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  • 1
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    Mitochondrial Atpif1 regulates haem synthesis in developing erythroblasts (2012)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2012-11-09
    Description: Defects in the availability of haem substrates or the catalytic activity of the terminal enzyme in haem biosynthesis, ferrochelatase (Fech), impair haem synthesis and thus cause human congenital anaemias. The interdependent functions of regulators of mitochondrial homeostasis and enzymes responsible for haem synthesis are largely unknown. To investigate this we used zebrafish genetic screens and cloned mitochondrial ATPase inhibitory factor 1 (atpif1) from a zebrafish mutant with profound anaemia, pinotage (pnt (tq209)). Here we describe a direct mechanism establishing that Atpif1 regulates the catalytic efficiency of vertebrate Fech to synthesize haem. The loss of Atpif1 impairs haemoglobin synthesis in zebrafish, mouse and human haematopoietic models as a consequence of diminished Fech activity and elevated mitochondrial pH. To understand the relationship between mitochondrial pH, redox potential, [2Fe-2S] clusters and Fech activity, we used genetic complementation studies of Fech constructs with or without [2Fe-2S] clusters in pnt, as well as pharmacological agents modulating mitochondrial pH and redox potential. The presence of [2Fe-2S] cluster renders vertebrate Fech vulnerable to perturbations in Atpif1-regulated mitochondrial pH and redox potential. Therefore, Atpif1 deficiency reduces the efficiency of vertebrate Fech to synthesize haem, resulting in anaemia. The identification of mitochondrial Atpif1 as a regulator of haem synthesis advances our understanding of the mechanisms regulating mitochondrial haem homeostasis and red blood cell development. An ATPIF1 deficiency may contribute to important human diseases, such as congenital sideroblastic anaemias and mitochondriopathies.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉   〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3504625/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Shah, Dhvanit I -- Takahashi-Makise, Naoko -- Cooney, Jeffrey D -- Li, Liangtao -- Schultz, Iman J -- Pierce, Eric L -- Narla, Anupama -- Seguin, Alexandra -- Hattangadi, Shilpa M -- Medlock, Amy E -- Langer, Nathaniel B -- Dailey, Tamara A -- Hurst, Slater N -- Faccenda, Danilo -- Wiwczar, Jessica M -- Heggers, Spencer K -- Vogin, Guillaume -- Chen, Wen -- Chen, Caiyong -- Campagna, Dean R -- Brugnara, Carlo -- Zhou, Yi -- Ebert, Benjamin L -- Danial, Nika N -- Fleming, Mark D -- Ward, Diane M -- Campanella, Michelangelo -- Dailey, Harry A -- Kaplan, Jerry -- Paw, Barry H -- K01 DK085217/DK/NIDDK NIH HHS/ -- P01 HL032262/HL/NHLBI NIH HHS/ -- P30 DK072437/DK/NIDDK NIH HHS/ -- R01 DK052380/DK/NIDDK NIH HHS/ -- R01 DK070838/DK/NIDDK NIH HHS/ -- R01 DK096051/DK/NIDDK NIH HHS/ -- R01 HL082945/HL/NHLBI NIH HHS/ -- T32 GM007223/GM/NIGMS NIH HHS/ -- England -- Nature. 2012 Nov 22;491(7425):608-12. doi: 10.1038/nature11536. Epub 2012 Nov 7.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Medicine, Division of Hematology, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/23135403" target="_blank"〉PubMed〈/a〉
    Keywords: Anemia, Sideroblastic/genetics/metabolism/pathology ; Animals ; Disease Models, Animal ; Erythroblasts/cytology/*metabolism ; *Erythropoiesis ; Ferrochelatase/metabolism ; Genetic Complementation Test ; Heme/*biosynthesis ; Humans ; Hydrogen-Ion Concentration ; Mice ; Mitochondria/*metabolism/pathology ; Mitochondrial Proteins/deficiency/genetics/*metabolism ; Oxidation-Reduction ; Proteins/genetics/*metabolism ; Zebrafish/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
    Published by Nature Publishing Group (NPG)
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  • 2
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    Sea surface temperature control on the distribution of far-traveled Southern Ocean ice-rafted detritus during the Pliocene (2014)
    Wiley
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    Publication Date: 2014-05-09
