Räumlich-zeitliche Optimierung der Laserimpulse Yb3+ -basierter Hochleistungs-Lasersysteme

Alternativ zu bereits etablierten Lasersystemen werden direkt diodengepumpte Petawatt-Lasersysteme auf der Basis Yb3+-dotierter Lasermaterialien entwickelt, welche sowohl Impulsenergien von > 100 J als auch Impulsdauern von < 100 fs erzeugen können. Die Verwendung von schmalbandigen Hochleistungslaserdioden als Pumplichtquelle erlaubt hierbei eine effiziente Anregung des Lasermaterials was eine signifikante Erhöhung der Repetitionsrate ermöglicht. Für die erfolgreiche Anwendung dieser Lasersysteme in Experimenten müssen diese jedoch sowohl räumlich als auch zeitlich in Hinsicht auf die erforderlichen Experimentparameter optimiert werden. Hierbei sind vor allem eine maximale fokussierte Spitzenintensität, sowie ein höchstmöglicher zeitlicher Intensitätskontrast von Bedeutung. Im Rahmen der dieser Arbeit werden die Möglichkeiten für die räumlich-zeitliche Optimierung der Impulse Yb3+-basierter Lasersysteme untersucht. Zum einen wird die Auswirkung der spektralen Eigenschaften Yb3+-dotierter Materialien auf das verstärkte Spektrum der Laserimpulse untersucht und durch die Entwicklung spektraler Transmissionsfiltern optimiert, was eine vergrößerte Bandbreite und somit eine Verringerung der Impulsdauer zur Folge hat. Zum anderen wird die räumliche Optimierung der Laserimpulsverstärkung vorgestellt, wobei zunächst die Einflüsse des räumlichen Verstärkungsprofils und der pumpinduzierten Phasenaberrationen untersucht werden. Die Optimierung wird anschließend durch die Entwicklung einer neuartigen, abbildenden Verstärkeranordnung demonstriert. Abschließend wird die Optimierung des zeitlichen Intensitätskontrasts vorgestellt. Durch neu entwickelte Methoden konnten intensive Vorpulse vollständig vermieden werden. Ebenfalls wird eine detaillierte Analyse der Erzeugung spontaner verstärkter Emission in Hochleistungslasersystemen hergeleitet. Das analytische Modell ermöglicht erstmalig eine umfassende Konzeptionierung von Hochkontrast-Lasersystemen mit hohen Spitzenleistungen

helyOS: A customized off-the-shelf solution for autonomous driving applications in delimited areas

Microservice Architectures (MSA), known to successfully handle complex software systems, are emerging as the new paradigm for automotive software. The design of an MSA requires correct subdivision of the software system and implementation of the communication between components. These tasks demand both software expertise and domain knowledge. In this context, we developed an MSA framework pre-tailored to meet the requirements of autonomous driving applications in delimited areas - the helyOS framework. The framework decomposes complex applications in predefined microservice domains and provides a communication backbone for event messages and data. This paper demonstrates how such a tailored MSA framework can accelerate the development by prompting a quick start for the integration of motion planning algorithms, device controllers, vehicles simulators and web-browser interfaces

Prediction of Physical Frailty in Orthogeriatric Patients Using Sensor Insole–Based Gait Analysis and Machine Learning Algorithms: Cross-sectional Study

Background: Assessment of the physical frailty of older patients is of great importance in many medical disciplines to be able to implement individualized therapies. For physical tests, time is usually used as the only objective measure. To record other objective factors, modern wearables offer great potential for generating valid data and integrating the data into medical decision-making. Objective: The aim of this study was to compare the predictive value of insole data, which were collected during the Timed-Up-and-Go (TUG) test, to the benchmark standard questionnaire for sarcopenia (SARC-F: strength, assistance with walking, rising from a chair, climbing stairs, and falls) and physical assessment (TUG test) for evaluating physical frailty, defined by the Short Physical Performance Battery (SPPB), using machine learning algorithms. Methods: This cross-sectional study included patients aged >60 years with independent ambulation and no mental or neurological impairment. A comprehensive set of parameters associated with physical frailty were assessed, including body composition, questionnaires (European Quality of Life 5-dimension [EQ 5D 5L], SARC-F), and physical performance tests (SPPB, TUG), along with digital sensor insole gait parameters collected during the TUG test. Physical frailty was defined as an SPPB score≤8. Advanced statistics, including random forest (RF) feature selection and machine learning algorithms (K-nearest neighbor [KNN] and RF) were used to compare the diagnostic value of these parameters to identify patients with physical frailty. Results: Classified by the SPPB, 23 of the 57 eligible patients were defined as having physical frailty. Several gait parameters were significantly different between the two groups (with and without physical frailty). The area under the receiver operating characteristic curve (AUROC) of the TUG test was superior to that of the SARC-F (0.862 vs 0.639). The recursive feature elimination algorithm identified 9 parameters, 8 of which were digital insole gait parameters. Both the KNN and RF algorithms trained with these parameters resulted in excellent results (AUROC of 0.801 and 0.919, respectively). Conclusions: A gait analysis based on machine learning algorithms using sensor soles is superior to the SARC-F and the TUG test to identify physical frailty in orthogeriatric patients

