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At least 109 records · Page 6

A mutation in the Arabidopsis HYL1 gene encoding a dsRNA binding protein affects responses to abscisic acid, auxin, and cytokinin

Both physiological and genetic evidence indicate interconnections among plant responses to different hormones. We describe a pleiotropic recessive Arabidopsis transposon insertion mutation, designated hyponastic leaves (hyl1), that alters the plant's responses to several hormones. The mutant is characterized by shorter stature, delayed flowering, leaf hyponasty, reduced fertility, decreased rate of root growth, and an altered root gravitropic response. It also exhibits less sensitivity to auxin and cytokinin and hypersensitivity to abscisic acid (ABA). The auxin transport inhibitor 2,3,5-triiodobenzoic acid normalizes the mutant phenotype somewhat, whereas another auxin transport inhibitor, N-(1-naph-thyl)phthalamic acid, exacerbates the phenotype. The gene, designated HYL1, encodes a 419-amino acid protein that contains two double-stranded RNA (dsRNA) binding motifs, a nuclear localization motif, and a C-terminal repeat structure suggestive of a protein-protein interaction domain. We present evidence that the HYL1 gene is ABA-regulated and encodes a nuclear dsRNA binding protein. We hypothesize that the HYL1 protein is a regulatory protein functioning at the transcriptional or post-transcriptional level.

NASA Discipline Plant Biology↗

Progressive growth of the solid–electrolyte interphase towards the Si anode interior causes capacity fading

The solid–electrolyte interphase (SEI), a layer formed on the electrode surface, is essential for electrochemical reactions in batteries and critically governs the battery stability. Active materials, especially those with extremely high energy density, such as silicon (Si), often inevitably undergo a large volume swing upon ion insertion and extraction, raising a critical question as to how the SEI interactively responds to and evolves with the material and consequently controls the cycling stability of the battery. Here, by integrating sensitive elemental tomography, an advanced algorithm and cryogenic scanning transmission electron microscopy, we unveil, in three dimensions, a correlated structural and chemical evolution of Si and SEI. Furthermore, corroborated with a chemomechanical model, we demonstrate progressive electrolyte permeation and SEI growth along the percolation channel of the nanovoids due to vacancy injection and condensation during the delithiation process. Consequently, the Si–SEI spatial configuration evolves from the classic ‘core–shell’ structure in the first few cycles to a ‘plum-pudding’ structure following extended cycling, featuring the engulfing of Si domains by the SEI, which leads to the disruption of electron conduction pathways and formation of dead Si, contributing to capacity loss. The spatially coupled interactive evolution model of SEI and active materials, in principle, applies to a broad class of high-capacity electrode materials, leading to a critical insight for remedying the fading of high-capacity electrodes.

36 MATERIALS SCIENCE↗

A transmission hologram for slitless spectrophotometry on a convergent telescope beam. 1. Focus and resolution

We report in this paper the test of a plane holographic optical element to be used as an aberration-corrected grating for a slitless spectrograph, inserted in a convergent telescope beam. Our long-term objective is the optimization of a specific hologram to switch the auxiliary telescope imager of the Vera Rubin Observatory into an accurate slitless spectrograph, dedicated to the atmospheric transmission measurement. We present and discuss here the promising results of tests performed with prototype holograms at the CTIO $0.9\,$m telescope during a run of 17 nights in 2017 May–June. After their on-sky geometrical characterization, the performances of the holograms as aberration-balanced dispersive optical elements have been established by analysing spectra obtained from spectrophotometric standard stars and narrow-band emitter planetary nebulae. Thanks to their additional optical function, our holographic disperser prototypes allow us to produce significantly better focused spectra within the full visible wavelength domain $[370,1050]\,$nm than a regular grating, which suffers from strong defocusing and aberrations when used in similar conditions. We show that the resolution of our slitless on-axis spectrograph equipped with the hologram approaches its theoretical performance. While estimating the benefits of a hologram for the spectrum resolution, the roadmap to produce a competitive holographic element for the Vera Rubin Observatory auxiliary telescope has been established.

