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At least 739 records · Page 41

Integrated Traction Drive Thermal Management: Keystone Project 3

The presentation represents a report of accomplishments during FY 2022 and is prepared for 2022 DOE VTO Annual Merit Review. The project goal is facilitation of achieving DOE 2025 target of 33 kW/L system power density for an electric traction drive through support of other EDT consortium members in design and development of thermal management systems for their respective integrated drive concepts. Namely, identifying pathways enabling high-performance, compact, and reliable integrated electric drives. Specific objectives are: 1) Research and evaluation of motor-integrated power electronics packaging technologies and thermal management approaches. 2) Development of thermal management system and its sub-components to enable integrated electric drive DOE power density targets in collaboration with project partners. 3) Supporting activities of DOE's Electric Drive Technologies (EDT) consortium members, Oak Ridge National Laboratory (ORNL) and University of Wisconsin research teams in thermal management component design and thermal modeling of their integrated traction drives. 4) Identifying candidate driveline fluids suitable for direct cooling of traction-drive components and high-voltage power electronics and evaluate their convective cooling performance.

ADVANCED PROPULSION SYSTEMS↗

Integrated Traction Drive Thermal Management: Keystone Project 3

The presentation represents a report of accomplishments during FY 2024 and is prepared for 2024 DOE VTO Annual Merit Review. The project goal is identifying pathways enabling high-performance, compact, and reliable integrated electric drives and facilitation of achieving DOE 2025 target of 33 kW/L system power density for an electric traction drive through support of other EDT consortium members in design and development of thermal management systems for their respective integrated drive concepts. Specific objectives are: 1) research and evaluation of motor-integrated power electronics packaging technologies and thermal management approaches; 2) explore novel materials and manufacturing options (3D printing with thermally enhanced polymers or ceramic materials) for key thermal management system components; 3) develop thermal management system and its sub-components to enable integrated electric drive DOE power density targets in collaboration with project partners; 4) support activities of DOE's Electric Drive Technologies (EDT) consortium members, Oak Ridge National Laboratory (ORNL), University of Wisconsin and Georgia Tech research teams in thermal management component design and thermal modeling of their integrated traction drives.

ADVANCED PROPULSION SYSTEMS↗

Peptide inhibitors of CRISPR-Cas9

Specific and broad-spectrum inhibitory peptides to CRISPR Cas9 variants (SpyCas9, SauCas9, and CjeCas9) are disclosed. A method of making and using these peptides with therapeutic CRISPR Cas9 (to improve desired targeting) or against harmful CRISPR Cas9 components (already active in a patient) is also disclosed. The peptides combined with a delivery system is also disclosed.

Harmon, Brooke Nicole↗

Targeting tissues via dynamic human systems modeling in generative design

Drug discovery is a complex, costly process with high failure rates. A successful drug should bind to a target, be deliverable to an intended site of activity, and promote a desired pharmacological effect without causing toxicity. Typically, these factors are evaluated in series over the course of a pipeline where the number of candidates is sequentially whittled down from a very large initial pool. One promise of AI-driven discovery is the opportunity to evaluate multiple facets of drug performance in parallel. However, despite ML-driven advancements, current models for pharmacological property prediction are exclusively trained to predict molecular properties, ignoring important, dynamic biodistribution and bioactivity effects. Here, we present our progress towards incorporating quantitative systems physiology models into an AI-enabled drug design and molecular generation pipeline. Within a genetic algorithm, we include human-relevant physiologically based pharmacokinetic (PBPK) models. These PBPK models leverage properties that are predicted by a fine-tuned molecular language model. Together, these models will aid in capturing the mapping between molecules and therapeutic outcomes that is necessary to accelerate the drug discovery process.

