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BackgroundEpithelioid inflammatory myofibroblastic sarcoma (eIMS) is characterised by perinuclear ALK localisation, CD30 expression and early relapse despite crizotinib treatment. We aimed to identify therapies to prevent and/or treat ALK inhibitor resistance.MethodsMalignant ascites, from an eIMS patient at diagnosis and following multiple relapses, were used to generate matched diagnosis and relapse xenografts.ResultsXenografts were validated by confirmation ofRANBP2-ALKrearrangement, perinuclear ALK localisation and CD30 expression. Although brentuximab-vedotin (BV) demonstrated single-agent activity, tumours regrew during BV therapy. BV resistance was associated with reduced CD30 expression and induction of ABCB1. BV resistance was reversed in vitro by tariquidar, but combination BV and tariquidar treatment only briefly slowed xenograft growth compared with BV alone. Combining BV with either crizotinib or ceritinib resulted in marked tumour shrinkage in both xenograft models, and resulted in prolonged tumour-free survival in the diagnosis compared with the relapse xenograft.ConclusionsCD30 is a therapeutic target in eIMS. BV efficacy is limited by the rapid emergence of resistance. Prolonged survival with combination ALK and CD30-targeted-therapy in the diagnosis model provides the rationale to trial this combination in eIMS patients at diagnosis. This combination could also be considered for other CD30-positive,ALK-rearranged malignancies.

The study of eukaryotic extremophiles is relatively novel, and, therefore, documentation of the structure and function of micro-organisms in continental hydrothermal systems globally is limited. In...

On March 26, 2019, in keeping with President Trump's Space Policy Directive-1, Vice President Pence charged NASA with landing the first woman and the next man on the South Pole of the Moon by 2024, followed by a sustained presence on and around the Moon by 2028. NASA's Human Landing System (HLS) Program is responsible for the final mode of transportation in deep space that will carry humans to and from the surface of the Moon, to be designed and developed by American companies for NASA's Artemis lunar exploration program. This paper examines the approach for Artemis human landing systems for both the initial missions and future sustained missions. While achieving the 2024 goal requires a focus on speed and the use of mature technologies, planning toward sustained operations to and from the lunar surface requires a focus on reliability and reusability. The two approaches, however, are not mutually exclusive, as demonstrated by the HLS prime contractors' integrated lander system proposals. On April 30, 2020, NASA announced that Blue Origin of Kent, Washington, Dynetics (a Leidos company) of Huntsville, Alabama, and SpaceX of Hawthorne, California, were the awardees for NASA's Human Landing System contracts under Appendix H of the NextSTEP-2 Broad Agency Announcement. The companies began work in a 10-month base period during which NASA teams worked with the companies to streamline the review of required products and to share the agency's expertise in human spaceflight systems development. Following the base period, NASA will determine which companies will develop the human landers for the initial missions, including the 2024 landing, and which companies will develop landers for future sustained missions toward the end of the decade.

In response to the 2018 White House Space Policy Directive-1, to lead an innovative and sustainable lunar exploration, and to the Vice President's March 2019 direction to do so by 2024, NASA is working to establish humanity's presence on and around the Moon by: 1) sending payloads to its surface, 2) assembling the Gateway outpost in orbit and 3) demonstrating the first human lunar landings since 1972. NASA's Artemis program is implementing a multi-faceted and coordinated agency-wide approach with a focus on the lunar South Pole. The Artemis missions will demonstrate new technologies, capabilities and business approaches needed for future exploration, including Mars. Assessing options to accelerate development of required systems, NASA is utilizing public-private engagements through the Human Exploration and Operations (HEO) Mission Directorate's NextSTEP Broad Agency Announcements. The design, development and demonstration of the Human Landing System (HLS) is expected to be led by commercial partners. Utilizing efforts across mission directorates, the Artemis effort will benefit from programs from the Science Mission Directorate (SMD) and Space Technology Mission Directorate (STMD). SMD's Commercial Lunar Payload Services (CLPS) initiative will procure commercial robotic lunar delivery services and the development of science instruments and technology demonstration payloads. The Space Technology Mission Directorate (STMD) portfolio of technology advancements relative to HLS include lunar lander components and technologies for pointing, navigation and tracking, fuel storage and transfer, autonomy and mobility, communications, propulsion and power. In addition to describing the objectives and requirements of the 2024 Artemis mission, this paper will present NASA's approach to accessing the lunar surface with an affordable human-rated landing system, current status and the role of U.S. industry in 2024 and for a sustainable lunar presence.

