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"Busby, Robert"
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A switch to feeding on cycads generates parallel accelerated evolution of toxin tolerance in two clades of Eumaeus caterpillars (Lepidoptera: Lycaenidae)
We assembled a complete reference genome of Eumaeus atala, an aposematic cycad-eating hairstreak butterfly that suffered near extinction in the United States in the last century. Based on an analysis of genomic sequences of Eumaeus and 19 representative genera, the closest relatives of Eumaeus are Theorema and Mithras. We report natural history information for Eumaeus, Theorema, and Mithras. Using genomic sequences for each species of Eumaeus, Theorema, and Mithras (and three outgroups), we trace the evolution of cycad feeding, coloration, gregarious behavior, and other traits. The switch to feeding on cycads and to conspicuous coloration was accompanied by little genomic change. Soon after its origin, Eumaeus split into two fast evolving lineages, instead of forming a clump of close relatives in the phylogenetic tree. Significant overlap of the fast evolving proteins in both clades indicates parallel evolution. The functions of the fast evolving proteins suggest that the caterpillars developed tolerance to cycad toxins with a range of mechanisms including autophagy of damaged cells, removal of cell debris by macrophages, and more active cell proliferation.
Journal Article
Evolutionary trade-offs between male secondary sexual traits revealed by a phylogeny of the hyperdiverse tribe Eumaeini (Lepidoptera: Lycaenidae)
Male butterflies in the hyperdiverse tribe Eumaeini possess an unusually complex and diverse repertoire of secondary sexual characteristics involved in pheromone production and dissemination. Maintaining multiple sexually selected traits is likely to be metabolically costly, potentially resulting in trade-offs in the evolution of male signals. However, a phylogenetic framework to test hypotheses regarding the evolution and maintenance of male sexual traits in Eumaeini has been lacking. Here, we infer a comprehensive, time-calibrated phylogeny from 379 loci for 187 species representing 91% of the 87 described genera. Eumaeini is a monophyletic group that originated in the late Oligocene and underwent rapid radiation in the Neotropics. We examined specimens of 818 of the 1096 described species (75%) and found that secondary sexual traits are present in males of 91% of the surveyed species. Scent pads and scent patches on the wings and brush organs associated with the genitalia were probably present in the common ancestor of Eumaeini and are widespread throughout the tribe. Brush organs and scent pads are negatively correlated across the phylogeny, exhibiting a trade-off in which lineages with brush organs are unlikely to regain scent pads and vice versa. In contrast, scent patches seem to facilitate the evolution of scent pads, although they are readily lost once scent pads have evolved. Our results illustrate the complex interplay between natural and sexual selection in the origin and maintenance of multiple male secondary sexual characteristics and highlight the potential role of sexual selection spurring diversification in this lineage.
Journal Article
Metopimazine is primarily metabolized by a liver amidase in humans
Metopimazine (MPZ) is a peripherally restricted, dopamine D2 receptor antagonist used for four decades to treat acute nausea and vomiting. MPZ is currently under clinical investigation for the treatment of gastroparesis (GP). MPZ undergoes high first‐pass metabolism that produces metopimazine acid (MPZA), the major circulating metabolite in humans. Despite a long history of use, the enzymes involved in the metabolism of MPZ have not been identified. Here we report a series of studies designed to identify potential MPZ metabolites in vitro, determine their clinical relevance in humans, and elucidate the enzymes responsible for their formation. The findings demonstrated that the formation of MPZA was primarily catalyzed by human liver microsomal amidase. Additionally, human liver cytosolic aldehyde oxidase (AO) catalyzes the formation of MPZA, in vitro, although to a much lesser extent. Neither cytochrome P450 enzymes nor flavin‐monooxygenases (FMO) were involved in the formation MPZA, although two minor oxidative pathways were catalyzed by CYP3A4 and CYP2D6 in vitro. Analysis of plasma samples from subjects dosed 60 mg of MPZ verified that these oxidative pathways are very minor and that CYP enzyme involvement was negligible compared to microsomal amidase/hydrolase in overall MPZ metabolism in humans. The metabolism by liver amidase, an enzyme family not well defined in small molecule drug metabolism, with minimal metabolism by CYPs, differentiates this drug from current D2 antagonists used or in development for the treatment of GP. Metopimazine acid is the predominant circulating metabolite, present at many fold the plasma concentrations of the parent, and yet the metabolic route to that metabolite has not been defined. Through a series of studies, we identified potential MPZ metabolites in vitro, determined their clinical relevance in humans, and elucidated the enzymes responsible for their formation.
Journal Article
Male secondary sexual structures and the systematics of the Thereus oppia species group (Lepidoptera, Lycaenidae, Eumaeini)
The Thereus oppia species group includes species with and without a scent pad, which is a histologically and morphologically characterized male secondary sexual structure on the dorsal surface of the forewing. To assess the hypothesis that these structures are lost evolutionarily, but not regained (Dollo's Law), the taxonomy of this species group is revised. Thereus lomalarga sp. n., and Thereus brocki sp. n., are described. Diagnostic traits, especially male secondary structures, within the Thereus oppia species group are illustrated. Distributional and biological information is summarized for each species. Three species have been reared, and the caterpillars eat Loranthaceae. An inferred phylogeny is consistent with the hypothesis that scent pads in the Thereus oppia species group have been lost evolutionarily twice (in allopatry), and not re-gained.
