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  • 1
    Publication Date: 2016-02-04
    Description: Clusters are geographic concentrations of industries related by knowledge, skills, inputs, demand and/or other linkages. There is an increasing need for cluster-based data to support research, facilitate comparisons of clusters across regions and support policymakers in defining regional strategies. This article develops a novel clustering algorithm that systematically generates and assesses sets of cluster definitions (i.e., groups of closely related industries). We implement the algorithm using 2009 data for U.S. industries (six-digit NAICS), and propose a new set of benchmark cluster definitions that incorporates measures of inter-industry linkages based on co-location patterns, input–output links, and similarities in labor occupations. We also illustrate the algorithm’s ability to compare alternative sets of cluster definitions by evaluating our new set against existing sets in the literature. We find that our proposed set outperforms other methods in capturing a wide range of inter-industry linkages, including the grouping of industries within the same three-digit NAICS.
    Keywords: C38-Classification Methods ; Cluster Analysis ; Factor Models
    Print ISSN: 1468-2702
    Electronic ISSN: 1468-2710
    Topics: Geography , Economics
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  • 2
    Publication Date: 2016-10-17
    Description: Turbulence is a key ingredient for the evolution of the intracluster medium, whose properties can be predicted with high-resolution numerical simulations. We present initial results on the generation of solenoidal and compressive turbulence in the intracluster medium during the formation of a small-size cluster using highly resolved, non-radiative cosmological simulations, with a refined monitoring in time. In this first of a series of papers, we closely look at one simulated cluster whose formation was distinguished by a merger around z  ~ 0.3. We separate laminar gas motions, turbulence and shocks with dedicated filtering strategies and distinguish the solenoidal and compressive components of the gas flows using Hodge–Helmholtz decomposition. Solenoidal turbulence dominates the dissipation of turbulent motions (~95 per cent) in the central cluster volume at all epochs. The dissipation via compressive modes is found to be more important (~30 per cent of the total) only at large radii (≥0.5 r vir ) and close to merger events. We show that enstrophy (vorticity squared) is good proxy of solenoidal turbulence. All terms ruling the evolution of enstrophy (i.e. baroclinic, compressive, stretching and advective terms) are found to be significant, but in amounts that vary with time and location. Two important trends for the growth of enstrophy in our simulation are identified: first, enstrophy is continuously accreted into the cluster from the outside, and most of that accreted enstrophy is generated near the outer accretion shocks by baroclinic and compressive processes. Secondly, in the cluster interior vortex, stretching is dominant, although the other terms also contribute substantially.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 3
    Publication Date: 2016-07-09
    Description: DNA double-strand breaks (DSBs) are toxic lesions, which if improperly repaired can result in cell death or genomic instability. DSB repair is usually facilitated by the classical non-homologous end joining (C-NHEJ), or homologous recombination (HR) pathways. However, a mutagenic alternative NHEJ pathway, microhomology-mediated end joining (MMEJ), can also be deployed. While MMEJ is suppressed by C-NHEJ, the relationship between HR and MMEJ is less clear. Here, we describe a role for HR genes in suppressing MMEJ in human cells. By monitoring DSB mis-repair using a sensitive HPRT assay, we found that depletion of HR proteins, including BRCA2, BRCA1 or RPA, resulted in a distinct mutational signature associated with significant increases in break-induced mutation frequencies, deletion lengths and the annealing of short regions of microhomology (2–6 bp) across the break-site. This signature was dependent on CtIP, MRE11, POLQ and PARP, and thus indicative of MMEJ. In contrast to CtIP or MRE11, depletion of BRCA1 resulted in increased partial resection and MMEJ, thus revealing a functional distinction between these early acting HR factors. Together these findings indicate that HR factors suppress mutagenic MMEJ following DSB resection.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 4
    Publication Date: 2012-04-25
    Description: The stability of RNAs bearing AU-rich elements in their 3'-UTRs, and thus the level of expression of their protein products, is regulated by interactions with cytoplasmic RNA-binding proteins. Binding by HuR generally leads to mRNA stabilization and increased protein production, whereas binding by AUF1 isoforms generally lead to rapid degradation of the mRNA and reduced protein production. The exact nature of the interplay between these and other RNA-binding proteins remains unclear, although recent studies have shown close interactions between them and even suggested competition between the two for binding to their cognate recognition sequences. Other recent reports have suggested that the sequences recognized by the two proteins are different. We therefore performed a detailed in vitro analysis of the binding site(s) for HuR and AUF1 present in androgen receptor mRNA to define their exact target sequences, and show that the same sequence is contacted by both proteins. Furthermore, we analysed a proposed HuR target within the 3'-UTR of MTA1 mRNA, and show that the contacted bases lie outside of the postulated motif and are a better match to a classical ARE than the postulated motif. The defining features of these HuR binding sites are their U-richness and single strandedness.
