Interspecies Differences in 6PPD-Quinone Toxicity Across Seven Fish Species: Metabolite Identification and Semiquantification.

N-(1,3-Dimethylbutyl)-N'-phenyl-p-phenylenediamine-quinone (6PPD-Q) is a recently identified contaminant that originates from the oxidation of the tire antidegradant 6PPD. 6PPD-Q is acutely toxic to select salmonids at environmentally relevant concentrations, while other fish species display tolerance to concentrations that surpass those measured in the environment. The reasons for these marked differences in sensitivity are presently unknown. The objective of this research was to explore potential toxicokinetic drivers of species sensitivity by characterizing biliary metabolites of 6PPD-Q in sensitive and tolerant fishes. For the first time, we identified an O-glucuronide metabolite of 6PPD-Q using high-resolution mass spectrometry. The semiquantified levels of this metabolite in tolerant species or life stages, including white sturgeon (Acipenser transmontanus), chinook salmon (Oncorhynchus tshawytscha), westslope cutthroat trout (Oncorhynchus clarkii lewisi), and nonfry life stages of Atlantic salmon (Salmo salar), were greater than those in sensitive species, including coho salmon (Oncorhynchus kisutch), brook trout (Salvelinus fontinalis), and rainbow trout (Oncorhynchus mykiss), suggesting that tolerant species might detoxify 6PPD-Q more effectively. Thus, we hypothesize that differences in species sensitivity are a result of differences in basal expression of biotransformation enzyme across various fish species. Moreover, the semiquantification of 6PPD-Q metabolites in bile extracted from wild-caught fish might be a useful biomarker of exposure to 6PPD-Q, thereby being valuable to environmental monitoring and risk assessment.

Multi-frame, ultrafast, x-ray microscope for imaging shockwave dynamics.

Inertial confinement fusion (ICF) holds increasing promise as a potential source of abundant, clean energy, but has been impeded by defects such as micro-voids in the ablator layer of the fuel capsules. It is critical to understand how these micro-voids interact with the laser-driven shock waves that compress the fuel pellet. At the Matter in Extreme Conditions (MEC) instrument at the Linac Coherent Light Source (LCLS), we utilized an x-ray pulse train with ns separation, an x-ray microscope, and an ultrafast x-ray imaging (UXI) detector to image shock wave interactions with micro-voids. To minimize the high- and low-frequency variations of the captured images, we incorporated principal component analysis (PCA) and image alignment for flat-field correction. After applying these techniques we generated phase and attenuation maps from a 2D hydrodynamic radiation code (xRAGE), which were used to simulate XPCI images that we qualitatively compare with experimental images, providing a one-to-one comparison for benchmarking material performance. Moreover, we implement a transport-of-intensity (TIE) based method to obtain the average projected mass density (areal density) of our experimental images, yielding insight into how defect-bearing ablator materials alter microstructural feature evolution, material compression, and shock wave propagation on ICF-relevant time scales.

Anthropogenic strath terrace formation caused by reduced sediment retention.

Across North America, human activities have been shown to cause river incision into unconsolidated alluvium. Human-caused erosion through bedrock, however, has only been observed in local and isolated outcrops. Here, we test whether splash-dam logging, which decreased in-stream alluvial cover by removing much of the alluvium-trapping wood, caused basin-wide bedrock river incision in a forested mountain catchment in Washington State. We date incision of the youngest of four strath terraces, using dendrochronology and radiocarbon, to between 1893 CE and 1937 CE in the Middle Fork Teanaway River and 1900 CE and 1970 CE in the West Fork Teanaway River, coincident with timber harvesting and splash damming in the basins. Other potential drivers of river incision lack a recognized mechanism to cause T1 incision or are not synchronous with T1 incision. Hence, the close temporal correspondence suggests that reduced sediment retention triggered by splash damming led to the observed 1.1 mm⋅y-1 to 23 mm⋅y-1 of bedrock river incision and reduction of the active floodplain to 20% and 53% of its preincision extent on the Middle and West Forks, respectively. The development of such anthropogenic bedrock terraces may be an emerging, globally widespread physiographic signature of the Anthropocene.

GAG Builder: a web-tool for modeling 3D structures of glycosaminoglycans.

