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Evaluation of pharmacodynamic (PD) markers in vivo.

Supplemental Table S1. IC50 values for Nultin-3a, Carboplatin, and 1:1 Combination; Supplemental Material and Methods; Supplemental Figure Legends

Cellular solids (e.g., foams and honeycombs) are widely found in natural and engineering systems because of their high mechanical efficiency and tailorable properties. While these materials are often based on polycrystalline or amorphous constituents, here we report an unusual dual-scale, single-crystalline microlattice found in the biomineralized skeleton of the knobby starfish, Protoreaster nodosus . This structure has a diamond-triply periodic minimal surface geometry (lattice constant, approximately 30 micrometers), the [111] direction of which is aligned with the c -axis of the constituent calcite at the atomic scale. This dual-scale crystallographically coaligned microlattice, which exhibits lattice-level structural gradients and dislocations, combined with the atomic-level conchoidal fracture behavior of biogenic calcite, substantially enhances the damage tolerance of this hierarchical biological microlattice, thus providing important insights for designing synthetic architected cellular solids.

To evaluate the mechanisms driving nanoscale trace element mobility in radiation-damaged zircon, we analyzed two well-characterized Archean zircons from the Kaapvaal Craton (southern Africa): one zircon remained untreated and the other was experimentally heated in the laboratory at 1450 °C for 24 h. Atom probe tomography (APT) of the untreated zircon reveals homogeneously distributed trace elements. In contrast, APT of the experimentally heated zircon shows that Y, Mg, Al, and Pb+Yb segregate to a set of two morphologically and crystallographically distinct cluster populations that range from 5 nm tori to 25 nm toroidal polyhedra, which are confirmed to be dislocation loops by transmission electron microscopy (TEM). The dislocation loops lie in {100} and {001} planes; the edges are aligned with , , and . The largest loops (up to 25 nm diameter) are located in {100} and characterized by high concentrations of Mg and Al, which are aligned with . The 207Pb/206Pb measured from Pb atoms located within all of the loops (0.264 ± 0.025; 1σ) is consistent with present-day segregation and confirms that the dislocation loops formed during our experimental treatment. These experimentally induced loops are similar to clusters observed in zircon affected by natural geologic processes. We interpret that differences in cluster distribution, density, and composition between experimentally heated and geologically affected zircon are a function of the radiation dose, the pressure-temperature-time history, and the original composition of the zircon. These findings provide a framework for interpreting the significance of clustered trace elements and their isotopic characteristics in zircon. Our findings also suggest that the processes driving cluster formation in zircon can be replicated under laboratory conditions over human timescales, which may have practical implications for the mineralogical entrapment of significant nuclear elements.

Background Character strengths and virtues may shape responses to stressors and risk for anxious and depressive distress. However, most studies have relied on cross-sectional designs, and it remains unclear whether virtues directly predict distress in daily life or buffer context-specific stressors. We tested whether higher-order intellectual (inquisitiveness), intrapersonal (self-control), and interpersonal virtues (caring) prospectively predicted coping responses and lower symptoms, and moderated effects of specific stressors on distress. Methods Treatment-seeking individuals diagnosed with anxiety/depression (N = 81; Study 1) and students (N = 112; Study 2) completed the VIA Inventory of Strengths survey at baseline, then experience-sampling of daily symptoms and situational responses (perceptions and/or coping strategies) over seven days (Study 1) or five weeks (Study 2). Results Multilevel models generally linked virtues to more adaptive daily responses during individuals' worst and best daily events (Study 1) and worst events (Study 2), but inquisitiveness unexpectedly predicted higher symptoms in both studies. Additionally, virtues buffered against the within-person effects of specific stressor perceptions on distress (Study 2). Conclusions The relevance of character virtues for anxiety, stress, and coping may be complex, predicting higher or lower symptoms depending on both the virtue and the situational context.

Detailed bedrock mapping, structural geology, meta-igneous whole rock geochemistry, and U-Pb geochronology from rocks sampled along a portion of a complexly deformed tectonic boundary between the Ordovician peri-Gondwanan Liberty-Orrington belt and Silurian syn-orogenic strata of the Fredericton trough (a.k.a. the Dog Bay Line) in mid-coastal Maine aid in deciphering the Silurian-Devonian tectonic evolution of the region. The new results provide constraints on several key events. First, initial terrane juxtapositioning occurred along the east-verging Boothbay thrust fault (D1). This tectonism occurred prior to 423 Ma and is associated with the accretion of the Ganderian microcontinent to the Laurentian margin (that is, the Salinic orogeny). Subsequently, intrusion of an ultra-potassic magma, the protolith of the Edgecomb Gneiss, occurred at ca. 413 Ma. Its distinctive whole rock geochemical signature allows for correlation with rocks of similar composition and age along a relatively narrow 140 kilometer long distance on the northwestern margin of the Fredericton trough. This restricted area of ultra-potassic magma generation is attributed to the breakoff of the descending Salinic oceanic slab that triggered decompression melting of a previously metasomatized mantle wedge region beneath the accreted Ganderian microcontinent. Early thrust faults (D1) and the ca. 413 Edgecomb Gneiss igneous protolith were overprinted by an episode of upright folding (D2) and low-pressure amphibolite facies metamorphism associated with the Early to Middle Devonian Acadian orogeny. Zircon overgrowths in the Edgecomb Gneiss dated at ca. 399 Ma grew during this tectonic episode. Comparisons with previous geochronological studies across the region suggest this dominant phase of Acadian deformation and metamorphism was long-lived (ca. 40 m.y.) and associated with the outboard accretion of the Avalonian microcontinent. Dextral shear structures represent the final phase of deformation (D3) superimposed on this terrane boundary and are associated with the Norumbega fault and shear zone system that was active in Middle Devonian-Carboniferous time.

