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At least 955 records · Page 53

Fabrication and Modification of Nanoporous Silicon Particles

Silicon-based nanoporous particles as biodegradable drug carriers are advantageous in permeation, controlled release, and targeting. The use of biodegradable nanoporous silicon and silicon dioxide, with proper surface treatments, allows sustained drug release within the target site over a period of days, or even weeks, due to selective surface coating. A variety of surface treatment protocols are available for silicon-based particles to be stabilized, functionalized, or modified as required. Coated polyethylene glycol (PEG) chains showed the effective depression of both plasma protein adsorption and cell attachment to the modified surfaces, as well as the advantage of long circulating. Porous silicon particles are micromachined by lithography. Compared to the synthesis route of the nanomaterials, the advantages include: (1) the capability to make different shapes, not only spherical particles but also square, rectangular, or ellipse cross sections, etc.; (2) the capability for very precise dimension control; (3) the capacity for porosity and pore profile control; and (4) allowance of complex surface modification. The particle patterns as small as 60 nm can be fabricated using the state-of-the-art photolithography. The pores in silicon can be fabricated by exposing the silicon in an HF/ethanol solution and then subjecting the pores to an electrical current. The size and shape of the pores inside silicon can be adjusted by the doping of the silicon, electrical current application, the composition of the electrolyte solution, and etching time. The surface of the silicon particles can be modified by many means to provide targeted delivery and on-site permanence for extended release. Multiple active agents can be co-loaded into the particles. Because the surface modification of particles can be done on wafers before the mechanical release, asymmetrical surface modification is feasible. Starting from silicon wafers, a treatment, such as KOH dipping or reactive ion etching (RIE), may be applied to make the surface rough. This helps remove the nucleation layer. A protective layer is then deposited on the wafer. The protective layer, such as silicon nitride film or photoresist film, protects the wafer from electrochemical etching in an HF-based solution. A lithography technique is applied to pattern the particles onto the protective film. The undesired area of the protective film is removed, and the protective film on the back side of the wafer is also removed. Then the pattern is exposed to HF/surfactant solution, and a larger DC electrical current is applied to the wafers for a selected time. This step removes the nucleation layer. Then a DC current is applied to generate the nanopores. Next, a large electrical current is applied to generate a release layer. The particles are mechanically suspended in the solvent and collected by filtration or centrifuge.

Ferrari, Mauro↗

IXPE: The Imaging X-ray Polarimetry Explorer, Implementing a Dedicated Polarimetry Mission

Only a few experiments have conducted x-ray polarimetry of cosmic sources since Weisskopf et al confirmed the 19% polarization of the Crab Nebula with the Orbiting Solar Observatory (OSO-8) in the 70's center dot The challenge is to measure a faint polarized component against a background of non-polarized signal (as well as the other, typical background components) center dot Typically, for a few % minimum detectable polarization, 106 photons are required. center dot So, a dedicated mission is vital with instruments that are designed specifically to measure polarization (with minimal systematic effects) Over the proposed mission life (2- 3 years), IXPE will first survey representative samples of several categories of targets: magnetars, isolated pulsars, pulsar wind nebula and supernova remnants, microquasars, active galaxies etc. The survey results will guide detailed follow-up observations. Precise calibration of IXPE is vital to ensuring sensitivity goals are met. The detectors will be characterized in Italy, and then a full calibration of the complete instrument will be performed at MSFC's stray light facility. Polarized flux at different energies Heritage: X-ray Optics at MSFC polarimetry mission.

