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  • 1
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    ViRBase: a resource for virus-host ncRNA-associated interactions (2015)
    Oxford University Press
    Details
    Publication Date: 2015-01-16
    Description: Increasing evidence reveals that diverse non-coding RNAs (ncRNAs) play critically important roles in viral infection. Viruses can use diverse ncRNAs to manipulate both cellular and viral gene expression to establish a host environment conducive to the completion of the viral life cycle. Many host cellular ncRNAs can also directly or indirectly influence viral replication and even target virus genomes. ViRBase ( http://www.rna-society.org/virbase ) aims to provide the scientific community with a resource for efficient browsing and visualization of virus-host ncRNA-associated interactions and interaction networks in viral infection. The current version of ViRBase documents more than 12 000 viral and cellular ncRNA-associated virus–virus, virus–host, host–virus and host–host interactions involving more than 460 non-redundant ncRNAs and 4400 protein-coding genes from between more than 60 viruses and 20 hosts. Users can query, browse and manipulate these virus–host ncRNA-associated interactions. ViRBase will be of help in uncovering the generic organizing principles of cellular virus–host ncRNA-associated interaction networks in viral infection.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Nucleolar stress and impaired stress granule formation contribute to C9orf72 RAN translation-induced cytotoxicity (2015)
    Oxford University Press
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    Publication Date: 2015-04-04
    Description: Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are the two common neurodegenerative diseases that have been associated with the GGGGCC·GGCCCC repeat RNA expansion in a noncoding region of C9orf72 . It has been previously reported that unconventional repeat-associated non-ATG (RAN) translation of GGGGCC·GGCCCC repeats produces five types of dipeptide-repeat proteins (referred to as RAN proteins): poly-glycine-alanine (GA), poly-glycine-proline (GP), poly-glycine-arginine (GR), poly-proline-arginine (PR) and poly-proline-alanine (PA). Although protein aggregates of RAN proteins have been found in patients, it is unclear whether RAN protein aggregation induces neurotoxicity. In the present study, we aimed to understand the biological properties of all five types of RAN proteins. Surprisingly, our results showed that none of these RAN proteins was aggregate-prone in our cellular model and that the turnover of these RAN proteins was not affected by the ubiquitin–proteasome system or autophagy. Moreover, poly-GR and poly-PR, but not poly-GA, poly-GP or poly-PA, localized to the nucleolus and induced the translocation of the key nucleolar component nucleophosmin, leading to nucleolar stress and cell death. This poly-GR- and poly-PR-mediated defect in nucleolar function was associated with the suppression of ribosomal RNA synthesis and the impairment of stress granule formation. Taken together, the results of the present study suggest a simple model of the molecular mechanisms underlying RAN translation-mediated cytotoxicity in C9orf72 -linked ALS/FTD in which nucleolar stress, but not protein aggregation, is the primary contributor to C9orf72 -linked neurodegeneration.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 3
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    Travelling wave solutions in integro-difference competition system (2013)
    Oxford University Press
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    Publication Date: 2013-05-23
    Description: In this paper, we first establish the existence theorem of travelling wave solutions in an integro-difference competition system by Schauder's fixed-point theorem, the cross-iteration and the upper and lower solutions method. To illustrate our result, we present an application to an integro-difference competition system by choosing a special kernel.