Atom probe tomography (APT) is used to quantify atomic-scale elemental and isotopic compositional variations within a very small volume of material (typically µm3). The small analytical volume ideally contains specific compositional or microstructural targets that can be placed within the context of the previously characterized surface in order to facilitate a correct interpretation of APT data. In this regard, careful targeting and preparation are paramount to ensure that the desired target, which is often smaller than 100 nm, is optimally located within the APT specimen. Needle-shaped specimens required for atom probe analysis are commonly prepared using a focused ion beam scanning electron microscope (FIB-SEM). Here, we utilize FIB-SEM-based time-of-flight secondary ion mass spectrometry (ToF-SIMS) to illustrate a novel approach to targeting

Nanoscale analyses of zircon have demonstrated that trace elements, including Pb, can be mobilized to discrete sites in radiation damaged zircon. Although several mechanisms for trace element mobility and segregation in zircon have been proposed, most of this work has been conducted on zircon grains with complex geologic histories, making it difficult to directly determine the mechanisms driving trace element mobility and segregation in zircon. To test among the existing hypotheses for mechanisms driving trace element mobility and segregation, we analyzed both untreated and experimentally heated (1450°C for 24h) Archean zircon using atom probe tomography and transmission electron microscopy (TEM). The sample has a simple, well-characterized thermal history, with no significant thermal events since original crystallization. Despite a high calculated radiation dose (>4 x 1018 a/g), the untreated zircon does not contain anomalous nanoscale features. In contrast, the experimentally heated zircon contains abundant clusters of Y, Mg, Al, Pb + Yb that range from 5 nm to 25 nm in diameter with toroidal polyhedral morphologies. The 207Pb/206Pb measured from Pb atoms located within these features is consistent with present-day segregation, thus confirming that these nanoscale features were produced by experimental heating in the laboratory. TEM analysis determined that the clusters are dislocation loops, and that cluster morphology is therefore crystallographically controlled. The largest loops are located in {100} and contain high concentrations of Mg and Al.These experimentally induced, trace-element-enriched clusters are similar in size, morphology, composition, and crystallographic orientation to clusters observed in zircon affected by natural geologic processes (cf. Valley et al., 2015; Peterman et al., 2016). Although the calculated radiation doses for all analyzed grains are high, comparison of the nanoscale features indicates no apparent correlation between the radiation dose and the density or distribution of clusters. We also observe that trace-element-enriched clusters are conspicuously absent from zircon grains that lack younger igneous or metamorphic rims. These findings suggest that the pressure-temperature-time (P-T-t) history and the dT/dt significantly impact both the nanoscale redistribution of trace elements and the density of these features within zircon. Systematic evaluation of the composition and distribution of these features provides a framework for understanding the nanoscale record of metamorphism. References:Peterman, E.M., Reddy, S.M, Saxey, D.W., Snoeyenbos, D.R., Rickard, W.D.A., Fougerouse, D., and Kylander-Clark, A.R.C. (2016) Nanogeochronology of discordant zircon measured by atom probe microscopy of Pb-enriched dislocation loops. Science Advances, 2, e:1601218.Valley, J.W., Reinhard, D.A., Cavosie, A.J., Ushikubo, T., Lawrence, D.F., Larson, D.J., Kelly, T.F., Snoeyenbos, DR., and Strickland, A. (2015) Nano-and micro-geochronology in Hadean and Archean zircons by atom-probe tomography and SIMS: New tools for old minerals. American Mineralogist, 100, 1355-1377.

This paper describes my research on fish population dynamics, which has aimed to improve the information available for management and conservation. Through numerous collaborations, my research program addressed three main objectives. (1) Increase the understanding of spatial and temporal variation in productivity of fish populations. (2) Quantify uncertainties and risks in fishery systems and their implications for management and conservation. (3) Develop methods to reduce those uncertainties and risks. To help young scientists, I present 11 general lessons, as well as some specific advice, that emerged from that research. The general lessons include pursuing a path of continuous learning, going beyond your comfort zone to broaden your skills and knowledge, and collaborating with others. More specific advice for fisheries scientists includes evaluating the bias and precision of parameter estimation methods via Monte Carlo simulations, and considering multiple models of whole fishery systems. This paper also illustrates, with examples, how the understanding of some aspects of fish population dynamics has evolved, at least from the limited perspective of my own group's research.