Ramsey, Brian↗

Optimized FPGA Implementation of Multi-Rate FIR Filters Through Thread Decomposition

Multirate (decimation/interpolation) filters are among the essential signal processing components in spaceborne instruments where Finite Impulse Response (FIR) filters are often used to minimize nonlinear group delay and finite-precision effects. Cascaded (multi-stage) designs of Multi-Rate FIR (MRFIR) filters are further used for large rate change ratio, in order to lower the required throughput while simultaneously achieving comparable or better performance than single-stage designs. Traditional representation and implementation of MRFIR employ polyphase decomposition of the original filter structure, whose main purpose is to compute only the needed output at the lowest possible sampling rate. In this paper, an alternative representation and implementation technique, called TD-MRFIR (Thread Decomposition MRFIR), is presented. The basic idea is to decompose MRFIR into output computational threads, in contrast to a structural decomposition of the original filter as done in the polyphase decomposition. Each thread represents an instance of the finite convolution required to produce a single output of the MRFIR. The filter is thus viewed as a finite collection of concurrent threads. The technical details of TD-MRFIR will be explained, first showing its applicability to the implementation of downsampling, upsampling, and resampling FIR filters, and then describing a general strategy to optimally allocate the number of filter taps. A particular FPGA design of multi-stage TD-MRFIR for the L-band radar of NASA's SMAP (Soil Moisture Active Passive) instrument is demonstrated; and its implementation results in several targeted FPGA devices are summarized in terms of the functional (bit width, fixed-point error) and performance (time closure, resource usage, and power estimation) parameters.

DSP↗

The NASA Advanced Space Power Systems Project

The goal of the NASA Advanced Space Power Systems Project is to develop advanced, game changing technologies that will provide future NASA space exploration missions with safe, reliable, light weight and compact power generation and energy storage systems. The development effort is focused on maturing the technologies from a technology readiness level of approximately 23 to approximately 56 as defined in the NASA Procedural Requirement 7123.1B. Currently, the project is working on two critical technology areas: High specific energy batteries, and regenerative fuel cell systems with passive fluid management. Examples of target applications for these technologies are: extending the duration of extravehicular activities (EVA) with high specific energy and energy density batteries; providing reliable, long-life power for rovers with passive fuel cell and regenerative fuel cell systems that enable reduced system complexity. Recent results from the high energy battery and regenerative fuel cell technology development efforts will be presented. The technical approach, the key performance parameters and the technical results achieved to date in each of these new elements will be included. The Advanced Space Power Systems Project is part of the Game Changing Development Program under NASAs Space Technology Mission Directorate.

batteries↗

Shape Sensing for Wings with Spars and Ribs Using Simulated Strain

Active trim shape control can be used to minimize error between target and actual aircraft trim shape during flight. Trim shape sensing for aircraft during flight is not only important for highly flexible aircraft, such as the National Aeronautics and Space Administration (NASA) Helios Prototype remotely piloted flying wing aircraft, but also for a delta-wing type aircraft, such as a supersonic commercial transport aircraft. A two-step theory utilizing distributed strain for a real-time shape sensing of a full three-dimensional structure has been introduced previously. This study focuses on the application of the two-step theory to finite element models of a wing with spars and ribs such as the X-59 QueSST aircraft (Lockheed Martin Corporation, Bethesda, Maryland), a tapered wing, a dihedral/anhedral wing, and a stiffened dihedral/anhedral wing. A finely meshed finite element structural model is desired to capture accurate curvature distributions along the neutral axes of the wing cross sections during pre-test analysis for shape sensing of a wing with ribs and spars. The two-step theory used in this study gives excellent deformation correlation with the MSC/NASTRAN (MSC Software, Newport Beach, California) results along the neutral axis for all test cases used in this study except the X-59 QueSST aircraft.

strain↗

(abstract) The Alpha-Proton-X-ray Spectrometer Deployment Mechanism -- An Anthropomorphic Approach to Sensor Placement on Martian Rocks and Soil

The Mars Pathfinder mission promises to reap a harvest of geological information about Mars. One of the nearly half dozen instruments making this science data possible is the alpha proton X ray spectrometer (APXS). Using a curium source and backscattering techniques, the APXS will determine the elemental composition of rocks and the soil around the landing site. To ensure information of high fidelity, the APXS sensor face must be aligned to within 20° to the surface of each rock and soil sampling location and be held there for up to 10 hours. This is accomplished through the anthropomorphic deployment mechanism (ADM). The ADM mounts on the back of the Mars rover. Working with the rover, the ADM both actively and passively positions the APXS sensor head against a chosen target. The ADM is an amalgamation of unique solutions to some very challenging design problems. The resulting design is light, flexible, and nearly autonomous. Its straightforward operation rivals that of the human arm in simplicity and elegance.