79 ASTRONOMY AND ASTROPHYSICS↗

Discovery of amivantamab (JNJ-61186372), a bispecific antibody targeting EGFR and MET

A bispecific antibody (BsAb) targeting the epidermal growth factor receptor (EGFR) and mesenchymal–epithelial transition factor (MET) pathways represents a novel approach to overcome resistance to targeted therapies in patients with non–small cell lung cancer. In this study, we sequentially screened a panel of BsAbs in a combinatorial approach to select the optimal bispecific molecule. The BsAbs were derived from different EGFR and MET parental monoclonal antibodies. Initially, molecules were screened for EGFR and MET binding on tumor cell lines and lack of agonistic activity toward MET. Hits were identified and further screened based on their potential to induce untoward cell proliferation and cross-phosphorylation of EGFR by MET via receptor colocalization in the absence of ligand. After the final step, we selected the EGFR and MET arms for the lead BsAb and added low fucose Fc engineering to generate amivantamab (JNJ-61186372). The crystal structure of the anti-MET Fab of amivantamab bound to MET was solved, and the interaction between the two molecules in atomic details was elucidated. Amivantamab antagonized the hepatocyte growth factor (HGF)-induced signaling by binding to MET Sema domain and thereby blocking HGF β-chain—Sema engagement. The amivantamab EGFR epitope was mapped to EGFR domain III and residues K443, K465, I467, and S468. Furthermore, amivantamab showed superior antitumor activity over small molecule EGFR and MET inhibitors in the HCC827-HGF in vivo model. Based on its unique mode of action, amivantamab may provide benefit to patients with malignancies associated with aberrant EGFR and MET signaling.

59 BASIC BIOLOGICAL SCIENCES↗

Structure of metallochaperone in complex with the cobalamin-binding domain of its target mutase provides insight into cofactor delivery

G-protein metallochaperone MeaB in bacteria [methylmalonic aciduria type A (MMAA) in humans] is responsible for facilitating the delivery of adenosylcobalamin (AdoCbl) to methylmalonyl-CoA mutase (MCM), the only AdoCbl-dependent enzyme in humans. Genetic defects in the switch III region of MMAA lead to the genetic disorder methylmalonic aciduria in which the body is unable to process certain lipids. Here, we present a crystal structure of Methylobacterium extorquens MeaB bound to a nonhydrolyzable guanosine triphosphate (GTP) analog guanosine-5'-[(β,γ)-methyleno]triphosphate (GMPPCP) with the Cbl-binding domain of its target mutase enzyme (MeMCM cbl ). This structure provides an explanation for the stimulation of the GTP hydrolyase activity of MeaB afforded by target protein binding. We find that upon MCM cbl association, one protomer of the MeaB dimer rotates ~180°, such that the inactive state of MeaB is converted to an active state in which the nucleotide substrate is now surrounded by catalytic residues. Importantly, it is the switch III region that undergoes the largest change, rearranging to make direct contacts with the terminal phosphate of GMPPCP. These structural data additionally provide insights into the molecular basis by which this metallochaperone contributes to AdoCbl delivery without directly binding the cofactor. Our data suggest a model in which GTP-bound MeaB stabilizes a conformation of MCM that is open for AdoCbl insertion, and GTP hydrolysis, as signaled by switch III residues, allows MCM to close and trap its cofactor. Substitutions of switch III residues destabilize the active state of MeaB through loss of protein:nucleotide and protein:protein interactions at the dimer interface, thus uncoupling GTP hydrolysis from AdoCbl delivery.

59 BASIC BIOLOGICAL SCIENCES↗

Clearance Sensitivity Mitigation in Small Core Compressors

As future aircraft become lighter and more aerodynamically efficient, thrust requirements will decrease, reducing the core size of the engine. Furthermore, in the pursuit of improved fuel burn, engine overall pressure ratio and bypass ratio will increase, further driving down engine core size. These drivers together mean that the core size, or corrected mass flow rate at the compressor exit, for future single-aisle aircraft applications will shrink below 3.0 lbm/s. Traditionally, this small core compressor size is in the domain of axi-centrifugal designs, machines that are typically less efficient and limited to pressure ratios of ~25 due to stress and thermomechanical fatigue in the centrifugal impeller. In this light, NASA, Pratt & Whitney and the Raytheon Technologies Research Center embarked upon a program to develop technologies to enable an all-axial high-pressure compressor with a core size below 3.0 lbm/s and an overall pressure ratio greater than 50. One of the challenges with an all-axial high-pressure compressor at this core size is the small span at the rear of the compressor. As core size is scaled down, the rotor tip clearances do not scale with span, leading to significant efficiency penalties. This paper documents a numerical and experimental effort to mitigate this penalty through design optimization and technology insertion, enabling an estimated 5 to 10% fuel burn reduction relative to 2020 best-in-class. The experimental program consisted of two builds of a high-speed rig: a baseline build and a second build to insert technology to manage large rotor tip gap/span ratios. The results demonstrated a reduction in the sensitivity of the compressor to large clearance ratios, which would be likely at the end-of-life of a small core application. The test campaign demonstrated that, with the insertion of technology, small core compressors can maintain a similar efficiency to current best-in-class large core size compressors. In addition to advancing the state-of-the-art of technology, the program also advanced the modeling standards for multistage compressors with large clearance-to-span ratios. The validation of this approach is described in the paper.

