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  • 1
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    The Global Phosphorylation Landscape of SARS-CoV-2 Infection (2020)
    Cell Press
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    Publication Date: 2020-08-01
    Print ISSN: 0092-8674
    Electronic ISSN: 1097-4172
    Topics: Biology , Medicine
    Published by Cell Press
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  • 2
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    Dynamical mass ejection from binary neutron star mergers (2016)
    Oxford University Press
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    Publication Date: 2016-06-19
    Description: We present fully general-relativistic simulations of binary neutron star mergers with a temperature and composition dependent nuclear equation of state. We study the dynamical mass ejection from both quasi-circular and dynamical-capture eccentric mergers. We systematically vary the level of our treatment of the microphysics to isolate the effects of neutrino cooling and heating and we compute the nucleosynthetic yields of the ejecta. We find that eccentric binaries can eject significantly more material than quasi-circular binaries and generate bright infrared and radio emission. In all our simulations the outflow is composed of a combination of tidally- and shock-driven ejecta, mostly distributed over a broad ~60° angle from the orbital plane, and, to a lesser extent, by thermally driven winds at high latitudes. Ejecta from eccentric mergers are typically more neutron rich than those of quasi-circular mergers. We find neutrino cooling and heating to affect, quantitatively and qualitatively, composition, morphology, and total mass of the outflows. This is also reflected in the infrared and radio signatures of the binary. The final nucleosynthetic yields of the ejecta are robust and insensitive to input physics or merger type in the regions of the second and third r-process peaks. The yields for elements on the first peak vary between our simulations, but none of our models is able to explain the Solar abundances of first-peak elements without invoking additional first-peak contributions from either neutrino and viscously-driven winds operating on longer time-scales after the mergers, or from core-collapse supernovae.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 3
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    A mutation in the human CBP4 ortholog UQCC3 impairs complex III assembly, activity and cytochrome b stability (2014)
    Oxford University Press
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    Publication Date: 2014-11-07
    Description: Complex III (cytochrome bc 1 ) is a protein complex of the mitochondrial inner membrane that transfers electrons from ubiquinol to cytochrome c . Its assembly requires the coordinated expression of mitochondrial-encoded cytochrome b and nuclear-encoded subunits and assembly factors. Complex III deficiency is a severe multisystem disorder caused by mutations in subunit genes or assembly factors. Sequence-profile-based orthology predicts C11orf83 , hereafter named UQCC3 , to be the ortholog of the fungal complex III assembly factor CBP4 . We describe a homozygous c.59T〉A missense mutation in UQCC3 from a consanguineous patient diagnosed with isolated complex III deficiency, displaying lactic acidosis, hypoglycemia, hypotonia and delayed development without dysmorphic features. Patient fibroblasts have reduced complex III activity and lower levels of the holocomplex and its subunits than controls. They have no detectable UQCC3 protein and have lower levels of cytochrome b protein. Furthermore, in patient cells, cytochrome b is absent from a high-molecular-weight complex III. UQCC3 is reduced in cells depleted for the complex III assembly factors UQCC1 and UQCC2. Conversely, absence of UQCC3 in patient cells does not affect UQCC1 and UQCC2. This suggests that UQCC3 functions in the complex III assembly pathway downstream of UQCC1 and UQCC2 and is consistent with what is known about the function of Cbp4 and of the fungal orthologs of UQCC1 and UQCC2, Cbp3 and Cbp6. We conclude that UQCC3 functions in complex III assembly and that the c.59T〉A mutation has a causal role in complex III deficiency.