Mars↗

Lignin-First Biorefinery Development

Cost-effective biomass fractionation is an enabling, grand challenge for biorefining, especially when both carbohydrates and lignin are targeted for valorization. The advent of Reductive Catalytic Fractionation (RCF) - an active stabilization approach that solubilizes lignin from biomass and catalytically depolymerizes it into a narrow slate of monomers and oligomers - represents a potential step forward for this important goal. In the Lignin-First Biorefinery Development project, we are employing techno-economic analysis (TEA) and life cycle assessment (LCA) to guide bench-scale R&D efforts towards cost-effective RCF-based biorefining. This project is critical to lignin valorization efforts and could enable the use of woody feedstocks in a traditional biochemical conversion context. To date, we have conducted the first rigorous TEA and LCA study of the RCF process, developed a flow-through system to separate biomass and the chemical catalyst in RCF chemistry, developed models for solvolysis chemistry and transport phenomena for poplar, and co-led an international, authoritative perspective on guidelines for the research community on how to best practice lignin-first biorefining. The primary challenges for the lignin-first RCF process going forward are catalyst stability, the need to utilize, recover, and recycle high boiling point solvents to lower RCF reactor pressure, and the challenge of operating RCF continuously - all of which are being directly tackled by this project.

biomass↗

Development of a VRC01-class germline targeting immunogen derived from anti-idiotypic antibodies

An effective HIV-1 vaccine will likely need to elicit broadly neutralizing antibodies (bNAbs). Broad and potent VRC01-class bNAbs have been isolated from multiple infected individuals, suggesting that they could be reproducibly elicited by vaccination. Several HIV-1 envelope-derived germline-targeting immunogens have been designed to engage naive VRC01-class precursor B cells. However, they also present off-target epitopes that could hinder development of VRC01-class bNAbs. We characterize a panel of anti-idiotypic monoclonal antibodies (ai-mAbs) raised against inferred-germline (iGL) VRC01-class antibodies. By leveraging binding, structural, and B cell sorting data, we engineered a bispecific molecule derived from two aimAbs; one specific for VRC01-class heavy chains and one specific for VRC01-class light chains. The bispecific molecule preferentially activates iGL-VRC01 B cells in vitro and induces specific antibody responses in a murine adoptive transfer model with a diverse polyclonal B cell repertoire. This molecule represents an alternative non-envelope-derived germline-targeting immunogen that can selectively activate VRC01-class precursors in vivo.

59 BASIC BIOLOGICAL SCIENCES↗

Activity profiling and crystal structures of inhibitor-bound SARS-CoV-2 papain-like protease: A framework for anti–COVID-19 drug design

Viral papain-like cysteine protease (PLpro, NSP3) is essential for SARS-CoV-2 replication and represents a promising target for the development of antiviral drugs. Here, we used a combinatorial substrate library and performed comprehensive activity profiling of SARS-CoV-2 PLpro. On the scaffold of the best hits from positional scanning, we designed optimal fluorogenic substrates and irreversible inhibitors with a high degree of selectivity for SARS PLpro. We determined crystal structures of two of these inhibitors in complex with SARS-CoV-2 PLpro that reveals their inhibitory mechanisms and provides a molecular basis for the observed substrate specificity profiles. Last, we demonstrate that SARS-CoV-2 PLpro harbors deISGylating activity similar to SARSCoV-1 PLpro but its ability to hydrolyze K48-linked Ub chains is diminished, which our sequence and structure analysis provides a basis for. Together, this work has revealed the molecular rules governing PLpro substrate specificity and provides a framework for development of inhibitors with potential therapeutic value or drug repurposing.

