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  • 1
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    Human Pompe disease-induced pluripotent stem cells for pathogenesis modeling, drug testing and disease marker identification (2012)
    Oxford University Press
    Details
    Publication Date: 2012-05-11
    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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    Low-frequency germline variants across 6p22.2-6p21.33 are associated with non-obstructive azoospermia in Han Chinese men (2015)
    Oxford University Press
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    Publication Date: 2015-09-12
    Description: Genome-wide association studies (GWAS) have identified several common loci contributing to non-obstructive azoospermia (NOA). However, a substantial fraction of NOA heritability remains undefined, especially those low-frequency [defined here as having a minor allele frequency (MAF) between 0.5 and 5%] and rare (MAF below 0.5%) variants. Here, we performed a 3-stage exome-wide association study in Han Chinese men to evaluate the role of low-frequency or rare germline variants in NOA development. The discovery stage included 962 NOA cases and 1348 healthy male controls genotyped by exome chips and was followed by a 2-stage replication with an additional 2168 cases and 5248 controls. We identified three low-frequency variants located at 6p22.2 (rs2298090 in HIST1H1E encoding p.Lys152Arg: OR = 0.30, P = 2.40 x 10 –16 ) and 6p21.33 (rs200847762 in FKBPL encoding p.Pro137Leu: OR = 0.11, P = 3.77 x 10 –16 ; rs11754464 in MSH5 : OR = 1.78, P = 3.71 x 10 –7 ) associated with NOA risk after Bonferroni correction. In summary, we report an instance of newly identified signals for NOA risk in genes previously undetected through GWAS on 6p22.2–6p21.33 in a Chinese population and highlight the role of low-frequency variants with a large effect in the process of spermatogenesis.
    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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    Synthesis, base pairing and structure studies of geranylated RNA (2016)
    Oxford University Press
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    Publication Date: 2016-07-28
    Description: Natural RNAs utilize extensive chemical modifications to diversify their structures and functions. 2-Thiouridine geranylation is a special hydrophobic tRNA modification that has been discovered very recently in several bacteria, such as Escherichia coli, Enterobacter aerogenes, Pseudomonas aeruginosa and Salmonella Typhimurium . The geranylated residues are located in the first anticodon position of tRNAs specific for lysine, glutamine and glutamic acid. This big hydrophobic terpene functional group affects the codon recognition patterns and reduces frameshifting errors during translation. We aimed to systematically study the structure, function and biosynthesis mechanism of this geranylation pathway, as well as answer the question of why nature uses such a hydrophobic modification in hydrophilic RNA systems. Recently, we have synthesized the deoxy-analog of S-geranyluridine and showed the geranylated T-G pair is much stronger than the geranylated T-A pair and other mismatched pairs in the B-form DNA duplex context, which is consistent with the observation that the geranylated tRNA Glu UUC recognizes GAG more efficiently than GAA. In this manuscript we report the synthesis and base pairing specificity studies of geranylated RNA oligos. We also report extensive molecular simulation studies to explore the structural features of the geranyl group in the context of A-form RNA and its effect on codon–anticodon interaction during ribosome binding.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 4
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    Functional interplay between SA1 and TRF1 in telomeric DNA binding and DNA-DNA pairing (2016)
    Oxford University Press
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    Publication Date: 2016-07-28
    Description: Proper chromosome alignment and segregation during mitosis depend on cohesion between sister chromatids. Cohesion is thought to occur through the entrapment of DNA within the tripartite ring (Smc1, Smc3 and Rad21) with enforcement from a fourth subunit (SA1/SA2). Surprisingly, cohesin rings do not play a major role in sister telomere cohesion. Instead, this role is replaced by SA1 and telomere binding proteins (TRF1 and TIN2). Neither the DNA binding property of SA1 nor this unique telomere cohesion mechanism is understood. Here, using single-molecule fluorescence imaging, we discover that SA1 displays two-state binding on DNA: searching by one-dimensional (1D) free diffusion versus recognition through subdiffusive sliding at telomeric regions. The AT-hook motif in SA1 plays dual roles in modulating non-specific DNA binding and subdiffusive dynamics over telomeric regions. TRF1 tethers SA1 within telomeric regions that SA1 transiently interacts with. SA1 and TRF1 together form longer DNA–DNA pairing tracts than with TRF1 alone, as revealed by atomic force microscopy imaging. These results suggest that at telomeres cohesion relies on the molecular interplay between TRF1 and SA1 to promote DNA–DNA pairing, while along chromosomal arms the core cohesin assembly might also depend on SA1 1D diffusion on DNA and sequence-specific DNA binding.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Fucosyltransferase VII improves the function of selectin ligands on cord blood hematopoietic stem cells (2013)
    Oxford University Press
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    Publication Date: 2013-09-08