    Print ISSN: 0021-924X
    Electronic ISSN: 1756-2651
    Topics: Biology , Chemistry and Pharmacology
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  • 5
    Publication Date: 2012-07-28
    Description: Niemann–Pick disease type C (NPC) is a lysosomal storage disorder characterized by liver disease and progressive neurodegeneration. Deficiency of either NPC1 or NPC2 leads to the accumulation of cholesterol and glycosphingolipids in late endosomes and early lysosomes. In order to identify pathological mechanisms underlying NPC and uncover potential biomarkers, we characterized liver gene expression changes in an Npc1 mouse model at six ages spanning the pathological progression of the disease. We identified altered gene expression at all ages, including changes in asymptomatic, 1-week-old mice. Biological pathways showing early altered gene expression included: lipid metabolism, cytochrome P450 enzymes involved in arachidonic acid and drug metabolism, inflammation and immune responses, mitogen-activated protein kinase and G-protein signaling, cell cycle regulation, cell adhesion and cytoskeleton remodeling. In contrast, apoptosis and oxidative stress appeared to be late pathological processes. To identify potential biomarkers that could facilitate monitoring of disease progression, we focused on a subset of 103 differentially expressed genes that encode secreted proteins. Further analysis identified two secreted proteins with increased serum levels in NPC1 patients: galectin-3 (LGALS3), a pro-inflammatory molecule, and cathepsin D (CTSD), a lysosomal aspartic protease. Elevated serum levels of both proteins correlated with neurological disease severity and appeared to be specific for NPC1. Expression of Lgals3 and Ctsd was normalized following treatment with 2-hydroxypropyl-β-cyclodextrin, a therapy that reduces pathological findings and significantly increases Npc1 –/– survival. Both LGALS3 and CTSD have the potential to aid in diagnosis and serve as biomarkers to monitor efficacy in therapeutic trials.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 6
    Publication Date: 2015-03-29
    Description: When modelling an ionized plasma, all spectral synthesis codes need the thermally averaged free–free Gaunt factor defined over a very wide range of parameter space in order to produce an accurate prediction for the spectrum. Until now no data set exists that would meet these needs completely. We have therefore produced a table of relativistic Gaunt factors over a much wider range of parameter space than has ever been produced before. We present tables of the thermally averaged Gaunt factor covering the range 10 log 2  = –6 to 10 and 10 log u  = –16 to 13 for all atomic numbers Z  = 1 through 36. The data were calculated using the relativistic Bethe–Heitler–Elwert (BHE) approximation and were subsequently merged with accurate non-relativistic results in those parts of the parameter space where the BHE approximation is not valid. These data will be incorporated in the next major release of the spectral synthesis code cloudy . We also produced tables of the frequency integrated Gaunt factor covering the parameter space 10 log 2  = –6 to +10 for all values of Z between 1 and 36. All the data presented in this paper are available online.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
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  • 7
    Publication Date: 2015-03-01
    Description: The therapeutic use of antisense and siRNA oligonucleotides has been constrained by the limited ability of these membrane-impermeable molecules to reach their intracellular sites of action. We sought to address this problem using small organic molecules to enhance the effects of oligonucleotides by modulating their intracellular trafficking and release from endosomes. A high-throughput screen of multiple small molecule libraries yielded several hits that markedly potentiated the actions of splice switching oligonucleotides in cell culture. These compounds also enhanced the effects of antisense and siRNA oligonucleotides. The hit compounds preferentially caused release of fluorescent oligonucleotides from late endosomes rather than other intracellular compartments. Studies in a transgenic mouse model indicated that these compounds could enhance the in vivo effects of a splice-switching oligonucleotide without causing significant toxicity. These observations suggest that selected small molecule enhancers may eventually be of value in oligonucleotide-based therapeutics.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
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  • 8
    Publication Date: 2015-02-27
