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β-Phenylalanine Ester Synthesis from Stable β-Keto Ester Substrate Using Engineered ω-Transaminases
(2018)
Many intrastate conflicts see more than one mediation effort. As the sequencing of mediation efforts in intrastate conflicts is neglected in existing research, this project addresses the question how and why previous mediation outcomes have an impact on subsequent mediation onset and subsequent mediation success. Drawing on bargaining theory, it is argued that governments and rebel groups engaged in intrastate conflicts account for previous mediation outcomes in their cost-benefit calculations on subsequent mediation onset, and, should subsequent talks set on, their behaviour during subsequent mediation efforts, which influences subsequent mediation success.
If mediation did not produce an agreement, the persistence of the private information problem is noted by the conflict parties. Yet, no new costs of mediation are uncovered, and hence the conflict parties will agree to subsequent mediation onset. Being aware of the necessity to overcome the private information and the commitment problem, the mediator will seek to account for the concerns of the conflict parties, and thereby work towards subsequent mediation success. If mediation produced a partial agreement, the benefits of mediation are underlined. The private information and the commitment problem seem solved with the assistance of the mediator. Subsequent mediation onset and eventually subsequent mediation success are observed. If a mediated agreement was reneged on by the rebel group, the government will refrain from further talks, pointing out the rebel group’s illegitimacy. If the government reneged on the agreement itself, it will also decide against subsequent mediation, as the previous mediation effort produced an agreement which did not mirror the power distribution in the dyad. Costs of mediation, which outweigh the benefits of it, were highlighted. Rebel groups will opt for mediation regardless which side reneged on an agreement. As both governments and rebel groups have to agree to subsequent mediation for talks to set on, subsequent mediation onset is unlikely if a mediated agreement was reneged on. Given the onset of subsequent mediation after a mediated agreement was reneged on, subsequent mediation success is unlikely to be observed, due to the previously underlined hazards of sharing private information and the persistence of the commitment problem.
The theoretical argument is tested with a mixed-methods approach. The quantitative analysis accounts for mediation efforts in African intrastate conflicts between 1993 and 2007. The qualitative analysis scrutinises the mediation efforts between the Government of Uganda and the Lord’s Resistance Army. The results of both parts of analysis largely go hand-in-hand, and show that partial mediation success and mediation which did not produce an agreement have a positive impact on subsequent mediation onset in particular, but also on subsequent mediation success. Reneged on mediated agreements have a severe negative impact on subsequent mediation onset and subsequent mediation success though.
By addressing the question which impact previous mediation outcomes have on subsequent mediation efforts, this research shows that mediation which does not produce an agreement is not the mediation outcome which needs to be feared by the international community. Instead, the deteriorating impact of short-lived agreements, a mediation outcome which is unaccounted for in existing research as an explanatory variable, becomes apparent. This research has important policy implications, especially for mediators, as it suggests that accepting mediation efforts to end without an agreement is more conducive for subsequent mediation efforts. Moreover, this research points towards the necessity of including reneged on agreements in mediation research as an explanatory variable more extensively, thereby shedding more light onto the dynamics at play in consecutive mediation efforts.
Der Beitrag behandelt eine Problematik aus dem Bereich der
mittelbaren Täterschaft gem. § 25 I Alt. 2 StGB, die spätestens seit der berühmten Entscheidung des Bundesgerichtshofs im Mauerschützenfall (BGHSt 40, 218) zu den umstrittensten Fragen der deutschen Beteiligungsdogmatik zählt:
die Rechtsfigur der Organisationsherrschaft und ihre prinzipielle Übertragbarkeit auf Wirtschaftsunternehmen. Anliegen des Beitrags ist es, die Entwicklung der Organisationsherrschaft nachzuzeichnen, das kaum mehr überschaubaren
Meinungsspektrum zur Thematik in seinen wesentlichen
Leitlinien zusammenzufassen und so das nötige examensrelevante Wissen für das universitäre Schwerpunktstudium
zu vermitteln.
Three-year-olds and 4-year-olds have severe difficulties solving standard mental rotation tasks. Only 5-year-olds solve such tasks above chance reliably. In contrast studies relying on simplified mental rotation tasks indicate that infants discriminate between an object and its mirror image. Furthermore in another simplified mental rotation task with 3-year-olds, a linear relation between angular disparity and reaction time typical for mental rotation was revealed. Therefore it was assumed that 3-year-olds’ capabilities are underestimated. In the current study, 3-year-olds were trained in two isolated sessions to solve standard mental rotation tasks and were tested in a third session. Three-year-olds solved this test above chance as a group – a substantial number of them doing so on an individual level. However, a linear relation between angular disparity and reaction time, that would indicate an analog mental transformation, was not discernable. Nevertheless, these findings are in accordance with a continuous line describing mental rotation in infants and older children. And, these also indicate that children’s mental rotation capabilities might be underestimated.
