Vaccination directed against the human endogenous retrovirus-K envelope protein inhibits tumor growth in a murine model system

Human endogenous retrovirus (HERV) genomes are chromosomally integrated in all cells of an individual. They are normally transcriptionally silenced and transmitted only vertically. Enhanced expression of HERV-K accompanied by the emergence of anti-HERV-K-directed immune responses has been observed in tumor patients and HIV-infected individuals. As HERV-K is usually not expressed and immunological tolerance development is unlikely, it is an appropriate target for the development of immunotherapies. We generated a recombinant vaccinia virus (MVA-HKenv) expressing the HERV-K envelope glycoprotein (ENV), based on the modified vaccinia virus Ankara (MVA), and established an animal model to test its vaccination efficacy. Murine renal carcinoma cells (Renca) were genetically altered to express E. coli beta-galactosidase (RLZ cells) or the HERV-K ENV gene (RLZ-HKenv cells). Intravenous injection of RLZ-HKenv cells into syngenic BALB/c mice led to the formation of pulmonary metastases, which were detectable by X-gal staining. A single vaccination of tumor-bearing mice with MVA-HKenv drastically reduced the number of pulmonary RLZ-HKenv tumor nodules compared to vaccination with wild-type MVA. Prophylactic vaccination of mice with MVA-HKenv precluded the formation of RLZ-HKenv tumor nodules, whereas wild-type MVA-vaccinated animals succumbed to metastasis. Protection from tumor formation correlated with enhanced HERV-K ENV-specific killing activity of splenocytes. These data demonstrate for the first time that HERV-K ENV is a useful target for vaccine development and might offer new treatment opportunities for diverse types of cancer

MVA-based H5N1 vaccine affords cross-clade protection in mice against influenza A/H5N1 viruses at low doses and after single immunization.

Human infections with highly pathogenic avian influenza viruses of the H5N1 subtype, frequently reported since 2003, result in high morbidity and mortality. It is feared that these viruses become pandemic, therefore the development of safe and effective vaccines is desirable. MVA-based H5N1 vaccines already proved to be effective when two immunizations with high doses were used. Dose-sparing strategies would increase the number of people that can be vaccinated when the amount of vaccine preparations that can be produced is limited. Furthermore, protective immunity is induced ideally after a single immunization. Therefore the minimal requirements for induction of protective immunity with a MVA-based H5N1 vaccine were assessed in mice. To this end, mice were vaccinated once or twice with descending doses of a recombinant MVA expressing the HA gene of influenza virus A/Vietnam/1194/04. The protective efficacy was determined after challenge infection with the homologous clade 1 virus and a heterologous virus derived from clade 2.1, A/Indonesia/5/05 by assessing weight loss, virus replication and histopathological changes. It was concluded that MVA-based vaccines allowed significant dose-sparing and afford cross-clade protection, also after a single immunization, which are favorable properties for an H5N1 vaccine candidate

Shock impedance matching experiments in foam-solid targets and implications for "foam buffered ICF"

We studied the influence of foams on laser produced shocks. Experiments were performed at LULI using a Nd laser converted to second harmonic, and at MPQ (Max Planck Institut für Quantenoptik) using the iodine Asterix laser converted to third harmonic. In both cases, sub-ns lasers with pulse energies of several tens of joules were focused on large focal spots (hundreds of microns) to reduce 2D effects. The laser beams were optically smoothed with phase zone plates (PZP) and directly focused on layered targets made of a foam layer on the laser side and a stepped Al layer on the other side. A visible streak camera was used to detect shock breakthrough at the base and at the step of the Al target, allowing shock velocity to be determined. Using the well known SESAME Al equation of state, we determined shock pressure. A stronger pressure increase was measured when foam was present, compared to what was obtained by focusing the laser beam directly on the Al target. This was due to the impedance mismatch effect at the Al-foam interface

Life Cycle of Multi Technology Machine Tools – Modularization and Integral Design