A composite 11.82 m-long (9876–-67 cal yr BP) sediment record from Yellowstone Lake, Wyoming was analyzed using a robust set of biological and geochemical proxies to investigate the paleoenvironmental evolution of the lake and its catchment in response to long-term climate forcing. Oxygen isotopes from diatom frustules were analyzed to reconstruct Holocene climate changes, and pollen, charcoal, diatom assemblages, and biogenic silica provided information on terrestrial and limnological responses. The long-term trends recorded in the terrestrial and limnic ecosystems over the last 9800 years reflect the influence of changes in the amplification of the seasonal cycle of insolation on regional climate. The early Holocene (9880–6700 cal yr BP) summer insolation maximum and strengthening of the northeastern Pacific subtropical high-pressure system created warm dry conditions and decreasing summer insolation in the middle (6700–3000 cal yr BP) and late (3000–-67 cal yr BP) Holocene resulted in progressively cooler, wetter conditions. Submillenial climate variation is also apparent, with a wetter/cooler interval between 7000 and 6800 cal yr BP and warmer and/or drier conditions from 4500 to 3000 cal yr BP and at ca. 1100 cal yr BP. These data show that the Yellowstone Lake basin had a climate history typical of a summer-dry region, which helps to better define the spatial variability of Holocene climate in the Greater Yellowstone Ecosystem.

Volcanic and hydrothermal processes produce disturbances by diverse mechanisms and ecological responses are varied. New and published pollen records from the Northern Rocky Mountains and Greater Yellowstone Ecosystem document the response of vegetation to three different types of volcanic and hydrothermal disturbances: (1) Pleistocene rhyolite lava flows in the central Greater Yellowstone Ecosystem created infertile landscapes that have shaped vegetation since rhyolite emplacement. Nutrient-poor, well-drained soils that developed on these flows supported low-diversity grassland during late-glacial time and Pinus contorta forests in interglacial periods. (2) Ash layers from eruptions of Pacific Northwest stratovolcanoes are commonly preserved in lake-sediment records in the Northern Rocky Mountains, and associated pollen records show enhancement of steppe vegetation for years to decades. (3) Local hydrothermal explosions have resulted in vegetation changes in hydrothermal areas that indicate tree mortality following deposition of explosion debris, followed by recovery in years. Thus, the type and duration of the vegetation response to volcanic and hydrothermal disturbances are highly contextual and governed by the antecedent plant communities and the magnitude and mechanism of the volcanic or hydrothermal disturbance. Vegetation resilience varied between disturbances, ranging from enduring ecosystem parameter changes to short-lived state changes in resilient plant communities.

Daprodustat, a small-molecule inhibitor of prolyl hydroxylases, prevents breakdown of hypoxia-inducible factor (HIF), leading to increased transcription of HIF-responsive genes. This randomized, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of a topical formulation of daprodustat in healthy volunteers (intact skin) and in patients with diabetic foot ulcers (DFUs) following single and/or 14-day repeat-dose administration. In the diabetic patients, exploratory assessments of wound area, volume, and depth were made to qualitatively assess effectiveness. Systemic absorption via topical application was limited across doses up to 1.0% at 100 mg/cm2 for 14 days. Systemic pharmacokinetics were quantifiable in a few samples from a few patients. Because only sporadic concentrations were observed versus pharmacokinetic profiles, pharmacokinetic parameters were not determined. Wound area, depth, and volume showed consistent but weak improvements in the treatment arm; however, the variability in response and small sample size of the standard-of-care and placebo arms limited the ability to assess trends in wound healing compared with the daprodustat arm. Overall, topically applied daprodustat was well tolerated, raised no safety concerns, and provided limited to nonquantifiable systemic exposures. The healing of DFUs will need to be evaluated in studies designed to test this hypothesis over a longer treatment duration.