Bacteria are exposed to oxidative stress as an unavoidable consequence of their aerobic lifestyle. Reactive oxygen species (ROS) are generated in the stepwise one-electron reduction of molecular oxygen during the respiration. Pathogens encounter ROS during the oxidative burst of macrophages as part of the host immune defense. Besides ROS, bacteria also have to cope with reactive chlorine, electrophilic and nitrogen species (RCS, RES, RNS). To cope with these reactive species, bacteria have evolved different defense and repair mechanisms. To maintain the reduced state of the cytoplasm, they utilize low molecular weight (LMW) thiols. LMW thiols are small thiol-containing compounds that can undergo post-translational thiolmodifications with protein thiols, termed as S-thiolations. S-thiolations function as major redox regulatory and thiol-protection mechanism under oxidative stress conditions. In eukaryotes and Gram-negative bacteria, the tripeptide glutathione (GSH) functions as major LMW thiol, which is present in millimolar concentrations. The Actinomycetes, such as Mycobacterium and Corynebacterium species do not produce GSH and utilize instead mycothiol (MSH) as their alternative LMW thiol. In Firmicutes, including Bacillus and Staphylococcus species, bacillithiol (BSH) functions as the major LMW thiol. LMW thiols protect protein thiols against the irreversible overoxidation of cystein residues to sulfinic and sulfonic acids. In addition, LMW thiols contribute to the virulence and survival of pathogens, function in metal homeostasis and serve as enzyme cofactors for detoxification of xenobiotics and antibiotics. In this doctoral thesis, we aimed to investigate the roles of MSH and BSH in redox regulation of main metabolic enzymes under oxidative stress in the pathogens Corynebacterium diphtheriae and Staphylococcus aureus. Previous redox proteomics studies identified the glyceraldehyde-3-phosphate dehydrogenase GapDH and the aldehyde dehydrogenase AldA as S-thiolated in S. aureus and C. diphtheriae. Thus, we aimed to study the redox regulation of the metabolic enzyme GapDH in C. diphtheriae in response to NaOCl and H2O2 stress by S-mycothiolation, which is described in chapter 1. Moreover, we studied the involvement of the mycoredoxin-1 (Mrx1) and thioredoxin (Trx) pathways in reactivation of S-mycothiolated GapDH in vitro. Using shotgun proteomics, 26 S-mycothiolated proteins were identified under NaOCl stress in C. diphtheriae. These are involved in energy metabolism (Ndh, GlpD) and in the biosynthesis of amino acids (ThrA, LeuB), purines (PurA) and cell wall metabolites (GlmS). The glycolytic GapDH was identified as conserved target for S-thiolation across Gram-positive bacteria. GapDH was the most abundant protein, contributing with 0.75 % to the total cystein proteome. Moreover, GapDH is a conserved target for redox regulation and S-glutathionylation in response to oxidative stress in several prokaryotic and eukaryotic organisms. Treatment of GapDH with NaOCl and H2O2 in the absence of MSH resulted in irreversible enzyme inactivation due to overoxidation. Pretreatment of GapDH with MSH prior to H2O2 or NaOCl exposure resulted in reversible inactivation due to S-mycothiolation of the active site Cys153. Since S-mycothiolation is faster compared to overoxidation, S-mycothiolation efficiently protects the GapDH active site against overoxidation. The activity of S-mycothiolated GapDH could be restored by both, the Mrx1 and Trx pathway in vitro. Interestingly, the recovery of Smycothiolated GapDH by Mrx1 was faster compared to its reduction by the Trx pathway. In previous studies, the reactivation of S-mycothiolated Mpx and MrsA by the mycoredoxin pathway occurred also faster compared to the Trx pathway, which is consistent with our results. We were further interested to analyze the redox regulation of the glyceraldehyde-3phosphate dehydrogenase Gap of S. aureus under NaOCl and H2O2 stress, which is described in chapter 2. Using the quantitative redox proteomic approach OxICAT, 58 NaOCl-sensitive cystein residues with >10% thiol oxidation under NaOCl stress were identified. Gap and AldA showed the highest oxidation increase of 29% under NaOCl stress at their active site cystein residues. Using shotgun proteomics, five S-bacillithiolated proteins were identified, including Gap, AldA, GuaB, RpmJ and PpaC. Gap contributed with 4 % as most abundant cystein protein to the total cystein proteome. Our activity assays demonstrated that Gap of S. aureus is highly sensitive to overoxidation by H2O2 and NaOCl in vitro in the absence of BSH. The active site Cys151 of Gap was oxidized to the BSH mixed disulfide under H2O2 and NaOCl stress in the presence of BSH in vitro, which resulted in the reversible Gap inactivation. Moreover, inactivation of Gap by NaOCl and H2O2 due to S-bacillithiolation was faster compared to overoxidation, indicating that S-bacillithiolation protects the Gap active site against overoxidation in vitro. We further showed