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Search Results: 1 - 10 of 4057 matches for " Claus-Henning Nagel? "
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Improper Tagging of the Non-Essential Small Capsid Protein VP26 Impairs Nuclear Capsid Egress of Herpes Simplex Virus
Claus-Henning Nagel, Katinka D?hner, Anne Binz, Rudolf Bauerfeind, Beate Sodeik
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0044177
Abstract: To analyze the subcellular trafficking of herpesvirus capsids, the small capsid protein has been labeled with different fluorescent proteins. Here, we analyzed the infectivity of several HSV1(17+) strains in which the N-terminal region of the non-essential small capsid protein VP26 had been tagged at different positions. While some variants replicated with similar kinetics as their parental wild type strain, others were not infectious at all. Improper tagging resulted in the aggregation of VP26 in the nucleus, prevented efficient nuclear egress of viral capsids, and thus virion formation. Correlative fluorescence and electron microscopy showed that these aggregates had sequestered several other viral proteins, but often did not contain viral capsids. The propensity for aggregate formation was influenced by the type of the fluorescent protein domain, the position of the inserted tag, the cell type, and the progression of infection. Among the tags that we have tested, mRFPVP26 had the lowest tendency to induce nuclear aggregates, and showed the least reduction in replication when compared to wild type. Our data suggest that bona fide monomeric fluorescent protein tags have less impact on proper assembly of HSV1 capsids and nuclear capsid egress than tags that tend to dimerize. Small chemical compounds capable of inducing aggregate formation of VP26 may lead to new antiviral drugs against HSV infections.
Combination chemotherapy for metastatic colorectal cancer
Koehne Claus-Henning
Archive of Oncology , 2003, DOI: 10.2298/aoo0303155k
The Herpes Simplex Virus Protein pUL31 Escorts Nucleocapsids to Sites of Nuclear Egress, a Process Coordinated by Its N-Terminal Domain
Christina Funk?,Melanie Ott?,Verena Raschbichler?,Claus-Henning Nagel,Anne Binz?,Beate Sodeik?,Rudolf Bauerfeind?,Susanne M. Bailer
PLOS Pathogens , 2015, DOI: 10.1371/journal.ppat.1004957
Abstract: Progeny capsids of herpesviruses leave the nucleus by budding through the nuclear envelope. Two viral proteins, the membrane protein pUL34 and the nucleo-phosphoprotein pUL31 form the nuclear egress complex that is required for capsid egress out of the nucleus. All pUL31 orthologs are composed of a diverse N-terminal domain with 1 to 3 basic patches and a conserved C-terminal domain. To decipher the functions of the N-terminal domain, we have generated several Herpes simplex virus mutants and show here that the N-terminal domain of pUL31 is essential with basic patches being critical for viral propagation. pUL31 and pUL34 entered the nucleus independently of each other via separate routes and the N-terminal domain of pUL31 was required to prevent their premature interaction in the cytoplasm. Unexpectedly, a classical bipartite nuclear localization signal embedded in this domain was not required for nuclear import of pUL31. In the nucleus, pUL31 associated with the nuclear envelope and newly formed capsids. Viral mutants lacking the N-terminal domain or with its basic patches neutralized still associated with nucleocapsids but were unable to translocate them to the nuclear envelope. Replacing the authentic basic patches with a novel artificial one resulted in HSV1(17+)Lox-UL31-hbpmp1mp2, that was viable but delayed in nuclear egress and compromised in viral production. Thus, while the C-terminal domain of pUL31 is sufficient for the interaction with nucleocapsids, the N-terminal domain was essential for capsid translocation to sites of nuclear egress and a coordinated interaction with pUL34. Our data indicate an orchestrated sequence of events with pUL31 binding to nucleocapsids and escorting them to the inner nuclear envelope. We propose a common mechanism for herpesviral nuclear egress: pUL31 is required for intranuclear translocation of nucleocapsids and subsequent interaction with pUL34 thereby coupling capsid maturation with primary envelopment.