    Print ISSN: 0272-4960
    Electronic ISSN: 1464-3634
    Topics: Mathematics
    Published by Oxford University Press
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  • 4
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    Epigenome-wide association study (EWAS) of BMI, BMI change and waist circumference in African American adults identifies multiple replicated loci (2015)
    Oxford University Press
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    Publication Date: 2015-07-07
    Description: Obesity is an important component of the pathophysiology of chronic diseases. Identifying epigenetic modifications associated with elevated adiposity, including DNA methylation variation, may point to genomic pathways that are dysregulated in numerous conditions. The Illumina 450K Bead Chip array was used to assay DNA methylation in leukocyte DNA obtained from 2097 African American adults in the Atherosclerosis Risk in Communities (ARIC) study. Mixed-effects regression models were used to test the association of methylation beta value with concurrent body mass index (BMI) and waist circumference (WC), and BMI change, adjusting for batch effects and potential confounders. Replication using whole-blood DNA from 2377 White adults in the Framingham Heart Study and CD4+ T cell DNA from 991 Whites in the Genetics of Lipid Lowering Drugs and Diet Network Study was followed by testing using adipose tissue DNA from 648 women in the Multiple Tissue Human Expression Resource cohort. Seventy-six BMI-related probes, 164 WC-related probes and 8 BMI change-related probes passed the threshold for significance in ARIC ( P 〈 1 x 10 –7 ; Bonferroni), including probes in the recently reported HIF3A , CPT1A and ABCG1 regions. Replication using blood DNA was achieved for 37 BMI probes and 1 additional WC probe. Sixteen of these also replicated in adipose tissue, including 15 novel methylation findings near genes involved in lipid metabolism, immune response/cytokine signaling and other diverse pathways, including LGALS3BP , KDM2B , PBX1 and BBS2 , among others. Adiposity traits are associated with DNA methylation at numerous CpG sites that replicate across studies despite variation in tissue type, ethnicity and analytic approaches.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 5
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    Optimal timing control of switched stochastic systems (2015)
    Oxford University Press
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    Publication Date: 2015-09-15
    Description: This paper considers an optimal control problem for switched stochastic systems. The controlled parameter consists of the switching times, and the cost criterion has the form of the mixed integral and endpoint cost terms of performance functions defined on the system's state trajectory. An approach to finding the optimal switching times is proposed. First, we derive the derivative of the cost with respect to the switching time for one switching time case. Then, for the problem with multi-switching times, we present the corresponding gradient formula. The obtained formulas have an especially simple form and can be directly used in gradient descent algorithms to locate the optimal switching instants. Finally, the validity of the proposed method is demonstrated by two numerical examples.
    Print ISSN: 0265-0754
    Electronic ISSN: 1471-6887
    Topics: Mathematics
    Published by Oxford University Press
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  • 6
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    Accurate read-based metagenome characterization using a hierarchical suite of unique signatures (2015)
    Oxford University Press
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    Publication Date: 2015-05-29
    Description: A major challenge in the field of shotgun metagenomics is the accurate identification of organisms present within a microbial community, based on classification of short sequence reads. Though existing microbial community profiling methods have attempted to rapidly classify the millions of reads output from modern sequencers, the combination of incomplete databases, similarity among otherwise divergent genomes, errors and biases in sequencing technologies, and the large volumes of sequencing data required for metagenome sequencing has led to unacceptably high false discovery rates (FDR). Here, we present the application of a novel, gene-independent and signature-based metagenomic taxonomic profiling method with significantly and consistently smaller FDR than any other available method. Our algorithm circumvents false positives using a series of non-redundant signature databases and examines G enomic O rigins T hrough T axonomic CHA llenge (GOTTCHA). GOTTCHA was tested and validated on 20 synthetic and mock datasets ranging in community composition and complexity, was applied successfully to data generated from spiked environmental and clinical samples, and robustly demonstrates superior performance compared with other available tools.
    Keywords: Genomics
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Structures of an all-{alpha} protein running along the DNA major groove (2016)
    Oxford University Press
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    Publication Date: 2016-05-06
    Description: Despite over 3300 protein–DNA complex structures have been reported in the past decades, there remain some unknown recognition patterns between protein and target DNA. The silkgland-specific transcription factor FMBP-1 from the silkworm Bombyx mori contains a unique DNA-binding domain of four tandem STPRs, namely the score and three amino acid peptide repeats. Here we report three structures of this STPR domain (termed Bm STPR) in complex with DNA of various lengths. In the presence of target DNA, Bm STPR adopts a zig-zag structure of three or four tandem α-helices that run along the major groove of DNA. Structural analyses combined with binding assays indicate Bm STPR prefers the AT-rich sequences, with each α-helix covering a DNA sequence of 4 bp. The successive AT-rich DNAs adopt a wider major groove, which is in complementary in shape and size to the tandem α-helices of Bm STPR. Substitutions of DNA sequences and affinity comparison further prove that Bm STPR recognizes the major groove mainly via shape readout. Multiple-sequence alignment suggests this unique DNA-binding pattern should be highly conserved for the STPR domain containing proteins which are widespread in animals. Together, our findings provide structural insights into the specific interactions between a novel DNA-binding protein and a unique deformed B-DNA.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Next-generation sequencing: a challenge to meet the increasing demand for training workshops in Australia (2013)
