it is not known whether the adaptor regulates other aspects of signaling. SKAP-55 could potentially act as a node to coordinate the modulation of adhesion with downstream signaling. In this regard, the GTPase p21ras and the extracellular signal-regulated kinase (ERK) pathway play central roles in T-cell function. In this study, we report that SKAP-55 has opposing effects on adhesion and the activation of the p21ras -ERK pathway in T-cells. SKAP-55 deficient primary T-cells showed a defect in LFA-1 adhesion concurrent with the hyper-activation of the ERK pathway relative to wild-type cells. RNAi knock down (KD) of SKAP-55 in T-cell lines also showed an increase in p21ras activation, while over-expression of SKAP-55 inhibited activation of ERK and its transcriptional target ELK. Three observations implicated the p21ras activating exchange factor RasGRP1 in the process. Firstly, SKAP-55 bound to RasGRP1 via its C-terminus, while secondly, the loss of binding abrogated SKAP-55 inhibition of ERK and ELK activation. Thirdly, SKAP-55−/− primary T-cells showed an increased presence of RasGRP1 in the trans-Golgi network (TGN) following TCR activation, the site where p21ras becomes activated. Our findings indicate that SKAP-55 has a dual role in regulating p21ras-ERK pathway via RasGRP1, as a possible mechanism to restrict activation during T-cell adhesion.
For a virtual screening study, we introduce a combination of machine learning techniques, employing a graph kernel, Gaussian process regression and clustered cross-validation. The aim was to find ligands of peroxisome-proliferator activated receptor gamma (PPAR-y). The receptors in the PPAR family belong to the steroid-thyroid-retinoid superfamily of nuclear receptors and act as transcription factors. They play a role in the regulation of lipid and glucose metabolism in vertebrates and are linked to various human processes and diseases. For this study, we used a dataset of 176 PPAR-y agonists published by Ruecker et al. ...
Poster presentation at 5th German Conference on Cheminformatics: 23. CIC-Workshop Goslar, Germany. 8-10 November 2009 We demonstrate the theoretical and practical application of modern kernel-based machine learning methods to ligand-based virtual screening by successful prospective screening for novel agonists of the peroxisome proliferator-activated receptor gamma (PPARgamma) [1]. PPARgamma is a nuclear receptor involved in lipid and glucose metabolism, and related to type-2 diabetes and dyslipidemia. Applied methods included a graph kernel designed for molecular similarity analysis [2], kernel principle component analysis [3], multiple kernel learning [4], and, Gaussian process regression [5]. In the machine learning approach to ligand-based virtual screening, one uses the similarity principle [6] to identify potentially active compounds based on their similarity to known reference ligands. Kernel-based machine learning [7] uses the "kernel trick", a systematic approach to the derivation of non-linear versions of linear algorithms like separating hyperplanes and regression. Prerequisites for kernel learning are similarity measures with the mathematical property of positive semidefiniteness (kernels). The iterative similarity optimal assignment graph kernel (ISOAK) [2] is defined directly on the annotated structure graph, and was designed specifically for the comparison of small molecules. In our virtual screening study, its use improved results, e.g., in principle component analysis-based visualization and Gaussian process regression. Following a thorough retrospective validation using a data set of 176 published PPARgamma agonists [8], we screened a vendor library for novel agonists. Subsequent testing of 15 compounds in a cell-based transactivation assay [9] yielded four active compounds. The most interesting hit, a natural product derivative with cyclobutane scaffold, is a full selective PPARgamma agonist (EC50 = 10 ± 0.2 microM, inactive on PPARalpha and PPARbeta/delta at 10 microM). We demonstrate how the interplay of several modern kernel-based machine learning approaches can successfully improve ligand-based virtual screening results.