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  • 1
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    Activating the translational repressor 4E-BP or reducing S6K-GSK3{beta} activity prevents accelerated axon growth induced by hyperactive mTOR in vivo (2015)
    Oxford University Press
    Details
    Publication Date: 2015-09-25
    Description: Abnormal axonal connectivity and hyperactive mTOR complex 1 (mTORC1) are shared features of several neurological disorders. Hyperactive mTORC1 alters axon length and polarity of hippocampal neurons in vitro , but the impact of hyperactive mTORC1 on axon growth in vivo and the mechanisms underlying those effects remain unclear. Using in utero electroporation during corticogenesis, we show that increasing mTORC1 activity accelerates axon growth without multiple axon formation. This was prevented by counteracting mTORC1 signaling through p70S6Ks (S6K1/2) or eukaryotic initiation factor 4E-binding protein (4E-BP1/2), which both regulate translation. In addition to regulating translational targets, S6K1 indirectly signals through GSK3β, a regulator of axogenesis. Although blocking GSK3β activity did not alter axon growth under physiological conditions in vivo , blocking it using a dominant-negative mutant or lithium chloride prevented mTORC1-induced accelerated axon growth. These data reveal the contribution of translational and non-translational downstream effectors such as GSK3β to abnormal axon growth in neurodevelopmental mTORopathies and open new therapeutic options for restoring long-range connectivity.
    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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    Electromagnetic responses to an earthquake source due to the motional induction effect in a 2-D layered model (2019)
    Oxford University Press
    Details
    Publication Date: 2019
    Description: 〈span〉〈div〉Summary〈/div〉Movement of the conductive earth medium in the ambient geomagnetic field can generate an electromotive force and a motional induction current, which further cause the disturbances of the electromagnetic (EM) fields. Such a mechanoelectric coupling is known as the motional induction (MI) effect and has been proposed to be a possible mechanism for the generation of the observed EM signals during earthquakes. In this paper, we study the EM responses to an earthquake source due to such a MI effect in a 2-D horizontally layered model. First we transform the governing equations that couple the elastodynamic equations and Maxwell equations into a set of first-order ordinary depth-dependent differential equations. Then we solve the seismic and EM responses to a moment tensor source. Finally, we transform the 2-D seismic and EM responses to 3-D responses using a simple amplitude correction method. We conduct several numerical examples to investigate the properties of the EM signals generated by the earthquake source. The results show that two types of EM signals can be observed. The first one is the coseismic electric/magnetic field that accompanies the seismic 〈span〉P〈/span〉 and 〈span〉S〈/span〉 waves as well as the Rayleigh wave. The second one is the early EM signal which arrives before the 〈span〉P〈/span〉 wave. The numerical results show that the EM signals change with the inclination angle of the geomagnetic field, the azimuth angle between the wave propagation plane and the geomagnetic vertical plane, and the medium conductivity. Increase in the conductivity can enhance the coseismic electric and magnetic signals. Our simulation also shows that an EM wave can be generated by a seismic wave at the interface separating two different media. The radiation pattern of the interface EM wave generated by a 〈span〉P〈/span〉 wave is similar to that of a horizontal electric dipole located on the interface.〈/span〉
    Print ISSN: 2051-1965
    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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    Electrokinetic effect combined with surface-charge assumption: a possible generation mechanism of coseismic EM signals (2014)
    Oxford University Press
    Details
    Publication Date: 2014-12-17
    Description: According to field observations, electromagnetic (EM) signals accompanying seismic waves can be recorded. The orders of magnitude of observed coseismic electric and magnetic signals associated with earthquakes are usually around 1 to 10 1 mV km –1 and 10 –2 to 1 nT, respectively. In this paper, we carry out numerical simulation of coseismic EM signals associated with seismic waves due to electrokinetic effect and compare with field observations. The seismic source is represented by a finite fault measuring 15 x 9 km 2 with a max slip displacement 1.5 m, corresponding to a M w 5.9 earthquake. While using the EM surface boundary condition of continuous horizontal EM components, the magnetic signals only accompany the late-arriving S waves at receiver near the ground surface. This is obviously different from field observations. Thus, we adopt another EM surface boundary condition which assumes the ground surface carries surface charge. For the used half-space model, a surface-charge density magnitude | Q sc | in excess of 10 –4 C m –2 is sufficient to make horizontal magnetic components clearly show up at the whole time duration of seismic waves. When | Q sc | increases, the contribution of surface-charge density to coseismic EM signals becomes more and more dominant comparing with that of the seismically induced streaming-current. We estimate the Q sc expected at the Earth's surface might be a value between –5 x 10 –4 and –0.1 C m –2 by the comparison between numerical results and field observations. The vertical magnetic signals only accompany the late-arriving seismic waves, because they are theoretically only induced by SH wave. The field observation results of vertical magnetic signals may be resulted from the scattering effect or the seismic dynamo effect. We conclude that electrokinetic effect combined with surface-charge assumption is one possible generation mechanism of the observed coseismic EM signals.