Axial Compressors↗

Clearance Sensitivity Mitigation in Small Core Compressors

As future aircraft become lighter and more aerodynamically efficient, thrust requirements will decrease, reducing the core size of the engine. Furthermore, in the pursuit of improved fuel burn, engine overall pressure ratio and bypass ratio will increase, further driving down engine core size. These drivers together mean that the core size, or corrected mass flow rate at the compressor exit, for future single-aisle aircraft applications will shrink below 3.0 lb/s. Traditionally, this small core compressor size is in the domain of axi-centrifugal designs, machines that are typically less efficient and limited to pressure ratios of ~25 due to stress and thermomechanical fatigue in the centrifugal impeller. In this light, NASA, Pratt & Whitney and the Raytheon Technologies Research Center embarked upon a program to develop technologies to enable an all-axial high-pressure compressor with a core size below 3.0 lb/s and an overall pressure ratio greater than 50. One of the challenges with an all-axial high-pressure compressor at this core size is the small span at the rear of the compressor. As core size is scaled down, the rotor tip clearances do not scale with span, leading to significant efficiency penalties. This paper documents a numerical and experimental effort to mitigate this penalty through design optimization and technology insertion, enabling an estimated 5 to 10% fuel burn reduction relative to 2020 best-in-class. The experimental program consisted of two builds of a high-speed rig: a baseline build and a second build to insert technology to manage large rotor tip gap/span ratios. The results demonstrated a reduction in the sensitivity of the compressor to large clearance ratios, which would be likely at the end-of-life of a small core application. The test campaign demonstrated that, with the insertion of technology, small core compressors can maintain a similar efficiency to current best-in-class large core size compressors. In addition to advancing the state-of-the-art of technology, the program also advanced the modeling standards for multistage compressors with large clearance-to-span ratios. The validation of this approach is described in the paper.

Axial Compressors↗

Enhanced Elliptic Grid Generation

An enhanced method of elliptic grid generation has been invented. Whereas prior methods require user input of certain grid parameters, this method provides for these parameters to be determined automatically. "Elliptic grid generation" signifies generation of generalized curvilinear coordinate grids through solution of elliptic partial differential equations (PDEs). Usually, such grids are fitted to bounding bodies and used in numerical solution of other PDEs like those of fluid flow, heat flow, and electromagnetics. Such a grid is smooth and has continuous first and second derivatives (and possibly also continuous higher-order derivatives), grid lines are appropriately stretched or clustered, and grid lines are orthogonal or nearly so over most of the grid domain. The source terms in the grid-generating PDEs (hereafter called "defining" PDEs) make it possible for the grid to satisfy requirements for clustering and orthogonality properties in the vicinity of specific surfaces in three dimensions or in the vicinity of specific lines in two dimensions. The grid parameters in question are decay parameters that appear in the source terms of the inhomogeneous defining PDEs. The decay parameters are characteristic lengths in exponential- decay factors that express how the influences of the boundaries decrease with distance from the boundaries. These terms govern the rates at which distance between adjacent grid lines change with distance from nearby boundaries. Heretofore, users have arbitrarily specified decay parameters. However, the characteristic lengths are coupled with the strengths of the source terms, such that arbitrary specification could lead to conflicts among parameter values. Moreover, the manual insertion of decay parameters is cumbersome for static grids and infeasible for dynamically changing grids. In the present method, manual insertion and user specification of decay parameters are neither required nor allowed. Instead, the decay parameters are determined automatically as part of the solution of the defining PDEs. Depending on the shape of the boundary segments and the physical nature of the problem to be solved on the grid, the solution of the defining PDEs may provide for rates of decay to vary along and among the boundary segments and may lend itself to interpretation in terms of one or more physical quantities associated with the problem.