Fox, Zach↗

Development of an autonomous video rendezvous and docking system, phase 2

The critical elements of an autonomous video rendezvous and docking system were built and used successfully in a physical laboratory simulation. The laboratory system demonstrated that a small, inexpensive electronic package and a flight computer of modest size can analyze television images to derive guidance information for spacecraft. In the ultimate application, the system would use a docking aid consisting of three flashing lights mounted on a passive target spacecraft. Television imagery of the docking aid would be processed aboard an active chase vehicle to derive relative positions and attitudes of the two spacecraft. The demonstration system used scale models of the target spacecraft with working docking aids. A television camera mounted on a 6 degree of freedom (DOF) simulator provided imagery of the target to simulate observations from the chase vehicle. A hardware video processor extracted statistics from the imagery, from which a computer quickly computed position and attitude. Computer software known as a Kalman filter derived velocity information from position measurements.

Tietz, J. C.↗

Flexor bias of joint position in humans during spaceflight

The ability to estimate ankle and elbow joint position was tested before, during, and after a 17-day spaceflight. Subjects estimated targeted joint angles during isovelocity (IsoV) joint movements with agonist muscle groups either active or relaxed. These movements included elbow extension (EE) and elbow flexion (EF), and plantarflexion (PF) and dorsiflexion (DF) of the ankle. Subjects also estimated these joint positions while moving the dynamometer at their chosen (variable) velocity (VarV) during EE and PF. For IsoV tests, no differences were observed between active and passive movements for either the ankle or elbow. Compared with those of pre-flight test days, estimates of targeted elbow joint angles were approximately 5 degrees to 15 degrees more flexed in-flight, and returned toward the pre-flight values during recovery. The spaceflight effects for the ankle were inconsistent and less prevalent than those for the elbow. The VarV PF test condition for the 120 degrees target angle at the ankle exhibited approximately 5 degrees to 7 degrees more DF target angle estimates in-flight compared with those pre- or post-flight. In contrast, during IsoV PF there was a tendency for ankle estimates to be approximately 2 degrees to 3 degrees more PF after 2-3 days exposure to spaceflight. These data indicate that during spaceflight the perception of elbow extension is greater than actuality, and are consistent with the interpretation that microgravity induced a flexor bias in the estimation of the actual elbow joint position. Moreover, these effects in joint proprioception during spaceflight were observed in individual isolated single-joint movements during tasks in which vestibular function in maintaining posture were minimal.

STS-78 Shuttle Project↗

Effect of Spaceflight on the Functions of NK and LAK Cells

Spaceflight-associated stress alters some aspects of the human immune response. In this study, we determined the effects of 10 days aboard the Space Shuttle on the cytotoxic activity of NK and LAK cells. The subjects of this study were crewmembers of two 10-day shuttle flights. Ten-ml blood specimens were obtained from ten astronauts 10 days before launch, immediately after landing, and 3 days after landing. PBMCs were separated from the blood specimens and stored at -800 C. All PBMCs were thawed simultaneously, and the cytotoxic activities of NK and LAK cells were measured by a 4-hour Cr-51 release assay. K562 cells were used to assess NK-cell cytotoxicity. After 4 days of IL-2 activation, the LAK cell cytotoxic activity was determined using K562 and Daudi cells as the target cells. NK-cell cytotoxicity was decreased at landing (p less than 0.0005) in 9/10 astronauts, and in most cases recovered to preflight levels by 3 days after landing; NK-cell cytotoxicity was increased in one astronaut at landing. LAK cytotoxic activity against K562 cells was decreased at landing in 6/10 astronauts (p=0.018), and activity against Daudi cells was decreased in 7/10 astronauts (p=0.01). Phenotyping of PBMCs and LAK cells showed alterations in some surface markers and adhesion molecules (CD1 1 b, CD1 1 c, CD1 1 a, CD1 6, L-Selectin and CD3). Thus spaceflight leads to a decrease in the functions of NK and LAK cells in most astronauts.

