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At least 937 records · Page 52

Evaluation of geophysical and anthropogenic sources of hydroacoustic noise in the Alaskan arctic

Quantifying the ocean soundscape is crucial for ocean-based seismoacoustic monitoring; it sets a baseline for the kinds and sizes of signals that can be detected above the background noise. As sea ice recedes, human activity in and around the Arctic Ocean is increasing, elevating sound levels and heightening the urgency of monitoring. Here, seven years of passive acoustic recordings from a National Oceanographic and Atmospheric Administration hydrophone in the Beaufort Sea are analyzed, focusing on frequencies between 1 and 125 Hz, a band of interest for detecting regional earthquakes and similar events. Sound is related to geophysical and anthropogenic sources, and seasonal and intraseasonal variations in the soundscape are examined. Sea ice emerges as a keystone feature of the Arctic Ocean acoustic environment, controlling or contributing to ambient sound levels at all frequencies studied. During low-ice months, sound levels are dominated by wind and sea surface waves, and in ice-covered months, wind-driven ice noise dominates. Seismic air gun surveys are prominent during low-ice periods, with sound levels decreasing with increasing distance and bathymetric complexity along the propagation path. The implications of this baseline soundscape for event detection in the Alaskan Arctic are discussed.

Niklasson, Siobhan [Los Alamos National Laboratory↗

3,3’-Diindolylmethane Exhibits Significant Metabolism After Oral Dosing in Humans

3,3’-Diindolylmethane (DIM), a major phytochemical derived from ingestion of cruciferous vegetables such as Brussels sprouts, is also a dietary supplement. In preclinical models, DIM is an effective cancer chemopreventive agent and has been studied in a number of clinical trials. Previous pharmacokinetic studies in preclinical and clinical models have not reported DIM metabolites in plasma or urine following oral dosing and the pharmacological actions of DIM on target tissues is assumed to be solely via the parent compound. Seven subjects (6 males and 1 female) ranging from 26-65 years of age, on a cruciferous vegetable-restricted diet prior to and during the study, took 2 BioResponse-DIM® 150 mg capsules (45.3 mg DIM/capsule) in the evening for one week with a final dose the morning of the first blood draw. A complete time course was performed with plasma and urine collected over 48 hours and analyzed by UPLC-MS/MS. In addition to parent DIM, two mono-hydroxylated (2-ox- and 3-methylenehydroxy-DIM) and 1 dihydroxylated (3-methylenehydroxy-2-ox-DIM) metabolites, along with their sulfate and glucuronide conjugates, were present in both plasma and urine. The results reported here are indicative of significant phase 1 and phase 2 metabolism and differ from previous pharmacokinetic studies in rodents and humans which reported only parent DIM present following oral administration.

Vermillion-Maier, Monica↗

Surface parameters and bedrock properties covary across a mountainous watershed: Insights from machine learning and geophysics

Bedrock property quantification is critical for predicting the hydrological response of watersheds to climate disturbances. Estimating bedrock hydraulic properties over watershed scales is inherently difficult, particularly in fracture-dominated regions. Our analysis tests the covariability of above- and belowground features on a watershed scale, by linking borehole geophysical data, near-surface geophysics, and remote sensing data. We use machine learning to quantify the relationships between bedrock geophysical/hydrological properties and geomorphological/vegetation indices and show that machine learning relationships can estimate most of their covariability. Although we can predict the electrical resistivity variation across the watershed, regions of lower variability in the input parameters are shown to provide better estimates, indicating a limitation of commonly applied geomorphological models. Our results emphasize that such an integrated approach can be used to derive detailed bedrock characteristics, allowing for identification of small-scale variations across an entire watershed that may be critical to assess the impact of disturbances on hydrological systems.

58 GEOSCIENCES↗

The future of Earth system prediction: Advances in model-data fusion

Predictions of the Earth system, such as weather forecasts and climate projections, require models informed by observations at many levels. Some methods for integrating models and observations are very systematic and comprehensive (e.g., data assimilation), and some are single purpose and customized (e.g., for model validation). We review current methods and best practices for integrating models and observations. We highlight how future developments can enable advanced heterogeneous observation networks and models to improve predictions of the Earth system (including atmosphere, land surface, oceans, cryosphere, and chemistry) across scales from weather to climate. As the community pushes to develop the next generation of models and data systems, there is a need to take a more holistic, integrated, and coordinated approach to models, observations, and their uncertainties to maximize the benefit for Earth system prediction and impacts on society.