    Description: The flux and provenance of ice-rafted detritus (IRD) deposited in the Southern Ocean can reveal information about the past instability of Antarctica's ice sheets during different climatic conditions. Here we present a Pliocene IRD provenance record based on the 40 Ar/ 39 Ar ages of ice-rafted hornblende grains from Ocean Drilling Program Site 1165, located near Prydz Bay in the Indian Ocean sector of the Southern Ocean, along with the results of modelled sensitivity tests of iceberg trajectories and their spatial melting patterns under a range of sea surface temperatures (SSTs). Our provenance results reveal that IRD and hence icebergs in the Prydz Bay area were mainly sourced from (i) the local Prydz Bay region, and (ii) the remote Wilkes Land margin located at the mouth of the low-lying Aurora Subglacial Basin. A series of IRD pulses, reaching up to ten times background IRD flux levels, were previously identified at Site 1165 between 3.3 to 3.0 Ma. Our new results reveal that the average proportion of IRD sourced from distal Wilkes Land margin doubles after 3.3 Ma. Our iceberg trajectory-melting models show that slower iceberg melting under cooling SSTs over this middle Pliocene interval allowed Wilkes Land icebergs to travel further before melting. Hence declining SSTs can account for a large part of the observed IRD provenance record at Site 1165. In Early Pliocene IRD layers, sampled at sub-orbital resolution around 4.6 Ma, we find evidence for significant increases in icebergs derived from Wilkes Land during very warm interglacials. This is suggestive of large-scale destabilisation of the East Antarctic ice sheet in the Aurora Subglacial Basin, as far-travelled icebergs would have to overcome enhanced melting in warmer SSTs. Our results highlight the importance of considering SSTs when interpreting IRD flux and provenance records in distal locations.
    Print ISSN: 0883-8305
    Electronic ISSN: 1944-9186
    Topics: Geosciences
    Published by Wiley on behalf of American Geophysical Union (AGU).
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  • 3
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    Abcb10 physically interacts with mitoferrin-1 (Slc25a37) to enhance its stability and function in the erythroid mitochondria (2009)
    National Academy of Sciences
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    Publication Date: 2009-09-04
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 4
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    A local complement response by RPE causes early-stage macular degeneration (2015)
    Oxford University Press
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    Publication Date: 2015-09-12
    Description: Inherited and age-related macular degenerations (AMDs) are important causes of vision loss. An early hallmark of these disorders is the formation of sub-retinal pigment epithelium (RPE) basal deposits. A role for the complement system in MDs was suggested by genetic association studies, but direct functional connections between alterations in the complement system and the pathogenesis of MD remain to be defined. We used primary RPE cells from a mouse model of inherited MD due to a p.R345W mutation in EGF-containing fibulin-like extracellular matrix protein 1 ( EFEMP1 ) to investigate the role of the RPE in early MD pathogenesis. Efemp1 R345W RPE cells recapitulate the basal deposit formation observed in vivo by producing sub-RPE deposits in vitro . The deposits share features with basal deposits, and their formation was mediated by EFEMP1 R345W or complement component 3a (C3a), but not by complement component 5a (C5a). Increased activation of complement appears to occur in response to an abnormal extracellular matrix (ECM), generated by the mutant EFEMP1 R345W protein and reduced ECM turnover due to inhibition of matrix metalloproteinase 2 by EFEMP1 R345W and C3a. Increased production of C3a also stimulated the release of cytokines such as interleukin (IL)-6 and IL-1B, which appear to have a role in deposit formation, albeit downstream of C3a. These studies provide the first direct indication that complement components produced locally by the RPE are involved in the formation of basal deposits. Furthermore, these results suggest that C3a generated by RPE is a potential therapeutic target for the treatment of EFEMP1 -associated MD as well as AMD.
