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At least 667 records · Page 37

Inhibition of USP7 activity selectively eliminates senescent cells in part via restoration of p53 activity

The accumulation of senescent cells (SnCs) is a causal factor of various age-related diseases as well as some of the side effects of chemotherapy. Pharmacological elimination of SnCs (senolysis) has the potential to be developed into novel therapeutic strategies to treat these diseases and pathological conditions. Here we show that ubiquitin-specific peptidase 7 (USP7) is a novel target for senolysis because inhibition of USP7 with an inhibitor or genetic depletion of USP7 by RNA interference induces apoptosis selectively in SnCs. The senolytic activity of USP7 inhibitors is likely attributable in part to the promotion of the human homolog of mouse double minute 2 (MDM2) ubiquitination and degradation by the ubiquitin–proteasome system. This degradation increases the levels of p53, which in turn induces the pro-apoptotic proteins PUMA, NOXA, and FAS and inhibits the interaction of BCL-XL and BAK to selectively induce apoptosis in SnCs. Further, we show that treatment with a USP7 inhibitor can effectively eliminate SnCs and suppress the senescence-associated secretory phenotype (SASP) induced by doxorubicin in mice. These findings suggest that small molecule USP7 inhibitors are novel senolytics that can be exploited to reduce chemotherapy-induced toxicities and treat age-related diseases.

59 BASIC BIOLOGICAL SCIENCES↗

Toward Understanding the Effect of Low-Activity Waste Glass Composition on Sulfur Solubility

The concentration of sulfur in nuclear waste glass melter feed must be maintained below the point where salt accumulates on the melt surface. The allowable concentrations may range from 0.37 to over 2.05 weight percent (of SO3 on a calcined oxide basis). If the amount of sulfur exceeds its tolerance level a molten salt will accumulate and upset melter operations and potentially shorten melter useful life. Therefore relatively conservative limits have been placed on sulfur loading in melter feed which in-turn significantly impacts the amount of glass that will be produced, in particular at the Hanford site. Crucible-scale sulfur solubility data and scaled melter sulfur tolerance data have been collected on simulated Hanford waste glasses over the last 15 years. These data were compiled and analyzed. A model was developed to predict the solubility of SO3 in glass based on 312 individual glass compositions. This model was shown to well represent the data, accounting for over 80% of the variation in data and was well validated. The model was also found to accurately predict the tolerance for sulfur in melter feed based on 19 scaled melter tests. The model is appropriate for control of waste glass processing which includes uncertainty quantification. The model also gives quantitative estimates of component concentration effects on sulfur solubility. The components that most increase sulfur solubility are Li2O > V2O5 ≈ TiO2 < CaO < P2O5 ≈ ZnO. The components that most decrease sulfur solubility are Cl > Cr2O3 > SiO2 ≈ ZrO2 > Al2O3.

Borosilicate↗

Exploration of structure-activity relationships for the SARS-CoV-2 macrodomain from shape-based fragment linking and active learning

The macrodomain of severe acute respiratory syndrome coronavirus 2 nonstructural protein 3 is required for viral pathogenesis and is an emerging antiviral target. We previously performed an x-ray crystallography–based fragment screen and found submicromolar inhibitors by fragment linking. However, these compounds had poor membrane permeability and liabilities that complicated optimization. Here, we developed a shape-based virtual screening pipeline—FrankenROCS. We screened the Enamine high-throughput collection of 2.1 million compounds, selecting 39 compounds for testing, with the most potent binding with a 130 μM median inhibitory concentration (IC 50 ). We then paired FrankenROCS with an active learning algorithm (Thompson sampling) to efficiently search the Enamine REAL database of 22 billion molecules, testing 32 compounds with the most potent binding with a 220 μM IC 50 . Further optimization led to analogs with IC 50 values better than 10 μM. This lead series has improved membrane permeability and is poised for optimization. FrankenROCS is a scalable method for fragment linking to exploit synthesis-on-demand libraries.