We expand on previous analyses of environmental factors related to productivity of Chinook salmon (Oncorhynchus tshawytscha) populations by analysing data on adult recruits per spawner from 24 wild (not hatchery) Chinook salmon stocks from Oregon through western Alaska. To determine the degree to which changes in productivity are shared and to help identify environmental variables that might be related to those changes, we estimated the magnitude and spatial characteristics of positive correlations in productivity trends among stocks separated by various distances. We used dynamic factor analysis to characterize shared time trends in productivity and found that these trends were most closely associated with the North Pacific Gyre Oscillation and, to a lesser extent, with the location of the bifurcation in the North Pacific Current as it reaches North America’s west coast. Chinook productivity patterns of separate populations have also become more synchronous in recent years, similar to results reported for other species of Pacific salmon. Such recent changes may reduce the resilience of the species to effects of climate change and habitat modification.

Background Cutaneous venous malformation (VM) can be associated with internal vascular anomalies. Our objective was to investigate the frequency of internal vascular anomalies in patients with an isolated genital venous malformation to assess the utility of screening for internal findings. Methods We retrospectively reviewed our Vascular Anomalies Center database for patients with a focal genital venous malformation presenting between 1999 and 2016. Abdominal and pelvic imaging reports were reviewed for internal vascular anomalies. Endoscopy reports were also reviewed when available. Results A focal genital venous malformation was found in 22 patients (14 female, 8 male). Ten (45%) had a venous malformation of at least one internal structure, most commonly the pelvic floor (n = 6), colon (n = 5), urethra (n = 4), and/or bladder (n = 3). Eight experienced hematuria, hematochezia, and/or rectorrhagia secondary to their internal venous malformation. In patients with internal venous malformations, the mean age of symptom presentation was 7.3 years (range 1-22 years). Two patients had malformed inferior mesenteric and portal veins visible using ultrasonography and magnetic resonance imaging. They required surgical intervention to prevent thrombosis and decrease urogenital and gastrointestinal bleeding. Conclusion Nearly half of our patients with a focal genital venous malformation had internal venous anomalies. Physicians should suspect urogenital or gastrointestinal venous malformations in patients with a focal genital venous malformation, especially if they develop hematuria, hematochezia, or rectorrhagia. Significant mesenteric venous trunk anomalies can also occur. Because these require surgical intervention, early recognition is important. We recommend that all patients with a focal genital venous malformation undergo abdominal and pelvic ultrasound to evaluate for internal venous anomalies.

Granite from a 50–200-m-wide damage zone adjacent to the brittle-ductile Kellyland Fault Zone contains healed fracture networks that exhibit almost all of the characteristics of dynamically pulverized rocks. Fracture networks exhibit only weak preferred orientations, are mutually cross-cutting, separate jigsaw-like interlocking fragments, and are associated with recrystallized areas likely derived from pervasively comminuted material. Fracture networks in samples with primary igneous grain shapes further indicate pulverization. Minimum fracture densities in microcline are ∼100 mm/mm 2 . Larger fractures in microcline and quartz are sometimes marked by neoblasts, but most fractures are optically continuous with host grains and only visible in cathodoluminescence images. Fractures in plagioclase are crystallographically controlled and typically biotite filled. Petrologic observations and cross-cutting relationships between brittle structures and mylonitic rocks show that fracturing occurred at temperatures of 400 °C or more and pressures of 200 MPa. These constraints extend the known range of pulverization to much higher temperature and pressure conditions than previously thought possible. The mutually cross-cutting healed fractures also provide the first record of repeated damage in pulverized rocks. Furthermore, pulverization must have had a significant but transient effect on wall-rock porosity, and biotite-filled fracture networks in plagioclase form weak zones that could accommodate future strain localization.

Several examples of zircon grains from high- to ultrahigh-pressure (UHP) and ultrahigh-temperature (UHT) metapelites exhibit a characteristic, yet atypical, core–rim interface domain

Background Infantile hemangiomas (IHs) are the most common tumors of infancy. The objective was to identify clinical and radiological patterns in patients with retroperitoneal IHs. Methods We reviewed patients from our Vascular Anomalies Center database with IHs and abdominal imaging presenting from 1999 to 2017 to identify retroperitoneal involvement. Results Eleven patients (10 females, one male) with retroperitoneal IHs were found. Cutaneous IHs were present in eight patients (five segmental (45%), three multifocal (27%)) and absent in 1 (9%). Segmental hemangiomas involved the face in 2/5 (40%) and lower body in 3/5 (60%). The most common symptoms were dyspnea (n = 4), hematochezia (n = 3), and/or ulceration (n = 2). Three patients were asymptomatic. Involved retroperitoneal organs included the duodenum (n = 4), pancreas (n = 3), and adrenal glands (n = 1). Non-retroperitoneal organ involvement included the liver (n = 5), non-duodenal small intestine (n = 4), and large intestine (n = 3). Perivascular retroperitoneal hemangiomas were seen in 6/11 patients (55%), most commonly surrounding the aorta (n = 5), iliac vessels (n = 2), and/or inferior vena cava (n = 2). Three of 11 patients (27%) had LUMBAR based on a segmental, sacral hemangioma with tethered cord or anorectal malformation. Follow-up information was available in 6/11 patients (55%): 5 symptomatically improved with treatment (propranolol, corticosteroids, and/or vincristine), while one succumbed from extensive hepatic involvement. Conclusion Retroperitoneal IHs are rare and tend to involve organs or surround vessels. Associated cutaneous IHs, if present, lack anatomical predilection and may be segmental or multifocal.

