915 research outputs found

    Comparative embryotoxicity of a pentabrominated diphenyl ether mixture to common terns (\u3ci\u3eSterna hirundo\u3c/i\u3e) and American kestrels (\u3ci\u3eFalco sparverius\u3c/i\u3e)

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    Concentrations of polybrominated diphenyl ethers (PBDEs) in Forster’s tern (Sterna forsteri) eggs from San Francisco Bay have been reported to range up to 63 µg g-1 lipid weight. This value exceeds the lowest-observed-adverse-effect level (1.8 µg g-1 egg wet weight; ~32 µg g-1 lipid weight) reported in an embryotoxicity study with American kestrels (Falco sparverius). As a surrogate for Forster’s terns, common tern (Sterna hirundo) eggs were treated by air cell injection with corn oil vehicle (control) or a commercial penta-BDE formulation (DE-71) at nominal concentrations of 0.2, 2, and 20 µg g-1 egg. As a positive control, kestrel eggs received vehicle or 20 µg DE-71 g-1 egg. In terns, there were no effects of DE-71 on embryonic survival, and pipping or hatching success; however, treated eggs hatched later (0.44 d) than controls. Organ weights, organ-to-body weight ratios, and bone lengths did not differ, and histopathological observations were unremarkable. Several measures of hepatic oxidative stress in hatchling terns were not affected by DE-71, although there was some evidence of oxidative DNA damage (8-hydroxy-deoxyguanosine; 8-OH-dG). Although DE-71 did not impair pipping and hatching of kestrels, it did result in a delay in hatch, shorter humerus length, and reduced total thyroid weight. Concentrations of oxidized glutathione, reduced glutathione, thiobarbituric acid reactive substances, and 8-OH-dG in liver were greater in DE-71-treated kestrels compared to controls. Our findings suggest common tern embryos, and perhaps other tern species, are less sensitive to PBDEs than kestrel embryos

    An analog of glibenclamide selectively enhances autophagic degradation of misfolded α1-antitrypsin Z

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    The classical form of α1-antitrypsin deficiency (ATD) is characterized by intracellular accumulation of the misfolded variant α1-antitrypsin Z (ATZ) and severe liver disease in some of the affected individuals. In this study, we investigated the possibility of discovering novel therapeutic agents that would reduce ATZ accumulation by interrogating a C. elegans model of ATD with high-content genome-wide RNAi screening and computational systems pharmacology strategies. The RNAi screening was utilized to identify genes that modify the intracellular accumulation of ATZ and a novel computational pipeline was developed to make high confidence predictions on repurposable drugs. This approach identified glibenclamide (GLB), a sulfonylurea drug that has been used broadly in clinical medicine as an oral hypoglycemic agent. Here we show that GLB promotes autophagic degradation of misfolded ATZ in mammalian cell line models of ATD. Furthermore, an analog of GLB reduces hepatic ATZ accumulation and hepatic fibrosis in a mouse model in vivo without affecting blood glucose or insulin levels. These results provide support for a drug discovery strategy using simple organisms as human disease models combined with genetic and computational screening methods. They also show that GLB and/or at least one of its analogs can be immediately tested to arrest the progression of human ATD liver disease.</div

    Deficient histone H3 propionylation by BRPF1-KAT6 complexes in neurodevelopmental disorders and cancer

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    Lysine acetyltransferase 6A (KAT6A) and its paralog KAT6B form stoichiometric complexes with bromodomain- and PHD finger-containing protein 1 (BRPF1) for acetylation of histone H3 at lysine 23 (H3K23). We report that these complexes also catalyze H3K23 propionylation in vitro and in vivo. Immunofluorescence microscopy and ATAC-See revealed the association of this modification with active chromatin. Brpf1 deletion obliterates the acylation in mouse embryos and fibroblasts. Moreover, we identify BRPF1 variants in 12 previously unidentified cases of syndromic intellectual disability and demonstrate that these cases and known BRPF1 variants impair H3K23 propionylation. Cardiac anomalies are present in a subset of the cases. H3K23 acylation is also impaired by cancer-derived somatic BRPF1 mutations. Valproate, vorinostat, propionate and butyrate promote H3K23 acylation. These results reveal the dual functionality of BRPF1-KAT6 complexes, shed light on mechanisms underlying related developmental disorders and various cancers, and suggest mutation-based therapy for medical conditions with deficient histone acylation

    Biomass production of herbaceous energy crops in the United States: field trial results and yield potential maps from the multiyear regional feedstock partnership