Pierson, Duane L.↗

Photonuclear Production of 67 Cu From Gallium

Copper-67 is a radioisotope of interest for medical imaging and therapy as well as for under- standing stellar and interstellar evolution pertaining to the formation of proton-rich nuclei. Since 67 Cu decays 100% to 67 Zinc, understanding this reaction can shed light on the abundance of this and other p-nuclei elements in the universe. Here, the photonuclear production of 67 Cu from 71 Ga and natural gallium is examined as an alternative to its photoproduction from zinc. Two research and development production runs were performed at Thomas Jefferson National Accelerator Facility using an electron linac. During the first run, an 805-W, 30.9-MeV beam was used to irradiate a 1-mm tungsten radiator to create a bremsstrahlung flux. The resulting gamma photons irradiated 50.9 g of natural gallium encased in a graphite crucible for 24.2 h; 7.02 Bq/W∙s∙kg of 67 Cu activity was produced. During the second run, a 4380-W, 31.5-MeV beam was used for 12.0 h on the same target containing 60 g of natural gallium; 6.41 Bq/W∙s∙kg of 67 Cu activity was produced. Because of the difficulties in spectroscopically differentiating 67 Cu from 67 Ga, prior to each run, an isotopically pure 71 Ga disk was irradiated using a 100-W beam for 1 h, at the same respective energies. Finally, these baseline irradiations allowed for separation of 67 Cu from 67 Ga in the spectroscopic measurements of the natural gallium targets.

07 ISOTOPE AND RADIATION SOURCES↗

Calculation of a mirror asymmetric effect in electron scattering from chiral targets

A dynamical calculation is presented of the helicity induced in an initially unpolarized electron beam after elastic scattering from an optically active medium, a process analogous to the circular polarization induced in unpolarized light following Rayleigh scattering from chiral targets. The calculation is based on the bound helical electron model of a chiral molecule, according to which the major contribution to the helicity is provided by the perturbation of the electron bound state by the spin-orbit interaction of the bound electrons moving in the electric field of the molecular core. The net helicity acquired is found to depend directly on a molecular asymmetry factor and the square of the atomic number of the heaviest atom in an asymmetric environment. For the case of carbon, the induced helicity is on the order of 0.00001, which would account for its lack of observation in a recent experiment. Results may have implications for the origin of optical activity in biological molecules by the differential ionization of D and L isomers by beta-decay electrons.

Rich, A.↗

Template and target-site recognition by human LINE-1 in retrotransposition

The long interspersed element-1 (LINE-1, hereafter L1) retrotransposon has generated nearly one-third of the human genome and serves as an active source of genetic diversity and human disease. L1 spreads through a mechanism termed target-primed reverse transcription, in which the encoded enzyme (ORF2p) nicks the target DNA to prime reverse transcription of its own or non-self RNAs. Here we purified full-length L1 ORF2p and biochemically reconstituted robust target-primed reverse transcription with template RNA and target-site DNA. We report cryo-electron microscopy structures of the complete human L1 ORF2p bound to structured template RNAs and initiating cDNA synthesis. The template polyadenosine tract is recognized in a sequence-specific manner by five distinct domains. Among them, an RNA-binding domain bends the template backbone to allow engagement of an RNA hairpin stem with the L1 ORF2p C-terminal segment. Moreover, structure and biochemical reconstitutions demonstrate an unexpected target-site requirement: L1 ORF2p relies on upstream single-stranded DNA to position the adjacent duplex in the endonuclease active site for nicking of the longer DNA strand, with a single nick generating a staggered DNA break. Our research provides insights into the mechanism of ongoing transposition in the human genome and informs the engineering of retrotransposon proteins for gene therapy.

