Integration of tools for the Design and Assessment of High-Performance, Highly Reliable Computing Systems (DAHPHRS), phase 1

Systems for Space Defense Initiative (SDI) space applications typically require both high performance and very high reliability. These requirements present the systems engineer evaluating such systems with the extremely difficult problem of conducting performance and reliability trade-offs over large design spaces. A controlled development process supported by appropriate automated tools must be used to assure that the system will meet design objectives. This report describes an investigation of methods, tools, and techniques necessary to support performance and reliability modeling for SDI systems development. Models of the JPL Hypercubes, the Encore Multimax, and the C.S. Draper Lab Fault-Tolerant Parallel Processor (FTPP) parallel-computing architectures using candidate SDI weapons-to-target assignment algorithms as workloads were built and analyzed as a means of identifying the necessary system models, how the models interact, and what experiments and analyses should be performed. As a result of this effort, weaknesses in the existing methods and tools were revealed and capabilities that will be required for both individual tools and an integrated toolset were identified

A conceptual-model-based sediment connectivity assessment for patchy agricultural catchments

The accelerated sediment supply from agricultural soils to riverine and lacustrine environments leads to negative off-site consequences. In particular, the sediment connectivity from agricultural land to surface waters is strongly affected by landscape patchiness and the linear structures that separate field parcels (e.g. roads, tracks, hedges, and grass buffer strips). Understanding the interactions between these structures and sediment transfer is therefore crucial for minimising off-site erosion impacts. Although soil erosion models can be used to understand lateral sediment transport patterns, model-based connectivity assessments are hindered by the uncertainty in model structures and input data. Specifically, the representation of linear landscape features in numerical soil redistribution models is often compromised by the spatial resolution of the input data and the quality of the process descriptions. Here we adapted the Water and Tillage Erosion Model and Sediment Delivery Model (WaTEM/SE-DEM) using high-resolution spatial data (2 m x 2 m) to analyse the sediment connectivity in a very patchy mesoscale catchment (73 km(2)) of the Swiss Plateau. We used a global sensitivity analysis to explore model structural assumptions about how linear landscape features (dis)connect the sediment cascade, which allowed us to investigate the uncertainty in the model structure. Furthermore, we compared model simulations of hillslope sediment yields from five sub-catchments to tributary sediment loads, which were calculated with long-term water discharge and suspended sediment measurements. The sensitivity analysis revealed that the assumptions about how the road network (dis)connects the sediment transfer from field blocks to water courses had a much higher impact on modelled sediment yields than the uncertainty in model parameters. Moreover, model simulations showed a higher agreement with tributary sediment loads when the road network was assumed to directly connect sediments from hillslopes to water courses. Our results ultimately illustrate how a high-density road network combined with an effective drainage system increases sediment connectivity from hillslopes to surface waters in agricultural landscapes. This further highlights the importance of considering linear landscape features and model structural uncertainty in soil erosion and sediment connectivity research

Laser ablation-based one-step generation and bio-functionalization of gold nanoparticles conjugated with aptamers

<p>Abstract</p> <p>Background</p> <p>Bio-conjugated nanoparticles are important analytical tools with emerging biological and medical applications. In this context, <it>in situ </it>conjugation of nanoparticles with biomolecules via laser ablation in an aqueous media is a highly promising one-step method for the production of functional nanoparticles resulting in highly efficient conjugation. Increased yields are required, particularly considering the conjugation of cost-intensive biomolecules like RNA aptamers.</p> <p>Results</p> <p>Using a DNA aptamer directed against streptavidin, <it>in situ </it>conjugation results in nanoparticles with diameters of approximately 9 nm exhibiting a high aptamer surface density (98 aptamers per nanoparticle) and a maximal conjugation efficiency of 40.3%. We have demonstrated the functionality of the aptamer-conjugated nanoparticles using three independent analytical methods, including an agglomeration-based colorimetric assay, and solid-phase assays proving high aptamer activity. To demonstrate the general applicability of the <it>in situ </it>conjugation of gold nanoparticles with aptamers, we have transferred the method to an RNA aptamer directed against prostate-specific membrane antigen (PSMA). Successful detection of PSMA in human prostate cancer tissue was achieved utilizing tissue microarrays.</p> <p>Conclusions</p> <p>In comparison to the conventional generation of bio-conjugated gold nanoparticles using chemical synthesis and subsequent bio-functionalization, the laser-ablation-based <it>in situ </it>conjugation is a rapid, one-step production method. Due to high conjugation efficiency and productivity, <it>in situ </it>conjugation can be easily used for high throughput generation of gold nanoparticles conjugated with valuable biomolecules like aptamers.</p

