Comparison of mainline and alternate approaches to fusion energy

The tokamak and tandem mirror concepts are compared with alternate confinement concepts using the criteria established in DOE/ET-0047, An Evaluation of Alternate Magnetic Fusion Concepts 1977. The concepts are evaluated and rated in each of three broad categories: confidence in physics and technology, and reactor desirability. The STARFIRE and MARS reactors are used as a basis for comparing the mainline tokamak and tandem mirror concepts with the alternate concepts evaluated in DOE/ET-0047. Two recent alternate concepts, theohmically heated toroidal experiment (OHTE) and thecompact reversed field pinch reactor (CRFPR), are also evaluated. Results indicate that the physics of the mainline tokamaks and tandem mirrors is better understood than that of most alternate concepts. Both mainline concepts rank near the middle for technology requirements, and both rank near or at the bottom when compared with the reactor desirability of alternate concepts.     

The behavior of small fatigue cracks at notches in corrosive environments

The behavior of small cracks growing out of the roots of blunt notches in compact type specimens of an austenitic steel was characterized under fatigue loading in wet H ₂ plus air environment. The growth rates of cracks in the size range of 0.125 mm to 0.75 mm were up to two orders of magnitude higher than the rates expected for conventional cracks at equal stress intensity range, K. It was also observed that the small cracks grew at these fast rates only in corrosive environments when the loading frequency was 0.02 Hz or less. At a frequency of 10 Hz, the behavior was in agreement with the trend predicted for conventional size cracks.The above observations are rationalized in terms of the breakdown of the concept of a single parameter representation of the crack tip stress and strain field by K or in terms of differences in crack tip environments between small and long cracks for the same bulk environment. A simple engineering model is proposed which adequately represents the observed small crack growth behavior.

---

Résumé On a procédé à la caractérisation, sous charges de fatigue en atmosphère humide de H ₂ et d'air, de petites fissures se développant à partir des racines d'entailles arrondies dans des éprouvettes compactes.Les vitesses de croissance des fissures d'une taille allant de 0,125 à 0,750 mm se sont révélé être de deux ordres de grandeur plus grandes que les vitesses prévues dans le cas de fissures conventionnelle, soumises aux mêmes variations de l'intensité de contrainte K. On a également observé que de petites fissures croissaient à ces grandes vitesses seulement dans des atmosphères corrosives, lorsque la fréquence de sollicitation était de 0,02 Hz ou moins. A la fréquence de 10 Hz, le comportement observé s'est trouvé en accord avec les tendances prévues pour des fissures de taille conventionnelle.Les observations ci-dessus sont rationnalisées en un élargissement du concept de représentation monoparamétrique par le facteur K du champ de contraintes et de dilatation à l'extrémité de la fissure, ou en termes des différences rencontrées dans l'environnement local de l'extrémité d'une fissure, selon que celle-ci est longue ou courte, et ce dans un même environnement global.On propose un modèle simple utilisable en pratique, pour représenter de manière adéquate le comportement à la croissance observé pour des petites fissures.

---

---

Metallurgy Department     

Intermediate temperature solid oxide fuel cell based on fully integrated plasma-sprayed components

This work addresses the fabrication of membrane-type solid oxide fuel cells (SOFCs) operating at medium temperatures, where all components are fabricated by plasma spray technology, and the evaluation of the performance of the SOFC single unit in a temperature range of 500 to 800 °C. Single cells composed of LaSrMgO₃ cathodes, LaSrGaMgO₃ (LSGM) electrolytes, and Ni/yttria-stabilized zirconia anodes were fabricated in successive atmospheric plasma-spraying processes. Plasma-spraying processes have been optimized and tailored to each layer to achieve highly porous cathode and anode layers as well as high-density electrolyte layers. A major effort has been devoted to the production of the LSGM electrolyte that has a high density and is free of cracks. Electrochemical impedance spectroscopy was used to investigate the conductivity of the electrode layers, and particularly the resistance of the electrolyte layer. It revealed that the heat treatment had a great influence on the specific conductivity of the sprayed electrolyte layers and that the specific conductivity of the heat-treated layers was dramatically increased to the same magnitude as is typical for sintered LSGM pellets. The experimental results have demonstrated that the plasma-spraying process has a great potential for the integrated fabrication of medium-temperature SOFC units. The original version of this article was published as part of the ASM Proceedings, Thermal Spray 2003: Advancing the Science and Applying the Technology, International Thermal Spray Conference (Orlando, FL), May 5–8, 2003, Basil R. Marple and Christian Moreau, Ed., ASM International, 2003.     

