Seismische Risikoanalyse unterirdischer Versorgungsleitungen

Seismically caused failure of buried lifelines can result in disastrous events. Due to the grave consequences of those failures in past earthquakes, the need for reliable models examining the dynamic response of lifelines under earthquake excitation grows. In the present work, a methodology is developed to analyse the damage risk of buried lifelines exposed to seismic wave propagation. In order to perform this analysis, a three-dimensional numerical model is developed to describe the dynamic response of pipelines embedded in soil. Thereby, the emphasis is placed on three topics: the incorporation of dynamic soil-structure interaction, the advanced modelling of seismic excitation, and the over-all consideration of uncertainties. A hybrid finite element (FE)-scaled boundary finite element method (SBFEM) is presented to examine soil- structure interaction. Whereas the FEM enables a detailed modelling of the near-field, the SBFEM fulfils the wave radiation condition at infinity. In the latter method, increase of efficiency is, amongst others, achieved by employing substructuring techniques without losses of accuracy. For modelling seismic wave propagation in the near-field, a two-step procedure based on the domain reduction method is introduced. In the first step, a large scale simulation of the earthquake is performed, whereon the near- field is examined by the hybrid model. Thus, realistic seismic wave propagation inside the near-field can be modelled. Thereupon, an integrated probabilistic analysis is performed, which includes parameters of the entire seismic wave propagation path. For this process, a point estimate method is employed which enables an efficient and reliable determination of the failure probability of the pipeline. Parameter studies demonstrate the applicability of the present methodology which is not only applicable to lifelines but to any other structure under seismic wave excitation.Das seismisch bedingte Versagen von unterirdischen Versorgungsleitungen (Lifelines) und dessen Folgen offenbaren die Notwendigkeit von verlässlichen Modellen, die das dynamische Antwortverhalten realistisch abbilden. In der vorliegenden Arbeit wird eine Methode entwickelt, durch welche das Schadensrisiko von Lifelines infolge von seismischen Wellenausbreitungseffekten bestimmt werden kann. Zur Durchführung der Analyse wird ein dreidimensionales numerisches Modell entwickelt, welches das dynamische Verhalten von erdverlegten Rohrleitungen beschreibt. Bei der Entwicklung werden drei Schwerpunkte gesetzt: die detaillierte Abbildung der dynamischen Boden-Bauwerk-Wechselwirkung, die realistische Modellierung der seismischen Anregung sowie die globale Berücksichtigung von Unsicherheiten. Zur Untersuchung der Boden-Bauwerk-Wechselwirkung wird eine hybride Finite Element (FE)-Scaled Boundary Finite Element Methode (SBFEM) verwendet, wobei letztere die Wellenabstrahlung ins Unendliche simuliert. Effizienzsteigerungen können unter anderem durch den Einsatz von Substrukturmethoden erreicht werden. Zur Modellierung der seismischen Wellenausbreitung im Nahfeld wird eine Zwei-Schritt-Prozedur basierend auf der Domain Reduction Method vorgestellt. Im ersten Schritt wird eine großmaßstäbliche Simulation des Erdbebens durchführt, woraufhin im zweiten Schritt das Nahfeld mit der hybriden Methode untersucht wird. Diese Prozedur ermöglicht die Modellierung von realistischer seismischer Wellenausbreitung innerhalb des Nahfeldes. Darauf aufbauend wird eine ganzheitliche probabilistische Analyse durchgeführt, die Parameter des kompletten Ausbreitungspfades der seismischen Wellen einbindet. Für dieses Verfahren zur Ermittlung der Versagenswahrscheinlichkeit wird ein Punktschätzverfahren effizient eingesetzt. Parameterstudien zeigen die Anwendbarkeit der vorgestellten Methode, die sich nicht nur auf Rohrleitungen sondern auch auf jede andere Struktur unter seismischer Wellenbelastung erstreckt

Transforming growth factor- directly induces p53-up-regulated modulator of apoptosis (PUMA) during the rapid induction of apoptosis in myc-driven B-cell lymphomas

Background: TGF-β induces apoptosis in Burkitt's lymphoma cells. Results: PUMA is a direct target gene of TGF-β signaling and is required for rapid apoptosis. Conclusion: TGF-β-mediated direct induction of PUMA contributes to apoptosis in human and murine c-Myc-driven lymphomas. Significance: These studies link TGF-β signaling and transcriptional activation of PUMA, two factors with critical roles in regulating B-cell survival