    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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  • 4
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    Folding a stable RNA pseudoknot through rearrangement of two hairpin structures (2014)
    Oxford University Press
    Details
    Publication Date: 2014-04-15
    Description: Folding messenger RNA into specific structures is a common regulatory mechanism involved in translation. In Escherichia coli , the operator of the rpsO gene transcript folds into a pseudoknot or double-hairpin conformation. S15, the gene product, binds only to the pseudoknot, thereby repressing its own synthesis when it is present in excess in the cell. The two RNA conformations have been proposed to exist in equilibrium. However, it remained unclear how structural changes can be achieved between these two topologically distinct conformations. We used optical tweezers to study the structural dynamics and rearrangements of the rpsO operator RNA at the single-molecule level. We discovered that the two RNA structures can be interchanged spontaneously and the pseudoknot can exist in conformations that exhibit various levels of stability. Conversion from the double hairpin to a pseudoknot through potential hairpin–hairpin interactions favoured the high-stability conformation. By contrast, mutations that blocked the formation of a hairpin typically resulted in alternative low-stability pseudoknots. These results demonstrate that specific tertiary interactions of RNA can be established and modulated based on the interactions and rearrangements between secondary structural components. Our findings provide new insight into the RNA folding pathway that leads to a regulatory conformation for target protein 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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    Transcriptome dynamics of the microRNA inhibition response (2016)
    Oxford University Press
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    Publication Date: 2016-05-20
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 6
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    Characterization of p38 MAPK isoforms for drug resistance study using systems biology approach (2014)
    Oxford University Press
    Details
    Publication Date: 2014-06-27
    Description: Motivation: p38 mitogen-activated protein kinase activation plays an important role in resistance to chemotherapeutic cytotoxic drugs in treating multiple myeloma (MM). However, how the p38 mitogen-activated protein kinase signaling pathway is involved in drug resistance, in particular the roles that the various p38 isoforms play, remains largely unknown. Method: To explore the underlying mechanisms, we developed a novel systems biology approach by integrating liquid chromatography–mass spectrometry and reverse phase protein array data from human MM cell lines with computational pathway models in which the unknown parameters were inferred using a proposed novel algorithm called modularized factor graph. Results: New mechanisms predicted by our models suggest that combined activation of various p38 isoforms may result in drug resistance in MM via regulating the related pathways including extracellular signal-regulated kinase (ERK) pathway and NFB pathway. ERK pathway regulating cell growth is synergistically regulated by p38 isoform, whereas nuclear factor kappa B (NFB) pathway regulating cell apoptosis is synergistically regulated by p38α isoform. This finding that p38 isoform promotes the phosphorylation of ERK1/2 in MM cells treated with bortezomib was validated by western blotting. Based on the predicted mechanisms, we further screened drug combinations in silico and found that a promising drug combination targeting ERK1/2 and NFB might reduce the effects of drug resistance in MM cells. This study provides a framework of a systems biology approach to studying drug resistance and drug combination selection. Availability and implementation: RPPA experimental Data and Matlab source codes of modularized factor graph for parameter estimation are freely available online at http://ctsb.is.wfubmc.edu/publications/modularized-factor-graph.php Contact: xizhou@wakehealth.edu or zhanglcq@swu.edu.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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  • 7
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    Origin and Evolution of the Eukaryotic SSU Processome Revealed by a Comprehensive Genomic Analysis and Implications for the Origin of the Nucleolus (2013)
    Oxford University Press
    Details
    Publication Date: 2013-12-04
    Description: As a nucleolar complex for small-subunit (SSU) ribosomal RNA processing, SSU processome has been extensively studied mainly in Saccharomyces cerevisiae but not in diverse organisms, leaving open the question of whether it is a ubiquitous mechanism across eukaryotes and how it evolved in the course of the evolution of eukaryotes. Genome-wide survey and identification of SSU processome components showed that the majority of all 77 yeast SSU processome proteins possess homologs in almost all of the main eukaryotic lineages, and 14 of them have homologs in archaea but few in bacteria, suggesting that the complex is ubiquitous in eukaryotes, and its evolutionary history began with abundant protein homologs being present in archaea and then a fairly complete form of the complex emerged in the last eukaryotic common ancestor (LECA). Phylogenetic analysis indicated that ancient gene duplication and functional divergence of the protein components of the complex occurred frequently during the evolutionary origin of the LECA from prokaryotes. We found that such duplications not only increased the complex’s components but also produced some new functional proteins involved in other nucleolar functions, such as ribosome biogenesis and even some nonnucleolar (but nuclear) proteins participating in pre-mRNA splicing, implying the evolutionary emergence of the subnuclear compartment—the nucleolus—has occurred in the LECA. Therefore, the LECA harbored not only complicated SSU processomes but also a nucleolus. Our analysis also revealed that gene duplication, innovation, and loss, caused further divergence of the complex during the divergence of eukaryotes.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    The ZorO-OrzO type I toxin-antitoxin locus: repression by the OrzO antitoxin (2014)
