Radiography Facility - Building 239 Independent Validation Review

The purpose of this task was to perform an Independent Validation Review to evaluate the successful implementation and effectiveness of Safety Basis controls, including new and revised controls, to support the implementation of a new DSA/TSR for B239. This task addresses Milestone 2 of FY10 PEP 7.6.6. As the first IVR ever conducted on a LLNL nuclear facility, it was designated a pilot project. The review follows the outline developed for Milestone 1 of the PEP, which is based on the DOE Draft Guide for Performance of Independent Verification Review of Safety Basis Controls. A formal Safety Basis procedure will be developed later, based on the lessons learned with this pilot project. Note, this review is termed a ''Validation'' in order to be consistent with the PEP definition and address issues historically raised about verification mechanisms at LLNL. Validation is intended to confirm that implementing mechanisms realistically establish the ability of TSR LCO, administrative control or safety management program to accomplish its intended safety function and that the controls are being implemented. This effort should not, however, be confused with a compliance assessment against all relevant DOE requirements and national standards. Nor is it used as a vehicle to question the derivation of controls already approved by LSO unless a given TSR statement simply cannot be implemented as stated

Existence theorems in the geometrically non-linear 6-parametric theory of elastic plates

In this paper we show the existence of global minimizers for the geometrically exact, non-linear equations of elastic plates, in the framework of the general 6-parametric shell theory. A characteristic feature of this model for shells is the appearance of two independent kinematic fields: the translation vector field and the rotation tensor field (representing in total 6 independent scalar kinematic variables). For isotropic plates, we prove the existence theorem by applying the direct methods of the calculus of variations. Then, we generalize our existence result to the case of anisotropic plates. We also present a detailed comparison with a previously established Cosserat plate model.Comment: 19 pages, 1 figur

USDA Plant Genome Research Program

The U.S. Congress appropriated funds in 1991 for the USDA Plant Genome Research Program, four years after its initial conception in 1987. The goal of the USDA Plant Genome Research Program is to improve plants (agronomic, horticultural, and forest tree species) by locating marker DNA or genes on chromosomes, determining gene structure, and transferring genes to improve plant performance with accompanying reduced environmental impact to meet marketplace needs and niches. The Plant Genome Research Program is one program with two parts: National Research Initiative and Plant Genome Database (PGD). The PGD is now a real and functioning information and data resource for agricultural and other plant science genome researchers, and it is in the public domain. Additional progress is given according to major plant groups. The PGD is a suite of several information products produced at the National Agricultural Library (NAL) in collaboration with the Agricultural Research Service and Forest Service species coordinators

Natural and human-induced Holocene paleoenvironmental changes on the Guadiana shelf (northern Gulf of Cadiz)

Three contrasting sedimentary environments on the continental shelf off the Guadiana River (northern Gulf of Cadiz) were integrated in a chronological framework and analysed in terms of sedimentology and benthic foraminiferal assemblages to understand the Holocene paleoenvironmental evolution. The analysed environments differ in terms of their depositional regimes and benthic foraminiferal assemblages. However, a dominant fluvial origin of the sand fraction was observed in all three environments. Holocene sedimentary processes were mainly controlled by natural (sea level changes and climate variations) and human-induced processes (e.g. deforestation, agriculture) along four evolutionary stages. The three older stages were mainly influenced by natural processes, such as sea level variations and fluvial inputs, whereas the most recent stage reflects a combination of climatic- and human-induced processes. A deepening of sedimentary environments related to a period of rapid sea level rise, strongly influenced by river discharges occurred from c. 11,500 to c. 10,000 cal. yr BP. A reduction in sediment export to the shelf, as a result of the continuous and rapid sea level rise and enhanced estuary infilling reflects the second stage, from c. 10,000 to c. 5000 cal. yr BP. The beginning of the third stage, from c. 5000 to c. 1500–1000 cal. yr BP, is marked by a sea-level slowdown and the relatively stable climate and environmental conditions. The fourth stage, from c. 1500–1000 cal. yr BP to Recent times, reflects the intensification of human-induced processes and climatic variability in the Guadiana River basin. This stage also reflects modern depositional conditions, with the formation of a proximal prodeltaic wedge and a distal muddy body

Insights into the Binding of Phenyltiocarbamide (PTC) Agonist to Its Target Human TAS2R38 Bitter Receptor