59 BASIC BIOLOGICAL SCIENCES↗

Target-Tracking Camera for a Metrology System

An analog electronic camera that is part of a metrology system measures the varying direction to a light-emitting diode that serves as a bright point target. In the original application for which the camera was developed, the metrological system is used to determine the varying relative positions of radiating elements of an airborne synthetic aperture-radar (SAR) antenna as the airplane flexes during flight; precise knowledge of the relative positions as a function of time is needed for processing SAR readings. It has been common metrology system practice to measure the varying direction to a bright target by use of an electronic camera of the charge-coupled-device or active-pixel-sensor type. A major disadvantage of this practice arises from the necessity of reading out and digitizing the outputs from a large number of pixels and processing the resulting digital values in a computer to determine the centroid of a target: Because of the time taken by the readout, digitization, and computation, the update rate is limited to tens of hertz. In contrast, the analog nature of the present camera makes it possible to achieve an update rate of hundreds of hertz, and no computer is needed to determine the centroid. The camera is based on a position-sensitive detector (PSD), which is a rectangular photodiode with output contacts at opposite ends. PSDs are usually used in triangulation for measuring small distances. PSDs are manufactured in both one- and two-dimensional versions. Because it is very difficult to calibrate two-dimensional PSDs accurately, the focal-plane sensors used in this camera are two orthogonally mounted one-dimensional PSDs.

Liebe, Carl↗

Improvements to In-Canal Assay of High Specific Activity 60Co at the ATR

Improvements to the quality of measurements in the assaying of High Specific Activity (HSA) cobalt 60 produced at the Advanced Test Reactor at the Idaho National Laboratory are presented. Such assays are conducted regularly between cycles at the ATR, and due to the radiological safety concerns, they are performed within the ATR canal. A standard ion chamber detector was placed in a collimated assay tube within the canal. Another tube, parallel to the detector, was used to position various cobalt 60 standards and targets. The collimated port between these tubes allows for the targets to be pulled across via a winch system. Previous measurements were performed at discrete 1.5-inch steps using a hand-cranked winch system. Charge was collected and integrated for 10 seconds at each discrete step during a scan. Two substantial improvements to the assay include an electronically controlled, motor-driven winch system and a software controlled continuous charge collection. Combined, these changes improved the quality of measurements as well as streamline the assay process. Further examination of these charge profiles indicated a reasonable amount of photon scattering, or shine, before a line-of-sight is established. This created inaccuracies in the reported activity of the cobalt targets. A series of MCNP-6.3 calculations were performed in an effort to quantify and correct for this shine effect. The results of the calculations and how they were employed to a create shine correction factor for the in-canal cobalt assay at the ATR are presented. The overall bias showed an overestimation of the HSA cobalt 60 activity by around 7-8%.

07 - ISOTOPES AND RADIATION SOURCES↗

Signature analysis of high-throughput transcriptomics screening data for mechanistic inference and chemical grouping

Abstract High-throughput transcriptomics (HTTr) uses gene expression profiling to characterize the biological activity of chemicals in in vitro cell-based test systems. As an extension of a previous study testing 44 chemicals, HTTr was used to screen an additional 1,751 unique chemicals from the EPA’s ToxCast collection in MCF7 cells using 8 concentrations and an exposure duration of 6 h. We hypothesized that concentration-response modeling of signature scores could be used to identify putative molecular targets and cluster chemicals with similar bioactivity. Clustering and enrichment analyses were conducted based on signature catalog annotations and ToxPrint chemotypes to facilitate molecular target prediction and grouping of chemicals with similar bioactivity profiles. Enrichment analysis based on signature catalog annotation identified known mechanisms of action (MeOAs) associated with well-studied chemicals and generated putative MeOAs for other active chemicals. Chemicals with predicted MeOAs included those targeting estrogen receptor (ER), glucocorticoid receptor (GR), retinoic acid receptor (RAR), the NRF2/KEAP/ARE pathway, AP-1 activation, and others. Using reference chemicals for ER modulation, the study demonstrated that HTTr in MCF7 cells was able to stratify chemicals in terms of agonist potency, distinguish ER agonists from antagonists, and cluster chemicals with similar activities as predicted by the ToxCast ER Pathway model. Uniform manifold approximation and projection (UMAP) embedding of signature-level results identified novel ER modulators with no ToxCast ER Pathway model predictions. Finally, UMAP combined with ToxPrint chemotype enrichment was used to explore the biological activity of structurally related chemicals. The study demonstrates that HTTr can be used to inform chemical risk assessment by determining in vitro points of departure, predicting chemicals’ MeOA and grouping chemicals with similar bioactivity profiles.