Kaul, Upender K.↗

Sublimation temperature sensor for temperature locale

The sublimation temperature sensor (or “sublime sensor”) provides a continuum of measurement locations in which certain maximum temperatures are achieved during a heat up/cool down cycle. A predetermined material is encapsulated within a vacuum-sealed, non-volatile long tube (i.e., both ends capped and L$\gg$ D). This assembly is then inserted and centered into a heated zone, such as a furnace, exhaust pipe, or reactor. As the temperature increases, the material will sublimate (i.e., a process of having both the solid and gaseous states of matter simultaneously present) and will begin to fill the void - moving outward in both directions toward the ends of the tube. Once beyond the elevated temperatures, the gas will de-sublimate (i.e., deposition) onto the inner wall of the tube. The desired result of the sensor is the ring of material that develops over a relatively short period of time. This material deposit can be equated with temperature at an exact location. There is no need to interpolate and/or extrapolate for the desired measurement. Accuracy has been recorded for temperature locations on the range of ±2 mm over a 1 m span. Likewise, the precision of the measurement is ±0.2% the overall sensor domain. Furthermore, individual tubes with unique materials and pressures can be bundled together to provide a complete temperature profile of the heated zone.

46 INSTRUMENTATION RELATED TO NUCLEAR SCIENCE AND ↗

SPARC: Structural properties associated with residue constraints

SPARC facilitates the generation of plausible hypotheses regarding underlying biochemical mechanisms by structurally characterizing protein sequence constraints. Such constraints appear as residues co-conserved in functionally related subgroups, as subtle pairwise correlations (i.e., direct couplings), and as correlations among these sequence features or with structural features. SPARC performs three types of analyses. First, based on pairwise sequence correlations, it estimates the biological relevance of alternative conformations and of homomeric contacts, as illustrated here for death domains. Second, it estimates the statistical significance of the correspondence between directly coupled residue pairs and interactions at heterodimeric interfaces. Third, given molecular dynamics simulated structures, it characterizes interactions among constrained residues or between such residues and ligands that: (a) are stably maintained during the simulation; (b) undergo correlated formation and/or disruption of interactions with other constrained residues; or (c) switch between alternative interactions. We illustrate this for two homohexameric complexes: the bacterial enhancer binding protein (bEBP) NtrC1, which activates transcription by remodeling RNA polymerase (RNAP) containing σ 54 , and for DnaB helicase, which opens DNA at the bacterial replication fork. Based on the NtrC1 analysis, we hypothesize possible mechanisms for inhibiting ATP hydrolysis until ADP is released from an adjacent subunit and for coupling ATP hydrolysis to restructuring of σ 54 binding loops. Based on the DnaB analysis, we hypothesize that DnaB ‘grabs’ ssDNA by flipping every fourth base and inserting it into cavities between subunits and that flipping of a DnaB-specific glutamine residue triggers ATP hydrolysis.

97 MATHEMATICS AND COMPUTING↗

SMC 2021 : Analyzing Resource Utilization and User Behavior on Titan Supercomputer

