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  • 1
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    Nebulin deficiency in adult muscle causes sarcomere defects and muscle-type-dependent changes in trophicity: novel insights in nemaline myopathy (2015)
    Oxford University Press
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    Publication Date: 2015-08-27
    Description: Nebulin is a giant filamentous protein that is coextensive with the actin filaments of the skeletal muscle sarcomere. Nebulin mutations are the main cause of nemaline myopathy (NEM), with typical adult patients having low expression of nebulin, yet the roles of nebulin in adult muscle remain poorly understood. To establish nebulin's functional roles in adult muscle, we studied a novel conditional nebulin KO (Neb cKO) mouse model in which nebulin deletion was driven by the muscle creatine kinase (MCK) promotor. Neb cKO mice are born with high nebulin levels in their skeletal muscles, but within weeks after birth nebulin expression rapidly falls to barely detectable levels Surprisingly, a large fraction of the mice survive to adulthood with low nebulin levels (〈5% of control), contain nemaline rods and undergo fiber-type switching toward oxidative types. Nebulin deficiency causes a large deficit in specific force, and mechanistic studies provide evidence that a reduced fraction of force-generating cross-bridges and shortened thin filaments contribute to the force deficit. Muscles rich in glycolytic fibers upregulate proteolysis pathways (MuRF-1, Fbxo30 /MUSA1, Gadd45a) and undergo hypotrophy with smaller cross-sectional areas (CSAs), worsening their force deficit. Muscles rich in oxidative fibers do not have smaller weights and can even have hypertrophy, offsetting their specific-force deficit. These studies reveal nebulin as critically important for force development and trophicity in adult muscle. The Neb cKO phenocopies important aspects of NEM (muscle weakness, oxidative fiber-type predominance, variable trophicity effects, nemaline rods) and will be highly useful to test therapeutic approaches to ameliorate muscle weakness.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    ERBB4 is over-expressed in human colon cancer and enhances cellular transformation (2015)
    Oxford University Press
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    Publication Date: 2015-07-10
    Description: The ERBB4 receptor tyrosine kinase promotes colonocyte survival. Herein, we tested whether ERBB4’s antiapoptotic signaling promotes transformation and colorectal tumorigenesis. ERBB4 alterations in a The Cancer Genome Atlas colorectal cancer (CRC) data set stratified survival, and in a combined Moffitt Cancer Center and Vanderbilt Medical Center CRC expression data set, ERBB4 message levels were increased at all tumor stages. Similarly, western blot and immunohistochemistry on additional CRC tissue banks showed elevated ERBB4 protein in tumors. ERBB4 was highly expressed in aggressive, dedifferentiated CRC cell lines, and its knockdown in LIM2405 cells reduced anchorage-independent colony formation. In nude mouse xenograft studies, ERBB4 alone was insufficient to induce tumor establishment of non-transformed mouse colonocytes, but its over-expression in cells harboring Apc min and v-Ha-Ras caused a doubling of tumor size. ERBB4-expressing xenografts displayed increased activation of survival pathways, including epidermal growth factor receptor and Akt phosphorylation and COX-2 expression, and decreased apoptotic signals. Finally, ERBB4 deletion from mouse intestinal epithelium impaired stem cell replication and in vitro enteroid establishment. In summary, we report that ERBB4 is over-expressed in human CRC, and in experimental systems enhances the survival and growth of cells driven by Ras and/or WNT signaling. Chronic ERBB4 over-expression in the context of, for example, inflammation may contribute to colorectal carcinogenesis. Tumors with high receptor levels are likely to have enhanced cell survival signaling through epidermal growth factor receptor, PI3K and COX-2. These results suggest ERBB4 as a novel therapeutic target in a subset of CRC.
    Print ISSN: 0143-3334
    Electronic ISSN: 1460-2180
    Topics: Medicine
    Published by Oxford University Press
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  • 3
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    Genome-wide identification and characterisation of human DNA replication origins by initiation site sequencing (ini-seq) (2016)
    Oxford University Press
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    Publication Date: 2016-12-04
    Description: Next-generation sequencing has enabled the genome-wide identification of human DNA replication origins. However, different approaches to mapping replication origins, namely (i) sequencing isolated small nascent DNA strands (SNS-seq); (ii) sequencing replication bubbles (bubble-seq) and (iii) sequencing Okazaki fragments (OK-seq), show only limited concordance. To address this controversy, we describe here an independent high-resolution origin mapping technique that we call initiation site sequencing (ini-seq). In this approach, newly replicated DNA is directly labelled with digoxigenin-dUTP near the sites of its initiation in a cell-free system. The labelled DNA is then immunoprecipitated and genomic locations are determined by DNA sequencing. Using this technique we identify 〉25,000 discrete origin sites at sub-kilobase resolution on the human genome, with high concordance between biological replicates. Most activated origins identified by ini-seq are found at transcriptional start sites and contain G-quadruplex (G4) motifs. They tend to cluster in early-replicating domains, providing a correlation between early replication timing and local density of activated origins. Origins identified by ini-seq show highest concordance with sites identified by SNS-seq, followed by OK-seq and bubble-seq. Furthermore, germline origins identified by positive nucleotide distribution skew jumps overlap with origins identified by ini-seq and OK-seq more frequently and more specifically than do sites identified by either SNS-seq or bubble-seq.