Matrix-comparative genomic hybridization from multicenter formalin-fixed paraffin-embedded colorectal cancer tissue blocks
Heiko Fensterer, Bernhard Radlwimmer, J?rn Str?ter, Malte Buchholz, Daniela E Aust, Catherine Julié, Fran?ois Radvanyi, Bernard Nordlinger, Claudio Belluco, Eric Van Cutsem, Claus-Henning K?hne, Hans A Kestler, Carsten Schwaenen, Michelle Nessling, Manfred P Lutz, Peter Lichter, Thomas M Gress, the EORTC Gastrointestinal (GI) Group
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-58
Abstract: To verify if this material is technically suitable to perform matrix-CGH, we performed a pilot study using macrodissected 29 formalin-fixed, paraffin-embedded tissue samples collected within the framework of the EORTC-GI/PETACC-2 trial for colorectal cancer. The scientific aim was to identify prognostic genomic signatures differentiating locally restricted (UICC stages II-III) from systemically advanced (UICC stage IV) colorectal tumours.The majority of archived tissue samples collected in the different centers was suitable to perform matrix-CGH. 5/7 advanced tumours displayed 13q-gain and 18q-loss. In locally restricted tumours, only 6/12 tumours showed a gain on 13q and 7/12 tumours showed a loss on 18q. Interphase-FISH and high-resolution array-mapping of the gain on 13q confirmed the validity of the array-data and narrowed the chromosomal interval containing potential oncogenes.Archival, paraffin-embedded tissue samples collected in multicentric clinical trials are suitable for matrix-CGH analyses and allow the identification of prognostic signatures and aberrations harbouring potential new oncogenes.Genomic copy number changes are frequently found in different types of cancer and are believed to contribute to their development and progression through inactivation of tumour suppressor genes, activation of oncogenes, or more subtle through gene dosage changes. Comparative genomic hybridization (CGH) [1] was developed to allow genome-wide screening for such copy number changes. Conventional CGH has a limited resolution and can detect losses of 10 Mb or greater [2]. High-level amplifications achieve a maximum resolution of 3 Mb [3]. The resolution of CGH has been improved by replacing the metaphase chromosomes, which have traditionally served as hybridization targets, with mapped and sequenced genomic DNA clones (bacterial artificial chromosomes, P1-derived artificial chromosome or cosmids) arrayed onto glass slides which was named "matrix-CGH" [4] or "array-CGH" [
Der Projektverbund
Lobin, Henning,Leggewie, Claus
Zeitenblicke , 2006,
Yield-determining factors in high-solids enzymatic hydrolysis of lignocellulose
Jan B Kristensen, Claus Felby, Henning J?rgensen
Biotechnology for Biofuels , 2009, DOI: 10.1186/1754-6834-2-11
Abstract: The decreasing conversion at increasing solids concentrations was found to be a generic or intrinsic effect, describing a linear correlation from 5 to 30% initial total solids content (w/w). Insufficient mixing has previously been shown not to be involved in the effect. Hydrolysis experiments with filter paper showed that neither lignin content nor hemicellulose-derived inhibitors appear to be responsible for the decrease in yields. Product inhibition by glucose and in particular cellobiose (and ethanol in simultaneous saccharification and fermentation) at the increased concentrations at high solids loading plays a role but could not completely account for the decreasing conversion. Adsorption of cellulases was found to decrease at increasing solids concentrations. There was a strong correlation between the decreasing adsorption and conversion, indicating that the inhibition of cellulase adsorption to cellulose is causing the decrease in yield.Inhibition of enzyme adsorption by hydrolysis products appear to be the main cause of the decreasing yields at increasing substrate concentrations in the enzymatic decomposition of cellulosic biomass. In order to facilitate high conversions at high solids concentrations, understanding of the mechanisms involved in high-solids product inhibition and adsorption inhibition must be improved.Climate changes and shortage of fossil fuels have sparked a growing demand for liquid biofuels which in turn has increased the amount of research into the production of lignocellulose-derived bioethanol [1,2]. However, being an insoluble and highly heterogeneous substrate, lignocellulosic materials pose several challenges in conversion to fermentable sugars. In addition to understanding complex enzyme system kinetics, these biomass-related challenges include recalcitrance to hydrolysis [3] and mixing difficulties [4]. Water content in the hydrolysis slurry is directly correlated to rheology, that is, viscosity and shear rate during mixing [5],