Resource utilization statistics of submitted jobs on a supercomputer can help us understand how users from various scientific domains use HPC platforms and better design a job scheduler. We explore to generate insight regarding workload distribution and usage pattern domains from job scheduler trace, GPU failure information, and project-specific information collected from Titan supercomputer. Furthermore, we want to know how the scheduler performance varies over time and how the users' scheduling behavior changes following a system failure. These observations have the potential to provide valuable insight, which is helpful to prepare for system failures. These practices will help us develop and apply novel machine learning algorithms in understanding system behavior, requirement, and better scheduling of HPC systems. There are two datasets, RUR and GPU. RUR: This dataset is the job scheduler traces collected from the Titan supercomputerfrom 01/01/2015 to 07/31/2019 (2015.csv - 2019.csv). These were collected usingResource Utilization Report (RUR), a Cray-developed resource-usage data collectionand reporting system. It contains the usage information of its critical resources (CPU,Memory, GPU, and I/O) of each running job on Titan during that period [2]. ProjectAreas: Every job is associated with a project ID. TheProjectAreas.csvdatasetprovides a mapping of the project ID to its domain science. GPU: There have been some hardware-related issues in the GPUs in Titan that caused some GPUs to fail, sometimes irrecoverably during some job runs. This dataset provides information regarding these failures during the execution of the submitted jobs. GPUs on Titan are uniquely identified by a serial number (SN), and they are installed in a location. A GPU can be installed in a location, then removed from that location following a failure, and then re-installed in a different location after fixing the problem. If the failure can't be recovered, the GPU might be removed entirely from Titan. There are two prominent types of failures that resulted in the removal of GPUs from Titan: Double Bit Error (DBE) and Out of the Bus (OTB). The dataset (gc_full.csv) has the following fields: 1. SN : Serial number of a GPU 2. location : The location where it is installed 3. insert : The time when it was inserted into that location 4. remove : The time when it was removed from that location 5. duration : Amount of time the GPU spent in this location 6. out : If the device was taken out entirely w/o a re-installment into a new location. 7. event : If the GPU was taken out entirely, the reason for its removal. To learn more about this dataset, please refer to the git repositoryhttps://github.com/olcf/TitanGPULifeand the related publication [1]. References [1] George Ostrouchov, Don Maxwell, Rizwan A Ashraf, Christian Engelmann, MallikarjunShankar, and James H Rogers. Gpu lifetimes on titan supercomputer: Survival analysisand reliability. InSC20: International Conference for High Performance Computing,Networking, Storage and Analysis, pages 1-14. IEEE, 2020. [2] Feiyi Wang, Sarp Oral, Satyabrata Sen, and Neena Imam. Learning from five-yearresource-utilization data of titan system. In2019 IEEE International Conference onCluster Computing (CLUSTER), pages 1-6. IEEE, 2019.

42 ENGINEERING↗

NASA High Efficiency, High OPR Capable Small Core Compressor

As future aircraft become lighter and more aerodynamically efficient, thrust requirements will decrease, reducing the core size of the engine. Furthermore, in the pursuit of improved fuel burn, engine overall pressure ratio and bypass ratio will increase, further driving down engine core size (core size being defined as high-pressure compressor [HPC] exit-corrected flow). These drivers together mean that the core size for future single-aisle aircraft applications will shrink below 3.0 lb/s. Traditionally, this small core compressor size is in the domain of axi-centrifugal designs, machines that are typically less efficient and limited to pressure ratios of ~25 due to stress and thermomechanical fatigue in the centrifugal impeller. In this light, NASA and Pratt & Whtiney (P&W) embarked upon a program to develop technologies to enable an all-axial high-pressure compressor with a core size below 3.0 lb/s and an overall pressure ratio greater than 50. The challenge with an all-axial high-pressure compressor at this core size is the small span at the rear of the compressor. As core size is scaled down, the rotor tip clearances, stator hub seal clearances, fillet sizes and leading edge thicknesses do not scale, leading to significant efficiency penalties. The goal of this program is to recover this lapse and realize the cycle benefits of small core size and high overall pressure ratio. The small core challenges described are mitigated through design optimization and technology insertion, enabling an estimated 5 to 10% fuel burn reduction relative to 2020 best-in-class. Three test rigs run at NASA Glenn Research Center evolved the small core design: a low-speed rig to vet technology and validate tools, and two high speeds rigs, the first to demonstrate an optimized meanline design and the second to validate technology to manage large rotor tip gaps. The efficiency improvement validated with these rigs has unlocked the small core design space, demonstrating that small core compressors can maintain a similar efficiency to current best-in-class large core size compressors. In addition to advancing the state-of-the-art of technology, the program has also advanced the modeling standards for multistage compressors with large clearance-to-span ratios. A best practice modeling standard was developed over the course of the program, incorporating learning from all three rig programs.

Axial Compressors↗

Mission Simulation Toolkit

The Mission Simulation Toolkit (MST) is a flexible software system for autonomy research. It was developed as part of the Mission Simulation Facility (MSF) project that was started in 2001 to facilitate the development of autonomous planetary robotic missions. Autonomy is a key enabling factor for robotic exploration. There has been a large gap between autonomy software (at the research level), and software that is ready for insertion into near-term space missions. The MST bridges this gap by providing a simulation framework and a suite of tools for supporting research and maturation of autonomy. MST uses a distributed framework based on the High Level Architecture (HLA) standard. A key feature of the MST framework is the ability to plug in new models to replace existing ones with the same services. This enables significant simulation flexibility, particularly the mixing and control of fidelity level. In addition, the MST provides automatic code generation from robot interfaces defined with the Unified Modeling Language (UML), methods for maintaining synchronization across distributed simulation systems, XML-based robot description, and an environment server. Finally, the MSF supports a number of third-party products including dynamic models and terrain databases. Although the communication objects and some of the simulation components that are provided with this toolkit are specifically designed for terrestrial surface rovers, the MST can be applied to any other domain, such as aerial, aquatic, or space.