Humans' bitter taste perception is mediated by the hTAS2R subfamily of the G protein-coupled membrane receptors (GPCRs). Structural information on these receptors is currently limited. Here we identify residues involved in the binding of phenylthiocarbamide (PTC) and in receptor activation in one of the most widely studied hTAS2Rs (hTAS2R38) by means of structural bioinformatics and molecular docking. The predictions are validated by site-directed mutagenesis experiments that involve specific residues located in the putative binding site and trans-membrane (TM) helices 6 and 7 putatively involved in receptor activation. Based on our measurements, we suggest that (i) residue N103 participates actively in PTC binding, in line with previous computational studies. (ii) W99, M100 and S259 contribute to define the size and shape of the binding cavity. (iii) W99 and M100, along with F255 and V296, play a key role for receptor activation, providing insights on bitter taste receptor activation not emerging from the previously reported computational models

Helix movement is coupled to displacement of the second extracellular loop in rhodopsin activation

The second extracellular loop (EL2) of rhodopsin forms a cap over the binding site of its photoreactive 11-cis retinylidene chromophore. A crucial question has been whether EL2 forms a reversible gate that opens upon activation or acts as a rigid barrier. Distance measurements using solid-state 13C NMR spectroscopy between the retinal chromophore and the β4 strand of EL2 show that the loop is displaced from the retinal binding site upon activation, and there is a rearrangement in the hydrogen-bonding networks connecting EL2 with the extracellular ends of transmembrane helices H4, H5 and H6. NMR measurements further reveal that structural changes in EL2 are coupled to the motion of helix H5 and breaking of the ionic lock that regulates activation. These results provide a comprehensive view of how retinal isomerization triggers helix motion and activation in this prototypical G protein-coupled receptor. © 2009 Nature America, Inc. All rights reserved

Ligand-Dependent Conformations and Dynamics of the Serotonin 5-HT2A Receptor Determine Its Activation and Membrane-Driven Oligomerization Properties

From computational simulations of a serotonin 2A receptor (5-HT2AR) model complexed with pharmacologically and structurally diverse ligands we identify different conformational states and dynamics adopted by the receptor bound to the full agonist 5-HT, the partial agonist LSD, and the inverse agonist Ketanserin. The results from the unbiased all-atom molecular dynamics (MD) simulations show that the three ligands affect differently the known GPCR activation elements including the toggle switch at W6.48, the changes in the ionic lock between E6.30 and R3.50 of the DRY motif in TM3, and the dynamics of the NPxxY motif in TM7. The computational results uncover a sequence of steps connecting these experimentally-identified elements of GPCR activation. The differences among the properties of the receptor molecule interacting with the ligands correlate with their distinct pharmacological properties. Combining these results with quantitative analysis of membrane deformation obtained with our new method (Mondal et al, Biophysical Journal 2011), we show that distinct conformational rearrangements produced by the three ligands also elicit different responses in the surrounding membrane. The differential reorganization of the receptor environment is reflected in (i)-the involvement of cholesterol in the activation of the 5-HT2AR, and (ii)-different extents and patterns of membrane deformations. These findings are discussed in the context of their likely functional consequences and a predicted mechanism of ligand-specific GPCR oligomerization

Homology modelling and spectroscopy, a never-ending love story

Homology modelling is normally the technique of choice when experimental structure data are not available but three-dimensional coordinates are needed, for example, to aid with detailed interpretation of results of spectroscopic studies. Herein, the state of the art of homology modelling will be described in the light of a series of recent developments, and an overview will be given of the problems and opportunities encountered in this field. The major topic, the accuracy and precision of homology models, will be discussed extensively due to its influence on the reliability of conclusions drawn from the combination of homology models and spectroscopic data. Three real-world examples will illustrate how both homology modelling and spectroscopy can be beneficial for (bio)medical research

The Arabidopsis protein phosphatase PP2C38 negatively regulates the central immune kinase BIK1

Plants recognize pathogen-associated molecular patterns (PAMPs) via cell surface-localized pattern recognition receptors (PRRs), leading to PRR-triggered immunity (PTI). The Arabidopsis cytoplasmic kinase BIK1 is a downstream substrate of several PRR complexes. How plant PTI is negatively regulated is not fully understood. Here, we identify the protein phosphatase PP2C38 as a negative regulator of BIK1 activity and BIK1-mediated immunity. PP2C38 dynamically associates with BIK1, as well as with the PRRs FLS2 and EFR, but not with the co-receptor BAK1. PP2C38 regulates PAMP-induced BIK1 phosphorylation and impairs the phosphorylation of the NADPH oxidase RBOHD by BIK1, leading to reduced oxidative burst and stomatal immunity. Upon PAMP perception, PP2C38 is phosphorylated on serine 77 and dissociates from the FLS2/EFR-BIK1 complexes, enabling full BIK1 activation. Together with our recent work on the control of BIK1 turnover, this study reveals another important regulatory mechanism of this central immune component