Here we report the launch of a web-tool (the GLYCAM-Web GAG Builder, www.glycam.org/gag) for the rapid and straightforward prediction of 3D structural models for glycosaminoglycans (GAGs). The tool provides the user with coordinate files (PDB format) for use in visualization, as well as files for performing MD simulation with the AMBER software package. Counter ions and water may also be added as desired. The tool is designed with the non-expert in mind, and as such has implemented typical default values for structural parameters, which the user may change if desired. Multiple GAG types are supported, including Heparin/Heparan Sulfate, Chondroitin Sulfate, Dermatan Sulfate, Keratan Sulfate, and Hyaluronan; however, the user may alter the default sulfation patterns to create novel sequences. The common non-natural unsaturated uronic acid (ΔUA) and its sulfated derivative are also supported.

Impact of a High-fat Diet on Tissue Acyl-CoA and Histone Acetylation Levels.

Cellular metabolism dynamically regulates the epigenome via availability of the metabolite substrates of chromatin-modifying enzymes. The impact of diet on the metabolism-epigenome axis is poorly understood but could alter gene expression and influence metabolic health. ATP citrate-lyase produces acetyl-CoA in the nucleus and cytosol and regulates histone acetylation levels in many cell types. Consumption of a high-fat diet (HFD) results in suppression of ATP citrate-lyase levels in tissues such as adipose and liver, but the impact of diet on acetyl-CoA and histone acetylation in these tissues remains unknown. Here we examined the effects of HFD on levels of acyl-CoAs and histone acetylation in mouse white adipose tissue (WAT), liver, and pancreas. We report that mice consuming a HFD have reduced levels of acetyl-CoA and/or acetyl-CoA:CoA ratio in these tissues. In WAT and the pancreas, HFD also impacted the levels of histone acetylation; in particular, histone H3 lysine 23 acetylation was lower in HFD-fed mice. Genetic deletion of Acly in cultured adipocytes also suppressed acetyl-CoA and histone acetylation levels. In the liver, no significant effects on histone acetylation were observed with a HFD despite lower acetyl-CoA levels. Intriguingly, acetylation of several histone lysines correlated with the acetyl-CoA: (iso)butyryl-CoA ratio in liver. Butyryl-CoA and isobutyryl-CoA interacted with the acetyltransferase P300/CBP-associated factor (PCAF) in liver lysates and inhibited its activity in vitro This study thus provides evidence that diet can impact tissue acyl-CoA and histone acetylation levels and that acetyl-CoA abundance correlates with acetylation of specific histone lysines in WAT but not in the liver.

Global Profiling of Acetyltransferase Feedback Regulation.

Lysine acetyltransferases (KATs) are key mediators of cell signaling. Methods capable of providing new insights into their regulation thus constitute an important goal. Here we report an optimized platform for profiling KAT-ligand interactions in complex proteomes using inhibitor-functionalized capture resins. This approach greatly expands the scope of KATs, KAT complexes, and CoA-dependent enzymes accessible to chemoproteomic methods. This enhanced profiling platform is then applied in the most comprehensive analysis to date of KAT inhibition by the feedback metabolite CoA. Our studies reveal that members of the KAT superfamily possess a spectrum of sensitivity to CoA and highlight NAT10 as a novel KAT that may be susceptible to metabolic feedback inhibition. This platform provides a powerful tool to define the potency and selectivity of reversible stimuli, such as small molecules and metabolites, that regulate KAT-dependent signaling.

Flexible thermoelectric fabrics based on self-assembled tellurium nanorods with a large power factor.

Highly-flexible thermoelectric fabrics were fabricated based on a layered structure, composed of a thin active layer of self-assembled tellurium nanorods and a substrate layer of polyvinylidene fluoride. The resulting thermoelectric fabrics show a high room temperature power factor of 45.8 µW m(-1) K(-2), which opens a new avenue to fabricate highly-flexible sustainable energy sources.

Increase in oxidative stress as measured by cerebrospinal fluid lipid peroxidation during treatment for childhood acute lymphoblastic leukemia.

Five-year survival from childhood acute lymphoblastic leukemia (ALL) approaches 90%, but 40% of survivors experience central nervous system (CNS) treatment-related cognitive problems. Despite considerable evidence for cognitive problems, less is known about mechanisms of neurological injury. Our purpose was to investigate oxidative stress, measured by lipid peroxidation, as a mechanism of CNS treatment-related neurological injury. The sample included 55 children (mean age at diagnosis=6.84 y, SD=3.40) who received intrathecal and intravenous chemotherapy for CNS-directed treatment according to Children's Oncology Group protocols. Glycerophospholipids were extracted from cerebrospinal fluid samples obtained at diagnosis and during intrathecal chemotherapy administration. Unoxidized and oxidized phosphatidylcholine (PC) and phosphatidylinositol (PI) were measured by normal phase high-performance liquid chromatography with diode array detection, and analyzed with a general linear model for repeated measures analysis of variance. Compared with the diagnostic cerebrospinal fluid sample, unoxidized and oxidized PC and PI increased significantly across treatment phases. Amount of intravenous methotrexate received was significantly correlated with oxidized PI, and age at time of ALL diagnosis was significantly associated with oxidized PC. These findings support our hypothesis that oxidative stress is a mechanism of neurological injury associated with CNS-directed treatment for ALL.

