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At least 73 records · Page 4

HIV-1 protease inhibitors with a P1 phosphonate modification maintain potency against drug-resistant variants by increased interactions with flap residues

Protease inhibitors are the most potent antivirals against HIV-1, but they still lose efficacy against resistant variants. Improving the resistance profile is key to developing more robust inhibitors, which may be promising candidates for simplified next-generation antiretroviral therapies. Here, in this study, we explored analogs of darunavir with a P1 phosphonate modification in combination with increasing size of the P1′ hydrophobic group and various P2′ moieties to improve potency against resistant variants. The phosphonate moiety substantially improved potency against highly mutated and resistant HIV-1 protease variants, but only when combined with more hydrophobic moieties at the P1′ and P2′ positions. Phosphonate analogs with a larger hydrophobic P1′ moiety maintained excellent antiviral potency against a panel of highly resistant HIV-1 variants, with significantly improved resistance profiles. The cocrystal structures indicate that the phosphonate moiety makes extensive hydrophobic interactions with the protease, especially with the flap residues. Many residues involved in these protease-inhibitor interactions are conserved, enabling the inhibitors to maintain potency against highly resistant variants. These results highlight the need to balance inhibitor physicochemical properties by simultaneous modification of chemical groups to further improve resistance profiles.

60 APPLIED LIFE SCIENCES↗

CG-Kit: Code Generation Toolkit for performant and maintainable variants of source code applied to Flash-X hydrodynamics simulations

CG-Kit is a new Code Generation tool-Kit that we have developed as a part of the solution for portability and maintainability for multiphysics computing applications. The development of CG-Kit is rooted in the urgent need created by the shifting landscape of high-performance computing platforms and the algorithmic complexities of a particular large-scale multiphysics application: Flash-X. To efficiently use computing resources on a heterogeneous node, an application must have a map of computation to resources and a mechanism to move the data and computation to the resources according to the map. Most existing performance portability solutions are focussed on abstracting the expression of computations so that a unified source code can be specialized to run on different resources. However, such an approach is insufficient for a code like Flash-X, which has a multitude of code components that can be assembled in various permutations and combinations to form different instances of applications. Similar challenges apply to any code that has composability, where a single specified way of apportioning work among devices may not be optimal. Additionally, use cases arise where the optimal control flow of computation may differ for different devices while the underlying numerics remain identical. This combination leads to unique challenges including handling an existing large code base in Fortran and/or C/C++, subdivision of code into a great variety of units supporting a wide range of physics and numerical methods, different parallelization techniques for distributed and shared memory systems and accelerator devices, and heterogeneity of computing platforms requiring coexisting variants of parallel algorithms. All of these challenges demand that scientific software developers apply existing knowledge about domain applications, algorithms, and computing platforms to determine custom abstractions and granularity for code generation. There is a critical lack of tools to tackle those problems. CG-Kit is designed to fill this gap by providing a user with the ability to express their desired control flow and computation-to-resource map in the form a pseudocode-like recipe. It consists of standalone tools that can be combined into highly specific and, we argue, highly effective portability and maintainability toolchains. Here we present the design of our new tools: parametrized source trees, control flow graphs, and recipes. The tools are implemented in Python. They are agnostic to the programming language of the source code targeted for code generation. In conclusion, we demonstrate the capabilities of the toolkit with two examples, first, multithreaded variants of the basic AXPY operation, and second, variants of parallel algorithms within a hydrodynamics solver, called Spark, from Flash-X that operates on block-structured adaptive meshes.

Algorithmic portability↗

Uncovering the Role of Sgf73 in Maintaining SAGA Deubiquitinating Module Structure and Activity

The SAGA (Spt-Ada-Gcn5-acetyltransferase) complex performs multiple functions in transcription activation including deubiquitinating histone H2B, which is mediated by a subcomplex called the deubiquitinating module (DUBm). The yeast DUBm comprises a catalytic subunit, Ubp8, and three additional subunits, Sgf11, Sus1 and Sgf73, all of which are required for DUBm activity. A portion of the non-globular Sgf73 subunit lies between the Ubp8 catalytic domain and the ZnF-UBP domain and has been proposed to contribute to deubiquitinating activity by maintaining the catalytic domain in an active conformation. We report structural and solution studies of the DUBm containing two different Sgf73 point mutations that disrupt deubiquitinating activity. We find that the Sgf73 mutations abrogate deubiquitinating activity by impacting the Ubp8 ubiquitin-binding fingers region and have an unexpected effect on the overall folding and stability of the DUBm complex. Finally, taken together, our data suggest a role for Sgf73 in maintaining both the organization and ubiquitin-binding conformation of Ubp8, thereby contributing to overall DUBm activity.

