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  1. Book ; Online: Age and chemical composition of apatites from five DSDP and ODP Sites in the Pacific, Atlantic and Indian Oceans, supplementary data to: Spiegel, Cornelia; Kohn, Barry; Raza, Asaf; Rainer, Thomas; Gleadow, Andrew (2007): The effect of long-term low-temperature exposure on apatite fission track stability: A natural annealing experiment in the deep ocean. Geochimica et Cosmochimica Acta, 71(18), 4512-4537

    Spiegel, Cornelia / Gleadow, Andrew / Kohn, Barry / Rainer, Thomas / Raza, Asaf

    2007  

    Abstract: Since studies on deep-sea cores were carried out in the early 1990s it has been known that ambient temperature may have a marked affect on apatite fission track annealing. Due to sluggish annealing kinetics, this effect cannot be quantified by laboratory ...

    Abstract Since studies on deep-sea cores were carried out in the early 1990s it has been known that ambient temperature may have a marked affect on apatite fission track annealing. Due to sluggish annealing kinetics, this effect cannot be quantified by laboratory annealing experiments. The unknown amount of low-temperature annealing remains one of the main uncertainties for extracting thermal histories from fission track data, particularly for samples which experienced slow cooling in shallow crustal levels. To further elucidate these uncertainties, we studied volcanogenic sediments from five deep-sea drill cores, that were exposed to maximum temperatures between ~10? and 70?C over geological time scales of ~15-120 Ma. Mean track lengths (MTL) and etch pit diameters (Dpar) of all samples were measured, and the chemical composition of each grain analyzed for age and track length measurements was determined by electron microprobe analysis. Thermal histories of the sampled sites were independently reconstructed, based on vitrinite reflectance measurements and/or 1D numerical modelling. These reconstructions were used to test the most widely used annealing models for their ability to predict low-temperature annealing. Our results show that long-term exposure to temperatures below the temperature range of the nominal apatite fission track partial annealing zone results in track shortening ranging between 4 and 11%. Both chlorine content and Dpar values explain the downhole annealing patterns equally well. Low chlorine apatite from one drill core revealed a systematic relation between Si-content and Dpar value. The question whether Si-substitution in apatite has direct and systematic effects on annealing properties however, cannot be addressed by our data. For samples, which remained at temperatures <30?C, and which are low in chlorine, the Laslett et al. [Laslett G., Green P., Duddy I. and Gleadow A. (1987) Thermal annealing of fission tracks in apatite. Chem. Geol. 65, 1-13] annealing model predicts MTL up to 0.6 ?m longer than those actually measured, whereas for apatites with intermediate to high chlorine content, which experienced temperatures >30?C, the predictions of the Laslett et al. (1987) model agree with the measured MTL data within error levels. With few exceptions, predictions by the Ketcham et al. [Ketcham R., Donelick R. and Carlson W. (1999) Variability of apatite fission-track annealing kinetics. III: Extrapolation to geological time scales. Am. Mineral. 84/9, 1235-1255] annealing model are consistent with the measured data for samples which remained at temperatures below ~30?C. For samples which experienced maximum temperatures between ~30 and 70?C, and which are rich in chlorine, the Ketcham et al. (1999) model overestimates track annealing.
    Language English
    Dates of publication 2007-9999
    Size Online-Ressource
    Publisher PANGAEA - Data Publisher for Earth & Environmental Science
    Publishing place Bremen/Bremerhaven
    Document type Book ; Online
    Note This dataset is supplement to doi:10.1016/j.gca.2007.06.060
    DOI 10.1594/PANGAEA.704785
    Database Library catalogue of the German National Library of Science and Technology (TIB), Hannover

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  2. Article ; Online: Hypocalcemia as the Initial Presentation of Type 2 Bartter Syndrome: A Family Report.

    London, Shira / Levine, Michael A / Li, Dong / Spiegel, Ronen / Lebel, Asaf / Halevy, Rephael / Tenenbaum-Rakover, Yardena

    The Journal of clinical endocrinology and metabolism

    2021  Volume 107, Issue 4, Page(s) e1679–e1688

    Abstract: Context: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. ... ...