Groups with Distance to Learning

Der Begriff ‚Bildungsferne’ – in Deutschland eher auf politischer als auf wissenschaftlicher Ebene verwendet – beschreibt mehr als das Fehlen (höherer) formaler Bildungsabschlüsse und ist deshalb nicht gleichzusetzen mit Geringqualifizierung. In seinem Zusammenhang steht auch die Frage nach den Bildungschancen, d.h. dem Zugang zu Bildungsmöglichkeiten. Bildungsferne bezeichnet damit zunächst eine Benachteiligung in Bezug auf Bildungschancen, v.a. gegründet auf soziodemographische Faktoren, wie soziale Herkunft und Sozialisation, regionale Herkunft, Migrationshintergrund, Alter, Behinderung etc. Wenn von bildungsfernen Gruppen die Rede ist, wird jedoch außerdem zumeist auf wirtschaftliche schwache, gering qualifizierte, lernungewohnte Bevölkerungsgruppen Bezug genommen, für die der Zugang zu (Weiter-)Bildungsmöglichkeiten aufgrund ihrer sozialen und ökonomischen Voraussetzungen eingeschränkt ist und in deren sozialen Milieus Bildung einen geringen Stellenwert einnimmt. m Rahmen eines interkulturellen Lehr-Forschungs-Projektes der Friedrich-Schiller-Universität Jena und der Eötvös-Loránd-Universität Budapest wurde in einer in beiden Ländern geführten empirischen Studie untersucht, ob Frauen in den beiden untersuchten Ländern eine bildungsferne Gruppe ausmachen, inwieweit Frauen in der ungarischen und der deutschen Gesellschaft heute noch benachteiligt sind und wie Bildung einer evtl. Benachteiligung entgegenwirken kann? Dazu wird zunächst die Situation von Frauen in der ungarischen und der deutschen Gesellschaft dargestellt und durch Gespräche mit Vertretern der Arbeitsämter sowie durch die Vorstellung von Bildungsangeboten speziell für Frauen in den beiden Ländern Antwort auf die Fragen gesucht. Weitere von anderen Gruppen in diesem Zwei-Länder-Projekt untersuchte Fragestellungen waren: o Potenziale des Alterns (http://www.db-thueringen.de/servlets/DocumentServlet?id=9749) o Fremdsprachenerwerb in der Erwachsenenbildung (http://www.db-thueringen.de/servlets/DocumentServlet?id=9894) ***************************The notion ‘Bildungsferne’ (appr. distance to learning), which is in Germany rather used on a political than on a scientific level, mainly describes the lack of (higher) formal educational achievements and is therefore not the same as lower qualification. Furthermore questions regarding the access to educational opportunities arise when examining this notion. First of all ‘Bildungsferne’ means discrimination with regard to educational opportunities, mainly based on sociodemographic factors, such as social background and socialization, regional provenance, migration background, age, disability, etc. When considering groups distal to learning one usually refers to people who are deprived, less qualified and who are not used to learning (anymore). Due to their social and economic prerequisites and because of the minor role which education plays within their social environment access to (further) educational opportunities is less important for this population group. In the context of an intercultural research project, which was realized by the Friedrich Schiller University of Jena and the Eötvös Loránd University of Budapest, it was examined, with the help of an empirical survey that was conducted in both countries, if women in both countries can be regarded as a group which is distal to learning, in how far women are still discriminated within the Hungarian and German society and in which way can education work against possible discrimination? Therefore the situation of women in the Hungarian and German society will be described and with the help of interviews, done with representatives of the respective employment centre, as well as the presentation of special educational opportunities for women, these questions will be answered. Further questions considered throughout this intercultural research project were: o Potentials of Senior Age (http://www.db-thueringen.de/servlets/DocumentServlet?id=9749) o How can adults learn foreign languages? (http://www.db-thueringen.de/servlets/DocumentServlet?id=9894) **************************