    Keywords: Replication, Massively Parallel (Deep) Sequencing
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Pseudo-nitzschia species composition varies concurrently with domoic acid concentrations during two different bloom events in the Southern California Bight (2018)
    Oxford University Press
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    Publication Date: 2018-03-06
    Description: The San Pedro Shelf (SPS) region of the Southern California Bight has witnessed an increase of Pseudo-nitzschia spp. blooms during the past decade, although the domoic acid (DA) concentrations observed during these events have varied considerably. This study compared the extent, timing and environmental controls of Pseudo-nitzschia blooms that were observed in two consecutive years on the SPS. Environmental conditions were characterized during shipboard surveys during spring 2013 and 2014 along an onshore–offshore transect at surface and subsurface depths. A Pseudo-nitzschia bloom of similar cell abundances was observed during each year, yet maximal DA concentrations differed by nearly two orders of magnitude. Environmental parameters were favorable for Pseudo-nitzschia spp. growth in both years, but few factors could be identified that specifically pertained to DA, with the exception that toxicity correlated negatively with dissolved silicic acid concentrations. Automated ribosomal intergenic spacer analysis for Pseudo-nitzschia species indicated that the relative abundance of toxin-producing species had a strong influence on DA concentrations between years, with high-DA concentrations corresponding to Pseudo-nitzschia communities dominated by P. australis/P. seriata . Factors explaining the preferential growth of particular Pseudo-nitzschia species remain enigmatic but are important for predicting toxic events attributable to these taxa.
    Print ISSN: 0142-7873
    Electronic ISSN: 1464-3774
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    The Rat Genome Database 2015: genomic, phenotypic and environmental variations and disease (2015)
    Oxford University Press
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    Publication Date: 2015-01-16
    Description: The Rat Genome Database (RGD, http://rgd.mcw.edu ) provides the most comprehensive data repository and informatics platform related to the laboratory rat, one of the most important model organisms for disease studies. RGD maintains and updates datasets for genomic elements such as genes, transcripts and increasingly in recent years, sequence variations, as well as map positions for multiple assemblies and sequence information. Functional annotations for genomic elements are curated from published literature, submitted by researchers and integrated from other public resources. Complementing the genomic data catalogs are those associated with phenotypes and disease, including strains, QTL and experimental phenotype measurements across hundreds of strains. Data are submitted by researchers, acquired through bulk data pipelines or curated from published literature. Innovative software tools provide users with an integrated platform to query, mine, display and analyze valuable genomic and phenomic datasets for discovery and enhancement of their own research. This update highlights recent developments that reflect an increasing focus on: (i) genomic variation, (ii) phenotypes and diseases, (iii) data related to the environment and experimental conditions and (iv) datasets and software tools that allow the user to explore and analyze the interactions among these and their impact on disease.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    The importance of a strong force majeure clause in an unstable geopolitical environment (2015)
    Oxford University Press
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    Publication Date: 2015-04-14
    Description: A number of recent governmental actions have impacted energy companies' abilities to perform under contracts relating to the extraction and export of natural resources in countries such as Russia, Iraq, and Libya. What steps can a company take to protect itself when relations between oil-rich countries and the West deteriorate? Should a company continue performing under its contract at the risk of violating economic sanctions or should it refrain from performing and risk contractual liability? While tempting to assume that the relevant contract's force majeure provision will provide sufficient protection, force majeure is not a magic talisman that can always be invoked to avoid contractual obligations that have become too difficult to perform. This article analyzes relevant case law and model clauses published by the Association of International Petroleum Negotiators and the International Chamber of Commerce to provide practical guidance on force majeure situations resulting from government action and civil unrest.