    Oxford University Press
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    Publication Date: 2013-09-13
    Description: The widespread adoption of high-throughput next-generation sequencing (NGS) technology among the Australian life science research community is highlighting an urgent need to up-skill biologists in tools required for handling and analysing their NGS data. There is currently a shortage of cutting-edge bioinformatics training courses in Australia as a consequence of a scarcity of skilled trainers with time and funding to develop and deliver training courses. To address this, a consortium of Australian research organizations, including Bioplatforms Australia, the Commonwealth Scientific and Industrial Research Organisation and the Australian Bioinformatics Network, have been collaborating with EMBL-EBI training team. A group of Australian bioinformaticians attended the train-the-trainer workshop to improve training skills in developing and delivering bioinformatics workshop curriculum. A 2-day NGS workshop was jointly developed to provide hands-on knowledge and understanding of typical NGS data analysis workflows. The road show–style workshop was successfully delivered at five geographically distant venues in Australia using the newly established Australian NeCTAR Research Cloud. We highlight the challenges we had to overcome at different stages from design to delivery, including the establishment of an Australian bioinformatics training network and the computing infrastructure and resource development. A virtual machine image, workshop materials and scripts for configuring a machine with workshop contents have all been made available under a Creative Commons Attribution 3.0 Unported License. This means participants continue to have convenient access to an environment they had become familiar and bioinformatics trainers are able to access and reuse these resources.
    Print ISSN: 1467-5463
    Electronic ISSN: 1477-4054
    Topics: Biology , Computer Science
    Published by Oxford University Press
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  • 9
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    Lack of CCM1 induces hypersprouting and impairs response to flow (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: Cerebral cavernous malformation (CCM) is a disease of vascular malformations known to be caused by mutations in one of three genes: CCM1 , CCM2 or CCM3 . Despite several studies, the mechanism of CCM lesion onset remains unclear. Using a Ccm1 knockout mouse model, we studied the morphogenesis of early lesion formation in the retina in order to provide insight into potential mechanisms. We demonstrate that lesions develop in a stereotypic location and pattern, preceded by endothelial hypersprouting as confirmed in a zebrafish model of disease. The vascular defects seen with loss of Ccm1 suggest a defect in endothelial flow response. Taken together, these results suggest new mechanisms of early CCM disease pathogenesis and provide a framework for further study.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 10
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    Long-term rescue of cone photoreceptor degeneration in retinitis pigmentosa 2 (RP2)-knockout mice by gene replacement therapy (2015)
    Oxford University Press
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    Publication Date: 2015-10-23
    Description: Retinal neurodegenerative diseases are especially attractive targets for gene replacement therapy, which appears to be clinically effective for several monogenic diseases. X-linked forms of retinitis pigmentosa (XLRP) are relatively severe blinding disorders, resulting from progressive photoreceptor dysfunction primarily caused by mutations in RPGR or RP2 gene. With a goal to develop gene therapy for the XLRP- RP2 disease, we first performed detailed characterization of the Rp2 -knockout ( Rp2 -KO) mice and observed early-onset cone dysfunction, which was followed by progressive cone degeneration, mimicking cone vision impairment in XLRP patients. The mice also exhibited distinct and significantly delayed falling phase of photopic b-wave of electroretinogram (ERG). Concurrently, we generated a self-complementary adeno-associated viral (AAV) vector carrying human RP2-coding sequence and demonstrated its ability to mediate stable RP2 protein expression in mouse photoreceptors. A long-term efficacy study was then conducted in Rp2 -KO mice following AAV- RP2 vector administration. Preservation of cone function was achieved with a wide dose range over 18-month duration, as evidenced by photopic ERG and optomotor tests. The slower b-wave kinetics was also completely restored. Morphologically, the treatment preserved cone viability, corrected mis-trafficking of M-cone opsin and restored cone PDE6 expression. The therapeutic effect was achieved even in mice that received treatment at an advanced disease stage. The highest AAV- RP2 dose group demonstrated retinal toxicity, highlighting the importance of careful vector dosing in designing future human trials. The wide range of effective dose, a broad treatment window and long-lasting therapeutic effects should make the RP2 gene therapy attractive for clinical development.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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