Science & Technology - Other Topics↗

Activity and Stability of (Pr 1-x Nd x ) 2 NiO 4 as Cathodes for Solid Oxide Fuel Cells: Part V. In Situ Studies of Phase Evolution

This study is to complement an early report (the manuscript is attached for review purpose) on the role of interlayer on activity and performance stability in praseodymium nickelates. The aforementioned report showed a remarkable 48% increase in power density while switching from common GDC interlayer to a new interlayer chemistry (PGCO). Furthermore, a stable long-term performance was linked with suppressed reaction between the cathode and PGCO interlayer. In this article, we report in situ studies of the phase evolution. The high energy XRD studies at a synchrotron source showed fully suppressed phase transition in praseodymium nickelates with PGCO interlayer, while the electrodes on the GDC interlayer undergo substantial phase transformation. Furthermore, in operando and post-test XRD analyses shown fully suppressed structural changes in electrodes operated in full cells at 750°C and 0.80 V for 500 hours. SEM-EDS analysis showed that the formation of PrO x at the cathode-interlayer interface may play a role in a decrease of mechanical integrity of the interfaces, due to thermal expansion mismatch, leading to a local stress between the two phases. Furthermore, phase evolution at a narrow interface may propagate toward the electrode bulk, leading to structural changes Q1 and performance degradation.

37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CH↗

Laser induced damage in coatings for cryogenic Yb:YAG active mirror amplifiers

We report results of a study of the laser induced damage threshold (LIDT) behavior of ion beam sputtered H f O 2 / S i O 2 multilayer coatings on Yb:YAG using 1-on-1 and N-on-1 test protocols. The tests were conducted at ambient, vacuum, and cryogenic conditions using 280 ps pulses at λ <#comment/> = 1030 n m . The 1-on-1 LIDT of antireflection (AR) stacks is found to be only slightly reduced under vacuum and cryogenic conditions, while that of high reflectivity (HR) stacks is insensitive to environmental conditions within the uncertainty of the measurements. Cryogenic N-on-1 tests show the LIDT of the HR coating is almost the same as in the 1-on-1 tests. Conversely, the cryogenic N-on-1 test of the AR coating shows damage at ∼ <#comment/> 13 J / c m 2 , a fluence lower than the 20.4 J / c m 2 of 1-on-1 tests. The AR damage behavior is found to be affected by imperfections at the Yb:YAG surface. These findings show that high surface quality is required to increase energy extraction from active mirror laser amplifiers.

Wang, Hanchen↗

Hierarchical Conceptual Model Event and Activity Domains for Forecasting State-Sponsored Civil Nuclear Power Activities

In FY20, the Savannah River National Laboratory and the Sanghani Center for Artificial Intelligence and Data Analytics (Virginia Tech) entered a collaboration funded by the Department of Energy’s Office of Defense Nuclear Nonproliferation Research and Development to develop a machine learning based modeling pipeline to extract proliferation events of interest from open data sources. The prototype modeling pipeline that was developed relies on the use of time dependent word embedding models to identify contextual shifts in key words and phrases that act as indicators of events of interest. The FY20- 21 efforts were focused on a narrow topical domain of forecasting “fissile core fabrication” at the Savannah River Site prior to its official announcement in 2018. In FY22, the research team was funded to continue development of the modeling pipeline by applying it to the problem of forecasting new, and/or significant changes to existing, civil nuclear power reactors around the world. In this effort, the development will focus on proving applicability to a broader topical domain and in data environments that may contain more sparse information, relative to the United States. In this report, the worldwide landscape of civil nuclear reactors is outlined, the timeline of interest is defined, and a hierarchical conceptual model is established to identify the activity domains of interest and the event domains of interest. This preliminary effort will guide the curation of a glossary of key terms for data acquisition, as well as the downstream modeling efforts.