In Vitro Determination of Drug Transfer from Drug-Coated Balloons
Anne Seidlitz, Nadine Kotzan, Stefan Nagel, Thomas Reske, Niels Grabow, Claus Harder, Svea Petersen, Katrin Sternberg, Werner Weitschies
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0083992
Abstract: Drug-coated balloons are medical devices designed to locally deliver drug to diseased segments of the vessel wall. For these dosage forms, drug transfer to the vessel wall needs to be examined in detail, since drug released into the blood is cleared from the site. In order to examine drug transfer, a new in vitro setup was developed combining the estimation of drug loss during advancement to the site of application in a model coronary artery pathway with a hydrogel compartment representing, as a very simplified model, the vessel wall. The transfer of fluorescent model substances as well as the drug paclitaxel from coated balloons to the simulated vessel wall was evaluated using this method. The model was suitable to quantify the fractions transferred to the hydrogel and also to qualitatively assess distribution patterns in the hydrogel film. In the case of fluorescein sodium, rhodamin b and paclitaxel, vast amounts of the coated substance were lost during the simulated passage and only very small fractions of about 1% of the total load were transferred to the gel. This must be attributed to good water solubility of the fluorescent substances and the mechanical instability of the paclitaxel coating. Transfer of the hydrophobic model substance triamterene was however nearly unaffected by the preliminary tracking procedure with transferred fractions ranging from 8% to 14%. Analysis of model substance distribution yielded inhomogeneous distributions indicating that the coating was not evenly distributed on the balloon surface and that a great fraction of the coating liquid did not penetrate the folds of the balloon. This finding is contradictory to the generally accepted assumption of a drug depot inside the folds and emphasizes the necessity to thoroughly characterize in vitro performance of drug-coated balloons to support the very promising clinical data.
Cellulosic ethanol: interactions between cultivar and enzyme loading in wheat straw processing
Jane Lindedam, Sander Bruun, Henning J?rgensen, Claus Felby, Jakob Magid
Biotechnology for Biofuels , 2010, DOI: 10.1186/1754-6834-3-25
Abstract: Significant interactions between enzyme loading and cultivars show that breeding for cultivars with high sugar yields under modest enzyme loading could be warranted. At an enzyme loading of 5 FPU g-1 dm pretreated straw, a significant difference in sugar yields of 17% was found between the highest and lowest yielding cultivars. Sugar yield from separately hydrolyzed particle-size fractions of each cultivar showed that finer particles had 11% to 21% higher yields than coarse particles. The amount of coarse particles from the cultivar with lowest sugar yield was negatively correlated with sugar conversion.We conclude that genetic differences in sugar yield and response to enzyme loading exist for wheat straw at pilot scale, depending on differences in removal of hemicellulose, accumulation of ash and particle-size distribution introduced by the pretreatment.Lignocellulosic biomass is commonly recognized as a potential sustainable source of mixed sugars for fermentation to biofuels. A challenge remains, however, to make the process of converting lignocellulosics to biofuels cost-competitive in a large-scale process [1]. One way of achieving cost reductions and yield increments for the conversion process could be attained through improving biofeedstock quality [2]. Ethanol yields from different cultivars have been found to vary with the cultivars. Examples are corn stover [3,4], grasses [5], winter triticale grain [6] and winter wheat straw [7]. These studies have all employed small-scale pretreatment and hydrolysis. Since small-scale assays do not fully reflect the conditions of running a full commercial-scale pretreatment and hydrolysis, it can be questioned whether results from the small-scale assays can be extrapolated to larger-scale plants.Previous work shows wheat straw ethanol yields varying from 31% to 84% of theoretical maximum value, depending on the pretreatment method applied, enzyme loading during hydrolysis [8] and yeast culture used [9-12], as well as cu