59 BASIC BIOLOGICAL SCIENCES↗

Human amniotic epithelial cell feeder layers maintain human iPS cell pluripotency via inhibited endogenous microRNA-145 and increased Sox2 expression

Currently, human induced pluripotent stem (iPS) cells were generated from patient or disease-specific sources and share the same key properties as embryonic stem cells. This makes them attractive for personalized medicine, drug screens or cellular therapy. Long-term cultivation and maintenance of normal iPS cells in an undifferentiated self-renewing state are a major challenge. Our previous studies have shown that human amniotic epithelial cells (HuAECs) could provide a good source of feeder cells for mouse and human embryonic stem cells, or spermatogonial stem cells, but the mechanism for this is unknown. Here, we examined the effect of endogenous microRNA-145 regulation on Sox2 expression in human iPS cells by HuAECs feeder cells regulation, and in turn on human iPS cells pluripotency. We found that human IPS cells transfected with a microRNA-145 mutant expressed Sox2 at high levels, allowing iPS to maintain a high level of AP activity in long-term culture and form teratomas in SCID mice. Expression of stem cell markers was increased in iPS transfected with the microRNA-145 mutant, compared with iPS was transfected with microRNA-145. Besides, the expression of Drosha proteins of the microRNA-processor complex, required for the generation of precursor pre-miRNA, was significantly increased in human iPS cells cultured on MEF but not on HuAECs. Taken together, these results suggest that endogenous Sox2 expression may be regulated by microRNA-145 in human iPS cells with HuAECs feeder cells, and Sox2 is a crucial component required for maintenance of them in an undifferentiated, proliferative state capable of self-renewal. Highlights: Black-Right-Pointing-Pointer microRNA-145 inhibits Sox2 expression in human iPS cells. Black-Right-Pointing-Pointer microRNA-145 suppresses the self-renewal and pluripotency of human iPS cells. Black-Right-Pointing-Pointer HuAECs regulate expression of microRNA-145 and Sox2 in human iPS cells. Black-Right-Pointing-Pointer HuAECs feeder layers maintain human iPS cells pluripotency. Black-Right-Pointing-Pointer HuAECs negatively regulates the synthesis of primary precursor miRNA in human iPS.

60 APPLIED LIFE SCIENCES↗

SIRT1 reduces epigenetic and non-epigenetic changes to maintain the quality of postovulatory aged oocytes in mice

Highlights: • The intensity of H3K9ac and H3K4me2/3 increased in postovulatory aged oocytes. • SIRT1 overexpression inhibited the increase of H3K9ac and H3K4me2/3. • SIRT1 overexpression ameliorated aging-induced epigenetic and non-epigenetic changes in oocytes. Postovulatory oocyte aging has a major influence on the development potential of embryos. Many antioxidants can delay oocyte aging by regulating the expression of SIRT1. However, there is a lack of knowledge on SIRT1 function in postovulatory oocyte aging. In vitro transcribed RNA of Sirt1 was injected into fresh oocytes to investigate the function of SIRT1 during postovulatory oocyte aging. In the present study, SIRT1 was found to be down-regulated in aged oocytes compared with fresh oocytes. Meanwhile the intensity of acetylation of H3K9 (H3K9ac) and H3K4 methylation increased in postovulatory aged oocytes. After the oocytes were injected with SIRT1 and aged for 12 h, the intensity of H3K9ac and H3K4 methylation markedly decreased compared with controls. Furthermore, SIRT1 overexpression also reduced the aging-induced oocyte morphological changes and reactive oxygen species accumulation, maintained the spindle normal morphology and attenuated the aging-associated abnormalities of mitochondrial function. The role of SIRT1 in protecting oocyte aging was diminished when oocytes with overexpressed SIRT1 were cultured with SIRT1 inhibitor EX-527. Briefly, these present results show that SIRT1 not only reduced the non-epigenetic changes such as abnormal oocyte morphology, ROS accumulation, spindle defects and mitochondrial dysfunctions but also regulated the epigenetic changes in order to maintain the quality of postovulatory aged oocytes.

60 APPLIED LIFE SCIENCES↗

Spinel Cu–Mn–Cr Oxide Nanoparticle-Pigmented Solar Selective Coatings Maintaining >94% Efficiency at 750 °C

High-temperature concentrating solar power (CSP) system is capable of harvesting and storing solar energy as heat towards cost-effective dispatchable solar electricity. Solar selective coating is a critical component to boost its efficiency by maximizing solar absorptance and minimizing thermal emittance losses. However, maintaining a high solar-thermal conversion efficiency >90% for long-term operation at ≥750 ºC remains a significant challenge. Herein, we report spray-coated spinel Cu-Mn-Cr oxide nanoparticle-pigmented solar selective coatings on Inconel tube sections maintaining ≥94% efficiency at 750 ºC and ≥92.5% at 800 ºC under 1000x solar concentration after 60 simulated day-night thermal cycles in air, each cycle comprising 12h at 750 ºC/800 ºC and 12h cooling to 25 ºC. The solar spectral selectivity is intrinsic to the band-to-band and d-d transitions of non-stoichiometric spinel Cu-Mn-Cr oxide nanoparticles. Furthermore, this feature offers a large fabrication tolerance in nanoparticle volume fraction and coating thickness, facilitating low-cost and scalable spray-coated high-efficiency solar selective absorbers for high-temperature CSP systems.