PHACE is an association between large infantile hemangiomas and brain, arterial, cardiac, and/or ocular abnormalities. Aortic or subclavian aberrations are the most common cardiovascular anomalies in PHACE, whereas complex congenital heart disease is rare. We report a case of Holmes heart and three cases of tetralogy of Fallot in PHACE association.

Highly restitic garnet-kyanite-phlogopite metapelitic schists from the Goshen Dome of western Massachusetts contain: a population of prograde monocrystalline, megacrystic garnet, some with significant P in substitution for Si; precipitates of hydroxylapatite and rutile; and 5 /mm 3 . The unusual P content and the abundant internal precipitate suite are similar to features reported in garnet from ultrahigh-pressure (UHP) and mantle settings, suggesting a potential (U)HP origin for the garnet megacrysts. Zircon included in megacrysts is surrounded by radial fractures, indicating in situ volumetric expansion or new growth. Cores display rare earth element (REE) profiles and cathodoluminescence (CL) zoning consistent with magmatic growth, and yield only Paleozoic dates (447–404 Ma). The embayed core-rim boundary is marked by a several micrometers wide band of CL-dark zircon enriched in Y, P, U, and Th that is interpreted as the accumulation of redistributed xenotime component from the original zircon rim during metamorphism. Outside of this band, the rim has elevated Hf, Th/U ≪ 1, and steep heavy REE profiles. The metamorphic rims yield concordant dates from 400 to 381 Ma. Matrix zircon grains have magmatic cores (1726–415 Ma) with similar core–rim boundaries enriched in Y, P, U, and Th. Metamorphic rims on matrix zircon yield slightly younger dates (393–365 Ma) and are compositionally heterogeneous. The difference between the youngest core and oldest rim indicates a short interval (ca. 4 Ma) between deposition of detrital zircon and the onset of metamorphism in the earliest Acadian. The oldest zircon rim dates are found within phosphatic garnet megacrysts of possible very high-pressure origin. The compositional uniformity of these rims indicates equilibrium with a single source; the anomalous composition suggests a combination of dissolution-reprecipitation and new growth of zircon that is derived from garnet. The range in both composition and dates indicates that matrix zircon rims formed in response to local changes in mineralogy and fluid/melt composition and/or availability. New growth of zircon on these grains cannot be confirmed, suggesting that dissolution-reprecipitation reactions during continued metamorphism may be the dominant mechanism that formed these rims. The data collectively suggest that dissolution-reprecipitation may be a common mechanism for producing metamorphic rims on zircon that does not require additional Zr and Hf, which are limited within most metamorphic settings.

Triple-negative breast cancers (TNBC) are typically resistant to treatment, and strategies that build upon frontline therapy are needed. Targeting the murine double minute 2 (Mdm2) protein is an attractive approach, as Mdm2 levels are elevated in many therapy-refractive breast cancers. The Mdm2 protein–protein interaction inhibitor Nutlin-3a blocks the binding of Mdm2 to key signaling molecules such as p53 and p73α and can result in activation of cell death signaling pathways. In the present study, the therapeutic potential of carboplatin and Nutlin-3a to treat TNBC was investigated, as carboplatin is under evaluation in clinical trials for TNBC. In mutant p53 TMD231 TNBC cells, carboplatin and Nutlin-3a led to increased Mdm2 and was strongly synergistic in promoting cell death in vitro. Furthermore, sensitivity of TNBC cells to combination treatment was dependent on p73α. Following combination treatment, γH2AX increased and Mdm2 localized to a larger degree to chromatin compared with single-agent treatment, consistent with previous observations that Mdm2 binds to the Mre11/Rad50/Nbs1 complex associated with DNA and inhibits the DNA damage response. In vivo efficacy studies were conducted in the TMD231 orthotopic mammary fat pad model in NOD.Cg-PrkdcscidIl2rgtm1Wjl/SzJ (NSG) mice. Using an intermittent dosing schedule of combined carboplatin and Nutlin-3a, there was a significant reduction in primary tumor growth and lung metastases compared with vehicle and single-agent treatments. In addition, there was minimal toxicity to the bone marrow and normal tissues. These studies demonstrate that Mdm2 holds promise as a therapeutic target in combination with conventional therapy and may lead to new clinical therapies for TNBC. Mol Cancer Ther; 14(12); 2850–63. ©2015 AACR.

Pathways linking climate to population dynamics of higher-trophic-level fish species such as Pacific salmon often involve a hierarchy in which regional-scale physical and biological processes mediate the effects of large-scale climate variability. We used probabilistic networks to investigate 17 potential ecological pathways linking climate to Oregon coho salmon (Oncorhynchus kisutch) recruitment. We found that pathways originating with the Pacific Decadal Oscillation were the most influential on recruitment, with the net effect being two to four times greater than for pathways originating with the North Pacific Gyre Oscillation or the Oceanic Niño Index. Among all environmental variables, sea surface temperature and an index of juvenile salmon prey biomass had the greatest effects on recruitment, with a 76% chance of recruitment being equal to or below average given that ocean temperatures were above average and a 34% chance of recruitment being below average given that prey biomass was above average. Our results provide evidence that shifts in climate patterns could strongly influence recruitment simultaneously through multiple ecological pathways and highlight the importance of quantifying cumulative effects of these pathways on higher-trophic-level species.

