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  • 1
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    A general approach to high-yield biosynthesis of chimeric RNAs bearing various types of functional small RNAs for broad applications (2015)
    Oxford University Press
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    Publication Date: 2015-04-21
    Description: RNA research and therapy relies primarily on synthetic RNAs. We employed recombinant RNA technology toward large-scale production of pre-miRNA agents in bacteria, but found the majority of target RNAs were not or negligibly expressed. We thus developed a novel strategy to achieve consistent high-yield biosynthesis of chimeric RNAs carrying various small RNAs (e.g. miRNAs, siRNAs and RNA aptamers), which was based upon an optimal noncoding RNA scaffold (OnRS) derived from tRNA fusion pre-miR-34a (tRNA/mir-34a). Multi-milligrams of chimeric RNAs (e.g. OnRS/miR-124, OnRS/GFP-siRNA, OnRS/Neg (scrambled RNA) and OnRS/MGA (malachite green aptamer)) were readily obtained from 1 l bacterial culture. Deep sequencing analyses revealed that mature miR-124 and target GFP-siRNA were selectively released from chimeric RNAs in human cells. Consequently, OnRS/miR-124 was active in suppressing miR-124 target gene expression and controlling cellular processes, and OnRS/GFP-siRNA was effective in knocking down GFP mRNA levels and fluorescent intensity in ES-2/GFP cells and GFP -transgenic mice. Furthermore, the OnRS/MGA sensor offered a specific strong fluorescence upon binding MG, which was utilized as label-free substrate to accurately determine serum RNase activities in pancreatic cancer patients. These results demonstrate that OnRS-based bioengineering is a common, robust and versatile strategy to assemble various types of small RNAs for broad applications.
    Keywords: Synthetic Biology and Assembly Cloning
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 2
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    Can the magnetic susceptibility record of Chinese Red Clay sequence be used for palaeomonsoon reconstructions? (2016)
    Oxford University Press
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    Publication Date: 2016-01-11
    Description: Red Clay underlying the loess-palaeosol sequences on the Chinese Loess Plateau is an eolian deposit. There is a controversy over whether magnetic susceptibility ( ) variations in Red Clay sequence can be used as an indicator of summer palaeomonsoon intensity. This study investigates the magnetic mineralogy, magnetic concentration and magnetic grain size distribution of Jiaxian Red Clay with multimagnetic methods. Our results indicate that the magnetic properties of Jiaxian Red Clay are similar to those of the Quaternary loess-palaeosol sequences, and ultrafine ferrimagnetic grains produced during pedogenesis are responsible for an increase in susceptibility, therefore the enhancement mechanism of Red Clay is similar to that of the overlying loess-palaeosol sequences. This paper explores variations in the Red Clay sequence through spatial and temporal analysis. The susceptibility variation of six sites along a NNE to SSW transect correlate to palaeoclimatic cycles, so can be used to trace the summer palaeomonsoon intensity from a spatial perspective. However, a simple loess-derived calibration function cannot be used to quantitative reconstruct the palaeomonsoon intensity variations thought time. An adjusted calibration function for palaeosols from Red Clay sequence needs to be developed, so that can be used to quantitative reconstruct palaeomonsoon intensity. Further study is necessary to develop such a transfer function.