    Description: Selectins and their carbohydrate ligands mediate the homing of hematopoietic stem/progenitor cells (HSPCs) to the bone marrow. We have previously shown that ex vivo fucosylation of selectin ligands on HSPCs by α1,3 fucosyltransferase VI (FUT6) leads to improved human cord blood (CB)-HSPC engraftment in non-obese diabetic (NOD)/severe combined immune deficient (SCID) mice. In the present study, we determined whether surface fucosylation with α1,3 fucosyltransferase VII (FUT7), which is primarily expressed by hematopoietic cells, improves the function of selectin ligands on CB-HSPCs in comparison with FUT6. A saturating amount of either FUT6 or FUT7, which generates comparable levels of expression of fucosylated epitopes on CB CD34 + cells, was used for these experiments. In vitro, FUT7-treated CB CD34 + cells exhibited greater binding to P- or E-selectin than that of FUT6-treated CB CD34 + cells under static or physiological flow conditions. In vivo, FUT7 treatment, like FUT6, improved the early engraftment of CB CD34 + cells in the bone marrow of sublethally irradiated NOD/SCID interleukin (IL)-2R null (NSG) mice. FUT7 also exhibited marginally—yet statistically significant—increased engraftment at 4 and 6 weeks after transplantation. In addition, FUT7-treated CB CD34 + cells exhibited increased homing to the bone marrow of irradiated NSG mice relative to sham-treated cells. These data indicate that FUT7 is effective at improving the function of selectin ligands on CB-HSPCs in vitro and enhancing early engraftment of treated CB-HSPCs in the bone marrow of recipients.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Degeneration of the Nonrecombining Regions in the Mating-Type Chromosomes of the Anther-Smut Fungi (2015)
    Oxford University Press
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    Publication Date: 2015-04-01
    Description: Dimorphic mating-type chromosomes in fungi are excellent models for understanding the genomic consequences of recombination suppression. Their suppressed recombination and reduced effective population size are expected to limit the efficacy of natural selection, leading to genomic degeneration. Our aim was to identify the sequences of the mating-type chromosomes (a 1 and a 2 ) of the anther-smut fungi and to investigate degeneration in their nonrecombining regions. We used the haploid a 1 Microbotryum lychnidis-dioicae reference genome sequence. The a 1 and a 2 mating-type chromosomes were both isolated electrophoretically and sequenced. Integration with restriction-digest optical maps identified regions of recombination and nonrecombination in the mating-type chromosomes. Genome sequence data were also obtained for 12 other Microbotryum species. We found strong evidence of degeneration across the genus in the nonrecombining regions of the mating-type chromosomes, with significantly higher rates of nonsynonymous substitution (d N /d S ) than in nonmating-type chromosomes or in recombining regions of the mating-type chromosomes. The nonrecombining regions of the mating-type chromosomes also showed high transposable element content, weak gene expression, and gene losses. The levels of degeneration did not differ between the a 1 and a 2 mating-type chromosomes, consistent with the lack of homogametic/heterogametic asymmetry between them, and contrasting with X/Y or Z/W sex chromosomes.
    Print ISSN: 0737-4038
    Electronic ISSN: 1537-1719
    Topics: Biology
    Published by Oxford University Press
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  • 7
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    Capture of the Canary mantle plume material by the Gibraltar arc mantle wedge during slab rollback (2015)
    Oxford University Press
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    Publication Date: 2015-04-16
    Description: Recent evidence suggests that a portion of the Canary plume travelled northeastwards below the lithosphere of the Atlas Mountains in North Africa towards the Alboran domain and was captured ~10 Ma ago by the Gibraltar subduction system in the Western Mediterranean. The capture would have been associated with the mantle return flow induced by the westward-retreating slab that would have dragged and trapped a portion of the plume material in the mantle wedge of the Gibraltar subduction zone. Such material eventually contaminated the subduction related volcanism in the Alboran region. In this work, we use scaled analogue models of slab–plume interaction to investigate the plausibility of the plume capture. An upper-mantle-scaled model combines a narrow (400 km) edge-fixed subduction plate with a laterally offset compositional plume. The subduction dominated by slab rollback and toroidal mantle flow is seen to increasingly impact on the plume dynamics as the area of influence of the toroidal flow cells at the surface is up to 500 x 1350 km 2 . While the plume head initially spreads axisymmetrically, it starts being distorted parallel to the plate in the direction of the trench as the slab trench approaches the plume edge at a separation distance of about 500 km, before getting dragged towards mantle wedge. When applied to the Canary plume–Gibraltar subduction system, our model supports the observationally based conceptual model that mantle plume material may have been dragged towards the mantle wedge by slab rollback-induced toroidal mantle flow. Using a scaling argument for the spreading of a gravity current within a channel, we also show that more than 1500 km of plume propagation in the sublithospheric Atlas corridor is dynamically plausible.