Chemical Geology 409 (2015) 28–41 Contents lists available at ScienceDirect Chemical Geology journal homepage: www.elsevier.com/locate/chemgeo Monazite response to ultrahigh-pressure subduction from U–Pb dating by laser ablation split stream Bradley R. Hacker a, ⁎ , Andrew R.C. Kylander-Clark a , Robert Holder a , Torgeir B. Andersen b , Emily M. Peterman c , Emily O. Walsh d , Jonathan K. Munnikhuis e a Earth Science, University California, Santa Barbara, CA 93106-9630, USA University of Oslo, Physics of Geological Processes, PO Box 1048, Blindern, 0316 Oslo, Norway Earth and Oceanographic Science, Bowdoin College, 6800 College Station, Brunswick, ME 04011, USA d Geology, Cornell College, Mount Vernon, IA 52314, USA e Geological Sciences, University of North Carolina, Chapel Hill, Campus Box #3315 Chapel Hill, NC 27599-3315, USA b c a r t i c l e i n f o Article history: Received 5 February 2015 Received in revised form 6 May 2015 Accepted 11 May 2015 Available online 22 May 2015 Editor: K. Mezger Keywords: Monazite Laser ablation Split stream Petrochronology a b s t r a c t To assess the response of monazite during subduction of continental crust to mantle depths, U–Pb isotopic ratios and elemental abundances were measured simultaneously by laser-ablation split-stream inductively-coupled plasma mass spectrometry (LASS) in rocks from the ultrahigh-pressure Western Gneiss Region of the Scandinavian Caledonides. Nearly seventy different samples of quartzofeldspathic basement and overlying metasedimentary rocks were studied. Pre-subduction monazite (chiefly 1.6 Ga and 1.0 Ga) is preserved locally in the structurally lowest, basement rocks because earlier, Precambrian tectonism produced coarse-grained, high-grade rocks that were resistant to further recrystallization in spite of syn-subduction temperatures and pressures of 650–800 °C and 2–3.5 GPa. A few of the monazite in the metasedimentary rocks atop the basement preserve syn-subduction U–Pb dates, but the majority continued to recrystallize during post-subduction exhumation and record a general westward decrease in age related to westward-progressing exhumation. The absence of Precambrian monazite in the metasedimentary rock atop the basement suggests that sedimentation postdated the 1.0–0.9 Ga high-grade metamorphism and was late Proterozoic to early Paleozoic. © 2015 Elsevier B.V. All rights reserved. 1. Introduction The development of techniques to analyze monazite U/Th–Pb dates in situ by electron probe [Suzuki et al., 1991], SIMS [Harrison et al., 1995], and LA-ICP-MS [Kosler et al., 2001] has spurred renewed interest in the petrogenesis of monazite, including understanding neocrystal- lization [Kingsbury et al., 1993], recrystallization [Finger, 1998], compo- sition [Franz et al., 1996], and thermometry [Gratz and Heinrich, 1997; Pyle et al., 2001]. Advances in these complementary tracks of analytical methods and petrologic interpretation have enabled increasing use of monazite as a petrochronometer—i.e., the interpretation of isotopic dates in the context of elemental or complementary isotopic informa- tion collected from the same mineral. One might infer from recent models [Kelsey, 2008] [Yakymchuk and Brown, 2014] that monazite is routinely recrystallized during high- temperature orogenesis and that its U–Pb age records only the final, cooling stage. Here we apply LASS (laser-ablation split-stream inductively-coupled plasma mass spectrometry) [Kylander-Clark et al., 2013] to monazite from the ultrahigh-pressure (UHP) Western Gneiss ⁎ Corresponding author. Tel.: +1 805 893 7952. E-mail address: hacker@geol.ucsb.edu (B.R. Hacker). http://dx.doi.org/10.1016/j.chemgeo.2015.05.008 0009-2541/© 2015 Elsevier B.V. All rights reserved. Region (WGR). Our objective in using in situ, combined U–Pb and trace-element analysis of monazite is to understand the broad-scale metamorphic response of monazite and its host rocks during subduc- tion to, and exhumation from, UHP conditions. The premise behind collecting trace-element and isotopic data simultaneously is that the trace elements provide insight into the petrological context of the isoto- pic dates: depressed heavy rare earth element concentrations may indi- cate that an interpreted U–Pb date coincides with the stability of garnet [Rubatto, 2002], elevated Eu and Sr may indicate HP recrystallization and plagioclase instability [Finger and Krenn, 2007; Holder et al., 2015], and Th and U help understand fluid availability [Hoskin and Schaltegger, 2003] and its potential role in monazite recrystallization [Seydoux-Guillaume et al., 2002]. We show that some monazite sur- vived amphibolite–granulite-facies metamorphism, partial melting, and subduction with its original age intact. 2. Geologic setting The Western Gneiss Region (WGR) of Norway contains one of Earth's largest ultrahigh-pressure terranes (Fig. 1). Like most well-exposed and extensively investigated UHP terranes, the WGR is dominated by quartzofeldspathic gneiss; eclogite and (U)HP