    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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    The Transcriptomic Evolution of Mammalian Pregnancy: Gene Expression Innovations in Endometrial Stromal Fibroblasts (2016)
    Oxford University Press
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    Publication Date: 2016-08-27
    Description: The endometrial stromal fibroblast (ESF) is a cell type present in the uterine lining of therian mammals. In the stem lineage of eutherian mammals, ESF acquired the ability to differentiate into decidual cells in order to allow embryo implantation. We call the latter cell type "neo-ESF" in contrast to "paleo-ESF" which is homologous to eutherian ESF but is not able to decidualize. In this study, we compare the transcriptomes of ESF from six therian species: Opossum ( Monodelphis domestica ; paleo-ESF), mink, rat, rabbit, human (all neo-ESF), and cow (secondarily nondecidualizing neo-ESF). We find evidence for strong stabilizing selection on transcriptome composition suggesting that the expression of approximately 5,600 genes is maintained by natural selection. The evolution of neo-ESF from paleo-ESF involved the following gene expression changes: Loss of expression of genes related to inflammation and immune response, lower expression of genes opposing tissue invasion, increased markers for proliferation as well as the recruitment of FOXM1 , a key gene transiently expressed during decidualization. Signaling pathways also evolve rapidly and continue to evolve within eutherian lineages. In the bovine lineage, where invasiveness and decidualization were secondarily lost, we see a re-expression of genes found in opossum, most prominently WISP2 , and a loss of gene expression related to angiogenesis. The data from this and previous studies support a scenario, where the proinflammatory paleo-ESF was reprogrammed to express anti-inflammatory genes in response to the inflammatory stimulus coming from the implanting conceptus and thus paving the way for extended, trans-cyclic gestation.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 5
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    Supernova seismology: gravitational wave signatures of rapidly rotating core collapse (2015)
    Oxford University Press
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    Publication Date: 2015-04-18
    Description: Gravitational waves (GW) generated during a core-collapse supernova open a window into the heart of the explosion. At core bounce, progenitors with rapid core rotation rates exhibit a characteristic GW signal which can be used to constrain the properties of the core of the progenitor star. We investigate the dynamics of rapidly rotating core collapse, focusing on hydrodynamic waves generated by the core bounce, and the GW spectrum they produce. The centrifugal distortion of the rapidly rotating proto-neutron star (PNS) leads to the generation of axisymmetric quadrupolar oscillations within the PNS and surrounding envelope. Using linear perturbation theory, we estimate the frequencies, amplitudes, damping times, and GW spectra of the oscillations. Our analysis provides a qualitative explanation for several features of the GW spectrum and shows reasonable agreement with non-linear hydrodynamic simulations, although a few discrepancies due to non-linear/rotational effects are evident. The dominant early post-bounce GW signal is produced by the fundamental quadrupolar oscillation mode of the PNS, at a frequency 0.70   f   0.80 kHz, whose energy is largely trapped within the PNS and leaks out on a ~10-ms time-scale. Quasi-radial oscillations are not trapped within the PNS and quickly propagate outwards until they steepen into shocks. Both the PNS structure and Coriolis/centrifugal forces have a strong impact on the GW spectrum, and a detection of the GW signal can therefore be used to constrain progenitor properties.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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  • 6
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    Dark matter-induced collapse of neutron stars: a possible link between fast radio bursts and the missing pulsar problem (2015)
    Oxford University Press
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    Publication Date: 2015-04-26
    Description: Fast radio bursts (FRBs) are an emerging class of short and bright radio transients whose sources remain enigmatic. Within the Galactic Centre, the non-detection of pulsars within the inner ~10 pc has created a missing pulsar problem that has intensified with time. With all reserve, we advance the notion that the two problems could be linked by a common solution: the collapse of neutron stars (NS) due to capture and sedimentation of dark matter (DM) within their cores. Bramante & Linden showed that certain DM properties allow for rapid NS collapse within the high DM density environments near galactic centres while permitting NS survival elsewhere. Each DM-induced collapse could generate an FRB as the NS magnetosphere is suddenly expelled. This scenario could explain several features of FRBs: their short time scales, large energies, locally produced scattering tails, and high event rates. We predict that FRBs are localized to galactic centres, and that our own galactic centre harbours a large population of NS-mass ( M  ~ 1.4 M ) black holes. The DM-induced collapse scenario is intrinsically unlikely because it can only occur in a small region of allowable DM parameter space. However, if observed to occur, it would place tight constraints on DM properties.
    Print ISSN: 1745-3925
    Electronic ISSN: 1745-3933
    Topics: Physics
    Published by Oxford University Press
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  • 7
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    Algal lectin binding to core ({alpha}1-6) fucosylated N-glycans: Structural basis for specificity and production of recombinant protein (2015)
    Oxford University Press
    Details
    Publication Date: 2015-04-28
    Description: We determined the specificity of BTL, a lectin from the red marine alga Bryothamnion triquetrum, toward fucosylated oligosaccharides. BTL showed a strict specificity for the core α1,6-fucosylation, which is an important marker for cancerogenesis and quality control of therapeutical antibodies. The double fucosylation α1,6 and α1,3 was also recognized, but the binding was totally abolished in the sole presence of the α1,3-fucosylation. A more detailed analysis of the specificity of BTL showed a preference for bi- and tri-antennary nonbisected N -glycans. Sialylation or fucosylation at the nonreducing end of N -glycans did not affect the recognition by the lectin. BTL displayed a strong affinity for a core α1,6-fucosylated octasaccharide with a K d of 12 μM by titration microcalorimetry. The structural characterization of the interaction between BTL and the octasaccharide was obtained by STD-NMR. It demonstrated an extended epitope for recognition that includes the fucose residue, the distal GlcNAc and one mannose residue. Recombinant rBTL was obtained in Escherichia coli and characterized. Its binding properties for carbohydrates were studied using hemagglutination tests and glycan array analysis. rBTL was able to agglutinate rabbit erythrocytes with strong hemagglutination activity only after treatment with papain and trypsin, indicating that its ligands were not directly accessible at the cell surface. The hemagglutinating properties of rBTL confirm the correct folding and functional state of the protein. The results show BTL as a potent candidate for cancer diagnosis and as a reagent for the preparation and quality control of antibodies lacking core α1,6-fucosylated N -glycans.