54 ENVIRONMENTAL SCIENCES↗

Cryo-EM visualization of DNA-PKcs structural intermediates in NHEJ

DNA double-strand breaks (DSBs), one of the most cytotoxic forms of DNA damage, can be repaired by the tightly regulated nonhomologous end joining (NHEJ) machinery (Stinson and Loparo and Zhao et al.). Core NHEJ factors form an initial long-range (LR) synaptic complex that transitions into a DNA-PKcs (DNA-dependent protein kinase, catalytic subunit)–free, short-range state to align the DSB ends (Chen et al.). Using single-particle cryo–electron microscopy, we have visualized three additional key NHEJ complexes representing different transition states, with DNA-PKcs adopting distinct dimeric conformations within each of them. Upon DNA-PKcs autophosphorylation, the LR complex undergoes a substantial conformational change, with both Ku and DNA-PKcs rotating outward to promote DNA break exposure and DNA-PKcs dissociation. We also captured a dimeric state of catalytically inactive DNA-PKcs, which resembles structures of other PIKK (Phosphatidylinositol 3-kinase-related kinase) family kinases, revealing a model of the full regulatory cycle of DNA-PKcs during NHEJ.

59 BASIC BIOLOGICAL SCIENCES↗

CDK4/6 inhibition enhances SHP2 inhibitor efficacy and is dependent upon RB function in malignant peripheral nerve sheath tumors

Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft tissue sarcomas with limited treatment options, and new effective therapeutic strategies are desperately needed. We observe antiproliferative potency of genetic depletion of PTPN11 or pharmacological inhibition using the SHP2 inhibitor (SHP2i) TNO155. Our studies into the signaling response to SHP2i reveal that resistance to TNO155 is partially mediated by reduced RB function, and we therefore test the addition of a CDK4/6 inhibitor (CDK4/6i) to enhance RB activity and improve TNO155 efficacy. In combination, TNO155 attenuates the adaptive response to CDK4/6i, potentiates its antiproliferative effects, and converges on enhancement of RB activity, with greater suppression of cell cycle and inhibitor-of-apoptosis proteins, leading to deeper and more durable antitumor activity in in vitro and in vivo patient-derived models of MPNST, relative to either single agent. Overall, our study provides timely evidence to support the clinical advancement of this combination strategy in patients with MPNST and other tumors driven by loss of NF1.

60 APPLIED LIFE SCIENCES↗

Optical and electronic functionality arising from controlled defect formation in nanoscale complex oxide lateral epitaxy

Epitaxial crystallization of complex oxides provides the means to create materials with precisely selected composition, strain, and orientation, thereby controlling their functionalities. Extending this control to nanoscale three-dimensional geometries can be accomplished via a three-dimensional analog of oxide solid-phase epitaxy, lateral epitaxial crystallization. The orientation of crystals within laterally crystallized SrTiO 3 systematically changes from the orientation of the SrTiO 3 substrate. This evolution occurs as a function of lateral crystallization distance, with a rate of approximately 50° μm -1 . The mechanism of the rotation is consistent with a steady-state stress of tens of megapascal over a 100–nanometer scale region near the moving amorphous/crystalline interface arising from the amorphous-crystalline density difference. Second harmonic generation and piezoelectric force microscopy reveal that the laterally crystallized SrTiO 3 is noncentrosymmetric and develops a switchable piezoelectric response at room temperature, illustrating the potential to use lateral crystallization to control the functionality of complex oxides.

