Evaluating Human Risk from Exposure to Alkylated PAHs in an Aquatic System

Polycyclic aromatic hydrocarbons (PAHs) are a large class of organic chemicals typically found as mixtures in the aquatic environment from natural, petrogenic, and pyrogenic sources. People can be exposed to PAHs through ingestion or dermal contact with contaminated sediments or through ingestion of finfish and shellfish exposed to contaminated sediments. Although more than 100 PAHs have been identified, human exposure and risk are commonly evaluated for 18 individual PAHs. Other PAHs, such as alkylated PAHs, likely contribute to biological activity of environmental PAH mixtures; however, insufficient toxicity data are available to quantify their potential risk. This article presents an initial evaluation of the potential for human health risk from exposure to alkylated PAHs in sediment and fish. Individual alkylated PAHs have been observed to have potentially mutagenic, tumor-promoting, or carcinogenic activity. However, except for 1-and 2-methylnaphthalene, insufficient toxicity data are available to quantify toxicity or cancer risk from exposure to individual alkylated PAHs or mixtures of alkylated PAHs. This article describes a proposed strategy to better understand the potential human health risk from exposure to alkylated PAHs. Implementation of this strategy will contribute to evaluations of human exposure to complex PAH mixtures in the environment.     

Are dendrites in Drosophila homologous to vertebrate dendrites?

Dendrites represent arborising neurites in both vertebrates and invertebrates. However, in vertebrates, dendrites develop on neuronal cell bodies, whereas in higher invertebrates, they arise from very different neuronal structures, the primary neurites, which also form the axons. Is this anatomical difference paralleled by principal developmental and/or physiological differences? We address this question by focussing on one cellular model, motorneurons of Drosophila and characterise the compartmentalisation of these cells. We find that motorneuronal dendrites of Drosophila share with typical vertebrate dendrites that they lack presynaptic but harbour postsynaptic proteins, display calcium elevation upon excitation, have distinct cytoskeletal features, develop later than axons and are preceded by restricted localisation of Par6-complex proteins. Furthermore, we demonstrate in situ and culture that Drosophila dendrites can be shifted from the primary neurite to their soma, i.e. into vertebrate-like positions. Integrating these different lines of argumentation, we propose that dendrites in vertebrates and higher invertebrates have a common origin, and differences in dendrite location can be explained through translocation of neuronal cell bodies introduced during the evolutionary process by which arthropods and vertebrates diverged from a common urbilaterian ancestor. Implications of these findings for studies of dendrite development, neuronal polarity, transport and evolution are discussed.     

Molecular basis of RNA recognition by the human alternative splicing factor Fox-1

The Fox-1 protein regulates alternative splicing of tissue-specific exons by binding to GCAUG elements. Here, we report the solution structure of the Fox-1 RNA binding domain (RBD) in complex with UGCAUGU. The last three nucleotides, UGU, are recognized in a canonical way by the four-stranded beta-sheet of the RBD. In contrast, the first four nucleotides, UGCA, are bound by two loops of the protein in an unprecedented manner. Nucleotides U1, G2, and C3 are wrapped around a single phenylalanine, while G2 and A4 form a base-pair. This novel RNA binding site is independent from the beta-sheet binding interface. Surface plasmon resonance analyses were used to quantify the energetic contributions of electrostatic and hydrogen bond interactions to complex formation and support our structural findings. These results demonstrate the unusual molecular mechanism of sequence-specific RNA recognition by Fox-1, which is exceptional in its high affinity for a defined but short sequence element.     

