Internal Friction and Vulnerability of Mixed Alkali Glasses

Based on a hopping model we show how the mixed alkali effect in glasses can be understood if only a small fraction c_V ofthe available sites for the mobile ions is vacant. In particular, we reproduce the peculiar behavior of the internal friction and the steep fall (''vulnerability'') of the mobility of the majority ion upon small replacements by the minority ion. The single and mixed alkali internal friction peaks are caused by ion-vacancy and ion-ion exchange processes. If c_V is small, they can become comparable in height even at small mixing ratios. The large vulnerability is explained by a trapping of vacancies induced by the minority ions. Reasonable choices of model parameters yield typical behaviors found in experiments.Comment: 4 pages, 4 figure

Development and analysis of microstructures for the transplantation of thermally sprayed coatings

Thermally sprayed coatings and tribological surfaces are a point of interest in many industrial sectors. They are used for better wear resistance of lightweight materials or for oil retention on surfaces. Lightweight materials are often used in the automotive industry as a weight-saving solution in the production of engine blocks. For this, it is necessary to coat the cylinder liners to ensure wear resistance. In most cases, the coating is sprayed directly onto the surface. Previous research has shown that it is possible to transfer these coatings inversely onto other surfaces. This was achieved with plasma sprayed coatings which were transplanted onto pressure-casted surfaces. These transplanted surfaces exhibited better adhesive strength, smoother surfaces, and lower form deviation compared to directly coated surfaces. Additionally, it was shown that even microstructures of a surface coated by plasma spraying can be transferred to pressure-casted surfaces. This paper presents the development and micromilling of different microstructures for transferring thermally sprayed coatings onto pressure-casted surfaces. In the development process, microstructures with different shapes and aspect ratios as well as thin tribological surfaces are designed in order to evaluate the advantages and limitations of the transplantation process. In subsequent experiments, the micromilling process and a simulation of the coating transplantation are presented and analyzed.DFG/Mo 881/9-1DFG/Bi 498/6-

Simple Lattice-Models of Ion Conduction: Counter Ion Model vs. Random Energy Model

The role of Coulomb interaction between the mobile particles in ionic conductors is still under debate. To clarify this aspect we perform Monte Carlo simulations on two simple lattice models (Counter Ion Model and Random Energy Model) which contain Coulomb interaction between the positively charged mobile particles, moving on a static disordered energy landscape. We find that the nature of static disorder plays an important role if one wishes to explore the impact of Coulomb interaction on the microscopic dynamics. This Coulomb type interaction impedes the dynamics in the Random Energy Model, but enhances dynamics in the Counter Ion Model in the relevant parameter range.Comment: To be published in Phys. Rev.

VESTIGE: Adjuvant Immunotherapy in Patients With Resected Esophageal, Gastroesophageal Junction and Gastric Cancer Following Preoperative Chemotherapy With High Risk for Recurrence (N+ and/or R1): An Open Label Randomized Controlled Phase-2-Study.

Background: Perioperative chemotherapy plus surgery is one recommended standard treatment for patients with resectable gastric and esophageal cancer. Even with a multimodality treatment more than half of patients will relapse following surgical resection. Patients who have a poor response to neoadjuvant chemotherapy and have an incomplete (R1) resection or have metastatic lymph nodes in the resection specimen (N+) are especially at risk of recurrence. Current clinical practice is to continue with the same chemotherapy in the adjuvant setting as before surgery. In the phase II randomized EORTC VESTIGE trial (NCT03443856), patients with high risk resected gastric or esophageal adenocarcinoma will be randomized to either adjuvant chemotherapy (as before surgery) or to immunotherapy with nivolumab and low dose ipilimumab (nivolumab 3 mg/kg IV Q2W plus Ipilimumab 1 mg/kg IV Q6W for 1 year). The primary endpoint of the study is disease free survival, with secondary endpoints of overall survival, safety and toxicity, and quality of life. This is an open label randomized controlled multi-center phase-2 superiority trial. Patients will be randomized in a 1:1 ratio to study arms. The trial will recruit 240 patients; recruitment commenced July 2019 and is anticipated to take 30 months. Detailed inclusion/exclusion criteria, toxicity management guidelines, and statistical plans for EORTC VESTIGE are described in the manuscript. Clinical Trial Registration: The trial is registered with www.ClinicalTrials.gov, identifier: NCT03443856

A model for two-proton emission induced by electron scattering

A model to study two-proton emission processes induced by electron scattering is developed. The process is induced by one-body electromagnetic operators acting together with short-range correlations, and by two-body $\Delta$ currents. The model includes all the diagrams containing a single correlation function. A test of the sensitivity of the model to the various theoretical inputs is done. An investigation of the relevance of the $\Delta$ currents is done by changing the final state angular momentum, excitation energy and momentum transfer. The sensitivity of the cross section to the details of the correlation function is studied by using realistic and schematic correlations. Results for $^{12}$C, $^{16}$O and $^{40}$Ca nuclei are presented.Comment: 30 pages, 18 figures, 3 table