AbstractFor reasons of high flexibility but still maximum productivity, machine tools integrating various production technologies have recently received particular attention. Combining and integrating multiple manufacturing techniques into one single system in early stages of the product emergence process is challenging. To keep the effort for implementation to a minimum, an initiation already in the concept phase is being actively pursued. Design guidelines are currently investigated based on the examination of different technology combinations.This approach focuses on systematic conceptual design for such hybrid machine technologies. Product architectures are used to describe the modularity and create a specific delimitation for standardization. Reference product architectures for Multi Technology Machine Tools (MTMT) carry high potential for saving expenses in product development. The main emphasis is on technology and system integration. A technological similarity assessment of the single processes involved forms the basis of this approach to assure potential for synergies. Monetary aspects in early stages of product development are considered. Based on the analysis a generic system model is connected with general product architectures for MTMT.The method introduced is validated by a Multi-Technology Machining Centre with two simultaneously usable workspaces integrating a milling spindle and two laser processing units. The research undertaken is part of the Cluster of Excellence “Integrative Production Technology for High-Wage Countries” and has been funded by German Research Foundation (DFG)

Determination of the color temperature in laser-produced shocks

Experimental results on the determination of the color temperature in shock waves produced with lasers are presented. The method is based on imaging the target rear side in two different spectral windows and on using phased zone plates to produce high-quality shocks. The shock velocity is also measured, allowing, with the use of the equation of state, the real shock temperature to be deduced and compared with the measured color temperature

Inhibitors of Helicobacter pylori Protease HtrA Found by ‘Virtual Ligand’ Screening Combat Bacterial Invasion of Epithelia

Background: The human pathogen Helicobacter pylori (H. pylori) is a main cause for gastric inflammation and cancer. Increasing bacterial resistance against antibiotics demands for innovative strategies for therapeutic intervention. Methodology/Principal Findings: We present a method for structure-based virtual screening that is based on the comprehensive prediction of ligand binding sites on a protein model and automated construction of a ligand-receptor interaction map. Pharmacophoric features of the map are clustered and transformed in a correlation vector (‘virtual ligand’) for rapid virtual screening of compound databases. This computer-based technique was validated for 18 different targets of pharmaceutical interest in a retrospective screening experiment. Prospective screening for inhibitory agents was performed for the protease HtrA from the human pathogen H. pylori using a homology model of the target protein. Among 22 tested compounds six block E-cadherin cleavage by HtrA in vitro and result in reduced scattering and wound healing of gastric epithelial cells, thereby preventing bacterial infiltration of the epithelium. Conclusions/Significance: This study demonstrates that receptor-based virtual screening with a permissive (‘fuzzy’) pharmacophore model can help identify small bioactive agents for combating bacterial infection

QGyro : Schlussbericht zum Verbundvorhaben Quanten-Inertialsensorsystem (QGyro)