Journal Article
Review of the species level taxonomy of the neotropical butterfly genus Oenomaus (Lycaenidae, Theclinae, Eumaeini)
Seven new species of the Neotropical hairstreak genus Oenomaus are described: Oenomaus mancha Busby & Faynel, sp. n. (type locality Ecuador); Oenomaus gwenish Robbins & Faynel, sp. n. (type locality Panama); Oenomaus lea Faynel & Robbins, sp. n. (type locality Ecuador); Oenomaus myrteana Busby, Robbins & Faynel, sp. n. (type locality Ecuador); Oenomaus mentirosa Faynel & Robbins, sp. n. (type locality Peru); Oenomaus andi Busby & Faynel, sp. n. (type locality Ecuador) and Oenomaus moseri Robbins & Faynel, sp. n. (type locality Brazil, Santa Catarina). For each new Oenomaus species, we present diagnostic characters and notes on its habitat and biology. We illustrate adults, genitalia, and distribution. New distributional and biological data are presented for 21 previously described Oenomaus species. Oenomaus melleus guyanensis Faynel, 2008 is treated as a new synonym of Oenomaus melleus melleus (Druce, 1907). Females are described and associated with males for ten species using a variety of factors, including mitochondrial COI DNA \"barcode\" sequences. We summarize the reasons why the number of recognized Oenomaus species has grown in the past decade from one species to 28 species. Finally, we overview the habitats that Oenomaus species occupy and note that the agricultural pest on Annonaceae, Oenomaus ortygnus, is the only Oenomaus species that regularly occurs in greatly disturbed habitats.
Journal Article
Matrix detachment and proteasomal inhibitors diminish Sulf-2 expression in breast cancer cell lines and mouse xenografts
Sulfatase 2 (Sulf-2) has been previously shown to be upregulated in breast cancer. Sulf-2 removes sulfate moieties on heparan sulfate proteoglycans which in turn modulate heparin binding growth factor signaling. Here we report that matrix detachment resulted in decreased Sulf-2 expression in breast cancer cells and increased cleavage of poly ADP-ribose polymerase. Silencing of Sulf-2 promotes matrix detachment induced cell death in MCF10DCIS cells. In an attempt to identify Sulf-2 specific inhibitor, we found that proteasomal inhibitors such as MG132, Lactacystin and Bortezomib treatment abolished Sulf-2 expression in multiple breast cancer cell lines. Additionally, we show that Bortezomib treatment of MCF10DCIS cell xenografts in mouse mammary fat pads significantly reduced tumor size, caused massive apoptosis and more importantly reduced Sulf-2 levels in vivo. Finally, our immunohistochemistry analysis of Sulf-2 expression in cohort of patient derived breast tumors indicates that Sulf-2 is significantly upregulated in autologous metastatic lesions compared to primary tumors (
p
< 0.037, Pearson correlation, Chi-Square analysis). In all, our data suggest that Sulf-2 might play an important role in breast cancer progression from ductal carcinoma in situ into an invasive ductal carcinoma potentially by resisting cell death.
Journal Article
Amplified Centrosomes in Breast Cancer: A Potential Indicator of Tumor Aggressiveness
Molecular mechanisms leading to genomic instability and phenotypic variation during tumor development and progression are poorly understood. Such instability represents a major problem in the management of breast cancer because of its contribution to more aggressive phenotypes as well as chemoresistance. In this study we analyzed breast carcinomas and tumor-derived cell lines to determine the relationship between centrosome amplification and established prognostic factors. Our results show that centrosome amplification can arise independent of ER or p53 status and is a common feature of aneuploid breast tumors. Centrosome amplification is associated with mitotic spindle abnormalities in breast carcinomas and thus may contribute to genomic instability and the development of more aggressive phenotypes during tumor progression.
Journal Article
Metabolism and disposition of MM‐433593, a selective FAAH‐1 inhibitor, in monkeys
MM‐433593 is a highly potent and selective inhibitor of fatty acid amide hydrolase‐1 (FAAH‐1) with potential utility as an orally administered treatment of pain, inflammation, and other disorders. In this study, we investigated the metabolism and pharmacokinetics of MM‐433593 in monkeys, and compared plasma and urine metabolites of this compound to the in vitro metabolites produced by monkey hepatocytes. Intravenous administration of MM‐433593 to cynomolgus monkeys produced a rapid distribution phase and slower elimination phase with a mean systemic clearance rate of 8–11 mL/min/kg. Absolute oral bioavailability was determined to be 14–21% with maximum plasma concentrations reached ~3 h (Tmax) following a 10 mg/kg oral dose. The average terminal half‐life of MM‐433593 was 17–20 h, and there were no qualitative sex differences in the metabolite profile of MM‐433593. The major site of metabolism was oxidation of the methyl group at the five position of the indole ring, which was confirmed by chromatography and mass spectrometry comparison to a synthesized authentic standard. This metabolite was further oxidized to the corresponding carboxylic acid and/or conjugated with sulfate, glucuronide, or glutathione. In all, 18 metabolites were found in plasma and urine. In vitro incubations of MM‐433593 with monkey hepatocytes yielded 13 metabolites, all of which were found in vivo, indicating a good correlation between the in vitro and in vivo metabolism data. A comprehensive pathway for the metabolism of MM‐433593 is proposed, including a plausible, five‐step biotransformation for the formation of N‐acetylcysteine conjugate metabolite (M18) from the hydroxylated parent (M5). e00059
Journal Article