    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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    Rasa3 in erythropoiesis and megakaryopoiesis [Genetics] (2012)
    National Academy of Sciences
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    Publication Date: 2012-07-25
    Description: Phenotype-driven approaches to gene discovery using inbred mice have been instrumental in identifying genetic determinants of inherited blood dyscrasias. The recessive mutant scat (severe combined anemia and thrombocytopenia) alternates between crisis and remission episodes, indicating an aberrant regulatory feedback mechanism common to erythrocyte and platelet formation. Here, we identify a missense mutation (G125V) in the scat Rasa3 gene, encoding a Ras GTPase activating protein (RasGAP), and elucidate the mechanism producing crisis episodes. The mutation causes mislocalization of RASA3 to the cytosol in scat red cells where it is inactive, leading to increased GTP-bound Ras. Erythropoiesis is severely blocked in scat crisis mice, and ∼94% succumb during the second crisis (∼30 d of age) from catastrophic hematopoietic failure in the spleen and bone marrow. Megakaryopoiesis is also defective during crisis. Notably, the scat phenotype is recapitulated in zebrafish when rasa3 is silenced. These results highlight a critical, conserved, and nonredundant role for RASA3 in vertebrate hematopoiesis.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 6
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    Tracking brain states under general anesthesia by using global coherence analysis [Neuroscience] (2011)
    National Academy of Sciences
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    Publication Date: 2011-05-25
    Description: Time and frequency domain analyses of scalp EEG recordings are widely used to track changes in brain states under general anesthesia. Although these analyses have suggested that different spatial patterns are associated with changes in the state of general anesthesia, the extent to which these patterns are spatially coordinated has not been systematically characterized. Global coherence, the ratio of the largest eigenvalue to the sum of the eigenvalues of the cross-spectral matrix at a given frequency and time, has been used to analyze the spatiotemporal dynamics of multivariate time-series. Using 64-lead EEG recorded from human subjects receiving computer-controlled infusions of the anesthetic propofol, we used surface Laplacian referencing combined with spectral and global coherence analyses to track the spatiotemporal dynamics of the brain's anesthetic state. During unconsciousness the spectrograms in the frontal leads showed increasing α (8–12 Hz) and δ power (0–4 Hz) and in the occipital leads δ power greater than α power. The global coherence detected strong coordinated α activity in the occipital leads in the awake state that shifted to the frontal leads during unconsciousness. It revealed a lack of coordinated δ activity during both the awake and unconscious states. Although strong frontal power during general anesthesia-induced unconsciousness—termed anteriorization—is well known, its possible association with strong α range global coherence suggests highly coordinated spatial activity. Our findings suggest that combined spectral and global coherence analyses may offer a new approach to tracking brain states under general anesthesia.
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 7
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    EEG signatures of propofol anesthesia [Medical Sciences] (2013)
    National Academy of Sciences
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    Publication Date: 2013-03-20
    Description: Unconsciousness is a fundamental component of general anesthesia (GA), but anesthesiologists have no reliable ways to be certain that a patient is unconscious. To develop EEG signatures that track loss and recovery of consciousness under GA, we recorded high-density EEGs in humans during gradual induction of and emergence from unconsciousness...
    Print ISSN: 0027-8424
    Electronic ISSN: 1091-6490
    Topics: Biology , Medicine , Natural Sciences in General
    Published by National Academy of Sciences
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  • 8
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    Sea surface temperature control on the distribution of far-traveled Southern Ocean ice-rafted detritus during the Pliocene (2014)
    American Geophysical Union
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    Publication Date: 2014-06-01
    Print ISSN: 2572-4517
    Electronic ISSN: 2572-4525
    Topics: Geosciences
    Published by American Geophysical Union
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