Widespread extension began across the northern and central Basin and Range Province at 17–16 Ma, contemporaneous with magmatism along the Nevada–Columbia Basin magmatic belt, a linear zone of dikes and volcanic centers that extends for >1000 km, from southern Nevada to the Columbia Basin of eastern Washington. This belt was generated above an elongated sublithospheric melt zone associated with arrival of the Yellowstone mantle plume, with a north-south tabular shape attributed to plume ascent through a propagating fracture in the Juan de Fuca slab. Dike orientation along the magmatic belt suggests an extension direction of 245°–250°, but this trend lies oblique to the regional extension direction of 280°–300° during coeval and younger Basin and Range faulting, an ∼45° difference. Field relationships suggest that this magmatic trend was not controlled by regional stress in the upper crust, but rather by magma overpressure from below and forceful dike injection with an orientation inherited from a deeper process in the sublithospheric mantle. The southern half of the elongated zone of mantle upwelling was emplaced beneath a cratonic lithosphere with an elevated surface derived from Late Cretaceous to mid-Tertiary crustal thickening. This high Nevadaplano was primed for collapse with high gravitational potential energy under the influence of regional stress, partly derived from boundary forces due to Pacific–North American plate interaction. Plume arrival at 17–16 Ma resulted in advective thermal weakening of the lithosphere, mantle traction, delamination, and added buoyancy to the northern and central Basin and Range. It was not the sole cause of Basin and Range extension, but rather the catalyst for extension of the Nevadaplano, which was already on the verge of regional collapse.

Yellowstone Lake, far from any ocean, hosts underwater hot springs similar to those on mid-ocean ridges. A research team is investigating the processes that drive the lake’s hydrothermal systems.

Rationale: Inflammatory myofibroblastic tumors (IMTs) are a particularly rare type of soft tissue sarcoma comprised of myofibroblastic spindle cells and an accompanying inflammatory infiltrate. There is an unmet clinical need for effective treatment regimens for patients diagnosed with IMT with anaplastic lymphoma kinase (ALK) rearrangement, who relapse following ALK inhibitor (ALKi) therapy or who present with aggressive disease. Fusion of RAN Binding Protein 2 (RANBP2) with ALK in IMT is associated with aggressive disease and has been correlated with tumor cell expression of CD30. This study investigated CD30 as a potential therapeutic target in IMT and the efficacy of the CD30-targeted antibody-monomethyl auristatin E conjugate, Brentuximab Vedotin (BV). Methods and Results: In a cohort of five recent IMT patients at the Sydney Children’s Hospital, RANBP2-ALK fusion was identified in three patients (IMT1, IMT2 and IMT3) by RNA capture sequencing, while patients IMT4 and IMT5 (who did not relapse) harbored CLTC-ALK or SEC31A-ALK fusions respectively. Expression of CD30 was confirmed two of three RANBP2-ALK fusion positive tumors by immunohistochemistry. We established cell cultures and xenografts from malignant ascites of IMT1, at diagnosis (IMT1A) and at relapse (IMT1D) after treatment with ALKi’s and low dose chemotherapy. CD30 expression was retained in the cell cultures and xenograft tumors, as demonstrated by flow cytometry and tumor histology. BV was investigated as a potential treatment for IMT with RANBP2-ALK fusion. BV reduced IMT1A and IMT1D cell viability in vitro in resazurin cell viability assays. IMT1A and IMT1D xenograft mice had a partial response to BV which significantly (p Conclusion: CD30 is a promising therapeutic target in RANBP2-ALK-rearranged IMT. BV successfully reduced IMT cell viability in vitro and prolonged survival in IMT xenografted mice, both as a single agent and when given in combination with crizotinib. Since BV is current clinical use for the treatment of Hodgkin lymphoma it may be possible to rapidly translate these findings into clinical practice for the treatment of IMT. Citation Format: Ashleigh M. Fordham, James Blackburn, Erin E. Heyer, Jinhan Xie, Emily V. Mould, Andrew J. Gifford, Lisa T. Morgan, Carol Wadham, Mitali Fadia, Jamie I. Fletcher, Karen L. MacKenzie, Toby N. Trahair. Targeting CD30 as a novel treatment strategy in RANBP2-ALK-rearranged inflammatory myofibroblastic tumor [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4824.