59 BASIC BIOLOGICAL SCIENCES↗

Antimicrobial properties of a multi-component alloy

High traffic touch surfaces such as doorknobs, countertops, and handrails can be transmission points for the spread of pathogens, emphasizing the need to develop materials that actively self-sanitize. Metals are frequently used for these surfaces due to their durability, but many metals also possess antimicrobial properties which function through a variety of mechanisms. This work investigates metallic alloys comprised of several metals which individually possess antimicrobial properties, with the target of achieving broad-spectrum, rapid sanitation through synergistic activity. An entropy-motivated stabilization paradigm is proposed to prepare scalable alloys of copper, silver, nickel and cobalt. Using combinatorial sputtering, thin-film alloys were prepared on 100 mm wafers with ≈50% compositional grading of each element across the wafer. The films were then annealed and investigated for alloy stability. Antimicrobial activity testing was performed on both the as-grown alloys and the annealed films using four microorganisms—Phi6, MS2, Bacillus subtilis and Escherichia coli —as surrogates for human viral and bacterial pathogens. Testing showed that after 30 s of contact with some of the test alloys, Phi6, an enveloped, single-stranded RNA bacteriophage that serves as a SARS-CoV-2 surrogate, was reduced up to 6.9 orders of magnitude (> 99.9999%). Additionally, the non-enveloped, double-stranded DNA bacteriophage MS2, and the Gram-negative E. coli and Gram-positive B. subtilis bacterial strains showed a 5.0, 6.4, and 5.7 log reduction in activity after 30, 20 and 10 min, respectively. Antimicrobial activity in the alloy samples showed a strong dependence on the composition, with the log reduction scaling directly with the Cu content. Concentration of Cu by phase separation after annealing improved activity in some of the samples. The results motivate a variety of themes which can be leveraged to design ideal antimicrobial surfaces.

36 MATERIALS SCIENCE↗

Targeting tRNA-synthetase interactions towards novel therapeutic discovery against eukaryotic pathogens

The development of chemotherapies against eukaryotic pathogens is especially challenging because of both the evolutionary conservation of drug targets between host and parasite, and the evolution of strain-dependent drug resistance. There is a strong need for new nontoxic drugs with broad-spectrum activity against trypanosome parasites such as Leishmania and Trypanosoma. A relatively untested approach is to target macromolecular interactions in parasites rather than small molecular interactions, under the hypothesis that the features specifying macromolecular interactions diverge more rapidly through coevolution. We computed tRNA Class-Informative Features in humans and independently in eight distinct clades of trypanosomes, identifying parasite-specific informative features, including base pairs and base mis-pairs, that are broadly conserved over approximately 250 million years of trypanosome evolution. Validating these observations, we demonstrated biochemically that tRNA:aminoacyl-tRNA synthetase (aaRS) interactions are a promising target for anti-trypanosomal drug discovery. From a marine natural products extract library, we identified several fractions with inhibitory activity toward Leishmania major alanyl-tRNA synthetase (AlaRS) but no activity against the human homolog. These marine natural products extracts showed cross-reactivity towards Trypanosoma cruzi AlaRS indicating the broad-spectrum potential of our network predictions. We also identified Leishmania major threonyl-tRNA synthetase (ThrRS) inhibitors from the same library. We discuss why chemotherapies targeting multiple aaRSs should be less prone to the evolution of resistance than monotherapeutic or synergistic combination chemotherapies targeting only one aaRS.

59 BASIC BIOLOGICAL SCIENCES↗

Temperature modulation of CAMTA3 gene induction activity is mediated through the DNA binding domain

The calmodulin-binding transcription activator (CAMTA) proteins of Arabidopsis thaliana play a major role in cold acclimation, contributing to the rapid induction of the C-REPEAT BINDING FACTOR (CBF) genes and other genes that impart freezing tolerance in plants exposed to cold temperature (4°C). The goal of this study was to better understand how the gene induction activity of CAMTA3 is modulated by temperature. Our results indicate that a severely truncated version of CAMTA3, CAMTA3 334 , which includes the N-terminal CG-1 DNA binding domain and a newly identified transcriptional activation domain (TAD), was able to rapidly induce the expression of CBF2 and two newly identified target genes, EXPANSIN-LIKE A1 (EXPL1) and NINE-CIS-EPOXYCAROTENOID DIOXYGENASE 3 (NCED3), in response to cold temperature. Additionally, CAMTA3 334 was able to restore freezing tolerance when expressed in a camta23 double mutant. The ability of CAMTA3 and CAMTA3 334 to induce target genes at cold temperature did not involve increased levels of these proteins or increased binding of these proteins to target gene promoters in cold-treated plants. Rather, domain-swapping experiments indicated that the CAMTA3 CG-1 domain conferred temperature dependence to the ability of the CAMTA3 TAD to induce gene expression. The CG-1 domain also enabled the TAD to induce the expression of target genes at a moderate temperature (22°C) in response to cycloheximide treatment, consistent with the TAD activity not being intrinsically temperature dependent. We propose a working model in which the temperature modulation of CAMTA3 gene induction activity occurs independently from the C-terminal calmodulin-binding domains that previously have been proposed to activate CAMTA3 transcriptional activity in response to cold temperature.