    Print ISSN: 1754-9957
    Electronic ISSN: 1754-9965
    Topics: Energy, Environment Protection, Nuclear Power Engineering , Law , Economics
    Published by Oxford University Press
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  • 7
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    Germline ESR2 mutation predisposes to medullary thyroid carcinoma and causes up-regulation of RET expression (2016)
    Oxford University Press
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    Publication Date: 2016-07-06
    Description: Familial medullary thyroid cancer (MTC) and its precursor, C cell hyperplasia (CCH), is associated with germline RET mutations causing multiple endocrine neoplasia type 2. However, some rare families with apparent MTC/CCH predisposition do not have a detectable RET mutation. To identify novel MTC/CCH predisposition genes we undertook exome resequencing studies in a family with apparent predisposition to MTC/CCH and no identifiable RET mutation. We identified a novel ESR2 frameshift mutation, c.948delT, which segregated with histological diagnosis following thyroid surgery in family members and demonstrated loss of ESR2 -encoded ERβ expression in the MTC tumour. ERα and ERβ form heterodimers binding DNA at specific oestrogen-responsive elements (EREs) to regulate gene transcription. ERβ represses ERα-mediated activation of the ERE and the RET promoter contains three EREs . In vitro , we showed that ESR2 c.948delT results in unopposed ERα mediated increased cellular proliferation, activation of the ERE and increased RET expression. In vivo , immunostaining of CCH and MTC using an anti-RET antibody demonstrated increased RET expression. Together these findings identify germline ESR2 mutation as a novel cause of familial MTC/CCH and provide important insights into a novel mechanism causing increased RET expression in tumourigenesis.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Characterization of Somatically-Eliminated Genes During Development of the Sea Lamprey (Petromyzon marinus) (2016)
    Oxford University Press
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    Publication Date: 2016-08-19
    Description: The sea lamprey ( Petromyzon marinus ) is a basal vertebrate that undergoes developmentally programmed genome rearrangements (PGRs) during early development. These events facilitate the elimination of ~20% of the genome from the somatic cell lineage, resulting in distinct somatic and germline genomes. Thus far only a handful of germline-specific genes have been definitively identified within the estimated 500 Mb of DNA that is deleted during PGR, although a few thousand germline-specific genes are thought to exist. To improve our understanding of the evolutionary/developmental logic of PGR, we generated computational predictions to identify candidate germline-specific genes within a new transcriptomic dataset derived from adult germline and the early embryonic stages during which PGR occurs. Follow-up validation studies identified 44 germline-specific genes and further characterized patterns of transcription and DNA loss during early embryogenesis. Expression analyses reveal that many of these genes are differentially expressed during early embryogenesis and presumably function in the early development of the germline. Ontology analyses indicate that many of these germline-specific genes play known roles in germline development, pluripotency, and oncogenesis (when misexpressed). These studies provide support for the theory that PGR serves to segregate molecular functions related to germline development/pluripotency in order to prevent their potential misexpression in somatic cells. This larger set of eliminated genes also allows us to extend the evolutionary/developmental breadth of this theory, as some deleted genes (or their gnathostome homologs) appear to be associated with the early development of somatic lineages, perhaps through the evolution of novel functions within gnathostome lineages.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    RNA Polymerase I and Fob1 contributions to transcriptional silencing at the yeast rDNA locus (2016)
    Oxford University Press
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    Publication Date: 2016-07-28
    Description: RNA polymerase II (Pol II)-transcribed genes embedded within the yeast rDNA locus are repressed through a Sir2-dependent process called ‘rDNA silencing’. Sir2 is recruited to the rDNA promoter through interactions with RNA polymerase I (Pol I), and to a pair of DNA replication fork block sites (Ter1 and Ter2) through interaction with Fob1. We utilized a reporter gene ( mURA3 ) integrated adjacent to the leftmost rDNA gene to investigate localized Pol I and Fob1 functions in silencing. Silencing was attenuated by loss of Pol I subunits or insertion of an ectopic Pol I terminator within the adjacent rDNA gene. Silencing left of the rDNA array is naturally attenuated by the presence of only one intact Fob1 binding site (Ter2). Repair of the 2nd Fob1 binding site (Ter1) dramatically strengthens silencing such that it is no longer impacted by local Pol I transcription defects. Global loss of Pol I activity, however, negatively affects Fob1 association with the rDNA. Loss of Ter2 almost completely eliminates localized silencing, but is restored by artificially targeting Fob1 or Sir2 as Gal4 DNA binding domain fusions. We conclude that Fob1 and Pol I make independent contributions to establishment of silencing, though Pol I also reinforces Fob1-dependent silencing.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 10
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    The correlation space of Gaussian latent tree models and model selection without fitting (2016)
    Oxford University Press
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    Publication Date: 2016-09-04
    Description: We provide a complete description of possible distributions consistent with any Gaussian latent tree model. This description consists of polynomial equations and inequalities involving covariances between the observed variables. Testing inequality constraints can be done using the inverse Wishart distribution and this leads to simple preliminary assessment of tree-compatibility. To test equality constraints we employ general techniques of tetrad analyses. This approach is effective even for small sample sizes and can be easily adjusted to test either entire models or just particular macrostructures of a tree. Our methods are simple to implement and do not require fitting of the model. The versatility of the techniques is illustrated by performing exploratory and confirmatory tetrad analyses in linguistic and biological settings respectively.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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