14 SOLAR ENERGY↗

Tailored laser pulse chirp to maintain optimum radiation pressure acceleration of ions

Ion beams generated with ultra-intense laser-plasma accelerators hold promises to provide compact and affordable beams of relativistic ions. One of the most efficient acceleration setups was demonstrated to be direct acceleration by the laser's radiation pressure. Due to plasma instabilities developing in the ultra-thin foils required for radiation pressure acceleration, however, it is challenging to maintain stable acceleration over long distances. Recent studies demonstrated, on the other hand, that specially tailored laser pulses can shorten the required acceleration distance suppressing the onset of plasma instabilities. Here, we extend the concept of specific laser pulse shapes to the experimentally accessible parameter of a frequency chirp. We present a novel analysis of how a laser pulse chirp may be used to drive a foil target constantly maintaining optimal radiation pressure acceleration conditions for in dependence on the target's areal density and the laser's local field strength. Our results indicate that an appropriately frequency chirped laser pulse yields a significantly enhanced acceleration to higher energies and over longer distances suppressing the onset of plasma instabilities.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Maintaining low-mode symmetry control with extended pulse shapes for lower-adiabat Bigfoot implosions on the National Ignition Facility

The Bigfoot approach to indirect-drive inertial confinement fusion has been developed as a compromise trading high convergence and areal densities for high implosion velocities, large adiabats, and hydrodynamic stability. Shape control and predictability are maintained by using relatively short laser pulses and merging the shocks within the deuterium-tritium-ice layer. These design choices ultimately limit the theoretically achievable performance, and one strategy to increase the 1D performance is to reduce the shell adiabat by extending the pulse shape. However, this can result in the loss of low-mode symmetry control, as the hohlraum “bubble,” the high-Z material launched by the outer-cone beams during the early part of the laser pulse, has more time to expand and will eventually intercept inner-cone beams preventing them from reaching the hohlraum waist, thus losing an equatorial capsule drive. Experiments were performed to study the shape control and predictability with extended pulse shapes in Bigfoot implosions, reducing the adiabat from nominally α~4 to α~3 and otherwise very similar experimental parameters. Lastly, the implosion shape was measured both in-flight and at stagnation, with near-round implosions and low levels of P 2 asymmetry throughout, indicating a maintained symmetry control with extended pulse shapes.

70 PLASMA PHYSICS AND FUSION TECHNOLOGY↗

Kaposi’s sarcoma–associated herpesvirus stably clusters its genomes across generations to maintain itself extrachromosomally

Genetic elements that replicate extrachromosomally are rare in mammals; however, several human tumor viruses, including the papillomaviruses and the gammaherpesviruses, maintain their plasmid genomes by tethering them to cellular chromosomes. We have uncovered an unprecedented mechanism of viral replication: Kaposi’s sarcoma–associated herpesvirus (KSHV) stably clusters its genomes across generations to maintain itself extrachromosomally. To identify and characterize this mechanism, we developed two complementary, independent approaches: live-cell imaging and a predictive computational model. The clustering of KSHV requires the viral protein, LANA1, to bind viral genomes to nucleosomes arrayed on both cellular and viral DNA. Clustering affects both viral partitioning and viral genome numbers of KSHV. The clustering of KSHV plasmids provides it with an effective evolutionary strategy to rapidly increase copy numbers of genomes per cell at the expense of the total numbers of cells infected.

59 BASIC BIOLOGICAL SCIENCES↗

4-twist helix snake to maintain polarization in multi-GeV proton rings

Solenoid Siberian snakes have successfully maintained polarization in particle rings below 1 GeV, but never in multi-GeV rings, because the spin rotation by a solenoid is inversely proportional to the beam momentum. High energy rings, such as Brookhaven’s 255 GeV Relativistic Heavy Ion Collider (RHIC), use only odd multiples of pairs of transverse B-field Siberian snakes directly opposite each other. When it became impractical to use a pair of Siberian Snakes in Fermilab’s 120 GeV/c Main Injector, we searched for a new type of single Siberian snake that could overcome all depolarizing resonances in the 8.9–120 GeV/c range. We found that a snake made of one 4-twist helix and 2 dipoles could maintain the polarization. Here, this snake design could solve the long-standing problem of significant polarization loss during acceleration of polarized protons from a few GeV to tens of GeV, such as in the AGS, before injecting them into multi-hundred GeV rings, such as RHIC.