Epoxyeicosatrienoic acids, substrates for soluble epoxide hydrolase (sEH), exhibit vasodilatory and antihypertrophic activities. Inhibitors of sEH might therefore hold promise as heart failure therapeutics. We examined the ability of sEH inhibitors GSK2188931 and GSK2256294 to modulate cardiac hypertrophy, fibrosis, and function after transverse aortic constriction (TAC) in rats and mice. GSK2188931 administration was initiated in rats 1 day before TAC, whereas GSK2256294 treatment was initiated in mice 2 weeks after TAC. Four weeks later, cardiovascular function was assessed, plasma was collected for drug and sEH biomarker concentrations, and left ventricle was isolated for messenger RNA and histological analyses. In rats, although GSK2188931 prevented TAC-mediated increases in certain genes associated with hypertrophy and fibrosis (α-skeletal actin and connective tissue growth factor), the compound failed to attenuate TAC-induced increases in left ventricle mass, posterior wall thickness, end-diastolic volume and pressure, and perivascular fibrosis. Similarly, in mice, GSK2256294 did not reverse cardiac remodeling or systolic dysfunction induced by TAC. Both compounds increased the sEH substrate/product (leukotoxin/leukotoxin diol) ratio, indicating sEH inhibition. In summary, sEH inhibition does not prevent cardiac remodeling or dysfunction after TAC. Thus, targeting sEH seems to be insufficient for reducing pressure overload hypertrophy.

Daprodustat (GSK1278863) is a prolyl hydroxylase inhibitor in phase 3 clinical studies for the treatment of anemia associated with chronic kidney disease. This study was conducted to evaluate the effect of daprodustat on cardiac repolarization and enrolled 55 healthy adult male (29) and female (26) subjects who received single-dose 75 and 500 mg daprodustat, 400 mg moxifloxacin, and placebo. Mean placebo-corrected change from baseline QT interval for daprodustat showed no statistically significant increase. However, statistically significant decreases in the ΔΔQTcF were observed for both doses of daprodustat, reaching a lowest value of –2.74 milliseconds for 75 mg and –5.93 milliseconds for 500 mg daprodustat; this minor shortening effect is not considered clinically significant. The moxifloxacin group showed a statistically significant increase in the ΔΔQTcF value, reaching a maximal increase of 11.47 milliseconds at 4 hours. Forty subjects (73%) reported at least 1 adverse event, with the highest incidence with 500 mg daprodustat. This group had a higher incidence of gastrointestinal adverse events compared to the other treatment groups. These results suggest that 500 mg daprodustat was not well tolerated; however, daprodustat at 75 mg was generally well tolerated. No new safety concerns were identified in subjects who received 500 mg daprodustat.

We report paleomagnetic and rock magnetic data from volcanic, volcaniclastic, and intrusive rocks of the 55–44 Ma Absaroka Volcanic Supergroup (AVS) exposed along the northeastern margin of Yellowstone National Park and adjacent areas. Demagnetization behavior and rock magnetic experiments indicate that the remanence in most samples is carried by low-Ti titanomagnetite, although high-coercivity phases are present in oxidized basalt flows. Paleomagnetic demagnetization and rock magnetic characteristics, the presence of normal and reverse polarity sites, consistency with previous results, and positive conglomerate tests suggest that the observed remanences are primary thermoremanent magnetizations of Eocene age (c. 50 Ma). An in situ grand-mean for 22 individual site- or cooling-unit means from this study that yield acceptable data combined with published data from Independence volcano yields a declination of 347.6° and inclination of 59.2° (k = 21.8, α95 = 6.8°) and a positive reversal test. Averaging 21 virtual geomagnetic poles (VGPs) that are well-grouped yields a mean at 137.1°E, 82.5°N (K = 17.6, A95 = 7.8°), similar to results previously obtained from published studies from the AVS. Combining the VGPs from our study with published data yields a combined AVS pole at 146.3°E, 83.1°N (K = 13.5, A95 = 6.2°, N = 42 VGPs). Both poles are indistinguishable from c. 50 Ma cratonic and synthetic reference poles for North America, and demonstrate the relative stability of this part of the Cordillera with respect to the craton.

Yellowstone Lake (Yellowstone National Park, WY, USA) is a large high-altitude (2200 m), fresh-water lake, which straddles an extensive caldera and is the center of significant geothermal activity. The primary goal of this interdisciplinary study was to evaluate the microbial populations inhabiting thermal vent communities in Yellowstone Lake (Yellowstone Lake) using 16S rRNA gene and random metagenome sequencing, and to determine how geochemical attributes of vent waters influence the distribution of specific microorganisms and their metabolic potential. Thermal vent waters and associated microbial biomass were sampled during two field seasons (2007 - 2008) using a remotely operated vehicle (ROV). Sublacustrine thermal vent waters (circa 50 - 90 oC) contained elevated concentrations of numerous constituents associated with geothermal activity including dissolved hydrogen, sulfide, methane and carbon dioxide. Microorganisms associated with sulfur-rich filamentous ‘streamer’ communities of Inflated Plain and West Thumb (pH range 5 - 6) were dominated by bacteria from the Aquificales, but also contained thermophilic archaea from the Crenarchaeota and Euryarchaeota. Novel groups of methanogens and members of the Korarchaeota were observed in vents from West Thumb and Elliot’s Crater (pH 5 - 6). Conversely, metagenome sequence from Mary Bay vent sediments did not yield large assemblies, and contained diverse thermophilic and nonthermophilic bacterial relatives. Analysis of functional genes associated with the major vent populations indicated a direct linkage to high concentrations of carbon dioxide, reduced sulfur (sulfide and/or elemental S), hydrogen and methane in the deep thermal ecosystems. Our observations show that sublacustrine thermal vents in Yellowstone Lake support novel thermophilic communities, which contain microorganisms with functional attributes not found to date in terrestrial geothermal systems of YNP.