Energy Metabolites as Biomarkers in Ischemic and Dilated Cardiomyopathy

With more than 25 million people affected, heart failure (HF) is a global threat. As energy production pathways are known to play a pivotal role in HF, we sought here to identify key metabolic changes in ischemic- and non-ischemic HF by using a multi-OMICS approach. Serum metabolites and mRNAseq and epigenetic DNA methylation profiles were analyzed from blood and left ventricular heart biopsy specimens of the same individuals. In total we collected serum from n = 82 patients with Dilated Cardiomyopathy (DCM) and n = 51 controls in the screening stage. We identified several metabolites involved in glycolysis and citric acid cycle to be elevated up to 5.7-fold in DCM (p = 1.7 × 10⁻⁶). Interestingly, cardiac mRNA and epigenetic changes of genes encoding rate-limiting enzymes of these pathways could also be found and validated in our second stage of metabolite assessment in n = 52 DCM, n = 39 ischemic HF and n = 57 controls. In conclusion, we identified a new set of metabolomic biomarkers for HF. We were able to identify underlying biological cascades that potentially represent suitable intervention targets.     

Dysregulated CD38 Expression on Peripheral Blood Immune Cell Subsets in SLE

Given its uniformly high expression on plasma cells, CD38 has been considered as a therapeutic target in patients with systemic lupus erythematosus (SLE). Herein, we investigate the distribution of CD38 expression by peripheral blood leukocyte lineages to evaluate the potential therapeutic effect of CD38-targeting antibodies on these immune cell subsets and to delineate the use of CD38 as a biomarker in SLE. We analyzed the expression of CD38 on peripheral blood leukocyte subsets by flow and mass cytometry in two different cohorts, comprising a total of 56 SLE patients. The CD38 expression levels were subsequently correlated across immune cell lineages and subsets, and with clinical and serologic disease parameters of SLE. Compared to healthy controls (HC), CD38 expression levels in SLE were significantly increased on circulating plasmacytoid dendritic cells, CD14⁺⁺CD16⁺ monocytes, CD56⁺ CD16^dim natural killer cells, marginal zone-like IgD⁺CD27⁺ B cells, and on CD4⁺ and CD8⁺ memory T cells. Correlation analyses revealed coordinated CD38 expression between individual innate and memory T cell subsets in SLE but not HC. However, CD38 expression levels were heterogeneous across patients, and no correlation was found between CD38 expression on immune cell subsets and the disease activity index SLEDAI-2K or established serologic and immunological markers of disease activity. In conclusion, we identified widespread changes in CD38 expression on SLE immune cells that highly correlated over different leukocyte subsets within individual patients, but was heterogenous within the population of SLE patients, regardless of disease severity or clinical manifestations. As anti-CD38 treatment is being investigated in SLE, our results may have important implications for the personalized targeting of pathogenic leukocytes by anti-CD38 monoclonal antibodies.     

Elucidation of the Clustered Nano-Architecture of Radiation-Induced DNA Damage Sites and Surrounding Chromatin in Cancer Cells: A Single Molecule Localization Microscopy Approach

In cancer therapy, the application of (fractionated) harsh radiation treatment is state of the art for many types of tumors. However, ionizing radiation is a “double-edged sword”—it can kill the tumor but can also promote the selection of radioresistant tumor cell clones or even initiate carcinogenesis in the normal irradiated tissue. Individualized radiotherapy would reduce these risks and boost the treatment, but its development requires a deep understanding of DNA damage and repair processes and the corresponding control mechanisms. DNA double strand breaks (DSBs) and their repair play a critical role in the cellular response to radiation. In previous years, it has become apparent that, beyond genetic and epigenetic determinants, the structural aspects of damaged chromatin (i.e., not only of DSBs themselves but also of the whole damage-surrounding chromatin domains) form another layer of complex DSB regulation. In the present article, we summarize the application of super-resolution single molecule localization microscopy (SMLM) for investigations of these structural aspects with emphasis on the relationship between the nano-architecture of radiation-induced repair foci (IRIFs), represented here by γH2AX foci, and their chromatin environment. Using irradiated HeLa cell cultures as an example, we show repair-dependent rearrangements of damaged chromatin and analyze the architecture of γH2AX repair clusters according to topological similarities. Although HeLa cells are known to have highly aberrant genomes, the topological similarity of γH2AX was high, indicating a functional, presumptively genome type-independent relevance of structural aspects in DSB repair. Remarkably, nano-scaled chromatin rearrangements during repair depended both on the chromatin domain type and the treatment. Based on these results, we demonstrate how the nano-architecture and topology of IRIFs and chromatin can be determined, point to the methodological relevance of SMLM, and discuss the consequences of the observed phenomena for the DSB repair network regulation or, for instance, radiation treatment outcomes.     