Optical Probing of Ultrafast Laser-Induced Solid-to-Overdense-Plasma Transitions

Understanding the target dynamics during its interaction with a relativistic ultrashort laser pulse is a challenging fundamental multi-physics problem involving at least atomic and solid-state physics, plasma physics, and laser physics. Already, the properties of the so-called pre-plasma formed as the laser pulse's rising edge ionizes the target are complicated to access in experiments and modeling, and many aspects of this laser-induced transition from solid to overdense plasma over picosecond time scales are still open questions. At the same time, applications like laser-driven ion acceleration require precise knowledge and control of the pre-plasma because the efficiency of the acceleration process itself crucially depends on the target properties at the arrival of the relativistic intensity peak of the pulse. By capturing the dynamics of the initial stage of the interaction, we report on a detailed visualization of the pre-plasma formation and evolution. Nanometer-thin diamond-like carbon foils are shown to transition from solid to plasma during the laser rising edge with intensities < 10^16 W/cm^2. Single-shot near-infrared probe transmission measurements evidence sub-picosecond dynamics of an expanding plasma with densities above 10^23 cm^-3 (about 100 times the critical plasma density). The complementarity of a solid-state interaction model and a kinetic plasma description provides deep insight into the interplay of ionization, collisions, and expansion

Selective inactivation of hypomethylating agents by SAMHD1 provides a rationale for therapeutic stratification in AML.

Hypomethylating agents decitabine and azacytidine are regarded as interchangeable in the treatment of acute myeloid leukemia (AML). However, their mechanisms of action remain incompletely understood, and predictive biomarkers for HMA efficacy are lacking. Here, we show that the bioactive metabolite decitabine triphosphate, but not azacytidine triphosphate, functions as activator and substrate of the triphosphohydrolase SAMHD1 and is subject to SAMHD1-mediated inactivation. Retrospective immunohistochemical analysis of bone marrow specimens from AML patients at diagnosis revealed that SAMHD1 expression in leukemic cells inversely correlates with clinical response to decitabine, but not to azacytidine. SAMHD1 ablation increases the antileukemic activity of decitabine in AML cell lines, primary leukemic blasts, and xenograft models. AML cells acquire resistance to decitabine partly by SAMHD1 up-regulation. Together, our data suggest that SAMHD1 is a biomarker for the stratified use of hypomethylating agents in AML patients and a potential target for the treatment of decitabine-resistant leukemia

Visualizing the Kinematics of Planet Formation

A stunning range of substructures in the dust of protoplanetary disks is routinely observed across a range of wavelengths. These gaps, rings and spirals are highly indicative of a population of unseen planets, hinting at the possibility of current observational facilities being able to capture planet-formation in action. Over the last decade, our understanding of the influence of a young planet on the dynamical structure of its parental disk has progressed significantly, revealing a host of potentially observable features which would betray the presence of a deeply embedded planet. In concert, recent observations have shown that subtle perturbations in the kinematic structure of protoplanetary disks are found in multiple sources, potentially the characteristic disturbances associated with embedded planets. In this work, we review the theoretical background of planet-disk interactions, focusing on the kinematical features, and the current methodologies used to observe these interactions in spatially and spectrally resolved observations. We discuss the potential pit falls of such kinematical detections of planets, providing best-practices for imaging and analysing interferometric data, along with a set of criteria to use as a benchmark for any claimed detection of embedded planets. We finish with a discussion on the current state of simulations in regard to planet-disk interactions, highlighting areas of particular interest and future directions which will provide the most significant impact in our search for embedded planets. This work is the culmination of the 'Visualizing the Kinematics of Planet Formation' workshop, held in October 2019 at the Center for Computational Astrophysics at the Flatiron Institute in New York City.Comment: To be submitted to PASA. Comments welcom

Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas

INTRODUCTION: ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients. METHODS: We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 μg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks. RESULTS: No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses ≥ 10 μg/kg). Disease progression occurred in 11 of the patients. CONCLUSION: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development

Molecular Design, Functional Characterization and Structural Basis of a Protein Inhibitor Against the HIV-1 Pathogenicity Factor Nef