that the bacilliredoxin Brx catalyzes the reduction of S-bacillithiolated Gap in vitro. Molecular docking of BSH into the Gap active site revealed that S-bacillithiolation does not require major structural changes. Apart from Gap, the aldehyde dehydrogenase AldA was identified as S-bacillithiolated at its active site Cys279 under NaOCl stress in S. aureus previously. Thus, the expression, function, redox regulation and structural changes of AldA were analysed under NaOCl and aldehyde stress in S. aureus as summarized in chapter 3. AldA was S-bacillithiolated in the presence of H2O2 and BSH as demonstrated in BSH-specific Western blots in vitro. The expression of aldA was previously shown to be regulated by the alternative sigma factor SigmaB in S. aureus. Transcription of aldA was strongly increased in a SigmaB-independent manner under formaldehyde, NaOCl and diamide stress in S. aureus. Using an aldA deletion mutant, we demonstrated that aldA is required for growth and survival under NaOCl stress in S. aureus. The purified AldA enzyme was shown to catalyze the oxidation of various aldehyde substrates, including formaldehyde, methylglyoxal, glycolaldehyde and acetaldehyde in vitro. In addition, the function of the conserved Cys279 for AldA activity was investigated in vivo and in vitro. The purified AldAC279S mutant was shown to be inactive for aldehyde oxidation in vitro. Moreover, the aldAC279S mutant was very sensitive under NaOCl stress in vivo, and this phenotype could be reversed using the aldA complemented strain. These experiments demonstrate the function of Cys279 for AldA activity both in vitro and in vivo. AldA activity assays showed that AldA is sensitive to overoxidation and irreversible inactivation by H2O2 alone in vitro. In the presence of BSH, AldA is protected against overoxidation by reversible Sbacillithiolation in vitro. Molecular docking and molecular dynamics simulations revealed that BSH occupies two different positions in the Cys279 active site, which depend on the NAD+ cofactor. In the apoenzyme, BSH forms the disulfide with Cys279 in the “resting” state position, while Cys279 is S-bacillithiolated in the “attacking” state position in the holoenzyme in the presence of the NAD+ cofactor.
As the tree of life is populated with sequenced genomes ever more densely, the new challenge is the accurate and consistent annotation of entire clades of genomes. In my dissertation, I address this problem with a new approach to comparative gene finding that takes a multiple genome alignment of closely related species and simultaneously predicts the location and structure of protein-coding genes in all input genomes, thereby exploiting negative selection and sequence conservation. The model prefers potential gene structures in the different genomes that are in agreement with each other, or—if not—where the exon gains and losses are plausible given the species tree. The multi-species gene finding problem is formulated as a binary labeling problem on a graph. The resulting optimization problem is NP hard, but can be efficiently approximated using a subgradient-based dual decomposition approach.
I tested the novel approach on whole-genome alignments of 12 vertebrate and 12 Drosophila species. The accuracy was evaluated for human, mouse and Drosophila melanogaster and compared to competing methods. Results suggest that the new method is well-suited for annotation of a large number of genomes of closely related species within a clade, in particular, when RNA-Seq data are available for many of the genomes. The transfer of existing annotations from one genome to another via the genome alignment is more accurate than previous approaches that are based on protein-spliced alignments, when the genomes are at close to medium distances. The method is implemented in C++ as part of the gene finder AUGUSTUS.
For the last two decades, heparins have been widely used as anticoagulants. Besides
numerous advantages, up to 5% patients with heparin administration suffer from a major adverse
drug effect known as heparin-induced thrombocytopenia (HIT). This typical HIT can result in deep
vein thrombosis, pulmonary embolism, occlusion of a limb artery, acute myocardial infarct, stroke, and
a systemic reaction or skin necrosis. The basis of HIT may lead to clinical insights. Recent studies using
single-molecule force spectroscopy (SMFS)-based atomic force microscopy revealed detailed binding
mechanisms of the interactions between platelet factor 4 (PF4) and heparins of different lengths in
typical HIT. Especially, SMFS results allowed identifying a new mechanism of the autoimmune HIT
caused by a subset of human-derived antibodies in patients without heparin exposure. The findings
proved that not only heparin but also a subset of antibodies induce thrombocytopenia. In this review,
the role of SMFS in unraveling a major adverse drug effect and insights into molecular mechanisms
inducing thrombocytopenia by both heparins and antibodies will be discussed.