Photographic art in exam rooms may reduce white coat hypertension.

INTRODUCTION: Blood pressure (BP) elevation in medical office settings in patients who are normotensive in nonmedical settings is an effect known as 'white coat hypertension'. This phenomenon is thought to be due to situational anxiety caused by the experience of visiting a doctor and the anxiety-inducing nature of the medical office. Our study was designed to determine if carefully selected photographic art could counter the anxiety that causes white coat hypertension and lead to lower BP recordings in some patients. METHODS: 117 adults, non-pregnant patients from the Louisiana State University Health Sciences Center Family Medicine Resident Clinic participated in this study. After the triage nurse measured the BP, the patients were randomly placed in either an exam room with standard medical posters (control room) or in an exam room with photographic art (photo room). The BP was measured in the exam room. After the medical visit, the patients switched rooms and the BP was measured a third time. The patients were asked to fill out a questionnaire to identify room preference. RESULTS: On average, the BP obtained in the control rooms was higher than that obtained in the photo rooms. There was a statistically significant difference between the mean arterial pressure, systolic BP and diastolic BP between the control room and the photo room. CONCLUSIONS: Landscape photographic art may have the beneficial effect of reducing BP in medical office examination rooms.

Chemoproteomic profiling of lysine acetyltransferases highlights an expanded landscape of catalytic acetylation.

Lysine acetyltransferases (KATs) play a critical role in the regulation of gene expression, metabolism, and other key cellular functions. One shortcoming of traditional KAT assays is their inability to study KAT activity in complex settings, a limitation that hinders efforts at KAT discovery, characterization, and inhibitor development. To address this challenge, here we describe a suite of cofactor-based affinity probes capable of profiling KAT activity in biological contexts. Conversion of KAT bisubstrate inhibitors to clickable photoaffinity probes enables the selective covalent labeling of three phylogenetically distinct families of KAT enzymes. Cofactor-based affinity probes report on KAT activity in cell lysates, where KATs exist as multiprotein complexes. Chemical affinity purification and unbiased LC-MS/MS profiling highlights an expanded landscape of orphan lysine acetyltransferases present in the human genome and provides insight into the global selectivity and sensitivity of CoA-based proteomic probes that will guide future applications. Chemoproteomic profiling provides a powerful method to study the molecular interactions of KATs in native contexts and will aid investigations into the role of KATs in cell state and disease.

Tibetan plateau river incision inhibited by glacial stabilization of the Tsangpo gorge.

A considerable amount of research has focused on how and when the Tibetan plateau formed in the wake of tectonic convergence between India and Asia. Although far less enquiry has addressed the controls on river incision into the plateau itself, widely accepted theory predicts that steep fluvial knick points (river reaches with very steep gradients) in the eastern Himalayan syntaxis at the southeastern plateau margin should erode rapidly, driving a wave of incision back into the plateau. Preservation of the plateau edge thus presents something of a conundrum that may be resolved by invoking either differential rock uplift matching erosional decay, or other mechanisms for retarding bedrock river incision in this region where high stream power excludes the potential for aridity as a simple limit to dissection of the plateau. Here we report morphologic evidence showing that Quaternary depression of the regional equilibrium line altitude, where long-term glacier mass gain equals mass loss, was sufficient to repeatedly form moraine dams on major rivers: such damming substantially impeded river incision into the southeastern edge of the Tibetan plateau through the coupled effects of upstream impoundment and interglacial aggradation. Such glacial stabilization of the resulting highly focused river incision centred on the Tsangpo gorge could further contribute to initiating and accentuating a locus of rapid exhumation, known as tectonic anaeurysm.

Enhancing the cellular uptake of Py-Im polyamides through next-generation aryl turns.