Increased spread of HIV-1 and rapid emergence of drug resistance warrants development of novel antiviral strategies. Nef, a critical viral pathogenicity factor that interacts with host cell factors but lacks enzymatic activity, is not targeted by current antiviral measures. Here we inhibit Nef function by simultaneously blocking several highly conserved protein interaction surfaces. This strategy, referred to as “wrapping Nef”, is based on structure-function analyses that led to the identification of four target sites: (i) SH3 domain interaction, (ii) interference with protein transport processes, (iii) CD4 binding and (iv) targeting to lipid membranes. Screening combinations of Nef-interacting domains, we developed a series of small Nef interacting proteins (NIs) composed of an SH3 domain optimized for binding to Nef, fused to a sequence motif of the CD4 cytoplasmic tail and combined with a prenylation signal for membrane association. NIs bind to Nef in the low nM affinity range, associate with Nef in human cells and specifically interfere with key biological activities of Nef. Structure determination of the Nef-inhibitor complex reveals the molecular basis for binding specificity. These results establish Nef-NI interfaces as promising leads for the development of potent Nef inhibitors

Intestinal B-cells license metabolic T-cell activation in NASH microbiota/antigen-independently and contribute to fibrosis by IgA-FcR signalling

BACKGROUND & AIMS The progression of nonalcoholic steatohepatitis (NASH) to fibrosis and hepatocellular carcinoma (HCC) is aggravated by auto-aggressive T cells. The gut-liver axis contributes to NASH, but the mechanisms involved and the consequences for NASH-induced fibrosis and liver cancer remain unknown. We investigated the role of gastrointestinal B cells in the development of NASH, fibrosis and NASH-induced HCC. METHODS C57BL/6J wild-type (WT), B cell-deficient and different immunoglobulin-deficient or transgenic mice were fed distinct NASH diets (for example, choline-deficient high-fat diet, CD-HFD) or chow diet for 6 or 12 months, whereafter NASH, fibrosis, and NASH-induced HCC were assessed and analysed. Specific pathogen-free/germ-free WT and μMT mice (containing B cells only in the gastrointestinal tract) were fed a CD-HFD, and treated with an anti-CD20 antibody, whereafter NASH and fibrosis were assessed. Tissue biopsy samples from patients with NAFL, NASH and cirrhosis were analysed to correlate the secretion of immunoglobulins to clinicopathological features. Flow cytometry, immunohistochemistry and scRNA-Seq analysis were performed in liver and gastrointestinal tissue for immune cells in mice and humans. RESULTS Activated intestinal B cells were increased in mouse and human NASH samples and licensed metabolic T-cell activation to induce NASH independently of antigen-specificity and gut microbiota. Genetic or therapeutic depletion of systemic or gastrointestinal B cells prevented or reverted NASH and liver fibrosis. IgA secretion was necessary for fibrosis induction by activating CD11b+CCR2+F4/80+CD11c-FCGR1+ hepatic myeloid cells through an IgA-FcR signalling axis. Similarly, patients with NASH had increased numbers of activated intestinal B-cells and showed a positive correlation between IgA levels and activated FcRγ+ hepatic myeloid cells as well extent of liver fibrosis. CONCLUSIONS Intestinal B cells and the IgA-FcR signalling axis represent potential therapeutic targets for treating NASH. IMPACT AND IMPLICATIONS Nonalcoholic steatohepatitis (NASH) is a chronic inflammatory condition on the rise and can lead to hepatocellular carcinoma (HCC), the 3rd most common cause of cancer-related death worldwide. Currently, there is no effective treatment for this progressive disease that correlates with a marked risk of HCC mortality and carries a substantial healthcare burden. To date, among all the solid tumours, especially in HCC, the incidence and mortality rates are almost the same, making it crucial to find curative treatments for chronic diseases, such as NASH, which highly predispose to tumorigenesis. We have previously shown that NASH is an auto-aggressive condition aggravated, amongst others, by T cells. Therefore, we hypothesized that B cells might have a role in disease induction and progression. Our present work highlights that B cells have a dual role in NASH pathogenesis, being implicated in the activation of auto-aggressive T cells and the development of fibrosis via activation of monocyte-derived macrophages by secreted immunoglobulins (e.g., IgA). Furthermore, we could show that the absence of B cells prevented HCC development. B-cell intrinsic signalling pathways, secreted immunoglobulins, and interactions of B cells with other immune cells are potential targets in combinatorial NASH therapies against inflammation and fibrosis