36 MATERIALS SCIENCE↗

Glaciers in California’s Sierra Nevada are likely disappearing for the first time in the Holocene

Mountain glaciers are sensitive climate indicators. Glaciers in the western United States are projected to disappear by 2100 CE, but whether they were previously absent in the current interglacial (past 11,700 years) remains debated. Here, we present evidence that two of the largest glaciers in California’s Sierra Nevada near Yosemite National Park persisted throughout the Holocene. Cosmogenic in situ carbon-14 and beryllium-10 exposure dating in newly exposed proglacial bedrock indicates continuous Holocene cover, likely by ice. At a nearby smaller glacier, bedrock exposure-burial ages suggest glacier expansion at ~7 thousand years ago, earlier than previously recognized. Moraine exposure ages at these sites and the Sierra Nevada’s largest glacier are distributed across the past several thousand years, suggesting that glaciers were near their preindustrial extent for much of the late Holocene. These findings imply that a glacier-free Sierra Nevada is unprecedented since before the Holocene. Future alpine glacial environments in California are thereby likely a no-analog scenario within the current interglacial.

Jones, Andrew G. [University of Wisconsin, Madison↗

Deep abiotic weathering of pyrite

Pyrite is a ubiquitous iron sulfide mineral that is oxidized by trace oxygen. The mineral has been largely absent from global sediments since the rise in oxygen concentration in Earth’s early atmosphere. We analyzed weathering in shale, the most common rock exposed at Earth’s surface, with chemical and microscopic analysis. By looking across scales from 10 −9 to 10 2 meters, we determined the factors that control pyrite oxidation. Under the atmosphere today, pyrite oxidation is rate-limited by diffusion of oxygen to the grain surface and regulated by large-scale erosion and clast-scale fracturing. We determined that neither iron- nor sulfur-oxidizing microorganisms control global pyrite weathering fluxes despite their ability to catalyze the reaction. This multiscale picture emphasizes that fracturing and erosion are as important as atmospheric oxygen in limiting pyrite reactivity over Earth’s history.

58 GEOSCIENCES↗

Atomic-scale polarization switching in wurtzite ferroelectrics

Ferroelectric wurtzites have the potential to revolutionize modern microelectronics because they are easily integrated with multiple mainstream semiconductor platforms. However, the electric fields required to reverse their polarization direction and unlock electronic and optical functions need substantial reduction for operational compatibility with complementary metal-oxide semiconductor (CMOS) electronics. To understand this process, we observed and quantified real-time polarization switching of a representative ferroelectric wurtzite (Al 0.94 B 0.06 N) at the atomic scale with scanning transmission electron microscopy. The analysis revealed a polarization reversal model in which puckered aluminum/boron nitride rings in the wurtzite basal planes gradually flatten and adopt a transient nonpolar geometry. Independent first-principles simulations reveal the details and energetics of the reversal process through an antipolar phase. Furthermore, this model and local mechanistic understanding are a critical initial step for property engineering efforts in this emerging material class.

36 MATERIALS SCIENCE↗

The military gear microbiome: risk factors surrounding the warfighter

ABSTRACT Combat extremity wounds are highly susceptible to contamination from surrounding environmental material. This bioburden could be partially transferred from materials in immediate proximity to the wound, including fragments of the uniform and gear. However, the assessment of the microbial bioburden present on military gear during operational conditions of deployment or training is relatively unexplored. Opportunistic pathogens that can survive on gear represent risk factors for infection following injury, especially following combat blasts, where fibers and other materials are embedded in wounded tissue. We utilized 16S rRNA sequencing to assess the microbiome composition of different military gear types (boot, trouser, coat, and canteen) from two operational environments (training in Hawai’i and deployed in Indonesia) across time (days 0 and 14). We found that microbiome diversity, stability, and composition were dependent on gear type, training location, and sampling timepoint. At day 14, species diversity was significantly higher in Hawai’i samples compared to Indonesia samples for boot, coat, and trouser swabs. In addition, we observed the presence of potential microbial risk factors, as opportunistic pathogenic species, such as Acinetobacter , Pseudomonas, and Staphylococcus , were found to be present in all sample types and in both study sites. These study outcomes will be used to guide the design of antimicrobial materials and uniforms and for infection control efforts following combat blasts and other injuries, thereby improving treatment guidance during military training and deployment. IMPORTANCE Combat extremity wounds are vulnerable to contamination from environments of proximity to the warfighter, leading to potential detrimental outcomes such as infection and delayed wound healing. Therefore, microbial surveillance of such environments is necessary to aid the advancement of military safety and preparedness through clinical diagnostics, treatment protocols, and uniform material design.