Delimiting species: comparing methods for Mendelian characters using lizards of the Sceloporus grammicus (Squamata: Phrynosomatidae) complex

Species form the fundamental units of analysis in many areas of biology and, therefore, rigorous delimitation of this unit is important to a broad array of researchers. Recently, many new empirical methods have been proposed to delimit species in nature, and a large literature exists on the theoretical merit and superiority of each method. However, few empirical studies actually compare the results of these methods applied in the same study system. We used a large allozyme and chromosome dataset to apply a number of genetic-distance, character-based, and tree-based methods to a well-studied, data-rich system: the Sceloporus grammicus lizard complex of central Mexico. We hypothesized species boundaries under a general lineage or evolutionary species conceptual framework in an a priori fashion using mapped restriction-site data (mitochondrial DNA and nuclear rDNA), allozymes, and morphology. We then compared the ability of different methods to recover the "hypothesized evolutionary species" (HES). Highton's genetic-distance method and a tree-based method consistently recovered all four HES, although sometimes with weak support. With two exceptions, other methods recovered the same HES, but additional groups were weakly delimited and nested within the HES. Given the apparent recent divergence of some of the chromosome races and distinct populations in this complex, these are encouraging results. We emphasize the value of specifying testable criteria as clearly as possible and testing these with methods that make use of different properties of a single dataset.     

Nitric oxide degradation by potato tuber mitochondria: evidence for the involvement of external NAD(P)H dehydrogenases

The mechanisms of nitric oxide (NO) synthesis in plants have been extensively investigated. NO degradation can be just as important as its synthesis in controlling steady-state levels of NO. Here, we examined NO degradation in mitochondria isolated from potato tubers and the contribution of the respiratory chain to this process. NO degradation was faster in mitochondria energized with NAD(P)H than with succinate or malate. Oxygen consumption and the inner membrane potential were transiently inhibited by NO in NAD(P)H-energized mitochondria, in contrast to the persistent inhibition seen with succinate. NO degradation was abolished by anoxia and superoxide dismutase, which suggested that NO was consumed by its reaction with superoxide anion (O2(-)). Antimycin-A stimulated and myxothiazol prevented NO consumption in succinate- and malate-energized mitochondria. Although favored by antimycin-A, NAD(P)H-mediated NO consumption was not abolished by myxothiazol, indicating that an additional site of O2(-) generation, besides complex III, stimulated NO degradation. Larger amounts of O2(-) were generated in NAD(P)H- compared to succinate- or malate-energized mitochondria. NAD(P)H-mediated NO degradation and O2(-) production were stimulated by free Ca2+ concentration. Together, these results indicate that Ca2+-dependent external NAD(P)H dehydrogenases, in addition to complex III, contribute to O2(-) production that favors NO degradation in potato tuber mitochondria.     

An IGF-I promoter polymorphism modifies the relationships between birth weight and risk factors for cardiovascular disease and diabetes at age 36

BACKGROUND: Biochemical testing for pheochromocytoma by measurement of fractionated plasma metanephrines is limited by false positive rates of up to 18% in people without known genetic predisposition to the disease. The plasma normetanephrine fraction is responsible for most false positives and plasma normetanephrine increases with age. The objective of this study was to determine if we could improve the specificity of fractionated plasma measurements, by statistically adjusting for age. METHODS: An age-adjusted metanephrine score was derived using logistic regression from 343 subjects (including 33 people with pheochromocytoma) who underwent fractionated plasma metanephrine measurements as part of investigations for suspected pheochromocytoma at Mayo Clinic Rochester (derivation set). The performance of the age-adjusted score was validated in a dataset of 158 subjects (including patients 23 with pheochromocytoma) that underwent measurements of fractionated plasma metanephrines at Mayo Clinic the following year (validation dataset). None of the participants in the validation dataset had known genetic predisposition to pheochromocytoma. RESULTS: The sensitivity of the age-adjusted metanephrine score was the same as that of traditional interpretation of fractionated plasma metanephrine measurements, yielding a sensitivity of 100% (23/23, 95% confidence interval [CI] 85.7%, 100%). However, the false positive rate with traditional interpretation of fractionated plasma metanephrine measurements was 16.3% (22/135, 95% CI, 11.0%, 23.4%) and that of the age-adjusted score was significantly lower at 3.0% (4/135, 95% CI, 1.2%, 7.4%) (p < 0.001 using McNemar's test). CONCLUSION: An adjustment for age in the interpretation of results of fractionated plasma metanephrines may significantly decrease false positives when using this test to exclude sporadic pheochromocytoma. Such improvements in false positive rate may result in savings of expenditures related to confirmatory imaging.