Alien Registration- Doucette, Lawrence J. (Saint Agatha, Aroostook County)

https://digitalmaine.com/alien_docs/33376/thumbnail.jp

Alien Registration- Doucette, Lawrence J. (Saint Agatha, Aroostook County)

https://digitalmaine.com/alien_docs/33376/thumbnail.jp

Review of Existing Terrestrial Bioaccumulation Models and Terrestrial Bioaccumulation Modeling Needs for Organic Chemicals

Protocols for terrestrial bioaccumulation assessments are far less-developed than for aquatic systems. This article reviews modeling approaches that can be used to assess the terrestrial bioaccumulation potential of commercial organic chemicals. Models exist for plant, invertebrate, mammal, and avian species and for entire terrestrial food webs, including some that consider spatial factors. Limitations and gaps in terrestrial bioaccumulation modeling include the lack of QSARs for biotransformation and dietary assimilation efficiencies for terrestrial species; the lack of models and QSARs for important terrestrial species such as insects, amphibians and reptiles; the lack of standardized testing protocols for plants with limited development of plant models; and the limited chemical domain of existing bioaccumulation models and QSARs (e.g., primarily applicable to nonionic organic chemicals). There is an urgent need for high-quality field data sets for validating models and assessing their performance. There is a need to improve coordination among laboratory, field, and modeling efforts on bioaccumulative substances in order to improve the state of the science for challenging substances

Structures of the G85R Variant of SOD1 in Familial Amyotrophic Lateral Sclerosis*S⃞

Mutations in the gene encoding human copper-zinc superoxide dismutase (SOD1) cause a dominant form of the progressive neurodegenerative disease amyotrophic lateral sclerosis. Transgenic mice expressing the human G85R SOD1 variant develop paralytic symptoms concomitant with the appearance of SOD1-enriched proteinaceous inclusions in their neural tissues. The process(es) through which misfolding or aggregation of G85R SOD1 induces motor neuron toxicity is not understood. Here we present structures of the human G85R SOD1 variant determined by single crystal x-ray diffraction. Alterations in structure of the metal-binding loop elements relative to the wild type enzyme suggest a molecular basis for the metal ion deficiency of the G85R SOD1 protein observed in the central nervous system of transgenic mice and in purified recombinant G85R SOD1. These findings support the notion that metal-deficient and/or disulfide-reduced mutant SOD1 species contribute to toxicity in SOD1-linked amyotrophic lateral sclerosis

Structural consequences of the familial amyotrophic lateral sclerosis SOD1 mutant His46Arg

The His46Arg (H46R) mutant of human copper-zinc superoxide dismutase (SOD1) is associated with an unusual, slowly progressing form of familial amyotrophic lateral sclerosis (FALS). Here we describe in detail the crystal structures of pathogenic H46R SOD1 in the Zn-loaded (Zn-H46R) and metal-free (apo-H46R) forms. The Zn-H46R structure demonstrates a novel zinc coordination that involves only three of the usual four liganding residues, His 63, His 80, and Asp 83 together with a water molecule. In addition, the Asp 124 “secondary bridge” between the copper- and zinc-binding sites is disrupted, and the “electrostatic loop” and “zinc loop” elements are largely disordered. The apo-H46R structure exhibits partial disorder in the electrostatic and zinc loop elements in three of the four dimers in the asymmetric unit, while the fourth has ordered loops due to crystal packing interactions. In both structures, nonnative SOD1–SOD1 interactions lead to the formation of higher-order filamentous arrays. The disordered loop elements may increase the likelihood of protein aggregation in vivo, either with other H46R molecules or with other critical cellular components. Importantly, the binding of zinc is not sufficient to prevent the formation of nonnative interactions between pathogenic H46R molecules. The increased tendency to aggregate, even in the presence of Zn, arising from the loss of the secondary bridge is consistent with the observation of an increased abundance of hyaline inclusions in spinal motor neurons and supporting cells in H46R SOD1 transgenic rats