Diffusion of point defects in oxide-dispersion strengthened steels

ODS steels are considered as promising materials for the next generation of fission reactors and future fusion reactors due to their outstanding combination of mechanical properties and resistance to radiation damage. The eponymous oxide precipitates are crucial for the properties of the material and the diffusion of yttrium is essential to their formation process. In the first part of this thesis an interatomic potential for the iron-yttrium system is presented that enables large-scale atomistic simulations. The potential is used to investigate the interaction between substitutional yttrium atoms and edge dislocations and shows a significant attraction between yttrium atoms and the stress field of the dislocation. This leads to yttrium segregation and pinning of dislocation motion. Calculation of vacancy jumps within the core of edge dislocations reveals a significant reduction of migration barriers, which leads to the conclusion that pipe diffusion can be a relevant diffusion mechanism of yttrium in ODS steels. The second part deals with the bulk diffusion of yttrium in bcc iron. Yttrium atoms and other oversized solutes show a high binding energy to vacancies and a considerable relaxation from their lattice site towards a neighboring vacancy. In the case of yttrium the relaxation is so prominent, that the resulting situation may also be considered as an interstitial atom sitting in between two vacancies. We calculate the yttrium-vacancy binding energy and the migration barriers of vacancy jumps in the vicinity of a yttrium atom by means of nudged-elastic band calculations using DFT calculations. These barriers are used in a kinetic Monte Carlo code to calculate the diffusivity of yttrium and investigate the diffusion mechanism of yttrium in bcc iron with a focus on correlation effects. The third part of this thesis deals with the impact of oxide precipitates on the radiation resistance of ODS steels. We address the question, if elastic strain fields around \ce{Y2O3} and \ce{Y2Ti2O7} particles cause a long-ranged interaction between the precipitates and point defects. We use kinetic Monte Carlo simulations to simulate the diffusion of point defects in these strain fields and to determine the resulting steady state point defect concentrations. We show, that there is essentially no vacancy-strain interaction while the sink strength of precipitates for interstitials increases with misfit strain between precipitate and matrix. The total change of point defect concentration with misfit strain is, however, rather limited