    Print ISSN: 0959-6658
    Electronic ISSN: 1460-2423
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 8
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    Conserved Cis-Regulatory Modules Control Robustness in Msx1 Expression at Single-Cell Resolution (2015)
    Oxford University Press
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    Publication Date: 2015-10-01
    Description: The process of transcription is highly stochastic leading to cell-to-cell variations and noise in gene expression levels. However, key essential genes have to be precisely expressed at the correct amount and time to ensure proper cellular development and function. Studies in yeast and bacterial systems have shown that gene expression noise decreases as mean expression levels increase, a relationship that is controlled by promoter DNA sequence. However, the function of distal cis- regulatory modules (CRMs), an evolutionary novelty of metazoans, in controlling transcriptional robustness and variability is poorly understood. In this study, we used live cell imaging of transfected reporters combined with a mathematical modelling and statistical inference scheme to quantify the function of conserved Msx1 CRMs and promoters in modulating single-cell real-time transcription rates in C2C12 mouse myoblasts. The results show that the mean expression–noise relationship is solely promoter controlled for this key pluripotency regulator. In addition, we demonstrate that CRMs modulate single-cell basal promoter rate distributions in a graded manner across a population of cells. This extends the rheostatic model of CRM action to provide a more detailed understanding of CRM function at single-cell resolution. We also identify a novel CRM transcriptional filter function that acts to reduce intracellular variability in transcription rates and show that this can be phylogenetically separable from rate modulating CRM activities. These results are important for understanding how the expression of key vertebrate developmental transcription factors is precisely controlled both within and between individual cells.
    Electronic ISSN: 1759-6653
    Topics: Biology
    Published by Oxford University Press
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  • 9
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    Mitochondrial defects and neurodegeneration in mice overexpressing wild-type or G399S mutant HtrA2 (2016)
    Oxford University Press
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    Publication Date: 2016-01-29
    Description: The protease HtrA2 has a protective role inside mitochondria, but promotes apoptosis under stress. We previously identified the G399S HtrA2 mutation in Parkinson's disease (PD) patients and reported mitochondrial dysfunction in vitro . Mitochondrial dysfunction is a common feature of PD and related to neurodegeneration. Complete loss of HtrA2 has been shown to cause neurodegeneration in mice. However, the full impact of HtrA2 overexpression or the G399S mutation is still to be determined in vivo . Here, we report the first HtrA2 G399S transgenic mouse model. Our data suggest that the mutation has a dominant-negative effect. We also describe a toxic effect of wild-type (WT) HtrA2 overexpression. Only low overexpression of the G399S mutation allowed viable animals and we suggest that the mutant protein is likely unstable. This is accompanied by reduced mitochondrial respiratory capacity and sensitivity to apoptotic cell death. Mice overexpressing WT HtrA2 were viable, yet these animals have inhibited mitochondrial respiration and significant induction of apoptosis in the brain leading to motor dysfunction, highlighting the opposing roles of HtrA2. Our data further underscore the importance of HtrA2 as a key mediator of mitochondrial function and its fine regulatory role in cell fate. The location and abundance of HtrA2 is tightly controlled and, therefore, human mutations leading to gain- or loss of function could provide significant risk for PD-related neurodegeneration.
    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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    A survey for hydroxyl in the THOR pilot region around W43 (2015)
    Oxford University Press
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    Publication Date: 2015-12-02
    Description: We report on observations of the hydroxyl radical (OH) within The H i , OH, Recombination line survey (THOR) pilot region. The region is bounded approximately between Galactic coordinates l = 29 $_{.}^{\circ}$ 2 to 31 $_{.}^{\circ}$ 5 and b = –1 $_{.}^{\circ}$ 0 to +1 $_{.}^{\circ}$ 0 and includes the high-mass star-forming region W43. We identify 103 maser sites, including 72 with 1612 MHz masers, 42 showing masers in either of the main-line transitions at 1665 and 1667 MHz and four showing 1720 MHz masers. Most maser sites with either main-line or 1720 MHz emission are associated with star formation, whereas most of the 1612 MHz masers are associated with evolved stars. We find that nearly all of the main-line maser sites are co-spatial with an infrared source, detected by GLIMPSE. We also find diffuse OH emission, as well as OH in absorption towards selected unresolved or partially resolved sites. Extended OH absorption is found towards the well-known star-forming complex W43 Main.
    Print ISSN: 0035-8711
    Electronic ISSN: 1365-2966
    Topics: Physics
    Published by Oxford University Press
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