59 BASIC BIOLOGICAL SCIENCES↗

Seismic Exploration of Small Bodies

As a result of the Phase I study, we have demonstrated that a mission to a smallbody (asteroid, comet) whose objective is to conduct a seismic experiment to understandthe interior structure, can be accomplished with small (<200 kg) spacecraft launched on asmall launch vehicle (Athena IIc).We modeled the seismic response of a small body and calculated that the energynecessary to propagate through the body and be detected by a seismometer. Thesecalculations provide guidance as to the type of energy source that is required. A simpleenergy source similar to a NASA standard initiator (NSI) can be used, although a singleNSI is insufficient. An NSI is an explosive pyrotechnic that is used to sever connectionson spacecraft. Use of such an energy source has illustrated two additional areas of study -anchoring of the source and sensor to the surface and understanding the efficiency ofenergy propagation from the source into the surface.The spacecraft has the ability to carry and deploy a series of source/sensors toconduct the experiment by placing them on the surface. We identified a suite of candidatenear-Earth asteroids as targets and used one 1991VG as the target to calculate the missiontrajectory and ∆V requirements. Spacecraft and launch vehicle performance are launchthat any of the candidates could be reached with appropriate mass and launch margins.Sources and sensors are deployed from arm attached to the spacecraft. Thespacecraft maneuvers next to the target body and presses the sensor against the surfaceand releases it. After emplacing all of the surface packages, the sensors are monitored fora period of time to measure the seismic noise. Finally, the active seismic experiment isconducted.The work conducted during Phase I demonstrates that a small mission can be designed to conduct an active seismic experiment on a small near-Earth body. Whileother targets may require more performance, the basic architecture is viable for anytarget.We have identified a number of specific technical areas that require more detailed study. Those areas are largely focused on the detailed analysis and design of the source mechanism and anchoring it to the surface. Such topics will be part of a Phase IIproposal.

Spacecraft↗

Triton Initiative: FY 2024 Communications, Outreach, and Engagement End-of-Year Report

The Department of Energy (DOE) Water Power Technologies Office (WPTO) Triton Initiative works to reduce barriers to permitting of marine energy testing and installation through environmental monitoring research that can help inform decision-makers on potential environmental effects associated with these systems. Communications, outreach, and engagement efforts are critical to Triton's success, which involves facilitating the effective communication and dissemination of environmental monitoring research information and results to end-users and fostering collaborations between researchers and industry partners to address the most pressing needs of this emerging industry. The Triton Initiative's communications, outreach, and engagement (TCOE) foundational goals are to educate and raise awareness of ME and the role of Triton's environmental monitoring research in supporting the industry, build trust with audiences through transparent communications and outreach, and evaluate and refine TCOE tactics based on feedback and metrics. The TCOE FY 2024-specific objectives were to (1) refine and grow Triton's audience network by reaching new individuals and communities within Triton's target audience base, and (2) improve the strategy and evaluation of TCOE efforts to demonstrate the value of communications and outreach for the ME community. This report presents the results and analysis of communications activities from September 1, 2023 through August 31, 2024. We assess the TCOE target audiences, highlight notable successes and lessons learned from FY2024, and identify the most effective channels and activities used to connect with those audiences to achieve the TCOE goals.