Bedeutung von Clostridium difficile Infektionen im Kindesalter

Clostridium difficile ist die häufigste Ursache von Durchfallerkrankungen in Krankenhäusern. Bisher liegen jedoch nur begrenzte Erkenntnisse über Clostridium difficile Infektionen (CDI) im Kindes- und Jugendalter vor. Deshalb wurde die Symptomatik pädiatrischer Patienten (Alter: 1 – 17 Jahre) mit nachgewiesener CDI anhand einer klinischen Kohortenstudie von Januar 2010 bis Oktober 2013 erforscht. Die in die Studie aufgenommenen Patienten mit CDI (N = 118) wiesen selten spezifische Begleitsymptome (z.B. Blutbeimengungen im Stuhl oder Fieber) (29,1 – 44,7%) neben dem Hauptsymptom der dünnflüssigen Stühle (100%) auf und erhielten nur in etwa einem Fünftel aller Fälle eine gegen C. difficile gerichtete Therapie (23,9%). Zwei Drittel (69,7%) aller Patienten hatten vor der CDI Antibiotika erhalten. Die nosokomiale CDI sowie das Vorhandensein von Komorbiditäten machten einen protrahierten bzw. schwereren Verlauf wahrscheinlich. Bei den jüngeren Patienten fanden sich häufiger virale Kopathogene des Gastrointestinaltraktes, bei älteren Kindern und Jugendlichen bestanden häufiger Komorbiditäten. Eine gegen C. difficile gerichtete Therapie erfolgte meist nur bei Patienten mit Grunderkrankungen und/oder schweren Durchfällen sowie positivem Toxinnachweis. Die Analyse der Epidemiologie von C. difficile von 2000 bis 2013 an der Universitätsklinik des Saarlandes ergab zunehmende Fallzahlen seit 2000. Die Anzahl der jährlich bei pädiatrischen Patienten nachgewiesenen CDI verzehnfachte sich im Untersuchungszeitraum. Kinder und Jugendliche (Alter: 0 – 17 Jahre) sowie Erwachsene höheren Alters (Alter: ≥65 Jahre) waren besonders häufig von einer CDI betroffen. Der Ribotyp 027 wurde mit steigendem Patientenalter zunehmend häufig, jedoch kein einziges Mal bei Kindern und Jugendlichen nachgewiesen. Die Ribotypisierung der C. difficile Isolate ist eine wichtige Voraussetzung für aussagekräftige infektionsepidemiologische Analysen. In dieser Arbeit kamen, erstmals in einer großen systematischen Untersuchung, vergleichend zwei der bedeutendsten Typisierungsmethoden zum Einsatz, die Surface-Layer-Protein-ASequenz- Typisierung (slpAST) und eine PCR-basierte Ribotypisierung. Insgesamt wurden 360 C. difficile Isolate mit beiden Methoden genotypisiert. Der Toxinstatus konnte durch eine Multiplex-PCR gesichert werden. Die PCR-Ribotypisierung erwies sich gegenüber der slpA-Sequenzierung als überlegen, da sie eine differenziertere Bestimmung des Ribotyps ermöglichte. Die slpA-Sequenzierung identifizierte 12 verschiedene Genotypen und eine große Gruppe von Sequenztypen, die in den bekannten Datenbanken bisher noch keinem Ribotyp zugeordnet sind. Hingegen konnten mittels PCR-basierter Ribotypisierung 46 genetisch unterschiedliche C. difficile Isolate differenziert werden. Einzig der durch die PCR-Ribotypisierung bestimmte Genotyp weist in 100% der Fälle einen identischen Toxinstatus auf. Die hypervirulenten Stämme 027 und 078 erkannten beide Methoden, mit in 94,7% bzw. 93,7% übereinstimmenden Ergebnissen, zuverlässig.Clostridium difficile is the most common cause of diarrhea in hospitals and other medical facilities. However, there is only limited knowledge about Clostridium difficile infections (CDI) in childhood and adolescence so far. Therefore, the symptoms of pediatric patients (aged 1 – 17 years) with proven CDI were explored using a clinical cohort study from January 2010 to October 2013. The patients with CDI (N = 118) enrolled in the study rarely exhibited specific secondary symptoms (e.g. blood particles in the stool or fever) (29,1 – 44,7%) beside the main symptom of thin stools (100%) and only about one-fifth of all cases received special therapy for C. difficile (23.9%). Two-thirds (69.7%) of all patients had received antibiotics prior to the CDI. The nosocomial CDI and the presence of comorbidities made a protracted or severe course likely. While there often was a viral copathogen of the gastrointestinal tract in younger patients, in older children and adolescents comorbidities were more frequent. A therapy for C. difficile was usually restricted to patients with underlying diseases and/or severe diarrhea and positive toxin detection. The analysis of the epidemiology of C. difficile from 2000 to 2013 at the Saarland University Hospital revealed an increasing number of cases since the year 2000. The number of CDI annually detected in pediatric patients increased tenfold during the investigation period. Children, adolescents (aged 0 – 17 years) and adults of a higher age (aged ≥65 years) were particularly vulnerable to a CDI. The ribotype 027 was detected with increasing frequency with increasing patient age, but not once in children and adolescents. The ribotyping of C. difficile isolates is an important prerequisite for significant infection-epidemiological analyses. In this study, for the first time in a large systematic investigation, two of the most important typing methods were used comparatively, the Surface-Layer-Protein A Sequence Typing (slpAST) and PCR-based ribotyping. A total of 360 C. difficile isolates were genotyped with both methods. The toxin status could be secured by using a multiplex PCR. The PCR-ribotyping proved to be superior to the slpAST because it enabled a more differentiated determination by the different ribotypes. The slpAST identified 12 different genotypes and a large group of sequence types, which have not been assigned yet to a ribotype in the known databases. On the other hand, 46 genetically distinct C. difficile isolates could be differentiated by PCR-based ribotyping. Only the genotype indicated by the PCR-based ribotyping shows in 100% of cases an identical toxin status. The hypervirulent strains 027 and 078 were recognized reliably by both methods with 94,7% and 93,3% matching results