Functional and Molecular Properties of DYT-SGCE Myoclonus-Dystonia Patient-Derived Striatal Medium Spiny Neurons

Myoclonus-dystonia (DYT-SGCE, formerly DYT11) is characterized by alcohol-sensitive, myoclonic-like appearance of fast dystonic movements. It is caused by mutations in the SGCE gene encoding ε-sarcoglycan leading to a dysfunction of this transmembrane protein, alterations in the cerebello-thalamic pathway and impaired striatal plasticity. To elucidate underlying pathogenic mechanisms, we investigated induced pluripotent stem cell (iPSC)-derived striatal medium spiny neurons (MSNs) from two myoclonus-dystonia patients carrying a heterozygous mutation in the SGCE gene (c.298T>G and c.304C>T with protein changes W100G and R102X) in comparison to two matched healthy control lines. Calcium imaging showed significantly elevated basal intracellular Ca²⁺ content and lower frequency of spontaneous Ca²⁺ signals in SGCE MSNs. Blocking of voltage-gated Ca²⁺ channels by verapamil was less efficient in suppressing KCl-induced Ca²⁺ peaks of SGCE MSNs. Ca²⁺ amplitudes upon glycine and acetylcholine applications were increased in SGCE MSNs, but not after GABA or glutamate applications. Expression of voltage-gated Ca²⁺ channels and most ionotropic receptor subunits was not altered. SGCE MSNs showed significantly reduced GABAergic synaptic density. Whole-cell patch-clamp recordings displayed elevated amplitudes of miniature postsynaptic currents and action potentials in SGCE MSNs. Our data contribute to a better understanding of the pathophysiology and the development of novel therapeutic strategies for myoclonus-dystonia.     

Chronically Elevated Exogenous Glucose Elicits Antipodal Effects on the Proteome Signature of Differentiating Human iPSC-Derived Pancreatic Progenitors

The past decade revealed that cell identity changes, such as dedifferentiation or transdifferentiation, accompany the insulin-producing β-cell decay in most diabetes conditions. Mapping and controlling the mechanisms governing these processes is, thus, extremely valuable for managing the disease progression. Extracellular glucose is known to influence cell identity by impacting the redox balance. Here, we use global proteomics and pathway analysis to map the response of differentiating human pancreatic progenitors to chronically increased in vitro glucose levels. We show that exogenous high glucose levels impact different protein subsets in a concentration-dependent manner. In contrast, regardless of concentration, glucose elicits an antipodal effect on the proteome landscape, inducing both beneficial and detrimental changes in regard to achieving the desired islet cell fingerprint. Furthermore, we identified that only a subgroup of these effects and pathways are regulated by changes in redox balance. Our study highlights a complex effect of exogenous glucose on differentiating pancreas progenitors characterized by a distinct proteome signature.     

Hemi- and Homozygous Loss-of-Function Mutations in DSG2 (Desmoglein-2) Cause Recessive Arrhythmogenic Cardiomyopathy with an Early Onset

About 50% of patients with arrhythmogenic cardiomyopathy (ACM) carry a pathogenic or likely pathogenic mutation in the desmosomal genes. However, there is a significant number of patients without positive familial anamnesis. Therefore, the molecular reasons for ACM in these patients are frequently unknown and a genetic contribution might be underestimated. Here, we used a next-generation sequencing (NGS) approach and in addition single nucleotide polymor-phism (SNP) arrays for the genetic analysis of two independent index patients without familial medical history. Of note, this genetic strategy revealed a homozygous splice site mutation (DSG2–c.378+1G>T) in the first patient and a nonsense mutation (DSG2–p.L772X) in combination with a large deletion in DSG2 in the second one. In conclusion, a recessive inheritance pattern is likely for both cases, which might contribute to the hidden medical history in both families. This is the first report about these novel loss-of-function mutations in DSG2 that have not been previously identi-fied. Therefore, we suggest performing deep genetic analyses using NGS in combination with SNP arrays also for ACM index patients without obvious familial medical history. In the future, this finding might has relevance for the genetic counseling of similar cases.