16 TIDAL AND WAVE POWER↗

NASA's Efforts to Commercialize Communications Services for Mission in Near-Earth Space

The National Aeronautics and Space Administration (NASA) Space Communications and Navigation (SCaN)Program enables high speed, robust, secure and cost-effective space communications and navigation services to current and future science and exploration missions. Consistent with National Space Policy, NASA is pursuing the use of demonstrated commercial services for all its future near-Earth requirements through a flexible, multi-provider approach that minimizes risks to the user missions and ensures costs to user missions are reasonable. Progress toward this goal is advancing in multiple key areas including direct to Earth (DTE), space-based relay, technology investments, required spectrum regulatory changes and mission engagement and infusion. The transition to commercial DTE services is already underway, with a target for transition by 2024. The primary functions to execute SCaN’s DTE strategy include increasing commercial service allocations by leveraging current commercial network providers and enabling seamless onboarding of additional providers into the network. Furthermore, moving away from government DTE services will allow operational costs to be optimized. A more gradual approach is planned for the transition to commercial space-based relay services to allow for demonstration and operationalization of commercial services for future users by 2030. In June of 2022, six American SATCOM vendors were awarded a combined $278.5 million through Funded Space Act Agreements (FSAAs) for the first cycle of demonstration and validation activities. The end-to-end service capabilities being targeted are based on existing NASA mission operational needs. Accordingly, each company has proposed a technical approach to lower costs, increase flexibility, and improve performance for a broad range of missions. Successful user mission transition to commercial services, both DTE and space-based relay, are dependent on the technologies and capabilities that address gaps in commercial capability. NASA is investing in technology development and pursuing a new strategic approach to the creation or adoption of space communications standards to move the agency toward a commercial paradigm. Wideband and multi-lingual user terminals are being developed to bridge differences in industry services. Building on ground demonstrations completed in 2021, the Johns Hopkins Applied Physics Lab (APL) will be flight testing a multi-lingual wideband terminal (payload) and demonstrating connectivity to both government and commercial relay services. NASA holds a leadership role in multiple civil space standards bodies and international coordination groups to ensure that standards supporting interoperability are developed with defined functions, interfaces, and performance. However, to successfully meet commercialization objectives, NASA seeks to collaborate with industry, and as applicable adopt or adapt to commercially defined standards. As such, NASA joined the 3rd Generation Partnership Project (3GPP) as an official member in 2021 to advocate for the inclusion of space missions as a unique user segment in future 5G non-terrestrial networks, and to better understand the scope of 3GPP releases and implications for space users. Further, engagement in Spectrum regulatory bodies is being undertaken to augment existing space-Earth and inter-satellite frequency allocations available for both government and commercial space systems. This paper addresses the recent progress toward NASA’s commercial space communications transition objectives and how key challenges are being navigated.

Gregory W Heckler↗

Characterization of Mammalian In Vivo Enhancers Using Mouse Transgenesis and CRISPR Genome Editing [Book Chapter]

Embryonic morphogenesis is strictly dependent on tight spatiotemporal control of developmental gene expression, which is typically achieved through the concerted activity of multiple enhancers driving cell type-specific expression of a target gene. Mammalian genomes are organized in topologically associated domains, providing a preferred environment and framework for interactions between transcriptional enhancers and gene promoters. While epigenomic profiling and three-dimensional chromatin conformation capture have significantly increased the accuracy of identifying enhancers, assessment of subregional enhancer activities via transgenic reporter assays in mice remains the gold standard for assigning enhancer activity in vivo. Once this activity is defined, the ideal method to explore the functional necessity of a transcriptional enhancer and its contribution to target gene dosage and morphological or physiological processes is deletion of the enhancer sequence from the mouse genome. Here we present detailed protocols for efficient introduction of enhancer-reporter transgenes and CRISPR-mediated genomic deletions into the mouse genome, including a step-by-step guide for pronuclear microinjection of fertilized mouse eggs. We provide instructions for the assembly and genomic integration of enhancer-reporter cassettes that have been used for validation of thousands of putative enhancer sequences accessible through the VISTA enhancer browser, including a recently published method for robust site-directed transgenesis at the H11 safe-harbor locus. Together, these methods enable rapid and large-scale assessment of enhancer activities and sequence variants in mice, which is essential to understand mammalian genome function and genetic diseases.

cis-regulatory elements↗