Analytical expression of the magneto-optical Kerr effect and Brillouin light scattering intensity arising from dynamic magnetization

Time-resolved magneto-optical Kerr effect (MOKE) and Brillouin light scattering (BLS) spectroscopy are important techniques for the investigation of magnetization dynamics. Within this article, we calculate analytically the MOKE and BLS signals from prototypical spin-wave modes in the ferromagnetic layer. The reliability of the analytical expressions is confirmed by optically exact numerical calculations. Finally, we discuss the dependence of the MOKE and BLS signals on the ferromagnetic layer thickness

Schema Model of the Self‐Concept

Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/98249/1/j.1547-5069.1995.tb00857.x.pd

Evolutionary genomics can improve prediction of species' responses to climate change

Global climate change (GCC) increasingly threatens biodiversity through the loss of species, and the transformation of entire ecosystems. Many species are challenged by the pace of GCC because they might not be able to respond fast enough to changing biotic and abiotic conditions. Species can respond either by shifting their range, or by persisting in their local habitat. If populations persist, they can tolerate climatic changes through phenotypic plasticity, or genetically adapt to changing conditions depending on their genetic variability and census population size to allow for de novo mutations. Otherwise, populations will experience demographic collapses and species may go extinct. Current approaches to predicting species responses to GCC begin to combine ecological and evolutionary information for species distribution modelling. Including an evolutionary dimension will substantially improve species distribution projections which have not accounted for key processes such as dispersal, adaptive genetic change, demography, or species interactions. However, eco-evolutionary models require new data and methods for the estimation of a species' adaptive potential, which have so far only been available for a small number of model species. To represent global biodiversity, we need to devise large-scale data collection strategies to define the ecology and evolutionary potential of a broad range of species, especially of keystone species of ecosystems. We also need standardized and replicable modelling approaches that integrate these new data to account for eco-evolutionary processes when predicting the impact of GCC on species' survival. Here, we discuss different genomic approaches that can be used to investigate and predict species responses to GCC. This can serve as guidance for researchers looking for the appropriate experimental setup for their particular system. We furthermore highlight future directions for moving forward in the field and allocating available resources more effectively, to implement mitigation measures before species go extinct and ecosystems lose important functions

Generation of a novel fully human non-superagonistic anti-CD28 antibody with efficient and safe T-cell co-stimulation properties

Antibody-based therapeutics represent an important class of biopharmaceuticals in cancer immunotherapy. CD3 bispecific T-cell engagers activate cytotoxic T-cells and have shown remarkable clinical outcomes against several hematological malignancies. The absence of a costimulatory signal through CD28 typically leads to insufficient T-cell activation and early exhaustion. The combination of CD3 and CD28 targeting products offers an attractive strategy to boost T-cell activity. However, the development of CD28-targeting therapies ceased after TeGenero's Phase 1 trial in 2006 evaluating a superagonistic anti-CD28 antibody (TGN1412) resulted in severe life-threatening side effects. Here, we describe the generation of a novel fully human anti-CD28 antibody termed "E1P2" using phage display technology. E1P2 bound to human and mouse CD28 as shown by flow cytometry on primary human and mouse T-cells. Epitope mapping revealed a conformational binding epitope for E1P2 close to the apex of CD28, similar to its natural ligand and unlike the lateral epitope of TGN1412. E1P2, in contrast to TGN1412, showed no signs of in vitro superagonistic properties on human peripheral blood mononuclear cells (PBMCs) using different healthy donors. Importantly, an in vivo safety study in humanized NSG mice using E1P2, in direct comparison and contrast to TGN1412, did not cause cytokine release syndrome. In an in vitro activity assay using human PBMCs, the combination of E1P2 with CD3 bispecific antibodies enhanced tumor cell killing and T-cell proliferation. Collectively, these data demonstrate the therapeutic potential of E1P2 to improve the activity of T-cell receptor/CD3 activating constructs in targeted immunotherapeutic approaches against cancer or infectious diseases