TLR1/2, TLR7, and TLR9 Signals Directly Activate Human Peripheral Blood Naive and Memory B Cell Subsets to Produce Cytokines, Chemokines, and Hematopoietic Growth Factors

Recently, it has been reported that using multiple signals, murine and human B cells secrete several cytokines with pro-inflammatory and immunoregulatory properties. We present the first comprehensive analysis of 24 cytokines, chemokines, and hematopoietic growth factors production by purified human peripheral blood B cells (CD19+), and naive (CD19+CD27-) and memory (CD19+CD27+) B cells in response to direct and exclusive signaling provided by toll-like receptor (TLR) ligands Pam3CSK (TLR1/TLR2), Imiquimod (TLR7), and GpG-ODN2006 (TLR9). All three TLR ligands stimulated B cells (CD19+) to produce cytokines IL-1α, IL-1β, IL-6, TNF-α, IL-13, and IL-10, and chemokines MIP-1α, MIP-1β, MCP-1, IP-10, and IL-8. However, GM-CSF and G-CSF production was predominantly induced by TLR2 agonist. Most cytokines/chemokines/hematopoietic growth factors were predominantly or exclusively produced by memory B cells, and in general, TLR2 signal was more powerful than signal provided viaTLR7 and TLR9. No significant secretion of eotaxin, IFN-α, IFN-γ, IL-2, IL-3, IL-4, IL-5, IL-7, IL-15, IL-17, IL-12p40, IL-12p70, and TNF-β (lymphotoxin) was observed. These data demonstrate that human B cells can be directly activated viaTLR1/TLR2, TLR7, and TLR9 to induce secretion of cytokines, chemokines, and hematopoietic growth factors and suggest a role of B cells in immune response against microbial pathogenesis and immune homeostasis

Toll-Like Receptor Agonists Synergize with CD40L to Induce Either Proliferation or Plasma Cell Differentiation of Mouse B Cells

In a classical dogma, pathogens are sensed (via recognition of Pathogen Associated Molecular Patterns (PAMPs)) by innate immune cells that in turn activate adaptive immune cells. However, recent data showed that TLRs (Toll Like Receptors), the most characterized class of Pattern Recognition Receptors, are also expressed by adaptive immune B cells. B cells play an important role in protective immunity essentially by differentiating into antibody-secreting cells (ASC). This differentiation requires at least two signals: the recognition of an antigen by the B cell specific receptor (BCR) and a T cell co-stimulatory signal provided mainly by CD154/CD40L acting on CD40. In order to better understand interactions of innate and adaptive B cell stimulatory signals, we evaluated the outcome of combinations of TLRs, BCR and/or CD40 stimulation. For this purpose, mouse spleen B cells were activated with synthetic TLR agonists, recombinant mouse CD40L and agonist anti-BCR antibodies. As expected, TLR agonists induced mouse B cell proliferation and activation or differentiation into ASC. Interestingly, addition of CD40 signal to TLR agonists stimulated either B cell proliferation and activation (TLR3, TLR4, and TLR9) or differentiation into ASC (TLR1/2, TLR2/6, TLR4 and TLR7). Addition of a BCR signal to CD40L and either TLR3 or TLR9 agonists did not induce differentiation into ASC, which could be interpreted as an entrance into the memory pathway. In conclusion, our results suggest that PAMPs synergize with signals from adaptive immunity to regulate B lymphocyte fate during humoral immune response

Lipid Motif of a Bacterial Antigen Mediates Immune Responses via TLR2 Signaling

The cross-talk between the innate and the adaptive immune system is facilitated by the initial interaction of antigen with dendritic cells. As DCs express a large array of TLRs, evidence has accumulated that engagement of these molecules contributes to the activation of adaptive immunity. We have evaluated the immunostimulatory role of the highly-conserved outer membrane lipoprotein P6 from non-typeable Haemophilus influenzae (NTHI) to determine whether the presence of the lipid motif plays a critical role on its immunogenicity. We undertook a systematic analysis of the role that the lipid motif plays in the activation of DCs and the subsequent stimulation of antigen-specific T and B cells. To facilitate our studies, recombinant P6 protein that lacked the lipid motif was generated. Mice immunized with non-lipidated rP6 were unable to elicit high titers of anti-P6 Ig. Expression of the lipid motif on P6 was also required for proliferation and cytokine secretion by antigen-specific T cells. Upregulation of T cell costimulatory molecules was abrogated in DCs exposed to non-lipidated rP6 and in TLR2−/− DCs exposed to native P6, thereby resulting in diminished adaptive immune responses. Absence of either the lipid motif on the antigen or TLR2 expression resulted in diminished cytokine production from stimulated DCs. Collectively; our data suggest that the lipid motif of the lipoprotein antigen is essential for triggering TLR2 signaling and effective stimulation of APCs. Our studies establish the pivotal role of a bacterial lipid motif on activating both innate and adaptive immune responses to an otherwise poorly immunogenic protein antigen