Two-Body Correlations in Nuclear Systems

Correlations in the nuclear wave-function beyond the mean-field or Hartree-Fock approximation are very important to describe basic properties of nuclear structure. Various approaches to account for such correlations are described and compared to each other. This includes the hole-line expansion, the coupled cluster or ``exponential S'' approach, the self-consistent evaluation of Greens functions, variational approaches using correlated basis functions and recent developments employing quantum Monte-Carlo techniques. Details of these correlations are explored and their sensitivity to the underlying nucleon-nucleon interaction. Special attention is paid to the attempts to investigate these correlations in exclusive nucleon knock-out experiments induced by electron scattering. Another important issue of nuclear structure physics is the role of relativistic effects as contained in phenomenological mean field models. The sensitivity of various nuclear structure observables on these relativistic features are investigated. The report includes the discussion of nuclear matter as well as finite nuclei.Comment: Review, 104 pages including figure

Comprehensive CRISPR-Cas9 screens identify genetic determinants of drug responsiveness in multiple myeloma

The introduction of new drugs in the past years has substantially improved outcome in multiple myeloma (MM). However, the majority of patients eventually relapse and become resistant to one or multiple drugs. While the genetic landscape of relapsed/ resistant multiple myeloma has been elucidated, the causal relationship between relapse-specific gene mutations and the sensitivity to a given drug in MM has not systematically been evaluated. To determine the functional impact of gene mutations, we performed combined whole-exome sequencing (WES) of longitudinal patient samples with CRISPR-Cas9 drug resistance screens for lenalidomide, bortezomib, dexamethasone, and melphalan. WES of longitudinal samples from 16 MM patients identified a large number of mutations in each patient that were newly acquired or evolved from a small subclone (median 9, range 1-55), including recurrent mutations in TP53, DNAH5, and WSCD2. Focused CRISPR-Cas9 resistance screens against 170 relapse-specific mutations functionally linked 15 of them to drug resistance. These included cereblon E3 ligase complex members for lenalidomide, structural genes PCDHA5 and ANKMY2 for dexamethasone, RB1 and CDK2NC for bortezomib, and TP53 for melphalan. In contrast, inactivation of genes involved in the DNA damage repair pathway, including ATM, FANCA, RAD54B, and BRCC3, enhanced susceptibility to cytotoxic chemotherapy. Resistance patterns were highly drug specific with low overlap and highly correlated with the treatment-dependent clonal evolution in patients. The functional association of specific genetic alterations with drug sensitivity will help to personalize treatment of MM in the future

Expression of yeast lipid phosphatase Sac1p is regulated by phosphatidylinositol-4-phosphate

<p>Abstract</p> <p>Background</p> <p>Phosphoinositides play a central role in regulating processes at intracellular membranes. In yeast, a large number of phospholipid biosynthetic enzymes use a common mechanism for transcriptional regulation. Yet, how the expression of genes encoding lipid kinases and phosphatases is regulated remains unknown.</p> <p>Results</p> <p>Here we show that the expression of lipid phosphatase Sac1p in the yeast <it>Saccharomyces cerevisiae </it>is regulated in response to changes in phosphatidylinositol-4-phosphate (PI(4)P) concentrations. Unlike genes encoding enzymes involved in phospholipid biosynthesis, expression of the <it>SAC1 </it>gene is independent of inositol levels. We identified a novel 9-bp motif within the 5' untranslated region (5'-UTR) of <it>SAC1 </it>that is responsible for PI(4)P-mediated regulation. Upregulation of <it>SAC1 </it>promoter activity correlates with elevated levels of Sac1 protein levels.</p> <p>Conclusion</p> <p>Regulation of Sac1p expression via the concentration of its major substrate PI(4)P ensures proper maintenance of compartment-specific pools of PI(4)P.</p

Local erythropoietin and endothelial progenitor cells improve regional cardiac function in acute myocardial infarction

<p>Abstract</p> <p>Background</p> <p>Expanded endothelial progenitor cells (eEPC) improve global left ventricular function in experimental myocardial infarction (MI). Erythropoietin beta (EPO) applied together with eEPC may improve regional myocardial function even further by anti-apoptotic and cardioprotective effects. Aim of this study was to evaluate intramyocardial application of eEPCs and EPO as compared to eEPCs or EPO alone in experimental MI.</p> <p>Methods and Results</p> <p>In vitro experiments revealed that EPO dosed-dependently decreased eEPC and leukocyte apoptosis. Moreover, in the presence of EPO mRNA expression in eEPC of proangiogenic and proinflammatory mediators measured by TaqMan PCR was enhanced. Experimental MI was induced by ligation and reperfusion of the left anterior descending coronary artery of nude rats (n = 8-9). After myocardial transplantation of eEPC and EPO CD68+ leukocyte count and vessel density were enhanced in the border zone of the infarct area. Moreover, apoptosis of transplanted CD31 + TUNEL + eEPC was decreased as compared to transplantation of eEPCs alone. Regional wall motion of the left ventricle was measured using Magnetic Resonance Imaging. After injection of eEPC in the presence of EPO regional wall motion significantly improved as compared to injection of eEPCs or EPO alone.</p> <p>Conclusion</p> <p>Intramyocardial transplantation of eEPC in the presence of EPO during experimental MI improves regional wall motion. This was associated with an increased local inflammation, vasculogenesis and survival of the transplanted cells. Local application of EPO in addition to cell therapy may prove beneficial in myocardial remodeling.</p