Yellowstone National Park is the site of one of the world9s largest calderas. The abundance of geothermal and tectonic activity in and around the caldera, including historic uplift and subsidence, makes it necessary to understand active geologic processes and their associated hazards. To that end, we here use an extensive grid of high-resolution seismic reflection profiles (∼450 km) to document hydrothermal and tectonic features and deposits in northern Yellowstone Lake. Sublacustrine geothermal features in northern Yellowstone Lake include two of the largest known hydrothermal explosion craters, Mary Bay and Elliott9s. Mary Bay explosion breccia is distributed uniformly around the crater, whereas Elliott9s crater breccia has an asymmetric distribution and forms a distinctive, ∼2-km-long, hummocky lobe on the lake floor. Hydrothermal vents and low-relief domes are abundant on the lake floor; their greatest abundance is in and near explosion craters and along linear fissures. Domed areas on the lake floor that are relatively unbreached (by vents) are considered the most likely sites of future large hydrothermal explosions. Four submerged shoreline terraces along the margins of northern Yellowstone Lake add to the Holocene record of postglacial lake-level fluctuations attributed to “heavy breathing” of the Yellowstone magma reservoir and associated geothermal system. The Lake Hotel fault cuts through northwestern Yellowstone Lake and represents part of a 25-km-long distributed extensional deformation zone. Three postglacial ruptures indicate a slip rate of ∼0.27 to 0.34 mm/yr. The largest (3.0 m slip) and most recent event occurred in the past ∼2100 yr. Although high heat flow in the crust limits the rupture area of this fault zone, future earthquakes of magnitude ∼5.3 to 6.5 are possible. Earthquakes and hydrothermal explosions have probably triggered landslides, common features around the lake margins. Few high-resolution seismic reflection surveys have been conducted in lakes in active volcanic areas. Our data reveal active geothermal features with unprecedented resolution and provide important analogues for recognition of comparable features and potential hazards in other subaqueous geothermal environments.

‘No portion of the American continent is perhaps so rich in wonders as the Yellow Stone’ (F.V. Hayden, September 2, 1874) Discoveries from multi-beam sonar mapping and seismic reflection surveys of the northern, central, and West Thumb basins of Yellowstone Lake provide new insight into the extent of post-collapse volcanism and active hydrothermal processes occurring in a large lake environment above a large magma chamber. Yellowstone Lake has an irregular bottom covered with dozens of features directly related to hydrothermal, tectonic, volcanic, and sedimentary processes. Detailed bathymetric, seismic reflection, and magnetic evidence reveals that rhyolitic lava flows underlie much of Yellowstone Lake and exert fundamental control on lake bathymetry and localization of hydrothermal activity. Many previously unknown features have been identified and include over 250 hydrothermal vents, several very large (>500 m diameter) hydrothermal explosion craters, many small hydrothermal vent craters (∼1–200 m diameter), domed lacustrine sediments related to hydrothermal activity, elongate fissures cutting post-glacial sediments, siliceous hydrothermal spire structures, sublacustrine landslide deposits, submerged former shorelines, and a recently active graben. Sampling and observations with a submersible remotely operated vehicle confirm and extend our understanding of the identified features. Faults, fissures, hydrothermally inflated domal structures, hydrothermal explosion craters, and sublacustrine landslides constitute potentially significant geologic hazards. Toxic elements derived from hydrothermal processes also may significantly affect the Yellowstone ecosystem.