Predictions of habitat-based assessment methods that are used to determine instream flow requirements for aquatic biota are uncertain, but instream flow practitioners and managers often ignore those uncertainties. Two commonly recognized uncertainties arise from (i) estimating the way in which physical habitat within a river changes with discharge and (ii) the suitability of certain types of physical habitat for organisms. We explored how these sources of uncertainty affect confidence in the results of the British Columbia Instream Flow Methodology (BCIFM), which is a commonly used transect-based habitat assessment tool for small-scale water diversions. We calculated the chance of different magnitudes of habitat loss resulting from water diversion using a high-gradient reach of the North Alouette River, BC, as a case study. We found that uncertainty in habitat suitability indices for juvenile rainbow trout generally dominated uncertainty in the results of the BCIFM when large (>15) numbers of transects were used. In contrast, with small numbers of transects, variation in physical habitat among sampled transects was the major source of uncertainty in the results of the BCIFM. Presentations of results of the BCIFM in terms of probabilities of different amounts of habitat loss for a given flow can help managers prescribe instream flow requirements based on their risk tolerance for fish habitat loss. Copyright © 2015 John Wiley & Sons, Ltd.

We investigated spatial and temporal components of phytoplankton dynamics in the Northeast Pacific Ocean to better understand the mechanisms linking biological oceanographic conditions to productivity of 27 pink salmon (Oncorhynchus gorbuscha) stocks. Specifically, we used spatial covariance functions in combination with multistock spawner–recruit analyses to model relationships among satellite-derived chlorophyll a concentrations, initiation date of the spring phytoplankton bloom, and salmon productivity. For all variables, positive spatial covariation was strongest at the regional scale (0–800 km) with no covariation beyond 1500 km. Spring bloom timing was significantly correlated with salmon productivity for both northern (Alaska) and southern (British Columbia) populations, although the correlations were opposite in sign. An early spring bloom was associated with higher productivity for northern populations and lower productivity for southern populations. Furthermore, the spring bloom initiation date was always a better predictor of salmon productivity than mean chlorophyll a concentration. Our results suggest that changes in spring bloom timing resulting from natural climate variability or anthropogenic climate change could potentially cause latitudinal shifts in salmon productivity.

Hepatic angiosarcoma is a rare, aggressive, malignant neoplasm with fewer than 50 cases reported in children. Prognosis is poor, with a minority surviving beyond 2 years after diagnosis. We report eight cases of pediatric hepatic angiosarcoma, diagnosed at a mean age of 3 years. Seven were initially diagnosed with an infantile hepatic hemangioendothelioma (IHHE) or hemangioma and the eighth with a "vascular tumor." Two patients, who received liver transplant, survived. We suggest hepatic hemangiomas can rarely transform into angiosarcomas and a subset of IHHEs (Type II) are actually a low-grade form of angiosarcoma rather than a benign lesion.

Background CLOVES syndrome is associated with somatic mosaic PIK3CA mutations and characterized by congenital lipomatous overgrowth, vascular malformations, epidermal nevi, and skeletal anomalies. Wilms tumor (WT) is a malignant embryonal renal neoplasm associated with hemihypertrophy and certain overgrowth disorders. After identifying WT in a child with CLOVES, we questioned whether ultrasonographic screening was necessary in these patients. Methods We retrospectively reviewed patients with CLOVES syndrome in our Vascular Anomalies Center at Boston Children's Hospital between 1998 and 2016 to identify those who developed WT. A PubMed literature search was also conducted to find other patients with both conditions. Results A total of 122 patients with CLOVES syndrome were found in our database (mean age 7.7 years, range 0–53 years). Four patients developed WT; all were diagnosed at 2 years of age. The incidence of WT in our CLOVES patient population (3.3%) was significantly greater than the incidence of WT in the general population (1/10,000) (P < 0.001). Four additional patients with WT and CLOVES syndrome were identified in our literature review. Conclusion Patients with CLOVES syndrome have an increased risk of WT. Given the benefits of early detection and treatment, children with CLOVES syndrome should be considered for quarterly abdominal ultrasonography until age 7 years. Screening may be most beneficial for patients under 3 years of age.