43 PARTICLE ACCELERATORS↗

Acquisitive root exploration strategies help maintain higher peak sap flux rates during summer drought, but more root biomass does not

Roots are responsible for soil water uptake, yet little is known about how variation in fine-root traits relates to whole-tree water movement, particularly during periods of drought. By combining a 3-yr dataset monitoring sap flow rates with measures of fine-root biomass, length, and morphology across 10 tree species, we addressed hypotheses concerning the role of fine-root system size and morphology in determining tree responses to summer drought as well as potential changes in their relative importance under more severe droughts. Greater fine-root biomass and length did not enable trees to maintain high rates of sap flow during drought, whereas the morphological traits, specific root length and specific root area, were linked to sustained sap flow rates during drought. We found that all species, irrespective of root traits, progressively reduced their sap flow under more extreme drought conditions, although more acquisitive root morphology was still associated with smaller reductions. Our results run counter to long-standing assumptions that larger root systems are better able to access soil water and maintain photosynthetic activity during drought. Instead, we find evidence that root morphology at least partially determines the capacity for water uptake and movement as soil moisture declines.

drought↗

Maintaining Continuity of Knowledge of Spent Fuel Pools: Field Testing (Final Report)

Maintaining Continuity of Knowledge (CoK) of spent fuel throughout its life cycle is a key objective of the International Atomic Energy Agency (IAEA). This report describes a project in which two specific technologies, cameras with infrared (IR) imaging capabilities and imaging sonar, were tested to determine their effectiveness in augmenting optical surveillance cameras currently used for maintaining CoK for spent nuclear fuel (SNF) staged in spent fuel pools. Furthermore, the project identifies any modifications required to the technologies to facilitate deployment for international safeguards purposes. This report presents results for the imaging sonar tested at Sandia National Laboratories (SNL) in a mockup spent nuclear fuel pool and for the IR-capable cameras tested by Pacific Northwest National Laboratory (PNNL) in the Oregon State University Training, Research, Isotopes, General Atomics (TRIGA) research reactor.

11 NUCLEAR FUEL CYCLE AND FUEL MATERIALS↗

Cantilever springs maintain tension in thermally expanded wires

Two deflected cantilever springs strung with wire provide force displacement compensation to maintain tension in the wires as they undergo thermal expansion. This method of maintaining tension in thermally expanded wires is used in electric space heaters and residential heat exchangers.

Terselic, R. A.↗

Continuous microbial cultures maintained by electronically-controlled device

Photocell-controlled instrument maintains microbial culture. It uses commercially available chemostat glassware, provides adequate aeration through bubbling of the culture, maintains the population size and density, continuously records growth rates over small increments of time, and contains a simple, sterilizable nutrient control mechanism.

Eisler, W. J., Jr.↗

Maintainability design criteria for packaging of spacecraft replaceable electronic equipment.

Maintainability must be designed into long-duration spacecraft and equipment to provide the required high probability of mission success with the least cost and weight. The ability to perform repairs quickly and easily in a space environment can be achieved by imposing specific maintainability design criteria on spacecraft equipment design and installation. A study was funded to investigate and define design criteria for electronic equipment that would permit rapid removal and replacement in a space environment. The results of the study are discussed together with subsequent simulated zero-g demonstration tests of a mockup with new concepts for packaging.

Kappler, J. R.↗

Using GPS and VLBI technology to maintain 14 digit synchronization

To facilitate the navigation of spacecraft to the outer planets, Jupiter and beyond, the JPL-NASA Deep Space Network (DSN) has implemented three ensembles of atomic clocks at widely separated locations. These clocks must be maintained, synchronized, to with a few parts in 10 to the 13th power of each other and, the entire group must be maintained, to a lesser degree, in synchronism with Coordinated Universal Time (UTC)NBS/USNO. Over the last 1 1/2 years the DSN has been using Global Positioning Satellites (GPS) and Very Long Baseline Interferometry (VLBI) technology to perform these critical Frequency and Time (F&T) synchronization tasks. A year of F&T synchronization data collected from the intercomparison of 3 sets of cesium and hydrogen maser driven clock ensembles through the use of GPS and VLBI techniques are covered. Also covered, are some of the problems met and limitations of these two techniques at their present level of technology.

Ward, S. C.↗

Maintainability planning for the Space Station

The planned NASA Space Station, which is expected to have many years of on-orbit operation, for the first time confronts spacecraft designers with major questions of maintainability in design. A Maintainability Guidelines Document has been distributed to all Space Station Definition and Preliminary Design personnel of the Space Station Program Office. Trade studies are being performed to determine the most economical balance between initial (reliability) cost and life cycle cost (crew time and replacement hardware) costs.

Egan, G. R.↗