    Keywords: Geomagnetism, Rock Magnetism and Palaeomagnetism
    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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  • 3
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    Distinct expression and function of whirlin isoforms in the inner ear and retina: an insight into pathogenesis of USH2D and DFNB31 (2015)
    Oxford University Press
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    Publication Date: 2015-10-10
    Description: Usher syndrome (USH) is the most common inherited deaf-blindness with the majority of USH causative genes also involved in nonsyndromic recessive deafness (DFNB). The mechanism underlying this disease variation of USH genes is unclear. Here, we addressed this issue by investigating the DFNB31 gene, whose mutations cause USH2D or DFNB31 depending on their position. We found that the mouse DFNB31 ortholog ( Dfnb31 ) expressed different mRNA variants and whirlin protein isoforms in the cochlea and retina, where these isoforms played different roles spatially and temporally. Full-length (FL-) whirlin in photoreceptors and hair cell stereociliary bases is important for the USH type 2 protein complex, while FL- and C-terminal (C-) whirlins in hair cell stereociliary tips participate in stereociliary elongation. Mutations in the whirlin N-terminal region disrupted FL-whirlin isoform in the inner ear and retina but not C-whirlin in the inner ear, and led to retinal degeneration as well as moderate to severe hearing loss. By contrast, a mutation in the whirlin C-terminal region eliminated all normal whirlin isoforms but generated a truncated N-terminal whirlin protein fragment, which was partially functional in the retina and thus prevented retinal degeneration. Mice with this mutation had profound hearing loss. In summary, disruption of distinct whirlin isoforms by Dfnb31 mutations leads to a variety of phenotype configurations and may explain the mechanism underlying the different disease manifestations of human DFNB31 mutations. Our findings have a potential to improve diagnosis and treatment of USH disease and quality of life in USH patients.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 4
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    Exome sequencing reveals mutation in GJA1 as a cause of keratoderma-hypotrichosis-leukonychia totalis syndrome (2015)
    Oxford University Press
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    Publication Date: 2015-10-23
    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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    MBTPS1/SKI-1/S1P proprotein convertase is required for ECM signaling and axial elongation during somitogenesis and vertebral development (2015)
    Oxford University Press
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    Publication Date: 2015-04-23
    Description: Caudal regression syndrome (sacral agenesis), which impairs development of the caudal region of the body, occurs with a frequency of about 2 live births per 100 000 newborns although this incidence rises to 1 in 350 infants born to mothers with gestational diabetes. The lower back and limbs can be affected as well as the genitourinary and gastrointestinal tracts. The axial skeleton is formed during embryogenesis through the process of somitogenesis in which the paraxial mesoderm periodically segments into bilateral tissue blocks, called somites. Somites are the precursors of vertebrae and associated muscle, tendons and dorsal dermis. Vertebral anomalies in caudal regression syndrome may arise through perturbation of somitogenesis or, alternatively, could result from defective bone formation and patterning. We discovered that MBTPS1/SKI-1/S1P, which proteolytically activates a class of transmembrane transcription factors, plays a critical role in somitogenesis and the pathogenesis of lumbar/sacral vertebral anomalies. Conditional deletion of Mbtps1 yields a viable mouse with misshapen, fused and reduced number of lumbar and sacral vertebrae, under-developed hind limb bones and a kinky, shortened tail. We show that Mbtps1 is required to (i) maintain the Fgf8 ‘wavefront’ in the presomitic mesoderm that underpins axial elongation, (ii) sustain the Lfng oscillatory ‘clock’ activity that governs the periodicity of somite formation and (iii) preserve the composition and character of the somitic extracellular matrix containing fibronectin, fibrillin2 and laminin. Based on this spinal phenotype and known functions of MBTPS1, we reason that loss-of-function mutations in Mbtps1 may cause the etiology of caudal regression syndrome.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    A modified acceleration-based monthly gravity field solution from GRACE data (2015)
    Oxford University Press
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    Publication Date: 2015-06-28
    Description: This paper describes an alternative acceleration approach for determining GRACE monthly gravity field models. The main differences compared to the traditional acceleration approach can be summarized as: (1) The position errors of GRACE orbits in the functional model are taken into account; (2) The range ambiguity is eliminated via the difference of the range measurements and (3) The mean acceleration equation is formed based on Cowell integration. Using this developed approach, a new time-series of GRACE monthly solution spanning the period January 2003 to December 2010, called Tongji_Acc RL01, has been derived. The annual signals from the Tongji_Acc RL01 time-series agree well with those from the GLDAS model. The performance of Tongji_Acc RL01 shows that this new model is comparable with the RL05 models released by CSR and JPL as well as with the RL05a model released by GFZ.