Monazite is a petrologically important and analytically promising target for (U–Th)/He thermochronology. Previous studies have reported highly variable He diffusion results from monazite from a single sample and demonstrated that composition can significantly affect He diffusion parameters. In this study, we performed incremental heating of single monazite grains to experimentally determine the 4He diffusion properties of reference monazite ‘554’ that occurs within a peraluminous two-mica granite from the Catnip Sill within the Catalina Core complex, Arizona. Assuming that the grain size defines the diffusion geometry, the six experiments yielded E a values of 212 to 238 ± 5 kJ mol − 1 (1σ) and D o values of 15.7 to 103 cm 2 s − 1 with one value of 784 cm 2 s − 1 . Monazite (U–Th)/He data from five grains yielded closure temperatures of 291 to 262 °C (± c. 15 °C) and ages of 23.8 – 20.3 ( ± ∼ 1.2 ; 2 σ ) Ma ; the weighted mean age is 21.8 ± 0.73 ( MSWD = 1.83 , n = 5 ) and the weighted mean closure temperature is 282 ± 6 ° C ( MSWD = 0.96 , n = 5 ; 1 σ ). We tested the accuracy of these results by comparing our monazite thermochronology data with monazite Th/Pb depth profiling results, the 40Ar/39Ar thermal history for the Catnip Sill constrained using coexisting muscovite, biotite, and K-feldspar, and published regional zircon and apatite fission track results. The monazite Th/Pb data indicate emplacement of the Catnip Sill at ∼ 45 Ma . The 40Ar/39Ar muscovite and biotite data indicate cooling from 460 to 350 °C from 27 to 26 Ma. K-feldspar MDD modeling suggests cooling from 360 to 240 °C from 26 to 24 Ma. Zircon fission track data indicate cooling through 250 °C between 29 and 20 Ma. Additional cooling through 110 °C is recorded by apatite fission track ages of 19–16 Ma. Because the monazite thermochronology results are reproducible and consistent with the thermal history constrained by the other chronometers, our results 1) confirm the accuracy of the 4He diffusion kinetics from monazite ‘554,’ and 2) demonstrate that monazite can be an effective (U–Th)/He thermochronometer, provided that He diffusion properties are either measured or reasonably assumed for each sample.

Assessments of extinction risk based on population declines are widely used, yet scientists have little quantitative understanding of their reliability. Incorrectly classifying whether a population is declining or not can lead to inappropriate conservation actions or management measures, with potentially profound societal costs. Here we evaluate key causes of misclassification of decline status and assess the reliability of 20 decline metrics using a stochastic model to simulate time series of population abundance of sockeye salmon (Oncorhynchus nerka). We show that between-year variability in population productivity (process variation) and, to a lesser extent, variability in abundance estimates (observation error) are important causes of unreliable identification of population status. We found that using all available data, rather than just the most recent three generations, consistently improved the reliability of risk assessments. The approach outlined here can improve understanding of the reliability of risk assessments, thereby reducing concerns that may impede their use for exploited taxa such as marine fishes.

We used empirically based simulation modelling of 48 sockeye salmon ( O. nerka ) populations to examine how reliably alternative monitoring designs and fish stock assessment methods can distinguish between changes in density-dependent versus density-independent components of productivity and identify the relative contribution of a climate-driven covariate. We explored a wide range of scenarios for ocean and freshwater conditions and the response of salmon productivity (adult recruits per spawner) to those conditions. Our results show that stock assessments based on historical relationships between salmon productivity and climate-driven oceanographic conditions will likely perform poorly when those relationships change, even when such changes are anticipated and incorporated into stock assessment models in a timely manner. Estimating the relative importance of climate-driven oceanographic influences as a driver of sockeye productivity will be difficult, especially if climatic changes occur rapidly and concurrently with other disturbances. Thus, better understanding of the mechanisms by which climatic changes and other drivers influence salmon productivity may be essential to avoid undesirable management outcomes. As well, an expansion of monitoring of juvenile salmon abundances on more salmon stocks is needed to help distinguish the effects of different drivers.

Canada has made numerous national and international commitments to sustain marine biodiversity. Given current and potential threats to biodiversity from climate change, fisheries, and aquaculture, we provide a summary review of Canada’s progress in fulfilling its obligations to protect, conserve, recover, and responsibly exploit marine biodiversity. We conclude that Canada has made little substantive progress, when compared to most developed nations, in meeting its biodiversity commitments. Much of Canada’s policy and rhetoric has not been operationalised, leaving many of the country’s national and international obligations unfulfilled in some key areas, such as the establishment of marine protected areas and incorporation of the precautionary approach to fisheries management. We conclude that regulatory conflict within Canada’s Department of Fisheries and Oceans (DFO) and the absolute discretion exercised by the national Minister of Fisheries and Oceans contribute significantly to an unduly slow rate of policy and statute implementation. We recommend new approaches and measures to sustain Canadian marine biodiversity and new research initiatives to support scientific advice to decision-makers. Many recommendations focus on management actions required to meet existing commitments to biodiversity conservation. Overall, we conclude that the most effective strategy is to protect existing biological diversity and to rebuild depleted populations and species to restore natural diversity. By improving and protecting the biodiversity in Canada’s oceans, such a strategy will restore the natural resilience of Canada’s ocean ecosystems to adapt to the challenges posed by climate change and other anthropogenic activities with consequent long-term benefits for food security and social and economic well-being.

Canada has made numerous international and national commitments to sustain marine biodiversity. International commitments include the implementation of ecosystem-based management, the establishment a network of marine protected areas, and the restoration of commercially exploited fish stocks. However, the international commitments tend to be quite general in nature with the precise governance implications of key principles, such as precaution and the ecosystem approach, being open to interpretation, thus leaving considerable room for discretion in implementation. Consequently, a plethora of soft law documents has emerged to provide more specific guidance to decision-makers and progressively develop international law and policy. Nationally, Canada has embraced a long list of commitments that are supportive of sustaining marine biodiversity through legislation and numerous policy-related documents. Nonetheless, Canada has left many of these commitments unfulfilled or inadequately fulfilled, such as (i) the development of integrated management plans for coastal and marine waters, (ii) the implementation of the precautionary approach for Canada’s fisheries, and (iii) the establishment of recovery strategies and identification of critical habitat for species at risk. Although the goal of effective protection of marine biodiversity in Canada appears to be guided by international and national commitments, there remains a clear need to fully implement, operationalize, and strengthen these commitments as articulated in the Oceans Act, fisheries management-related policies, the Species at Risk Act, and others.