Toxicology↗

The 3D laser radar vision processor system

Loral Defense Systems (LDS) developed a 3D Laser Radar Vision Processor system capable of detecting, classifying, and identifying small mobile targets as well as larger fixed targets using three dimensional laser radar imagery for use with a robotic type system. This processor system is designed to interface with the NASA Johnson Space Center in-house Extra Vehicular Activity (EVA) Retriever robot program and provide to it needed information so it can fetch and grasp targets in a space-type scenario.

Sebok, T. M.↗

Design, Synthesis, and Biological Activity of Novel Ornithine Decarboxylase (ODC) Inhibitors

We here describe the design, synthesis, and biological activity of novel ornithine decarboxylase (ODC) inhibitors that show significantly higher potency in vitro than α-difluoromethylornithine (DFMO), a U.S. Food and Drug Administration (FDA) approved drug. We report two X-ray structures of ODC complexed with new ODC inhibitors, computational docking, molecular dynamics, and binding free energy calculations to validate the experimental models. The X-ray structures reveal that covalent adducts with pyridoxal phosphate (PLP) are formed in the active site of the human ODC enzyme, as verified by their preparation and enzymatic testing. Finally, we verified that the cellular activity of endogenous ODC was inhibited, and polyamine levels were reduced. Given that ODC is a clinically validated target, combined with the fact that DFMO is currently the only ODC inhibitor in clinical use for several indications, the further development of more potent ODC inhibitors with superior activity and physical properties is warranted.

60 APPLIED LIFE SCIENCES↗

Mining a human transcriptome database for chemical modulators of NRF2

Nuclear factor erythroid-2 related factor 2 (NRF2) encoded by the NFE2L2 gene is a transcription factor critical for protecting cells from chemically-induced oxidative stress. We developed computational procedures to identify chemical modulators of NRF2 in a large database of human microarray data. A gene expression biomarker was built from statistically-filtered gene lists derived from microarray experiments in primary human hepatocytes and cancer cell lines exposed to NRF2-activating chemicals (oltipraz, sulforaphane, CDDOIm) or in which the NRF2 suppressor Keap1 was knocked down by siRNA. Directionally consistent biomarker genes were further filtered for those dependent on NRF2 using a microarray dataset from cells after NFE2L2 siRNA knockdown. The resulting 143-gene biomarker was evaluated as a predictive tool using the correlation-based Running Fisher algorithm. Using 59 gene expression comparisons from chemically-treated cells with known NRF2 activating potential, the biomarker gave a balanced accuracy of 93%. The biomarker was comprised of many well-known NRF2 target genes (AKR1B10, AKR1C1, NQO1, TXNRD1, SRXN1, GCLC, GCLM), 69% of which were found to be bound directly by NRF2 using ChIP-Seq. NRF2 activity was assessed across ~9840 microarray comparisons from ~1460 studies examining the effects of ~2260 chemicals in human cell lines. A total of 260 and 43 chemicals were found to activate or suppress NRF2, respectively, most of which have not been previously reported to modulate NRF2 activity. Using a NRF2-responsive reporter gene in HepG2 cells, we confirmed the activity of a set of chemicals predicted using the biomarker. The biomarker will be useful for future gene expression screening studies of environmentally-relevant chemicals.

59 BASIC BIOLOGICAL SCIENCES↗

In silico evaluation of a targeted metaproteomics strategy for broad screening of cellulolytic enzyme capacities in anaerobic microbiome bioreactors

Microbial-driven solubilization of lignocellulosic material is a natural mechanism that is exploited in anaerobic digesters (ADs) to produce biogas and other valuable bioproducts. Glycoside hydrolases (GHs) are the main enzymes that bacterial and archaeal populations use to break down complex polysaccharides in these reactors. Methodologies for rapidly screening the physical presence and types of GHs can provide information about their functional activities as well as the taxonomical diversity within AD systems but are largely unavailable. Targeted proteomic methods could potentially be used to provide snapshots of the GHs expressed by microbial consortia in ADs, giving valuable insights into the functional lignocellulolytic degradation diversity of a community. Such observations would be essential to evaluate the hydrolytic performance of a reactor or potential issues with it.