Short-term static-renewal studies were performed on Xenopus laevis embryos with 16 selected test materials from day 50 (stage 60) to day 64 (stage 66) (14-day test) to evaluate effects on tail resorption and thyroid function. Of the 16 test materials, nine were found to inhibit significantly the rate of tail resorption, four were found to stimulate metamorphosis and three had no appreciable effect on the rate of metamorphosis. In an effort to determine if the morphological effects observed were related to alteration in thyroid activity, measurement of triiodothyronine (T3) in the test organisms and coadministration studies using thyroxine (agonist) or propylthiouracil (antagonist) were performed based on the morphological response noted during tail resorption. Of the nine compounds found to inhibit the rate of tail resorption, six were found to reduce the levels of T3. In each case, the inhibitory response could be at least partially alleviated by the co-administration of thyroxine. Larvae exposed to the four stimulatory agents had somewhat elevated levels of T3 and were responsive to propylthiouracil antagonism. These results suggest that 12 of the 14 compounds tested in this study that altered the rate of tail resorption did so via the thyroid axis. Overall, the X. laevis model appeared to be a suitable system for evaluating the impact of environmental agents and chemical products on thyroid function.

Magma mixing may operate at any stage in the evolution of a magmatic system. The development of mixing is strongly controlled by fluid dynamics and its understanding requires a comprehensive physico-chemical approach in order to identify and interpret its occurrence in nature. Here, we experimentally study the physical and chemical interplays during the mixing of basaltic and rhyolitic natural melts from the Snake River Plains, USA. In particular, we present the results of the first high-temperature mixing experiments performed under controlled chaotic dynamic conditions, providing a new methodological approach to constrain the complexities of the mixing process between natural silicate melts. The mixing process is initially governed by the dynamics of stretching and folding of the melts, producing alternating flow bands. These bands increase the contact area between the end-members, which subsequently enhance chemical exchanges and thus contribute to the generation of regions with variable degrees of hybridization. We quantified the mobility of major and trace elements across contact areas, and analyzed the concentration variance decay induced by chemical diffusion. The analysis shows that elements diffuse with different efficiencies as the chemical gradient evolves and therefore, the achievement of hybrid compositions contrasts between elements. The approach introduced in this study can, in principle, be applied to mixing trends observed in nature in order to estimate the time-scales and degree of magma mixing evidenced across volcanic rocks/deposits.

The tradition of Rocky Mountain geology remains strong at all scales, spatially and temporally. This volume fosters that tradition with its collection of peer-reviewed papers associated with the 2010 GSA Annual Meeting in Denver, Colorado. Spatially, this volume discusses theories of continental mountain building events in tandem with microscopic observations and parts per billion trace element concentrations. Temporally, the volume covers geologic history from the Precambrian to modern issues of climate change and energy, groundwater contamination, geologic hazards, and landscape evolution. Many of the trips propose new interpretations of famous geologic ideas and environs such as Laramide deformation, the Colorado Mineral Belt, the Lewis and Clark Line, the Chalk Cliffs, and Garden of the Gods.

This fi eld trip highlights various stages in the evolution of the Snake River Plain– Yellowstone Plateau bimodal volcanic province, and associated faulting and uplift, also known as the track of the Yellowstone hotspot. The 16 Ma Yellowstone hotspot track is one of the few places on Earth where time-transgressive processes on continental crust can be observed in the volcanic and tectonic (faulting and uplift) record at the rate and direction predicted by plate motion. Recent interest in young and possible renewed volcanism at Yellowstone along with new discoveries and synthesis of previous studies, i.e., tomographic, deformation, bathymetric, and seismic surveys, provide a framework of evidence of plate motion over a mantle plume. This 3-day trip is organized to present an overview into volcanism and tectonism in this dynamically active region. Field trip stops will include the young basaltic Craters of the Moon, exposures of 12–4 Ma rhyolites and edges of their associated collapsed calderas on the Snake River Plain, and exposures of faults which show an age progression similar to the volcanic fi elds. An essential stop is Yellowstone National Park, where the last major caldera-forming event occurred 640,000 years ago and now is host to the world’s largest concentration of hydrothermal features (>10,000 hot springs and geysers). This trip presents a quick, intensive overview into volcanism and tectonism in this dynamically active region. Field stops are directly linked to conceptual models related to hotspot passage through this volcano-tectonic province. Features that may refl ect a tilted thermal mantle plume suggested in recent *lmorgan@usgs.gov, kpierce@usgs.gov, pshanks@usgs.gov Morgan, L.A., Pierce, K.L., and Shanks, W.C.P., 2008, Track of the Yellowstone hotspot: Young and ongoing geologic processes from the Snake River Plain to the Yellowstone Plateau and Tetons, in Raynolds, R.G., ed., Roaming the Rocky Mountains and Environs: Geological Field Trips: Geological Society of America Field Guide 10, p. XX–XX, doi: 10.1130/2007.fl d010(XX). For permission to copy, contact editing@geosociety.org. ©2008 The Geological Society of America. All rights reserved. 2 Morgan et al. FLD010-l.morgan 2nd pgs page 2