Atom probe yields geologically meaningful ages from nanoscale Pb-enriched dislocation loops in discordant zircon., Isotopic discordance is a common feature in zircon that can lead to an erroneous age determination, and it is attributed to the mobilization and escape of radiogenic Pb during its post-crystallization geological evolution. The degree of isotopic discordance measured at analytical scales of ~10 μm often differs among adjacent analysis locations, indicating heterogeneous distributions of Pb at shorter length scales. We use atom probe microscopy to establish the nature of these sites and the mechanisms by which they form. We show that the nanoscale distribution of Pb in a ~2.1 billion year old discordant zircon that was metamorphosed c. 150 million years ago is defined by two distinct Pb reservoirs. Despite overall Pb loss during peak metamorphic conditions, the atom probe data indicate that a component of radiogenic Pb was trapped in 10-nm dislocation loops that formed during the annealing of radiation damage associated with the metamorphic event. A second Pb component, found outside the dislocation loops, represents homogeneous accumulation of radiogenic Pb in the zircon matrix after metamorphism. The 207Pb/206Pb ratios measured from eight dislocation loops are equivalent within uncertainty and yield an age consistent with the original crystallization age of the zircon, as determined by laser ablation spot analysis. Our results provide a specific mechanism for the trapping and retention of radiogenic Pb during metamorphism and confirm that isotopic discordance in this zircon is characterized by discrete nanoscale reservoirs of Pb that record different isotopic compositions and yield age data consistent with distinct geological events. These data may provide a framework for interpreting discordance in zircon as the heterogeneous distribution of discrete radiogenic Pb populations, each yielding geologically meaningful ages.

To better manage living marine resources (LMRs), it has become clear that ecosystem-based fisheries management (EBFM) is a desired approach. To do EBFM, one of the key tools will be to use ecosystem models. To fully use ecosystem models and have their outputs adopted, there is an increasingly recognized need to address uncertainty associated with such modeling activities. Here we characterize uncertainty as applied to ecosystem models into six major factors, including: natural variability; observation error; inadequate communication among scientists, decision-makers and stakeholders; the structural complexity of the model(s) used; outcome uncertainty; and unclear management objectives. We then describe best practices to address each of these uncertainties as they particularly apply to ecosystem models being used in a LMR management context. We also present case studies to highlight examples of how these best practices have been implemented. Although we acknowledge that this work was compiled by ecosystem modelers in an LMR management context primarily for other ecosystem modelers, the principles and practices described herein are also germane for managers, stakeholders and other natural resource management communities. We conclude by emphasizing not only the need to address uncertainty in ecosystem models, but also the feasibility and benefits of doing so.

Although there are many indicators of endangerment (i.e., whether populations or species meet criteria that justify conservation action), their reliability has rarely been tested. Such indicators may fail to identify that a population or species meets criteria for conservation action (false negative) or may incorrectly show that such criteria have been met (false positive). To quantify the rate of both types of error for 20 com- monly used indicators of declining abundance (threat indicators), we used receiver operating characteristic curves derived from historical (1938-2007) data for 18 sockeye salmon (Oncorhynchus nerka) populations in the Fraser River, British Columbia, Canada. We retrospectively determined each population's yearly status (reflected by change in abundance over time) on the basis of each indicator. We then compared that popu- lation's status in a given year with the status in subsequent years (determined by the magnitude of decline in abundance across those years). For each sockeye population, we calculated how often each indicator of past status matched subsequent status. No single threat indicator provided error-free estimates of status, but indicators that reflected the extent (i.e., magnitude) of past decline in abundance (through comparison of current abundance with some historical baseline abundance) tended to better reflect status in subsequent years than the rate of decline over the previous 3 generations (a widely used indicator). We recommend that when possible, the reliability of various threat indicators be evaluated with empirical analyses before such indicators are used to determine the need for conservation action. These indicators should include estimates from the entire data set to take into account a historical baseline.

In this design study, we present an analysis and abstraction of the data and task in the domain of fisheries management, and the design and implementation of the Vismon tool to address the identified requirements. Vismon was designed to support sophisticated data analysis of simulation results by managers who are highly knowledgeable about the fisheries domain but not experts in simulation software and statistical data analysis. The previous workflow required the scientists who built the models to spearhead the analysis process. The features of Vismon include sensitivity analysis, comprehensive and global trade-offs analysis, and a staged approach to the visualization of the uncertainty of the underlying simulation model. The tool was iteratively refined through a multi-year engagement with fisheries scientists with a two-phase approach, where an initial diverging experimentation phase to test many alternatives was followed by a converging phase where the set of multiple linked views that proved effective were integrated together in a useable way. Several fisheries scientists have used Vismon to communicate with policy makers, and it is scheduled for deployment to policy makers in Alaska. © 2012 Wiley Periodicals, Inc.