09 BIOMASS FUELS↗

EP300/CBP is crucial for cAMP-PKA pathway to alleviate podocyte dedifferentiation via targeting Notch3 signaling

Podocyte injury is the hallmark of proteinuric glomerular diseases. Notch3 is neo-activated simultaneously in damaged podocytes and podocyte's progenitor cells of FSGS, indicating a unique role of Notch3. We previously showed that activation of cAMP-PKA pathway alleviated podocyte injury possibly via inhibiting Notch3 expression. However, the mechanisms are unknown. In the present study, Notch3 signaling was significantly activated in ADR-induced podocytes in vitro and in PAN nephrosis rats and patients with idiopathic FSGS in vivo, concomitantly with podocyte dedifferentiation. In cultured podocytes, pCPT-cAMP, a selective cAMP-PKA activator, dramatically blocked ADR-induced activation of Notch3 signaling as well as inhibition of cAMP-PKA pathway, thus alleviating the decreased cell viability and podocyte dedifferentiation. Bioinformatics analysis revealed EP300/CBP, a transcriptional co-activator, as a central hub for the crosstalk between these two signaling pathways. Additionally, CREB/KLF15 in cAMP-PKA pathway competed with RBP-J the major transcriptional factor of Notch3 signaling for binding to EP300/CBP. EP300/CBP siRNA significantly inhibited these two signaling transduction pathways and disrupted the interactions between the above major transcriptional factors. These data indicate a crucial role of EP300/CBP in regulating the crosstalk between cAMP-PKA pathway and Notch3 signaling and modulating the phenotypic change of podocytes, and enrich the reno-protective mechanisms of cAMP-PKA pathway.

60 APPLIED LIFE SCIENCES↗

In search of autophagy biomarkers in breast cancer: Receptor status and drug agnostic transcriptional changes during autophagy flux in cell lines

Autophagy drives drug resistance and drug-induced cancer cell cytotoxicity. Targeting the autophagy process could greatly improve chemotherapy outcomes. The discovery of specific inhibitors or activators has been hindered by challenges with reliably measuring autophagy levels in a clinical setting. We investigated drug-induced autophagy in breast cancer cell lines with differing ER/PR/Her2 receptor status by exposing them to known but divergent autophagy inducers each with a unique molecular target, tamoxifen, trastuzumab, bortezomib or rapamycin. Differential gene expression analysis from total RNA extracted during the earliest sign of autophagy flux showed both cell- and drug-specific changes. We analyzed the list of differentially expressed genes to find a common, cell- and drug-agnostic autophagy signature. Twelve mRNAs were significantly modulated by all the drugs and 11 were orthogonally verified with Q-RT-PCR (Klhl24, Hbp1, Crebrf, Ypel2, Fbxo32, Gdf15, Cdc25a, Ddit4, Psat1, Cd22, Ypel3). The drug agnostic mRNA signature was similarly induced by a mitochondrially targeted agent, MitoQ. In-silico analysis on the KM-plotter cancer database showed that the levels of these mRNAs are detectable in human samples and associated with breast cancer prognosis outcomes of Relapse-Free Survival in all patients (RSF), Overall Survival in all patients (OS), and Relapse-Free Survival in ER + Patients (RSF ER + ). High levels of Klhl24, Hbp1, Crebrf, Ypel2, CD22 and Ypel3 were correlated with better outcomes, whereas lower levels of Gdf15, Cdc25a, Ddit4 and Psat1 were associated with better prognosis in breast cancer patients. This gene signature uncovers candidate autophagy biomarkers that could be tested during preclinical and clinical studies to monitor the autophagy process.

60 APPLIED LIFE SCIENCES↗