Rapid Microfluidic Preparation of Niosomes for Targeted Drug Delivery

Niosomes are non-ionic surfactant-based vesicles with high promise for drug delivery applications. They can be rapidly prepared via microfluidics, allowing their reproducible production without the need of a subsequent size reduction step, by controlled mixing of two miscible phases of an organic (lipids dissolved in alcohol) and an aqueous solution in a microchannel. The control of niosome properties and the implementation of more complex functions, however, thus far are largely unknown for this method. Here we investigate microfluidics-based manufacturing of topotecan (TPT)-loaded polyethylene glycolated niosomes (PEGNIO). The flow rate ratio of the organic and aqueous phases was varied and optimized. Furthermore, the surface of TPT-loaded PEGNIO was modified with a tumor homing and penetrating peptide (tLyp-1). The designed nanoparticular drug delivery system composed of PEGNIO-TPT-tLyp-1 was fabricated for the first time via microfluidics in this study. The physicochemical properties were determined through dynamic light scattering (DLS) and zeta potential analysis. In vitro studies of the obtained formulations were performed on human glioblastoma (U87) cells. The results clearly indicated that tLyp-1-functionalized TPT-loaded niosomes could significantly improve anti-glioma treatment

Customizable 3D-printed (co-)cultivation systems for in vitro study of angiogenesis

Due to the ever-increasing resolution of 3D printing technology, additive manufacturing is now even used to produce complex devices for laboratory applications. Personalized experimental devices or entire cultivation systems of almost unlimited complexity can potentially be manufactured within hours from start to finish—an enormous potential for experimental parallelization in a highly controllable environment. This study presents customized 3D-printed co-cultivation systems, which qualify for angiogenesis studies. In these systems, endothelial and mesenchymal stem cells (AD-MSC) were indirectly co-cultivated—that is, both cell types were physically separated through a rigid, 3D-printed barrier in the middle, while still sharing the same cell culture medium that allows for the exchange of signalling molecules. Biochemical-based cytotoxicity assays initially confirmed that the 3D printing material does not exert any negative effects on cells. Since the material also enables phase contrast and fluorescence microscopy, the behaviour of cells could be observed over the entire cultivation via both. Microscopic observations and subsequent quantitative analysis revealed that endothelial cells form tubular-like structures as angiogenic feature when indirectly co-cultured alongside AD-MSCs in the 3D-printed co-cultivation system. In addition, further 3D-printed devices are also introduced that address different issues and aspire to help in varying experimental setups. Our results mark an important step forward for the integration of customized 3D-printed systems as self-contained test systems or equipment in biomedical applications. © 2020 by the authors. Licensee MDPI, Basel, Switzerland

Anti-angiogenic drugs: direct anti-cancer agents with mitochondrial mechanisms of action

Components of the mitochondrial electron transport chain have recently gained much interest as potential therapeutic targets. Since mitochondria are essential for the supply of energy that is required for both angiogenic and tumourigenic activity, targeting the mitochondria represents a promising potential therapeutic approach for treating cancer. Here we investigate the established anti-angiogenesis drugs combretastatin A4, thalidomide, OGT 2115 and tranilast that we hypothesise are able to exert a direct anti-cancer effect in the absence of vasculature by targeting the mitochondria. Drug cytotoxicity was measured using the MTT assay. Mitochondrial function was measured in intact isolated mitochondria using polarography, fluorimetry and enzymatic assays to measure mitochondrial oxygen consumption, membrane potential and complex I–IV activities respectively. Combretastatin A4, OGT 2115 and tranilast were both shown to decrease mitochondrial oxygen consumption. OGT 2115 and tranilast decreased mitochondrial membrane potential and reduced complex I activity while combretastatin A4 and thalidomide did not. OGT 2115 inhibited mitochondrial complex II–III activity while combretastatin A4, thalidomide and tranilast did not. Combretastatin A4, thalidomide and OGT 2115 induced bi-phasic concentration-dependent increases and decreases in mitochondrial complex IV activity while tranilast had no evident effect. These data demonstrate that combretastatin A4, thalidomide, OGT 2115 and tranilast are all mitochondrial modulators. OGT 2115 and tranilast are both mitochondrial inhibitors capable of eliciting concentration-dependent reductions in cell viability by decreasing mitochondrial membrane potential and oxygen consumption

3D-printed flow cells for aptamer-based impedimetric detection of e. coli crooks strain

Electrochemical spectroscopy enables rapid, sensitive, and label-free analyte detection without the need of extensive and laborious labeling procedures and sample preparation. In addition, with the emergence of commercially available screen-printed electrodes (SPEs), a valuable, disposable alternative to costly bulk electrodes for electrochemical (bio-)sensor applications was established in recent years. However, applications with bare SPEs are limited and many applications demand additional/supporting structures or flow cells. Here, high-resolution 3D printing technology presents an ideal tool for the rapid and flexible fabrication of tailor-made, experiment-specific systems. In this work, flow cells for SPE-based electrochemical (bio-)sensor applications were designed and 3D printed. The successful implementation was demonstrated in an aptamer-based impedimetric biosensor approach for the detection of Escherichia coli (E. coli) Crooks strain as a proof of concept. Moreover, further developments towards a 3D-printed microfluidic flow cell with an integrated micromixer also illustrate the great potential of high-resolution 3D printing technology to enable homogeneous mixing of reagents or sample solutions in (bio-)sensor applications