    Oxford University Press
    Details
    Publication Date: 2014-02-11
    Description: Type I toxin–antitoxin loci consist of two genes: a small, hydrophobic, potentially toxic protein, and a small RNA (sRNA) antitoxin. The sRNA represses toxin gene expression by base pairing to the toxin mRNA. A previous bioinformatics search predicted a duplicated type I locus within Escherichia coli O157:H7 (EHEC), which we have named the gene pairs zorO-orzO and zorP-orzP . We show that overproduction of the zorO gene is toxic to E. coli ; co-expression of the sRNA OrzO can neutralize this toxicity, confirming that the zorO-orzO pair is a true type I toxin–antitoxin locus. However, OrzO is unable to repress zorO in a strain deleted for RNase III, indicating that repression requires cleavage of the target mRNA. Sequence analysis and mutagenesis studies have elucidated a nucleotide sequence region (V1) that allows differential recognition of the zorO mRNA by OrzO and not OrzP, and a specific single nucleotide within the V1 of OrzO that is critical for repression of zorO . Although there are 18 nt of complementarity between the OrzO sRNA and the zorO mRNA, not all base pairing interactions are needed for repression; however, the amount needed is dependent on whether there is continuous or discontinuous complementarity to the target mRNA.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Electromagnetic responses to an earthquake source due to the motional induction effect in a 2D layered model (2019)
    Oxford University Press
    Details
    Publication Date: 2019
    Description: 〈span〉〈div〉Summary〈/div〉Movement of the conductive earth medium in the ambient geomagnetic field can generate an electromotive force and a motional induction current, which further cause the disturbances of the electromagnetic (EM) fields. Such a mechanoelectric coupling is known as the motional induction (MI) effect and has been proposed to be a possible mechanism for the generation of the observed EM signals during earthquakes. In this paper we study the EM responses to an earthquake source due to such a MI effect in a 2D horizontally-layered model. First we transform the governing equations that couple the elastodynamic equations and Maxwell equations into a set of first-order ordinary depth-dependent differential equations. Then we solve the seismic and EM responses to a moment tensor source. Finally, we transform the 2D seismic and EM responses to 3D responses using a simple amplitude correction method. We conduct several numerical examples to investigate the properties of the EM signals generated by the earthquake source. The results show that two types of EM signals can be observed. The first one is the coseismic electric/magnetic field that accompanies the seismic P and S waves as well as the Rayleigh wave. The second one is the early EM signal which arrives before the P wave. The numerical results show that the EM signals change with the inclination angle of the geomagnetic field, the azimuth angle between the wave propagation plane and the geomagnetic vertical plane, and the medium conductivity. Increase in the conductivity can enhance the coseismic electric and magnetic signals. Our simulation also shows that an EM wave can be generated by a seismic wave at the interface separating two different media. The radiation pattern of the interface EM wave generated by a P wave is similar to that of a horizontal electric dipole located on the interface.〈/span〉
    Print ISSN: 2051-1965
    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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  • 10
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    Transcriptome dynamics of the microRNA inhibition response (2015)
    Oxford University Press
    Details
    Publication Date: 2015-07-25
    Description: We report a high-resolution time series study of transcriptome dynamics following antimiR-mediated inhibition of miR-9 in a Hodgkin lymphoma cell-line—the first such dynamic study of the microRNA inhibition response—revealing both general and specific aspects of the physiological response. We show miR-9 inhibition inducing a multiphasic transcriptome response, with a direct target perturbation before 4 h, earlier than previously reported, amplified by a downstream peak at ~32 h consistent with an indirect response due to secondary coherent regulation. Predictive modelling indicates a major role for miR-9 in post-transcriptional control of RNA processing and RNA binding protein regulation. Cluster analysis identifies multiple co-regulated gene regulatory modules. Functionally, we observe a shift over time from mRNA processing at early time points to translation at later time points. We validate the key observations with independent time series qPCR and we experimentally validate key predicted miR-9 targets. Methodologically, we developed sensitive functional data analytic predictive methods to analyse the weak response inherent in microRNA inhibition experiments. The methods of this study will be applicable to similar high-resolution time series transcriptome analyses and provides the context for more accurate experimental design and interpretation of future microRNA inhibition studies.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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