59 BASIC BIOLOGICAL SCIENCES↗

Understanding Hepatitis B Virus Dynamics and the Antiviral Effect of Interferon Alpha Treatment in Humanized Chimeric Mice

Whereas the mode of action of lamivudine (LAM) against hepatitis B virus (HBV) is well established, the inhibition mechanism(s) of interferon alpha (IFN-α) is less completely defined. To advance our understanding, we, for this study, mathematically modeled HBV kinetics during 14-day pegylated IFN-α-2a (pegIFN), LAM, or pegIFN-plus-LAM (pegIFN+LAM) treatment of 39 chronically HBV-infected humanized uPA/SCID chimeric mice. Serum HBV DNA and intracellular HBV DNA were measured frequently. We developed a multicompartmental mathematical model and simultaneously fit it to the serum and intracellular HBV DNA data. Unexpectedly, even in the absence of an adaptive immune response, a biphasic decline in serum HBV DNA and intracellular HBV DNA was observed in response to all treatments. Kinetic analysis and modeling indicate that the first phase represents inhibition of intracellular HBV DNA synthesis and secretion, which was similar under all treatments with an overall mean efficacy of 98%. In contrast, there were distinct differences in HBV decline during the second phase, which was accounted for in the model by a time-dependent inhibition of intracellular HBV DNA synthesis, with the steepest decline observed during pegIFN+LAM treatment (1.28/day) and the slowest (0.1/day) during pegIFN monotherapy. Reminiscent of observations in patients treated with pegIFN and/or LAM, a biphasic HBV decline was observed in treated humanized mice in the absence of an adaptive immune response. Interestingly, combination treatment did not increase the initial inhibition of HBV production but rather enhanced second-phase decline, providing insight into the dynamics of HBV treatment response and the mode of action of IFN-α against HBV.

60 APPLIED LIFE SCIENCES↗

Modeling of hepatitis B virus infection spread in primary human hepatocytes

ABSTRACT Chronic hepatitis B virus (HBV) infection poses a significant global health threat, causing severe liver diseases including cirrhosis and hepatocellular carcinoma. We characterized HBV DNA kinetics in primary human hepatocytes (PHHs) over 32 days post-inoculation (p.i.) and modified ourin-vivoagent-based modeling (ABM) to gain insights into the HBV lifecycle and spreadin vitro. Parallel PHH cultures were mock-treated or treated with HBV entry inhibitor Myr-preS1 (6.25 µg/mL) was initiated 24 h p.i. In untreated PHH, three viral DNA kinetic patterns were identified: (i) an initial decline, followed by (ii) rapid amplification and (iii) slower amplification/accumulation. In the presence of Myr-preS1, viral DNA and infected cell numbers in phase 3 were effectively blocked, with minimal to no increase. This suggests that phase 2 represents viral amplification in initially infected cells, while phase 3 corresponds to viral spread to naïve cells. The ABM reproduced well the HBV kinetic patterns observed and predicted that the viral eclipse phase lasts between 18 and 38 h. After the eclipse phase, the viral production rate increased over time, starting with a slow production cycle of 1 virion per day, which gradually accelerated to 1 virion per hour after 3 days. Approximately 4 days later, virion production reached a steady state production rate of 4 virions/h. The estimated median efficacy of Myr-preS1 in blocking HBV spread was 91% (range: 90–92%). The HBV kinetics and the predicted estimates of the HBV eclipse phase duration and HBV production cycles in PHH are similar to those predicted in uPA/SCID mice with human livers. IMPORTANCE While primary human hepatocytes (PHHs) are the most physiologically relevant culture system for studying HBV infectionin vitro, a comprehensive understanding of HBV infection kinetics and spread in PHH is lacking. In this study, we characterize HBV viral kinetics and modify ourin vivoagent-based modeling (ABM) to provide quantitative insights into the HBV production cycle and viral spread in PHH. The ABM provides an estimate of the HBV eclipse phase duration, HBV production cycles, and Myr-preS1 efficacy in blocking HBV spread in PHH. The results resemble those predicted in uPA/SCID mice with human livers, demonstrating that estimated HBV infection kinetic parameters in PHHin vitromirror those observed in thein vivoHBV infection chimeric mouse model.

Virology↗