Pyrrole-imidazole (Py-Im) hairpin polyamides are a class of programmable, sequence-specific DNA binding oligomers capable of disrupting protein-DNA interactions and modulating gene expression in living cells. Methods to control the cellular uptake and nuclear localization of these compounds are essential to their application as molecular probes or therapeutic agents. Here, we explore modifications of the hairpin γ-aminobutyric acid turn unit as a means to enhance cellular uptake and biological activity. Remarkably, introduction of a simple aryl group at the turn potentiates the biological effects of a polyamide targeting the sequence 5'-WGWWCW-3' (W =A/T) by up to two orders of magnitude. Confocal microscopy and quantitative flow cytometry analysis suggest this enhanced potency is due to increased nuclear uptake. Finally, we explore the generality of this approach and find that aryl-turn modifications enhance the uptake of all polyamides tested, while having a variable effect on the upper limit of polyamide nuclear accumulation. Overall this provides a step forward for controlling the intracellular concentration of Py-Im polyamides that will prove valuable for future applications in which biological potency is essential.

Multi-scale curvature for automated identification of glaciated mountain landscapes.

Erosion by glacial and fluvial processes shapes mountain landscapes in a long-recognized and characteristic way. Upland valleys incised by fluvial processes typically have a V-shaped cross-section with uniform and moderately steep slopes, whereas glacial valleys tend to have a U-shaped profile with a changing slope gradient. We present a novel regional approach to automatically differentiate between fluvial and glacial mountain landscapes based on the relation of multi-scale curvature and drainage area. Sample catchments are delineated and multiple moving window sizes are used to calculate per-cell curvature over a variety of scales ranging from the vicinity of the flow path at the valley bottom to catchment sections fully including valley sides. Single-scale curvature can take similar values for glaciated and non-glaciated catchments but a comparison of multi-scale curvature leads to different results according to the typical cross-sectional shapes. To adapt these differences for automated classification of mountain landscapes into areas with V- and U-shaped valleys, curvature values are correlated with drainage area and a new and simple morphometric parameter, the Difference of Minimum Curvature (DMC), is developed. At three study sites in the western United States the DMC thresholds determined from catchment analysis are used to automatically identify 5 × 5 km quadrats of glaciated and non-glaciated landscapes and the distinctions are validated by field-based geological and geomorphological maps. Our results demonstrate that DMC is a good predictor of glacial imprint, allowing automated delineation of glacially and fluvially incised mountain landscapes.

Soil health: A common focus for one health and planetary health interventions.

Proponents of both the One Health and Planetary Health paradigms have acknowledged that current methods of agricultural food production are driving many environmental changes with negative human health consequences, including climate change, deforestation, and the emergence of zoonotic disease and antimicrobial resistance. Currently, the training of human health, veterinary, and public health professionals typically does not include aspects of soil health. Much of the resultant discussion in One Health and Planetary Health circles regarding interventions to address the health impact of agricultural practices has focused on measures such as advocating for dietary change toward plant based diets and increasing food safety, biosecurity, disease surveillance and antimicrobial stewardship. A greater understanding of soil health and its relationship to agricultural practices could prove foundational to many of the problems that the One Health and Planetary Health perspectives aim to address, including antimicrobial resistance, zoonotic disease emergence, food security, and climate change. A consequent global focus on the health of soils offers a promise of specific opportunities for preventive interventions and a greater convergence between the One Health and Planetary Health approaches.

Synthesis of cyclic Py-Im polyamide libraries.

Cyclic Py-Im polyamides containing two GABA turn units exhibit enhanced DNA binding affinity, but extensive studies of their biological properties have been hindered due to synthetic inaccessibility. A facile modular approach toward cyclic polyamides has been developed via microwave-assisted solid-phase synthesis of hairpin amino acid oligomer intermediates followed by macrocyclization. A focused library of cyclic polyamides 1-7 targeted to the androgen response element (ARE) and the estrogen response element (ERE) were synthesized in 12-17% overall yield. The Fmoc protection strategy also allows for selective modifications on the GABA turn units that have been shown to improve cellular uptake properties. The DNA binding affinities of a library of cyclic polyamides were measured by DNA thermal denaturation assays and compared to the corresponding hairpin polyamides. Fluorescein-labeled cyclic polyamides have been synthesized and imaged via confocal microscopy in A549 and T47D cell lines. The IC(50) values of compounds 1-7 and 9-11 were determined, revealing remarkably varying levels of cytotoxicity.

Glacier and landslide feedbacks to topographic relief in the Himalayan syntaxes.