With the widespread use of central venous catheters in children, the incidence of catheter-related bloodstream infections (CR-BSIs) is increasing. Current evidence-based practice strategies to decrease CR-BSIs include using maximum barrier techniques during insertion, practicing good hand hygiene, performing skin antisepsis with 2% chlorhexidine, using a chlorhexidine-impregnated patch (CIP) covered by a semipermeable polyurethane dressing, and promptly removing catheters when no longer needed. Implementation of evidence-based practice bundles, along with monthly monitoring of infection surveillance, has resulted in significant decreases in the average rates of CR-BSIs per 1,000 catheter days in many pediatric intensive care units.

Activities of vascular smooth muscle cells (SMCs) such as proliferation, migration, and matrix production contribute to restenosis following clinical interventions of angioplasty and stent placement. Because activation of platelet-derived growth factor (PDGF)-receptor tyrosine kinase (PDGFr-TK) influences these processes and promotes restenosis, TKI963, an inhibitor of the PDGFr-TK was discovered, and its efficacy was evaluated in blocking stent-induced restenosis as analyzed by intravascular ultrasound (IVUS). TKI963, a low-molecular-weight compound, inhibited the cell-free PDGFbetar-TK with a K(i) value of 56 +/- 14 nM. TKI963 also inhibited PDGF-dependent events in human aortic SMCs (e.g., in situ PDGFr autophosphorylation, mitogenesis, chemotaxis, and collagen production with median inhibitory concentration values of approximately 300 nM) without affecting the activity of a series of membrane receptor tyrosine kinases and intracellular serine/threonine kinases. In vivo, stent-induced restenosis in the swine coronary artery was reduced by oral administration of TKI963 (1.25, 2.5, and 5 mg/kg BID, for 28 days). Late lumen cross-sectional area (CSA) loss, plaque CSA growth, and plaque volume in the stent determined by IVUS were dose-relatedly decreased (33-62% at 1.25 mg/kg BID to 66-92% at 5 mg/kg BID, depending on the parameter) compared with controls. TKI963 treatment of

Article history: Received 11 February 2011 Accepted 21 February 2011 Available online 4 March 2011 connection across the present Continental Divide, we might better have cited the two papers on the worm (Rhynchelmis gustafsoni) rather than a personal communication. We agree with the qualifications (only organismal distribution, species may require taxonomic revision) noted in the Comment by Hershler and Lui (2011-this issue). We welcome this timely discussion between geologists and biogeographers who are pursuing very similar questions on topics of

Sets of adult male and female Xenopus laevis were administered a boron-deficient (-B) diet under low-boron culture conditions, a boron-supplemented (+B) diet under ambient boron culture conditions, a copper-deficient (-Cu) diet under low-copper culture conditions, or a copper-supplemented (+Cu) diet under ambient copper culture conditions, for 120 d. Adults from each group were' subsequently bred, and the progeny were cultured and bred. Results from these studies indicated that although pronounced effects on adult reproduction and early embryo-larval development were noted in the -B F1 generation, no effects on limb development were observed. No significant effects on reproduction, early embryogenesis, or limb development were noted in the +B group, irrespective of generation. Highly specific forelimb and hindlimb defects, including axial flexures resulting in crossed limbs and reduction deficits, were observed in -B F2 larvae, but not in the +B F2 larvae. As was noted in the boron-deficiency studies, significant effects on reproduction and early embryo development were observed in the -Cu F1 generation, but not in the +Cu F, generation. Unlike the effects associated with boron deficiency, maldevelopment of the hindlimbs (32 responders, n = 40) was found in the F1 generation.