    Keywords: Gravity, Geodesy and Tides
    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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  • 7
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    SUMOylation at K707 of DGCR8 controls direct function of primary microRNA (2015)
    Oxford University Press
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    Publication Date: 2015-09-19
    Description: DGCR8 (DiGeorge syndrome critical region gene 8) is essential for primary microRNA (pri-miRNA) processing in the cell nucleus. It specifically combines with Drosha, a nuclear RNase III enzyme, to form the Microprocessor complex (MC) that cleaves pri-miRNA to precursor miRNA (pre-miRNA), which is further processed to mature miRNA by Dicer, a cytoplasmic RNase III enzyme. Increasing evidences suggest that pri-/pre-miRNAs have direct functions in regulation of gene expression, however the underlying mechanism how it is fine-tuned remains unclear. Here we find that DGCR8 is modified by SUMO1 at the major site K 707 , which can be promoted by its ERK-activated phosphorylation. SUMOylation of DGCR8 enhances the protein stability by preventing the degradation via the ubiquitin proteasome pathway. More importantly, SUMOylation of DGCR8 does not alter its association with Drosha, the MC activity and miRNA biogenesis, but rather influences its affinity with pri-miRNAs. This altered affinity of DGCR8 with pri-miRNAs seems to control the direct functions of pri-miRNAs in recognition and repression of the target mRNAs, which is evidently linked to the DGCR8 function in regulation of tumorigenesis and cell migration. Collectively, our data suggest a novel mechanism that SUMOylation of DGCR8 controls direct functions of pri-miRNAs in gene silencing.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Scientific disclosure and commercialization mode selection for university technology transfer (2016)
    Oxford University Press
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    Publication Date: 2016-02-06
    Description: Much previous research has explored university–industry technology transfer, but few researchers have examined the more comprehensive technology transfer process from faculty to firm. This paper focuses on faculty’s decisions on invention disclosure and selection of the mode of commercialization, and it aims to fill this gap through developing game models involving faculty, university, and firm. The results reveal a series of specific conditions for each commercialization mode, indicating that faculty’s share of licensing revenue and non-economic benefit have a positive impact on invention disclosure and the amount of effort expended by faculty, while increasing licensing price, decreasing the invention disclosure rate, and not necessarily increasing the investment by the firm. The empirical evidence supports our theory and renders a practical interpretation in the context of the 35 Chinese universities with the most patent applications. Finally, this paper provides new insights for faculty, university, and firm, as well as implications for policy-makers.
    Print ISSN: 0302-3427
    Electronic ISSN: 1471-5430
    Topics: Nature of Science, Research, Systems of Higher Education, Museum Science
    Published by Oxford University Press
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  • 9
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    Estimating treatment effects with treatment switching via semicompeting risks models: an application to a colorectal cancer study (2012)
    Oxford University Press
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    Publication Date: 2012-04-19
    Description: Treatment switching is a frequent occurrence in clinical trials, where, during the course of the trial, patients who fail on the control treatment may change to the experimental treatment. Analysing the data without accounting for switching yields highly biased and inefficient estimates of the treatment effect. In this paper, we propose a novel class of semiparametric semicompeting risks transition survival models to accommodate treatment switches. Theoretical properties of the proposed model are examined and an efficient expectation-maximization algorithm is derived for obtaining the maximum likelihood estimates. Simulation studies are conducted to demonstrate the superiority of the model compared with the intent-to-treat analysis and other methods proposed in the literature. The proposed method is applied to data from a colorectal cancer clinical trial.
    Print ISSN: 0006-3444
    Electronic ISSN: 1464-3510
    Topics: Biology , Mathematics , Medicine
    Published by Oxford University Press
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  • 10
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    Interferon gamma (IFN-{gamma}) disrupts energy expenditure and metabolic homeostasis by suppressing SIRT1 transcription (2012)
    Oxford University Press
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    Publication Date: 2012-02-28
    Description: Chronic inflammation impairs metabolic homeostasis and is intimately correlated with the pathogenesis of type 2 diabetes. The pro-inflammatory cytokine IFN- is an integral part of the metabolic inflammation circuit and contributes significantly to metabolic dysfunction. The underlying mechanism, however, remains largely unknown. In the present study, we report that IFN- disrupts the expression of genes key to cellular metabolism and energy expenditure by repressing the expression and activity of SIRT1 at the transcription level. Further analysis reveals that IFN- requires class II transactivator (CIITA) to repress SIRT1 transcription. CIITA, once induced by IFN-, is recruited to the SIRT1 promoter by hypermethylated in cancer 1 (HIC1) and promotes down-regulation of SIRT1 transcription via active deacetylation of core histones surrounding the SIRT1 proximal promoter. Silencing CIITA or HIC1 restores SIRT1 activity and expression of metabolic genes in skeletal muscle cells challenged with IFN-. Therefore, our data delineate an IFN-/HIC1/CIITA axis that contributes to metabolic dysfunction by suppressing SIRT1 transcription in skeletal muscle cells and as such shed new light on the development of novel therapeutic strategies against type 2 diabetes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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