Linear and Branched Glyco-Lipopeptide Vaccines Follow Distinct Cross-Presentation Pathways and Generate Different Magnitudes of Antitumor Immunity

Glyco-lipopeptides, a form of lipid-tailed glyco-peptide, are currently under intense investigation as B- and T-cell based vaccine immunotherapy for many cancers. However, the cellular and molecular mechanisms of glyco-lipopeptides (GLPs) immunogenicity and the position of the lipid moiety on immunogenicity and protective efficacy of GLPs remain to be determined.We have constructed two structural analogues of HER-2 glyco-lipopeptide (HER-GLP) by synthesizing a chimeric peptide made of one universal CD4(+) epitope (PADRE) and one HER-2 CD8(+) T-cell epitope (HER(420-429)). The C-terminal end of the resulting CD4-CD8 chimeric peptide was coupled to a tumor carbohydrate B-cell epitope, based on a regioselectively addressable functionalized templates (RAFT), made of four alpha-GalNAc molecules. The resulting HER glyco-peptide (HER-GP) was then linked to a palmitic acid moiety, attached either at the N-terminal end (linear HER-GLP-1) or in the middle between the CD4+ and CD8+ T cell epitopes (branched HER-GLP-2). We have investigated the uptake, processing and cross-presentation pathways of the two HER-GLP vaccine constructs, and assessed whether the position of linkage of the lipid moiety would affect the B- and T-cell immunogenicity and protective efficacy. Immunization of mice revealed that the linear HER-GLP-1 induced a stronger and longer lasting HER(420-429)-specific IFN-gamma producing CD8(+) T cell response, while the branched HER-GLP-2 induced a stronger tumor-specific IgG response. The linear HER-GLP-1 was taken up easily by dendritic cells (DCs), induced stronger DCs maturation and produced a potent TLR- 2-dependent T-cell activation. The linear and branched HER-GLP molecules appeared to follow two different cross-presentation pathways. While regression of established tumors was induced by both linear HER-GLP-1 and branched HER-GLP-2, the inhibition of tumor growth was significantly higher in HER-GLP-1 immunized mice (p<0.005).These findings have important implications for the development of effective GLP based immunotherapeutic strategies against cancers

Impairments in Episodic-Autobiographical Memory and Emotional and Social Information Processing in CADASIL during Mid-Adulthood

Staniloiu A, Woermann FG, Markowitsch HJ. Impairments in Episodic-Autobiographical Memory and Emotional and Social Information Processing in CADASIL during Mid-Adulthood. Frontiers in Behavioral Neuroscience. 2014;8: 227.Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) – is the most common genetic source of vascular dementia in adults, being caused by a mutation in NOTCH3 gene. Spontaneous de novo mutations may occur, but their frequency is largely unknown. Ischemic strokes and cognitive impairments are the most frequent manifestations, but seizures affect up to 10% of the patients. Herein, we describe a 47-year-old male scholar with a genetically confirmed diagnosis of CADASIL (Arg133Cys mutation in the NOTCH3 gene) and a seemingly negative family history of CADASIL illness, who was investigated with a comprehensive neuropsychological testing battery and neuroimaging methods. The patient demonstrated on one hand severe and accelerated deteriorations in multiple cognitive domains such as concentration, long-term memory (including the episodic-autobiographical memory domain), problem solving, cognitive flexibility and planning, affect recognition, discrimination and matching, and social cognition (theory of mind). Some of these impairments were even captured by abbreviated instruments for investigating suspicion of dementia. On the other hand the patient still possessed high crystallized (verbal) intelligence and a capacity to put forth a façade of well-preserved intellectual functioning. Although no definite conclusions can be drawn from a single case study, our findings point to the presence of additional cognitive changes in CADASIL in middle adulthood, in particular to impairments in the episodic-autobiographical memory domain and social information processing (e.g., social cognition). Whether these identified impairments are related to the patient’s specific phenotype or to an ascertainment bias (e.g., a paucity of studies investigating these cognitive functions) requires elucidation by larger scale research