Designed Azolopyridinium Salts Block Protective Antigen Pores In Vitro and Protect Cells from Anthrax Toxin

Background:Several intracellular acting bacterial protein toxins of the AB-type, which are known to enter cells by endocytosis, are shown to produce channels. This holds true for protective antigen (PA), the binding component of the tripartite anthrax-toxin of Bacillus anthracis. Evidence has been presented that translocation of the enzymatic components of anthrax-toxin across the endosomal membrane of target cells and channel formation by the heptameric/octameric PA63 binding/translocation component are related phenomena. Chloroquine and some 4-aminoquinolones, known as potent drugs against Plasmodium falciparium infection of humans, block efficiently the PA63-channel in a dose dependent way.Methodology/Principal Findings:Here we demonstrate that related positively charged heterocyclic azolopyridinium salts block the PA63-channel in the μM range, when both, inhibitor and PA63 are added to the same side of the membrane, the cis-side, which corresponds to the lumen of acidified endosomal vesicles of target cells. Noise-analysis allowed the study of the kinetics of the plug formation by the heterocycles. In vivo experiments using J774A.1 macrophages demonstrated that the inhibitors of PA63-channel function also efficiently block intoxication of the cells by the combination lethal factor and PA63 in the same concentration range as they block the channels in vitro.Conclusions/Significance:These results strongly argue in favor of a transport of lethal factor through the PA63-channel and suggest that the heterocycles used in this study could represent attractive candidates for development of novel therapeutic strategies against anthrax. © 2013 Beitzinger et al

Elevated atmospheric [CO2] can dramatically increase wheat yields in semi-arid environments and buffer against heat waves

Wheat production will be impacted by increasing concentration of atmospheric CO2 [CO2], which is expected to rise from about 400 μmol mol−1 in 2015 to 550 μmol mol−1 by 2050. Changes to plant physiology and crop responses from elevated [CO2] (e[CO2]) are well documented for some environments, but field-level responses in dryland Mediterranean environments with terminal drought and heat waves are scarce. The Australian Grains Free Air CO2 Enrichment facility was established to compare wheat (Triticum aestivum) growth and yield under ambient (~370 μmol−1 in 2007) and e[CO2] (550 μmol−1) in semi-arid environments. Experiments were undertaken at two dryland sites (Horsham and Walpeup) across three years with two cultivars, two sowing times and two irrigation treatments. Mean yield stimulation due to e[CO2] was 24% at Horsham and 53% at Walpeup, with some treatment responses greater than 70%, depending on environment. Under supplemental irrigation, e[CO2] stimulated yields at Horsham by 37% compared to 13% under rainfed conditions, showing that water limited growth and yield response to e[CO2]. Heat wave effects were ameliorated under e[CO2] as shown by reductions of 31% and 54% in screenings and 10% and 12% larger kernels (Horsham and Walpeup). Greatest yield stimulations occurred in the e[CO2] late sowing and heat stressed treatments, when supplied with more water. There were no clear differences in cultivar response due to e[CO2]. Multiple regression showed that yield response to e[CO2] depended on temperatures and water availability before and after anthesis. Thus, timing of temperature and water and the crop's ability to translocate carbohydrates to the grain postanthesis were all important in determining the e[CO2] response. The large responses to e[CO2] under dryland conditions have not been previously reported and underscore the need for field level research to provide mechanistic understanding for adapting crops to a changing climate