Despite longstanding research on the age and formation of the Tibetan Plateau, the controls on the erosional decay of its margins remain controversial. Pronounced aridity and highly localized rock uplift have traditionally been viewed as limits to the dissection of the plateau by bedrock rivers. Recently, however, glacier dynamics and landsliding have been argued to retard headward fluvial erosion into the plateau interior by forming dams and protective alluvial fill. Here, we report a conspicuous clustering of hundreds of natural dams along the Indus and the Tsangpo Rivers where these cross the Himalayan syntaxes. The Indus is riddled by hundreds of dams composed of debris from catastrophic rock avalanches, forming the largest concentration of giant landslide dams known worldwide, whereas the Tsangpo seems devoid of comparable landslide dams. In contrast, glacial dams such as river-blocking moraines in the headwaters of both rivers are limited to where isolated mountain ranges intersect the regional snowline. We find that to first-order, high local topographic relief along both rivers corresponds to conspicuously different knickzones and differences in the type and potential longevity of these dams. In both syntaxes, glacier and landslide dams act as a negative feedback in response to fluvial dissection of the plateau margins. Natural damming protects bedrock from river incision and delays headward knickpoint migration, thereby helping stabilize the southwestern and southeastern margins of the Tibetan Plateau in concert with the effects of upstream aridity and localized rock uplift.

Invited article: X-ray phase contrast imaging in inertial confinement fusion and high energy density research.

X-ray phase contrast imaging (XPCI) provides enhanced image contrast beyond absorption-based x-ray imaging alone due to refraction and diffraction from gradients in the object material density. It is sensitive to small variations in density, such as internal voids, cracks, grains, defects, and material flow, as well as to stronger density variations such as from a shock wave. Beyond its initial use in biology and materials science, XPCI is now routinely used in inertial confinement fusion (ICF) and high energy density (HED) research, first to characterize ICF capsules and targets, and later applied in dynamic experiments, where coherent x-ray sources, ultrafast x-ray pulses, and high temporal and spatial resolution are required. In this Review article, XPCI image formation theory is presented, its diverse use in ICF and HED research is discussed, the unique requirements for ultrafast XPCI imaging are given, as well as current challenges and issues in its use.

Trends in soil organic matter and topsoil thickness under regenerative practices at the University of Washington student farm.

Conventional methods of agriculture, especially tillage, are often accompanied by soil degradation in the form of erosion and organic matter depletion. Regenerative agricultural methods seek to repair soil ecosystems by building topsoil and soil organic matter (SOM), decreasing reliance on chemical fertilizers and increasing both water retention capacity and the diversity and quantity of soil microbial and fungal communities. The University of Washington (UW) student farm is an organic and regeneratively managed site on the UW Seattle campus. Over the past 20 years the farm gradually expanded so locations on the farm encompass both unimproved topsoil and soils managed regeneratively for periods of 5 to 20 years. This arrangement allows a time-trend analysis of soil development under regenerative methods. Measurements of topsoil thickness (defined as the distance from the ground surface to the base of the soil A horizon) and organic matter content were collected across 14 distinct plots on the farm to quantify trends over time and estimate net change in SOM (and soil organic carbon, or SOC). While SOM content weakly increased by 0.5% per year, topsoil thickness exhibited a significant linear increase of 0.86 cm per year. Over a twenty-year period under the management practices of the UW Farm total organic carbon storage in soils, determined using topsoil thickness, density, and SOC content, increased by between 4 and 14 t ha-1 yr-1. The general increases in topsoil thickness, SOM content, and total soil carbon demonstrate the potential of soil-health-focused practices to help maintain a productive and efficient urban growing space.

clotFoam: An open-source framework to simulate blood clot formation under arterial flow.

Blood clotting involves the coupled processes of platelet aggregation and coagulation. Simulating clotting under flow in complex geometries is challenging due to multiple temporal and spatial scales and high computational cost. clotFoam is an open-source software developed in OpenFOAM that employs a continuum model of platelet advection, diffusion, and aggregation in a dynamic fluid environment and a simplified coagulation model with proteins that advect, diffuse, and react within the fluid and with wall-bound species through reactive boundary conditions. Our framework provides the foundation on which one can build more complex models and perform reliable simulations in almost any computational domain.

clotFoam: An Open-Source Framework to Simulate Blood Clot Formation Under Arterial Flow.

Blood clotting involves the coupled processes of platelet aggregation and coagulation. Simulating clotting under flow in complex geometries is challenging due to multiple temporal and spatial scales and high computational cost. clotFoam is an open-source software developed in OpenFOAM that employs a continuum model of platelet advection, diffusion, and aggregation in a dynamic fluid environment and a simplified coagulation model with proteins that advect, diffuse, and react within the fluid and with wall-bound species through reactive boundary conditions. Our framework provides the foundation on which one can build more complex models and perform reliable simulations in almost any computational domain.