Cell-wall structural changes in wheat straw pretreated for bioethanol production
Jan B Kristensen, Lisbeth G Thygesen, Claus Felby, Henning J?rgensen, Thomas Elder
Biotechnology for Biofuels , 2008, DOI: 10.1186/1754-6834-1-5
Abstract: The hydrothermal pretreatment does not degrade the fibrillar structure of cellulose but causes profound lignin re-localisation. Results from the current work indicate that wax has been removed and hemicellulose has been partially removed. Similar changes were found in wheat straw pretreated by steam explosion.Results indicate that hydrothermal pretreatment increases the digestibility by increasing the accessibility of the cellulose through a re-localisation of lignin and a partial removal of hemicellulose, rather than by disruption of the cell wall.Research in bioethanol production from lignocellulosic plant materials has grown significantly over the last few decades as the depletion of non-renewable fuels and increasing greenhouse gas emissions continue to create an increasing need for an alternative non-fossil transportation fuel. Enzymatic hydrolysis of lignocellulosic biomass, such as agricultural residues, with subsequent fermentation of sugars into ethanol has long been recognised as an alternative to the existing starch and sucrose-based ethanol production, especially considering recent improvements in yields and enzyme prices [1-3]. Furthermore, lignocellulose may be used as a feedstock for biorefineries, and full-scale plants for cellulosic bioethanol production are planned or under construction in several countries.Two process steps are involved in the conversion of lignocellulose into bioethanol: (1) enzymatic hydrolysis of the cell-wall carbohydrates, cellulose and in some cases hemicellulose, into monomers; and (2) fermentation of the monomers into ethanol. Often the two processes are integrated into simultaneous saccharification and fermentation (SSF). A common feature of the enzymatic hydrolysis step is the need for pretreatment of the lignocellulosic material resulting in a more efficient reaction despite the recalcitrant nature of the plant cell wall [4].While a costly step in production, optimal pretreatment is important from an economic viewpoint,
Production and effect of aldonic acids during enzymatic hydrolysis of lignocellulose at high dry matter content
David Cannella, Chia-wen C Hsieh, Claus Felby, Henning J?rgensen
Biotechnology for Biofuels , 2012, DOI: 10.1186/1754-6834-5-26
Abstract: The Cellic CTec2 contained oxidative enzymes which produce gluconic acid from lignocellulose. Both gluconic and cellobionic acid were produced during hydrolysis of pretreated wheat straw at 30% WIS. Up to 4% of released glucose was oxidized into gluconic acid using Cellic CTec2, whereas no oxidized products were detected when using an earlier cellulase preparation Celluclast/Novozym188. However, the cellulose conversion yield was 25% lower using Celluclast/Novozym188 compared to Cellic CTec2. Despite the advantage of the oxidative enzymes, it was shown that aldonic acids could be problematic to the hydrolytic enzymes. Hydrolysis experiments revealed that cellobionic acid was hydrolyzed by β-glucosidase at a rate almost 10-fold lower than for cellobiose, and the formed gluconic acid was an inhibitor of the β-glucosidase.Interestingly, the level of gluconic acid varied significantly with temperature. At 50°C (SHF conditions) 35% less gluconic acid was produced compared to at 33°C (SSF conditions). We also found that in the presence of lignin, no reducing agent was needed for the function of the oxidative enzymes.The presence of oxidative enzymes in Cellic CTec2 led to the formation of cellobionic and gluconic acid during hydrolysis of pretreated wheat straw and filter paper. Gluconic acid was a stronger inhibitor of β-glucosidase than glucose. The formation of oxidized products decreased as the hydrolysis temperature was increased from 33° to 50°C. Despite end-product inhibition, the oxidative cleavage of the cellulose chains has a synergistic effect upon the overall hydrolysis of cellulose as the sugar yield increased compared to using an enzyme preparation without oxidative activity.
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