Pisaich, Gregory↗

The Effects of Partial Mechanical Loading and Ibandronate on Skeletal Tissues in the Adult Rat Hindquarter Suspension Model for Microgravity

We report initial data from a suspended rat model that quantitatively relates chronic partial weightbearing to bone loss. Chronic partial weightbearing is our simulation of the effect of limited artificial gravity aboard spacecraft or reduced planetary gravity. Preliminary analysis of bone by PQCT, histomorphometry, mechanical testing and biochemistry suggest that chronic exposure to half of Earth gravity is insufficient to prevent severe bone loss. The effect of episodic full weightbearing activity (Earth Gravity) on rats otherwise at 50% weightbearing was also explored. This has similarity to treatment by an Earth G-rated centrifuge on a spacecraft that normally maintained artificial gravity at half of Earth G. Our preliminary evidence, using the above techniques to analyze bone, indicate that 2 hours daily of full weightbearing was insufficient to prevent the bone loss observed in 50% weightbearing animals. The effectiveness of partial weightbearing and episodic full weightbearing as potential countermeasures to bone loss in spaceflight was compared with treatment by ibandronate. Ibandronate, a long-acting potent bisphosphonate proved more effective in preventing bone loss and associated functionality based upon structure than our first efforts at mechanical countermeasures. The effectiveness of ibandronate was notable by each of the testing methods we used to study bone from gross structure and strength to tissue and biochemistry. These results appear to be independent of generalized systemic stress imposed by the suspension paradigm. Preliminary evidence does not suggest that blood levels of vitamin D were affected by our countermeasures. Despite the modest theraputic benefit of mechanical countermeasures of partial weightbearing and episodic full weightbearing, we know that some appropriate mechanical signal maintains bone mass in Earth gravity. Moreover, the only mechanism that correctly assigns bone mass and strength to oppose regionally specific force applied to bone is mechanical, a process based upon bone strain. Substantial evidence indicates that the specifics of dynamic loading i.e. time-varying forces are critical. Bone strain history is a predictor of the effect that mechanical conditions have on bone structure mass and strength. Using servo-controlled force plates on suspended rats with implanted strain gauges we manipulated impact forces of ambulation in the frequency (Fourier) domain. Our results indicate that high frequency components of impact forces are particularly potent in producing bone strain independent of the magnitude of the peak force or peak energy applied to the leg. Because a servo-system responds to forces produced by the rat's own muscle activity during ambulation, the direction of ground-reaction loads act on bone through the rat's own musculature. This is in distinction to passive vibration of the floor where forces reach bone through the natural filters of soft tissue and joints. Passive vibration may also be effective, but it may or may not increase bone in the appropriate architectural pattern to oppose the forces of normal ambulatory activity. Effectiveness of high frequency mechanical stimulation in producing regional (muscle directed) bone response will be limited by 1. the sensitivity of bone to a particular range of frequencies and 2. the inertia of the muscles, limiting their response to external forces by increasing tension along insertions. We have begun mathematical modeling of normal ambulatory activity. Effectiveness of high frequency mechanical stimulation in producing regional (muscle directed) bone response will be limited by 1. the sensitivity of bone to a particular range of frequencies and 2. the inertia of the muscles, limiting their response to external forces by increasing tension along insertions. We have begun mathematical modeling of the rat forelimb as a transfer function between impact force and bone strain to predict optimal dynamic loading conditions for this system. We plan additional studies of mechanical counter-measures that incorporate improved dynamic loading, features relevant to anticipated evaluation of artificial gravity, exercise regimens and exposure to Martian gravity, The combination of mechanical countermeasures with ibandronate will also be investigated for signs of synergy.