Das Verbundvorhaben QGyro (Quanten-Inertialsensorsystem) ist ein Teil der High-Tech-Strategie der Bundesregierung und erhält Finanzierung durch das Bundesministerium für Wirtschaft und Klimaschutz (BMWK) mit Unterstützung der Raumfahrtagentur am Deutschen Zentrum für Luft- und Raumfahrt DLR e.V. (Förderkennzeichen 50RK1957). Im Rahmen dieses Forschungsvorhabens wurden mithilfe der Quantentechnologie innovative Konzepte für die Navigation von Plattformen entwickelt. Das Hauptziel des Projekts ist die Untersuchung von Hybridansätzen zur Inertialsensorik, bei der Quantensensoren mit klassischen inertialen Messeinheiten miteinander kombiniert werden um Fehler in der Positionsbestimmung zu reduzieren. Ein Hauptaugenmerk lag auf der Entwicklung neuartiger Quantensensoren. Ein erster Ansatz war die Schaffung eines einachsigen, quantenbasierten Inertialsensors als Proof-of-Concept. Dies beinhaltet den Sensorkopf, aber auch die Perepherie, wie Lasersysteme und Elektronik. Darüber hinaus wurden Entwicklungen in Richtung von sechsachsigen quantenbasierten Intertialsensoren angestoßen und Realisierungskonzepte erarbeitet. Ein besonderer Fokus lag auf der Stabilisierung und aktiven Ausrichtung des entwickelten Messkopfes, was durch Simulationen und experimentelle Tests nachgewiesen werden konnte. Dies beinhaltete die Entwicklung eines Teststandes, die Erarbeitung eines Atom-StrapDown-Algorithmus zur Kombination von Quanten-Inertialsensoren und klassischer Inertialsensorik sowie die Umsetzung einer stabilisierten Plattform für den Sensorkopf. Die erfolgreiche Umsetzung wurde in enger Zusammenarbeit mit Forschungseinrichtungen an der Leibniz Universität Hannover (Institut für Erdmessung, Institut für Quantenoptik) sowie etablierten Unternehmen wie der iMAR GmbH erreicht. Das Projekt QGyro trägt dazu bei, die High-Tech-Strategie der Bundesregierung im Bereich der Quantentechnologie und Navigation voranzutreiben.The collaborative project QGyro (quantum inertial sensor system) is part of the German Federal Government’s High-Tech Strategy and receives funding from the German Federal Ministry of Economics and Climate Protection (BMWK) with support from the Space Agency at the German Aerospace Center DLR e.V. (funding code 50 RK 1957). This research project used quantum technology to develop innovative concepts for the navigation of kinematic platforms. The main goal of the project is to investigate hybrid approaches for inertial sensors, combining quantum technology with classical inertial measurement devices in order to reduce errors in positioning. A primary focus has been the development of novel quantum sensors. A first approach considered the creation of a single-axis, quantum-based inertial sensor as a proof-of-concept. This includes the sensor head, and also the peripherals, such as laser systems and electronics. Furthermore, developments towards a six-axis quantum-based inertial sensor were initiated and realization concepts were elaborated. Further focus was on the stabilization and active alignment of the developed sensing head. For this purpose, a stabilized platform was designed and built that can compensate linear accelerations during the measurement time of the quantum sensor. A so-called Atom Strapdown algorithm was designed and implemented for inertial navigation for the combination of quantum inertial sensors and classical inertial sensors. This algorithm has been tested, optimized and validated in extensive simulation studies. Moreover, a successful application of the algorithm to real data was achieved by emulating the CAI observations with a navigation-grade IMU during the generation of the hybrid scenario. Algorithms for determining the uncertainties of the atomic interferometer were further developed and validated on prototype measurement series. Successful implementation was achieved in close collaboration with research institutions at Leibniz Universität Hannover (Institute of Geodesy, Institute of Quantum Optics) as well as established companies such as iMAR GmbH. The QGyro project contributes to advancing the German government’s high-tech strategy in the field of quantum technology and navigation.Deutsche Raumfahrtagentur im Deutschen Zentrum für Luft- und Raumfahrt e.V./Systemuntersuchungen und Technologie für die Satellitennavigation/BMWK 50 RK 1957/E

Prediction of Extracellular Proteases of the Human Pathogen Helicobacter pylori Reveals Proteolytic Activity of the Hp1018/19 Protein HtrA

Exported proteases of Helicobacter pylori (H. pylori) are potentially involved in pathogen-associated disorders leading to gastric inflammation and neoplasia. By comprehensive sequence screening of the H. pylori proteome for predicted secreted proteases, we retrieved several candidate genes. We detected caseinolytic activities of several such proteases, which are released independently from the H. pylori type IV secretion system encoded by the cag pathogenicity island (cagPAI). Among these, we found the predicted serine protease HtrA (Hp1019), which was previously identified in the bacterial secretome of H. pylori. Importantly, we further found that the H. pylori genes hp1018 and hp1019 represent a single gene likely coding for an exported protein. Here, we directly verified proteolytic activity of HtrA in vitro and identified the HtrA protease in zymograms by mass spectrometry. Overexpressed and purified HtrA exhibited pronounced proteolytic activity, which is inactivated after mutation of Ser205 to alanine in the predicted active center of HtrA. These data demonstrate that H. pylori secretes HtrA as an active protease, which might represent a novel candidate target for therapeutic intervention strategies