We report oxygen isotope compositions of phenocrysts and U-Pb ages of zircons in four large caldera-forming ignimbrites and post-caldera lavas of the Heise volcanic field, a nested caldera complex in the Snake River Plain, that preceded volcanism in Yellowstone. Early eruption of three normal δ 18 O voluminous ignimbrites with δ 18 O quartz = 6.4‰ and δ 18 O zircon = 4.8‰ started at Heise at 6.6 Ma, and was followed by a 2‰–3‰ δ 18 O depletion in the subsequent 4.45 Ma Kilgore caldera cycle that includes the 1800 km 3 Kilgore ignimbrite, and post-Kilgore intracaldera lavas with δ 18 O quartz = 4.3‰ and δ 18 O zircon = 1.5‰. The Kilgore ignimbrite represents the largest known low-δ 18 O magma in the Snake River Plain and worldwide. The post-Kilgore low δ 18 O volcanism likely represents the waning stages of silicic magmatism at Heise, prior to the reinitiation of normal δ 18 O silicic volcanism 100 km to the northeast at Yellowstone. The occurrence of low δ 18 O magmas at Heise and Yellowstone hallmarks a mature stage of individual volcanic cycles in each caldera complex. Sudden shifts in δ 18 O of silicic magmas erupted from the same nested caldera complexes argue against any inheritance of the low δ 18 O signature from mantle or crustal sources. Instead, δ 18 O age trends indicate progressive remelting of low δ 18 O hydrothermally altered intracaldera rocks of previous eruptions. This trend may be generally applicable to older caldera complexes in the Snake River Plain that are poorly exposed.

The Snake River Plain (SRP) developed over the last 16 Ma as a bimodal volcanic province in response to the southwest movement of the North American plate over a fixed melting anomaly. Volcanism along the SRP is dominatedby eruptions of explosive high-silica rhyolites and represents some of the largest eruptions known. Basaltic eruptions represent the final stages of volcanism, forming a thin cap above voluminous rhyolitic deposits. Volcanism progressed, generally from west to east, along the plain episodically in successive volcanic fields comprised of nested caldera complexes with major caldera-forming eruptions within a particular field separated by ca. 0.5-1 Ma, similar to, and in continuation with, the present-day Yellowstone Plateau volcanic field. Passage of the North American plate over the melting anomaly at a particular point in time and space was accompanied by uplift, regional tectonism, massive explosive eruptions, and caldera subsidence, and followed by basaltic volcanism and general subsidence. The Heise volcanic field in the eastern SRP, Idaho, represents an adjacent and slightly older field immediately to the southwest of the Yellowstone Plateau volcanic field. Five large-volume (>0.5 km 3 ) rhyolitic ignimbrites constitute a time-stratigraphic framework of late Miocene to early Pliocene volcanism for the study region. Field relations and high-precision 4 0 Ar/ 3 9 Ar age determinations establish that four of these regional ignimbrites were erupted from the Heise volcanic field and form the framework of the Heise Group. These are the Blacktail Creek Tuff (6.62 ′ 0.03 Ma), Walcott Tuff (6.27 ′ 0.04 Ma), Conant Creek Tuff (5.51 ′ 0.13 Ma), and Kilgore Tuff (4.45 ′ 0.05 Ma; all errors reported at ′ 2a). The fifth widespread ignimbrite in the region is the Arbon Valley Tuff Member of the Star-light Formation (10.21 ′ 0.03 Ma), which erupted from a caldera source outside of the Heise volcanic field. These results establish the Conant Creek Tuff as a distinct and widespread ignimbrite in the Heise volcanic field, eliminating former confusion resulting from previous discordant K/Ar and fission-track dates. New 4 0 Ar/ 3 9 Ar determinations, when combined with geochemical, lithologic, geophysical, and field data, define the volcanic and tectonic history of the Heise volcanic field and surrounding areas. Volcanic units erupted from the Heise volcanic field also provide temporal control for tectonic events associated with late Cenozoic extension in the Snake Range and with uplift of the Teton Range, Wyoming. In the Snake Range, movement of large (≥0.10 km 3 ) slide blocks of Mississippian limestone exposed 50 km to the east of the Heise field occurred between 6.3 and 5.5 Ma and may have been catastrophically triggered by the caldera eruption of the 5.51 ′ 0.13-Ma Conant Creek Tuff. This slide block movement of ∼300 vertical meters indicates that the Snake Range had significant relief by at least 5.5 Ma. In Jackson Hole, the distribution of outflow facies of the 4.45 ′ 0.05-Ma Kilgore Tuff related to eruption from the Kilgore caldera in the Heise volcanic field on the eastern SRP indicates that the northern Teton Range was not a significant topographic feature at this time.