Schultheis, Lester W.↗

The Story of 5d Metallocorroles: From Metal–Ligand Misfits to New Building Blocks for Cancer Phototherapeutics

Porphyrin chemistry is Shakespearean: over a century of study has not withered the field’s apparently infinite variety. Heme proteins continually astonish us with novel molecular mechanisms, while new porphyrin analogues bowl us over with unprecedented optical, electronic, and metal-binding properties. Within the latter domain, corroles occupy a special place, exhibiting a unique and rich coordination chemistry. The 5d metallocorroles are arguably the icing on that cake. New Zealand chemist Penny Brothers has used the word “misfit” to describe the interactions of boron, a small atom with a predilection for tetrahedral coordination, and porphyrins, classic square-planar ligands. Steve Jobs lionized misfits as those who see things differently and push humanity forward. Both perspectives have inspired us. The 5d metallocorroles are misfits in that they encapsulate a large 5d transition metal ion within the tight cavity of a contracted porphyrin ligand. Given the steric mismatch inherent in their structures, the syntheses of some 5d metallocorroles are understandably capricious, proceeding under highly specific conditions and affording poor yields. Three broad approaches may be distinguished. (a) In the metal–alkyl approach, a free-base corrole is exposed to an alkyllithium and the resulting lithio-corrole is treated with an early transition metal chloride; a variant of the method eschews alkyllithium and deploys a transition metal–alkyl instead, resulting in elimination of the alkyl group as an alkane and insertion of the metal into the corrole. This approach is useful for inserting transition metals from groups 4, 5, and, to some extent, 6, as well as lanthanides and actinides. (b) In our laboratory, we have often deployed a low-valent organometallic approach for the middle transition elements (groups 6, 7, 8, and 9). The reagents are low-valent metal–carbonyl or −olefin complexes, which lose one or more carbon ligands at high temperature, affording coordinatively unsaturated, sticky metal fragments that are trapped by the corrole nitrogens. (c) Finally, a metal acetate approach provides the method of choice for gold and platinum insertion (groups 10 and 11). This Account provides a first-hand perspective of the three approaches, focusing on the last two, which were largely developed in our laboratory. In general, the products were characterized with X-ray crystallography, electrochemistry, and a variety of spectroscopic methods. The physicochemical data, supplemented by relativistic DFT calculations, have provided fascinating insights into periodic trends and relativistic effects. An unexpected feature of many 5d metallocorroles, given their misfit character, is their remarkable stability under thermal, chemical, and photochemical stimulation. Many of them also exhibit long triplet lifetimes on the order of 100 μs and effectively sensitize singlet oxygen formation. Many exhibit phosphorescence in the near-infrared under ambient conditions. Furthermore, water-soluble ReO and Au corroles exhibit impressive photocytotoxicity against multiple cancer cell lines, promising potential applications as cancer phototherapeutics. We thus envision a bright future for the compounds as rugged building blocks for new generations of therapeutic and diagnostic (theranostic) agents.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Characterization of a Novel CD4 Mimetic Compound YIR-821 against HIV-1 Clinical Isolates

Small CD4-mimetic compound (CD4mc), which inhibits the interaction between gp120 with CD4, acts as an entry inhibitor and induces structural changes in the HIV-1 envelope glycoprotein trimer (Env) through its insertion within the Phe43 cavity of gp120. Here, we recently developed YIR-821, a novel CD4mc, that has potent antiviral activity and lower toxicity than the prototype NBD-556. To assess the possibility of clinical application of YIR-821, we tested its antiviral activity using a panel of HIV-1 pseudoviruses from different subtypes. YIR-821 displayed entry inhibitor activity against 53.5% (21/40) of the pseudoviruses tested and enhanced neutralization mediated by coreceptor binding site (CoRBS) antibodies in 50% (16/32) of these. Furthermore, when we assessed the antiviral effects using a panel of pseudoviruses and autologous plasma IgG, enhancement of antibody-mediated neutralization activity was observed for 48% (15/31) of subtype B strains and 51% (28/55) of non-B strains. The direct antiviral activity of YIR-821 as an entry inhibitor was observed in 53% of both subtype B (27/51) and non-B subtype (40/75) pseudoviruses. Enhancement of antibody-dependent cellular cytotoxicity was also observed with YIR-821 for all six selected clinical isolates, as well as for the transmitted/founder (T/F) CH58 virus-infected cells. The sequence diversity in the CD4 binding site as well as other regions, such as the gp120 inner domain layers or gp41, may be involved in the multiple mechanisms related to the sensitive/resistant phenotype of the virus to YIR-821. Our findings may facilitate the clinical application of YIR-821.

