Microgravity facilities for cold atom experiments

Microgravity platforms enable cold atom research beyond experiments in typical laboratories by removing restrictions due to the gravitational acceleration or compensation techniques. While research in space allows for undisturbed experimentation, technological readiness, availability and accessibility present challenges for experimental operation. In this work we focus on the main capabilities and unique features of ground-based microgravity facilities for cold atom research. A selection of current and future scientific opportunities and their high demands on the microgravity environment are presented, and some relevant ground-based facilities are discussed and compared. Specifically, we point out the applicable free fall times, repetition rates, stability and payload capabilities, as well as programmatic and operational aspects of these facilities. These are contrasted with the requirements of various cold atom experiments. Besides being an accelerator for technology development, ground-based microgravity facilities allow fundamental and applied research with the additional benefit of enabling hands-on access to the experiment for modifications and adjustments

Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-D-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR), it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2-C-methyl-D-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action

Discovery of novel drug-like antitubercular hits targeting the MEP pathway enzyme DXPS by strategic application of ligand-based virtual screening.

In the present manuscript, we describe how we successfully used ligand-based virtual screening (LBVS) to identify two small-molecule, drug-like hit classes with excellent ADMET profiles against the difficult to address microbial enzyme 1-deoxy-d-xylulose-5-phosphate synthase (DXPS). In the fight against antimicrobial resistance (AMR), it has become increasingly important to address novel targets such as DXPS, the first enzyme of the 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway, which affords the universal isoprenoid precursors. This pathway is absent in humans but essential for pathogens such as Mycobacterium tuberculosis, making it a rich source of drug targets for the development of novel anti-infectives. Standard computer-aided drug-design tools, frequently applied in other areas of drug development, often fail for targets with large, hydrophilic binding sites such as DXPS. Therefore, we introduce the concept of pseudo-inhibitors, combining the benefits of pseudo-ligands (defining a pharmacophore) and pseudo-receptors (defining anchor points in the binding site), for providing the basis to perform a LBVS against M. tuberculosis DXPS. Starting from a diverse set of reference ligands showing weak inhibition of the orthologue from Deinococcus radiodurans DXPS, we identified three structurally unrelated classes with promising in vitro (against M. tuberculosis DXPS) and whole-cell activity including extensively drug-resistant strains of M. tuberculosis. The hits were validated to be specific inhibitors of DXPS and to have a unique mechanism of inhibition. Furthermore, two of the hits have a balanced profile in terms of metabolic and plasma stability and display a low frequency of resistance development, making them ideal starting points for hit-to-lead optimization of antibiotics with an unprecedented mode of action

AI is a viable alternative to high throughput screening: a 318-target study

: High throughput screening (HTS) is routinely used to identify bioactive small molecules. This requires physical compounds, which limits coverage of accessible chemical space. Computational approaches combined with vast on-demand chemical libraries can access far greater chemical space, provided that the predictive accuracy is sufficient to identify useful molecules. Through the largest and most diverse virtual HTS campaign reported to date, comprising 318 individual projects, we demonstrate that our AtomNet® convolutional neural network successfully finds novel hits across every major therapeutic area and protein class. We address historical limitations of computational screening by demonstrating success for target proteins without known binders, high-quality X-ray crystal structures, or manual cherry-picking of compounds. We show that the molecules selected by the AtomNet® model are novel drug-like scaffolds rather than minor modifications to known bioactive compounds. Our empirical results suggest that computational methods can substantially replace HTS as the first step of small-molecule drug discovery

Entwicklung eines neuartigen Release-Caging Mechanismus für den GraviTower Bremen Prototypen

Development of a new kind of mechanical decoupling systems for microgravity platforms. This new kind of mechanisms allows a very fast decoupling and recoupling in any relative position. This work shows in detail all design criteria and the whole development process of the RCM Release-Caging mechanism which is used in the GraviTower Bremen prototype

Development of a new kind of release-caging mechanism for the GraviTower Bremen prototype

Development of a new kind of mechanical decoupling systems for microgravity platforms. This new kind of mechanisms allows a very fast decoupling and recoupling in any relative position. This work shows in detail all design criteria and the whole development process of the RCM Release-Caging mechanism which is used in the GraviTower Bremen prototype

Over 20% 13C Hyperpolarization for Pyruvate Using Deuteration and Rapid SLIC-SABRE in Mictrotesla Fields

Carbon-13 hyperpolarized pyruvate is about to become the next-generation contrast agent for molecular magnetic resonance imaging of cancer and other diseases. Here, efficient and rapid pyruvate hyperpolarization is achieved via Signal Amplification by Reversible Exchange (SABRE) with parahydrogen through synergistic use of substrate deuteration, alternating, and static microtesla magnetic fields. Up to 22% and 6% long-lasting 13C polarization (T1=3.7±0.25min and T1=1.7±0.1min) is demonstrated for the C1 and C2 nuclear sites, respectively. The remarkable polarization levels become possible due to favorable relaxation dynamics at the microtesla fields. The ultra-long polarization lifetimes will be conducive to yielding high polarization after purification, quality assurance, and injection of the hyperpolarized molecular imaging probes. These results pave the way to future in vivo translation of carbon-13 hyperpolarized molecular imaging probes prepared by this approach

Entwicklung und Test von Prototypkomponenten für ITER

Das Bundesministerium für Bildung und und Forschung (BMBF) stellte in 2007/2008 Mittel imRahmen der Projektförderung zur Verfügung, mit der Zielsetzung eine stärker sichtbareBeteiligung der deutschen Fusionsinstitute am Aufbau von ITER zu erreichen, sowie dieChancen deutscher Unternehmen auf die Übernahme von Aufträgen für den Aufbau vonITER zu stärken.Eine wichtige Zielsetzung des hier beschriebenen Forschungsvorhabens (Projektnummer03FUS0007) war es demnach, kritische Prototyp-Komponenten für ITER zu entwickeln undzu testen, sowie entsprechende Mess- und Prüfeinrichtungen aufzubauen. Gleichzeitigwurde in der Projektbearbeitung sehr eng mit einer ganzen Reihe von Unternehmenzusammengearbeitet, um so einen intensiven Know-How Transfer in beiden Richtungen imHinblick auf die Entwicklung von Komponenten für Fusionsanlagen zu erreiche