The Flavivirus genus (Flaviviridae family) comprises the most important arboviruses in the world such as dengue virus, West Nile virus (WNV), Zika virus (ZIKV), Japanese encephalitis virus and yellow fever virus (YFV). Every year, several outbreaks caused by flaviviruses are reported worldwide (i.e.: ZIKV and YFV outbreaks in South America) with a huge impact on economy and public health. In the last few decades, many aspects of the flavivirus biology and the interaction of flaviviruses with host cells have been elucidated. However, many underlying mechanisms concerning receptor usage, entry process and viral interaction with host cell factors are still not completely understood. Integrins, the major class of cell adhesion molecules have been implicated in the infectious cycle of different viruses including flaviviruses. A previous report proposed that a particular integrin, the αVβ3 integrin, might act as a cellular receptor for WNV. However, this hypothesis was not confirmed by other groups. In the present study, murine cell lines lacking the expression of one or more integrin subunits were used to evaluate the involvement of different integrins in the flavivirus infection cycle. Mouse fibroblasts lacking the expression of β1 integrin (MKF-β1-/-) or β3 integrin (MEF-β3-/-) subunits or αVβ3 integrin (MEF-αVβ3-/-) as well as their corresponding wild-type cells were utilized. A second model using Chinese hamster ovary cells (CHO-K1), a cell line that has been described to be refractory to some flaviviruses, were modified to express either αV (CHO-αV+/+) or β3 (CHO-β3+/+) integrin subunits. All cell lines were first characterized by confocal laser microscopy, flow cytometry and functional assays prior to infection to assess their integrin expression. The cell lines were then inoculated with different flaviviruses of public health relevance: WNV, YFV-17D, Usutu virus (USUV), Langat virus (LGTV) and ZIKV. Infection assays were designed in order to evaluate whether integrins influence i) cell susceptibility; ii) binding; iii) internalization and iv) replication of the investigated flaviviruses. Our findings clearly demonstrate that β1, β3 and αVβ3 integrins do not act as flavivirus cellular receptor or attachment factor since their ablation does not completely abrogate flavivirus infection in the investigated cell lines. Flavivirus binding to the cell surface of MEFs, MKFs and CHO cells was not disturbed by the genomic deletion of the above-mentioned integrins. The deletion of β1 and β3 integrin subunit did not affect internalization of any of the flaviviruses tested. In contrast to that, loss of αVβ3 integrin in the MEF-αVβ3-/- cells showed a statistically significant decrease in WNV and USUV internalization while ZIKV, YFV-17D and LGTV internalization remained unaffected suggesting that αVβ3 integrin might be involved in the internalization process of at least some flaviviruses. On the other hand, flavivirus replication was substantially impaired in the integrin-deficient cell lines in comparison to their corresponding wild-type cells. Both, MEF-β3-/- and MKF-β1-/- cells showed a statistically significant reduction on viral load for all flaviviruses tested in comparison to their respective wild-type cells. The MEF-αVβ3-/- cells in particular, showed a strong inhibition of flavivirus replication with a reduction of up to 99% on viral loads for all flaviviruses tested. Levels of flavivirus negative-strand RNA were substantially decreased in MEF-αVβ3-/- cells indicating that integrins might influence flavivirus RNA replication. The ectopic expression of either αV or β3 integrin subunits in CHO cells slightly increased the replication of all flaviviruses tested. Taken together, this is the first report highlighting the involvement of integrins in ZIKV, USUV, LGTV and YFV infection. The results strongly indicate that the investigated integrins play an important role in flavivirus infection and might represent a novel host cell factor that enhances flavivirus replication. Although the exact mechanism of interaction between integrins and flaviviruses is currently unknown, the results provided in this study deepen our insight into flavivirus - host cell interactions and open doors for further investigations.
Platelets transfusion is a safe process, but during or after the process, the recipient may experience an adverse reaction and occasionally a serious adverse reaction (SAR). In this review, we focus on the inflammatory potential of platelet components (PCs) and their involvement in SARs. Recent evidence has highlighted a central role for platelets in the host inflammatory and immune responses. Blood platelets are involved in inflammation and various other aspects of innate immunity through the release of a plethora of immunomodulatory cytokines, chemokines, and associated molecules, collectively termed biological response modifiers that behave like ligands for endothelial and leukocyte receptors and for platelets themselves. The involvement of PCs in SARs—particularly on a critically ill patient’s context—could be related, at least in part, to the inflammatory functions of platelets, acquired during storage lesions. Moreover, we focus on causal link between platelet activation and immune-mediated disorders (transfusion-associated immunomodulation, platelets, polyanions, and bacterial defense and alloimmunization). This is linked to the platelets’ propensity to be activated even in the absence of deliberate stimuli and to the occurrence of time-dependent storage lesions.