Author(s): Habib, Salman; Roser, Robert; Gerber, Richard; Antypas, Katie; Riley, Katherine; Williams, Tim; Wells, Jack; Straatsma, Tjerk; Almgren, A; Amundson, J; Bailey, S; Bard, D; Bloom, K; Bockelman, B; Borgland, A; Borrill, J; Boughezal, R; Brower, R; Cowan, B; Finkel, H; Frontiere, N; Fuess, S; Ge, L; Gnedin, N; Gottlieb, S; Gutsche, O; Han, T; Heitmann, K; Hoeche, S; Ko, K; Kononenko, O; LeCompte, T; Li, Z; Lukic, Z; Mori, W; Nugent, P; Ng, C-K; Oleynik, G; O'Shea, B; Padmanabhan, N; Petravick, D; Petriello, FJ; Power, J; Qiang, J; Reina, L; Rizzo, TJ; Ryne, R; Schram, M; Spentzouris, P; Toussaint, D; Vay, J-L; Viren, B; Wurthwein, F; Xiao, L | Abstract: This draft report summarizes and details the findings, results, and recommendations derived from the ASCR/HEP Exascale Requirements Review meeting held in June, 2015. The main conclusions are as follows. 1) Larger, more capable computing and data facilities are needed to support HEP science goals in all three frontiers: Energy, Intensity, and Cosmic. The expected scale of the demand at the 2025 timescale is at least two orders of magnitude -- and in some cases greater -- than that available currently. 2) The growth rate of data produced by simulations is overwhelming the current ability, of both facilities and researchers, to store and analyze it. Additional resources and new techniques for data analysis are urgently needed. 3) Data rates and volumes from HEP experimental facilities are also straining the ability to store and analyze large and complex data volumes. Appropriately configured leadership-class facilities can play a transformational role in enabling scientific discovery from these datasets. 4) A close integration of HPC simulation and data analysis will aid greatly in interpreting results from HEP experiments. Such an integration will minimize data movement and facilitate interdependent workflows. 5) Long-range planning between HEP and ASCR will be required to meet HEP's research needs. To best use ASCR HPC resources the experimental HEP program needs a) an established long-term plan for access to ASCR computational and data resources, b) an ability to map workflows onto HPC resources, c) the ability for ASCR facilities to accommodate workflows run by collaborations that can have thousands of individual members, d) to transition codes to the next-generation HPC platforms that will be available at ASCR facilities, e) to build up and train a workforce capable of developing and using simulations and analysis to support HEP scientific research on next-generation systems.
Cytochrome P450 1A (CYP 1A) is a member of a multigene family of xenobiotic metabolizing enzymes. CYP 1A is highly inducible by numerous environmental contaminants including polycyclic aromatic hydrocarbons (PAHs) and is widely used in biomonitoring studies. Therefore, understanding the regulation of this gene is important for accurate interpretation of biomarker data. We describe here the functional role of a metal response element (MRE) in the European flounder CYP 1A promoter region. To help elucidate the potential role of this MRE, reporter gene constructs, with or without site-directed mutagenesis, were used in conjunction with a dual-luciferase assay. The electrophoretic mobility shift assay (EMSA) was also used to investigate potential protein binding at this MRE site. Treatment with the prototypical PAH 3-methylcholanthrene (3MC) (1.0μM) produced a dose-dependent response at the CYP 1A promoter, whereas treatment with cadmium (0–1.0μM) produced little transcriptional activity at either the wild-type or mutated promoter. Cotreatment with cadmium (1.0μM) and 3MC (1.0μM) reduced induction at this promoter to 1.83-fold compared to 3MC treatment alone (4.0-fold induction). Mutation of the MRE site resulted in abolishment of this cadmium-related loss of 3MC-dependent activity. Furthermore, a retarded band was observed in the EMSA when the MRE was used as a probe and incubated with liver nuclear protein from flounder treated with cadmium. The results not only add to knowledge of the diversity in vertebrate CYP 1A regulation but also raise the complexity of interpretation of CYP 1A induction in monitoring studies that involve mixtures of PAHs and metals.
Abstract Laboratory studies were conducted to investigate potential adverse effects on development, growth, reproduction and biomarker responses (vitellogenin [VTG] and gonad histology) in fathead minnows ( Pimephales promelas ) exposed to tamoxifen citrate. Based on the results of a partial life cycle study (nominal [mean measured] concentrations ranged from 0.18 [0.11] to 18 [15.74] μg/L), a 284‐d fish full life‐cycle (FFLC) flow‐through study was conducted using newly fertilized embryos (<24 h postfertilization) exposed to nominal (mean measured) concentrations of 14 C‐tamoxifen citrate that ranged from 0.01 (0.007) to 5.12 (4.08) μg/L. Triethylene glycol (2.0 μl/L) was used as a solvent carrier, with 17β‐estradiol (E2) as a positive control (nominal 0.1 μg/L). Among the biomarkers measured, significant effects on VTG and gonad histology were observed, although these results required care in their interpretation. Among important population‐relevant endpoints, no effects on reproduction were observed at nominal concentrations ≤5.12 μg/L. Effects on growth (length and weight) were observed in some treatments; however, some of these showed irregular concentration‐response relationships, which made interpretation uncertain, or were deemed transient in nature (e.g., reduction in growth of F1 28‐d posthatch larval fish at nominal concentrations of 0.08, 0.64, and 5.12 μg/L) and judged not to be biologically significant. Interpretation of results from fish chronic studies is challenging and frequently calls for scientific judgement about statistical and biological significance and what constitutes an adverse effect. Using the principles used in mammalian toxicology studies, data from partial and FFLC studies were evaluated from both statistical and biological perspectives in order to determine no‐observed‐adverse effect concentrations (expressed as adverse NOEC) for use in environmental risk assessment. Careful consideration of both biological and statistical outcomes from these studies suggested overall adverse NOEC concentration and lowest‐observed‐effect concentration ( adverse LOEC) values for tamoxifen citrate of 5.12 μg/L and 5.6 μg/L, respectively.
'%3e%3cpath fill='%23012169' d='M0 0v30h60V0z'/%3e%3cpath stroke='%23fff' stroke-width='6' d='m0 0 60 30m0-30L0 30'/%3e%3cpath stroke='%23C8102E' stroke-width='4' d='m0 0 60 30m0-30L0 30' clip-path='url(%23b)'/%3e%3cpath stroke='%23fff' stroke-width='10' d='M30 0v30M0 15h60'/%3e%3cpath stroke='%23C8102E' stroke-width='6' d='M30 0v30M0 15h60'/%3e%3c/g%3e%3c/svg%3e)