    Description: Motivation: Modern lipidomics is largely dependent upon structural ontologies because of the great diversity exhibited in the lipidome, but no automated lipid classification exists to facilitate this partitioning. The size of the putative lipidome far exceeds the number currently classified, despite a decade of work. Automated classification would benefit ongoing classification efforts by decreasing the time needed and increasing the accuracy of classification while providing classifications for mass spectral identification algorithms. Results: We introduce a tool that automates classification into the LIPID MAPS ontology of known lipids with 〉95% accuracy and novel lipids with 63% accuracy. The classification is based upon simple chemical characteristics and modern machine learning algorithms. The decision trees produced are intelligible and can be used to clarify implicit assumptions about the current LIPID MAPS classification scheme. These characteristics and decision trees are made available to facilitate alternative implementations. We also discovered many hundreds of lipids that are currently misclassified in the LIPID MAPS database, strongly underscoring the need for automated classification. Availability and implementation: Source code and chemical characteristic lists as SMARTS search strings are available under an open-source license at https://www.github.com/princelab/lipid_classifier . Contact: ryanmt@byu.net Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
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  • 9
    Publication Date: 2015-11-06
    Description: Type 2 brittle cornea syndrome (BCS2) is an inherited connective tissue disease with a devastating ocular phenotype caused by mutations in the transcription factor PR domain containing 5 ( PRDM5 ) hypothesized to exert epigenetic effects through histone and DNA methylation. Here we investigate clinical samples, including skin fibroblasts and retinal tissue from BCS2 patients, to elucidate the epigenetic role of PRDM5 and mechanisms of its dysregulation in disease. First we report abnormal retinal vascular morphology in the eyes of two cousins with BCS2 ( PRDM5 exons 9–14) using immunohistochemistry, and mine data from skin fibroblast expression microarrays from patients with PRDM5 mutations p.Arg590* and exons 9–14, as well as from a PRDM5 ChIP-sequencing experiment. Gene ontology analysis of dysregulated PRDM5-target genes reveals enrichment for extracellular matrix (ECM) genes supporting vascular integrity and development. Q-PCR and ChIP-qPCR confirm upregulation of critical mediators of ECM stability in vascular structures ( COL13A1 , COL15A1 , NTN1 , CDH5 ) in patient fibroblasts. We identify H3K9 di-methylation (H3K9me2) at these PRDM5-target genes in fibroblasts, and demonstrate that the BCS2 mutation p.Arg83Cys diminishes interaction of PRDM5 with repressive complexes, including NuRD complex protein CHD4, and the repressive chromatin interactor HP1BP3, by co-immunoprecipitation combined with mass spectrometry. We observe reduced heterochromatin protein 1 binding protein 3 (HP1BP3) staining in the retinas of two cousins lacking exons 9–14 by immunohistochemistry, and dysregulated H3K9me2 in skin fibroblasts of three patients (p.Arg590*, p.Glu134* and exons 9–14) by western blotting. These findings suggest that defective interaction of PRDM5 with repressive complexes, and dysregulation of H3K9me2, play a role in PRDM5-associated disease.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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  • 10
    Publication Date: 2015-11-21
    Description: Understanding the mechanisms of chromosomal double-strand break repair (DSBR) provides insight into genome instability, oncogenesis and genome engineering, including disease gene correction. Research into DSBR exploits rare-cutting endonucleases to cleave exogenous reporter constructs integrated into the genome. Multiple reporter constructs have been developed to detect various DSBR pathways. Here, using a single endogenous reporter gene, the X-chromosomal disease gene encoding hypoxanthine phosphoribosyltransferase ( HPRT ), we monitor the relative utilization of three DSBR pathways following cleavage by I-Sce I or CRISPR/Cas9 nucleases. For I-Sce I, our estimated frequencies of accurate or mutagenic non-homologous end-joining and gene correction by homologous recombination are 4.1, 1.5 and 0.16%, respectively. Unexpectedly, I-Sce I and Cas9 induced markedly different DSBR profiles. Also, using an I-Sce I-sensitive HPRT minigene, we show that gene correction is more efficient when using long double-stranded DNA than single- or double-stranded oligonucleotides. Finally, using both endogenous HPRT and exogenous reporters, we validate novel cell cycle phase-specific I-Sce I derivatives for investigating cell cycle variations in DSBR. The results obtained using these novel approaches provide new insights into template design for gene correction and the relationships between multiple DSBR pathways at a single endogenous disease gene.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
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