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    Current knowledge of yield potential and best agronomic management practices for perennial bioenergy grasses is primarily derived from small-scale and short-term studies, yet these studies inform policy at the national scale. In an effort to learn more about how bioenergy grasses perform across multiple locations and years, the U.S. Department of Energy (US DOE)/Sun Grant Initiative Regional Feedstock Partnership was initiated in 2008. The objectives of the Feedstock Partnership were to (1) provide a wide range of information for feedstock selection (species choice) and management practice options for a variety of regions and (2) develop national maps of potential feedstock yield for each of the herbaceous species evaluated. The Feedstock Partnership expands our previous understanding of the bioenergy potential of switchgrass, Miscanthus, sorghum, energycane, and prairie mixtures on Conservation Reserve Program land by conducting long-term, replicated trials of each species at diverse environments in the U.S. Trials were initiated between 2008 and 2010 and completed between 2012 and 2015 depending on species. Field-scale plots were utilized for switchgrass and Conservation Reserve Program trials to use traditional agricultural machinery. This is important as we know that the smaller scale studies often overestimated yield potential of some of these species. Insufficient vegetative propagules of energycane and Miscanthus prohibited farm-scale trials of these species. The Feedstock Partnership studies also confirmed that environmental differences across years and across sites had a large impact on biomass production. Nitrogen application had variable effects across feedstocks, but some nitrogen fertilizer generally had a positive effect. National yield potential maps were developed using PRISM-ELM for each species in the Feedstock Partnership. This manuscript, with the accompanying supplemental data, will be useful in making decisions about feedstock selection as well as agronomic practices across a wide region of the country

    Differential gene expression in male and female rainbow trout embryos prior to the onset of gross morphological differentiation of the gonads

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    <p>Abstract</p> <p>Background</p> <p>There are large differences between the sexes at the genetic level; these differences include heterogametic sex chromosomes and/or differences in expression of genes between the sexes. In rainbow trout (<it>Oncorhynchus mykiss</it>) qRT-PCR studies have found significant differences in expression of several candidate sex determining genes. However, these genes represent a very small fraction of the genome and research in other species suggests there are large portions of the transcriptome that are differentially expressed between the sexes. These differences are especially noticeable once gonad differentiation and maturation has occurred, but less is known at earlier stages of development. Here we use data from a microarray and qRT-PCR to identify genes differentially expressed between the sexes at three time points in pre-hatch embryos, prior to the known timing of sexual differentiation in this species.</p> <p>Results</p> <p>The microarray study revealed 883 differentially expressed features between the sexes with roughly equal numbers of male and female upregulated features across time points. Most of the differentially expressed genes on the microarray were not related to sex function, suggesting large scale differences in gene expression between the sexes are present early in development. Candidate gene analysis revealed <it>sox9</it>, <it>DMRT1</it>, <it>Nr5a1 </it>and <it>wt1 </it>were upregulated in males at some time points and <it>foxl2</it>, <it>ovol1</it>, <it>fst </it>and <it>cyp19a1a </it>were upregulated in females at some time points.</p> <p>Conclusion</p> <p>This is the first study to identify sexual dimorphism in expression of the genome during embryogenesis in any fish and demonstrates that transcriptional differences are present before the completion of gonadogenesis.</p

    Characterizing wing tears in common pipistrelles (Pipistrellus pipistrellus): investigating tear distribution, wing strength, and possible causes

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    Bats have large, thin wings that are particularly susceptible to tearing. Anatomical specializations, such as fiber reinforcement, strengthen the wing and increase its resistance to puncture, and an extensive vasculature system across the wing also promotes healing. We investigated whether tear positioning is associated with anatomy in common pipistrelles (Pipistrellus pipistrellus). Wing anatomy was described using histological techniques, imaging, and material testing. Tear information, including type, position, time in rehabilitation, and possible causes, was collected from rehabilitators of injured bats across the United Kingdom. Results suggest that the position of the plagiopatagium (the most proximal wing section to the body), rather than its anatomy, influenced the number, location, and orientation of wing tears. While material testing did not identify the plagiopatagium as being significantly weaker than the chiropatagium (the more distal sections of the wing), the plagiopatagium tended to have the most tears. The position of the tears, close to the body and toward the trailing edge, suggests that they are caused by predator attacks, such as from a cat (Felis catus), rather than collisions. Consistent with this, 38% of P. pipistrellus individuals had confirmed wing tears caused by cats, with an additional 38% identified by rehabilitators as due to suspected cat attacks. The plagiopatagium had the lowest number of blood vessels and highest amounts of elastin fibers, suggesting that healing may take longer in this section. Further investigations into the causes of tears, and their effect on flight capabilities, will help to improve bat rehabilitation

    CMS physics technical design report : Addendum on high density QCD with heavy ions

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