60 APPLIED LIFE SCIENCES↗

ExMC Technology Watch

The Technology Watch (Tech Watch) project is a NASA endeavor conducted under the Human Research Programs (HRP) Exploration Medical Capability (ExMC) element, and focusing on ExMC technology gaps. The project involves several NASA centers, including the Johnson Space Center (JSC), Glenn Research Center (GRC), Ames Research Center (ARC), and the Langley Research Center (LaRC). The objective of Tech Watch is to identify emerging, high-impact technologies that augment current NASA HRP technology development efforts. Identifying such technologies accelerates the development of medical care and research capabilities for the mitigation of potential health issues encountered during human space exploration missions. The aim of this process is to leverage technologies developed by academia, industry and other government agencies and to identify the effective utilization of NASA resources to maximize the HRP return on investment. The establishment of collaborations with these entities is beneficial to technology development, assessment and/or insertion and further NASAs goal to provide a safe and healthy environment for human exploration. In 2011, the major focus areas for Tech Watch included information dissemination, education outreach and public accessibility to technology gaps and gap reports. The dissemination of information was accomplished through site visits to research laboratories and/or companies, and participation at select conferences where Tech Watch objectives and technology gaps were presented. Presentation of such material provided researchers with insights on NASA ExMC needs for space exploration and an opportunity to discuss potential areas of common interest. The second focus area, education outreach, was accomplished via two mechanisms. First, several senior student projects, each related to an ExMC technology gap, were sponsored by the various NASA centers. These projects presented ExMC related technology problems firsthand to collegiate laboratories. Second, a RASC-AL (Revolutionary Aerospace Systems Concepts Academic Linkage) topic for FY12 was developed for medical systems and astronaut health under the Human-Focused Mars Mission Systems and Technologies theme. Announcement of the competition was made to the public in August 2011. Finally, critical Tech Watch information was prepared for public release in the form of gap reports. Complementing the ExMC technology gaps in the public domain, gap reports were generated, reviewed and revised through a series of technical, medical and subject matter expert reviews before approval for public release. An important vehicle for the public release of such documents was development of the ExMC wiki website, which will continue to be populated with gap reports and relevant documents throughout the upcoming year.

Krihak, M.↗

ExMC Technology Watch

The Technology Watch (Tech Watch) project is a NASA endeavor conducted under the Human Research Program's (HRP) Exploration Medical Capability (ExMC) element, and focusing on ExMC technology gaps. The project involves several NASA centers, including the Johnson Space Center (JSC), Glenn Research Center (GRC), Ames Research Center (ARC), and the Langley Research Center (LaRC). The objective of Tech Watch is to identify emerging, high-impact technologies that augment current NASA HRP technology development efforts. Identifying such technologies accelerates the development of medical care and research capabilities for the mitigation of potential health issues encountered during human space exploration missions. The aim of this process is to leverage technologies developed by academia, industry and other government agencies and to identify the effective utilization of NASA resources to maximize the HRP return on investment. The establishment of collaborations with these entities is beneficial to technology development, assessment and/or insertion and further NASA's goal to provide a safe and healthy environment for human exploration. In 2011, the major focus areas for Tech Watch included information dissemination, education outreach and public accessibility to technology gaps and gap reports. The dissemination of information was accomplished through site visits to research laboratories and/or companies, and participation at select conferences where Tech Watch objectives and technology gaps were presented. Presentation of such material provided researchers with insights on NASA ExMC needs for space exploration and an opportunity to discuss potential areas of common interest. The second focus area, education outreach, was accomplished via two mechanisms. First, several senior student projects, each related to an ExMC technology gap, were sponsored by the various NASA centers. These projects presented ExMC related technology problems firsthand to collegiate laboratories. Second, a RASC-AL (Revolutionary Aerospace Systems Concepts - Academic Linkage) topic for FY12 was developed for medical systems and astronaut health under the Human-Focused Mars Mission Systems and Technologies theme. Announcement of the competition was made to the public in August 2011. Finally, critical Tech Watch information was prepared for public release in the form of gap reports. Complementing the ExMC technology gaps in the public domain, gap reports were generated, reviewed and revised through a series of technical, medical and subject matter expert reviews before approval for public release. An important vehicle for the public release of such documents was development of the ExMC wiki website, which will continue to be populated with gap reports and relevant documents throughout the upcoming year.

Exploration medical capability↗