    Keywords: Express Letters, Geodynamics and Tectonics
    Print ISSN: 0956-540X
    Electronic ISSN: 1365-246X
    Topics: Geosciences
    Published by Oxford University Press on behalf of The Deutsche Geophysikalische Gesellschaft (DGG) and the Royal Astronomical Society (RAS).
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  • 8
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    Relativistic mergers of black hole binaries have large, similar masses, low spins and are circular (2016)
    Oxford University Press
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    Publication Date: 2016-04-02
    Description: Gravitational waves are a prediction of general relativity, and with ground-based detectors now running in their advanced configuration, we will soon be able to measure them directly for the first time. Binaries of stellar-mass black holes are among the most interesting sources for these detectors. Unfortunately, the many different parameters associated with the problem make it difficult to promptly produce a large set of waveforms for the search in the data stream. To reduce the number of templates to develop, one must restrict some of the physical parameters to a certain range of values predicted by either (electromagnetic) observations or theoretical modelling. In this work, we show that ‘hyperstellar’ black holes (HSBs) with masses 30 M BH /M 100, i.e black holes significantly larger than the nominal 10 M , will have an associated low value for the spin, i.e. a 〈 0.5. We prove that this is true regardless of the formation channel, and that when two HSBs build a binary, each of the spin magnitudes is also low, and the binary members have similar masses. We also address the distribution of the eccentricities of HSB binaries in dense stellar systems using a large suite of three-body scattering experiments that include binary–single interactions and long-lived hierarchical systems with a highly accurate integrator, including relativistic corrections up to ${\cal O}(1/c^5)$ . We find that most sources in the detector band will have nearly zero eccentricities. This correlation between large, similar masses, low spin and low eccentricity will help to accelerate the searches for gravitational-wave signals.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 9
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    al3c: high-performance software for parameter inference using Approximate Bayesian Computation (2015)
    Oxford University Press
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    Publication Date: 2015-10-21
    Description: Motivation: The development of Approximate Bayesian Computation (ABC) algorithms for parameter inference which are both computationally efficient and scalable in parallel computing environments is an important area of research. Monte Carlo rejection sampling, a fundamental component of ABC algorithms, is trivial to distribute over multiple processors but is inherently inefficient. While development of algorithms such as ABC Sequential Monte Carlo (ABC-SMC) help address the inherent inefficiencies of rejection sampling, such approaches are not as easily scaled on multiple processors. As a result, current Bayesian inference software offerings that use ABC-SMC lack the ability to scale in parallel computing environments. Results: We present al3c , a C++ framework for implementing ABC-SMC in parallel. By requiring only that users define essential functions such as the simulation model and prior distribution function, al3c abstracts the user from both the complexities of parallel programming and the details of the ABC-SMC algorithm. By using the al3c framework, the user is able to scale the ABC-SMC algorithm in parallel computing environments for his or her specific application, with minimal programming overhead. Availability and implementation: al3c is offered as a static binary for Linux and OS-X computing environments. The user completes an XML configuration file and C++ plug-in template for the specific application, which are used by al3c to obtain the desired results. Users can download the static binaries, source code, reference documentation and examples (including those in this article) by visiting https://github.com/ahstram/al3c . Contact: astram@usc.edu Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 10
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    BioCircos.js: an interactive Circos JavaScript library for biological data visualization on web applications (2016)
    Oxford University Press
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    Publication Date: 2016-06-01
    Description: : We here present BioCircos.js, an interactive and lightweight JavaScript library especially for biological data interactive visualization. BioCircos.js facilitates the development of web-based applications for circular visualization of various biological data, such as genomic features, genetic variations, gene expression and biomolecular interactions. Availability and implementation: BioCircos.js and its manual are freely available online at http://bioinfo.ibp.ac.cn/biocircos/ . Contact: rschen@ibp.ac.cn Supplementary information: Supplementary data are available at Bioinformatics online.
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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