22 GENERAL STUDIES OF NUCLEAR REACTORS↗

CHANDRA X-RAY AND HUBBLE SPACE TELESCOPE IMAGING OF OPTICALLY SELECTED KILOPARSEC-SCALE BINARY ACTIVE GALACTIC NUCLEI. II. HOST GALAXY MORPHOLOGY AND AGN ACTIVITY

Binary active galactic nuclei (AGNs) provide clues to how gas-rich mergers trigger and fuel AGNs and how supermassive black hole (SMBH) pairs evolve in a gas-rich environment. While significant effort has been invested in their identification, the detailed properties of binary AGNs and their host galaxies are still poorly constrained. In a companion paper, we examined the nature of ionizing sources in the double nuclei of four kiloparsec-scale binary AGNs with redshifts between 0.1 and 0.2. Here, we present their host galaxy morphology based on F336W ( U -band) and F105W ( Y -band) images taken by the Wide Field Camera 3 on board the Hubble Space Telescope . Our targets have double-peaked narrow emission lines and were confirmed to host binary AGNs with follow-up observations. We find that kiloparsec-scale binary AGNs occur in galaxy mergers with diverse morphological types. There are three major mergers with intermediate morphologies and a minor merger with a dominant disk component. We estimate the masses of the SMBHs from their host bulge stellar masses and obtain Eddington ratios for each AGN. Compared with a representative control sample drawn at the same redshift and stellar mass, the AGN luminosities and Eddington ratios of our binary AGNs are similar to those of single AGNs. The U − Y color maps indicate that clumpy star-forming regions could significantly affect the X-ray detection of binary AGNs, e.g., the hardness ratio. Considering the weak X-ray emission in AGNs triggered in merger systems, we suggest that samples of X-ray-selected AGNs may be biased against gas-rich mergers.

79 ASTRONOMY AND ASTROPHYSICS↗

Orbital operations study. Volume 2: Interfacing activities analyses. Part 3: Data management activity group

A summary of the findings of the data management group of the orbital operations study is presented. Element interfaces, alternate approaches, design concepts, operational procedures, functional requirements, design influences, and approach selection are described. The following interfacing activities are considered: (1) communications, (2) rendezvous, (3) stationkeeping, and (4) detached element operations.

Mehrbach, E.↗

Orbital operations study. Volume 2: Interfacing activities analysis. Part 4: Support operations activity group

The findings of the support operations activity group of the orbital operations study are presented. Element interfaces, alternate approaches, design concepts, operational procedures, functional requirements, design influences, and approach selection are presented. The following areas are considered: (1) crew transfer, (2) cargo transfer, (3) propellant transfer, (4) attached element operations, and (5) attached element transport.

Steinwachs, W. L.↗

The midlatitude ionospheric response to fluctuations in solar activity under low geomagnetic activity conditions

The ionospheric response, which is the sensitivity and delay of the electron content to the 270 day fluctuations of solar radiation has been theoretically analyzed. In the context of the present work the sensitivity is defined as the magnitude of the electron content fluctuation for a given change in solar flux, and the delay is defined as the timeshift of the response of the electron content to fluctuations in solar flux. Both the model in which the action of neutral winds on the F-2 layer is disregarded and that in which the wind effect is included as part of a positive feedback mechanism, are studied. It is shown that the neutral winds play a dominant role in the mentioned ionospheric response. The computed delays decrease with increasing solar activity in both models.

Bendito, J. L.↗

A method of predictions geomagnetic activity based on a coronal model of relations between solar and geomagnetic activities

A method developed to predict both disturbed and quiet geomagnetic periods is described. The method uses solar situations along the CM with the key role of filaments, giving indirect evidence of types of directly unobservable coronal structures above them. The time lag, not to be interpreted in terms of propagation speed, between the CM activity and the commencement of the geomagnetic response is about one to two days. Solar phenomena serve as indicators within approximately 10 deg of the CM and up to the zone of high latitude filaments.

Halenka, J.↗

Soviet short-term forecasts of active region evolution and flare activity

The structure and strength of the magnetic fields of the Sun's active regions were studied to obtain information for short term forecasting. Intensity forecasts were then made using the information obtained on the gradients of the magnetic fields between sunspots of opposite polarity. A comparison of flare forecasting methods is presented.

Severny, A. B.↗