    Abstract Context: Bartter syndrome (BS) is a group of rare autosomal-recessive tubulopathies characterized by hypokalemic, hypochloremic metabolic alkalosis in which the primary defect is a deficiency of transporters involved in sodium chloride reabsorption. Type 2 BS results from a defect in the renal outer medullary potassium channel encoded by the KCNJ1 gene. Type 2 BS presents with polyhydramnios, intrauterine growth retardation, prematurity, failure to thrive, polyuria, hypercalciuria, and life-threatening episodes of dehydration. Hypocalcemia is a very rare presenting symptom of BS, with only a few published cases reporting it as the initial manifestation of type 2 BS.
    Objective: To describe a child who presented with hypocalcemic seizure at the age of 2.3 years that was first related to vitamin D deficiency and high-phosphate soft drink consumption.
    Methods: Whole exome sequencing (WES) was used to evaluate the biochemical abnormalities of the proband.
    Results: We identified a previously described homozygous missense mutation c.212C>T, p.T71M in the KCNJ1 gene associated with type 2 BS. Six additional family members with the same mutation and diagnosed clinically with BS are also reported, 2 presenting with hypocalcemia associated with vitamin D deficiency.
    Conclusion: This report expands the clinical spectrum associated with KCNJ1 mutations and emphasizes the role of WES in unsolved cases of hypocalcemia when genetic disease is suspected. It also highlights the hazardous effects of phosphate-containing soft drinks on calcium metabolism.
    MeSH term(s) Alkalosis/complications ; Bartter Syndrome/complications ; Bartter Syndrome/diagnosis ; Bartter Syndrome/genetics ; Child ; Child, Preschool ; Female ; Humans ; Hypercalciuria/diagnosis ; Hypercalciuria/genetics ; Hypocalcemia/etiology ; Hypocalcemia/genetics ; Male ; Phosphates ; Pregnancy ; Vitamin D Deficiency/complications
    Chemical Substances Phosphates
    Language English
    Publishing date 2021-11-09
    Publishing country United States
    Document type Journal Article
    ZDB-ID 3029-6
    ISSN 1945-7197 ; 0021-972X
    ISSN (online) 1945-7197
    ISSN 0021-972X
    DOI 10.1210/clinem/dgab821
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling

    Eman Khatib-Massalha / Suditi Bhattacharya / Hassan Massalha / Adi Biram / Karin Golan / Orit Kollet / Anju Kumari / Francesca Avemaria / Ekaterina Petrovich-Kopitman / Shiri Gur-Cohen / Tomer Itkin / Isabell Brandenburger / Asaf Spiegel / Ziv Shulman / Zachary Gerhart-Hines / Shalev Itzkovitz / Matthias Gunzer / Stefan Offermanns / Ronen Alon /
    Amiram Ariel / Tsvee Lapidot

    Nature Communications, Vol 11, Iss 1, Pp 1-

    2020  Volume 18

    Abstract: Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases ... ...

    Abstract Lactate is a by-product of glycolysis that can function via its G protein receptor GPR81. Here the authors show that LPS or Salmonella infection enhances glycolytic metabolism in bone marrow neutrophils, resulting in lactate production, which increases endothelial barrier permeability and mobilization of these neutrophils by targeting endothelial GPR81.
    Keywords Science ; Q
    Language English
    Publishing date 2020-07-01T00:00:00Z
    Publisher Nature Portfolio
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Lactate released by inflammatory bone marrow neutrophils induces their mobilization via endothelial GPR81 signaling.

    Khatib-Massalha, Eman / Bhattacharya, Suditi / Massalha, Hassan / Biram, Adi / Golan, Karin / Kollet, Orit / Kumari, Anju / Avemaria, Francesca / Petrovich-Kopitman, Ekaterina / Gur-Cohen, Shiri / Itkin, Tomer / Brandenburger, Isabell / Spiegel, Asaf / Shulman, Ziv / Gerhart-Hines, Zachary / Itzkovitz, Shalev / Gunzer, Matthias / Offermanns, Stefan / Alon, Ronen /
    Ariel, Amiram / Lapidot, Tsvee

    Nature communications

    2020  Volume 11, Issue 1, Page(s) 3547

    Abstract: Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to ... ...

    Abstract Neutrophils provide first line of host defense against bacterial infections utilizing glycolysis for their effector functions. How glycolysis and its major byproduct lactate are triggered in bone marrow (BM) neutrophils and their contribution to neutrophil mobilization in acute inflammation is not clear. Here we report that bacterial lipopolysaccharides (LPS) or Salmonella Typhimurium triggers lactate release by increasing glycolysis, NADPH-oxidase-mediated reactive oxygen species and HIF-1α levels in BM neutrophils. Increased release of BM lactate preferentially promotes neutrophil mobilization by reducing endothelial VE-Cadherin expression, increasing BM vascular permeability via endothelial lactate-receptor GPR81 signaling. GPR81
    MeSH term(s) Animals ; Bone Marrow/blood supply ; Bone Marrow Cells/immunology ; Bone Marrow Cells/metabolism ; Disease Models, Animal ; Endothelium, Vascular/metabolism ; Female ; Humans ; Lactic Acid/metabolism ; Lipopolysaccharides/immunology ; Male ; Mice ; Mice, Knockout ; Neutrophils/immunology ; Neutrophils/metabolism ; Receptors, G-Protein-Coupled/genetics ; Receptors, G-Protein-Coupled/metabolism ; Salmonella Infections/immunology ; Salmonella Infections/microbiology ; Salmonella typhimurium/immunology ; Signal Transduction/immunology
    Chemical Substances Hcar1 protein, mouse ; Lipopolysaccharides ; Receptors, G-Protein-Coupled ; Lactic Acid (33X04XA5AT)
    Language English
    Publishing date 2020-07-15
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2553671-0
    ISSN 2041-1723 ; 2041-1723
    ISSN (online) 2041-1723
    ISSN 2041-1723
    DOI 10.1038/s41467-020-17402-2
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  5. Article ; Online: Stem cell regulation via dynamic interactions of the nervous and immune systems with the microenvironment.

    Spiegel, Asaf / Kalinkovich, Alexander / Shivtiel, Shoham / Kollet, Orit / Lapidot, Tsvee

    Cell stem cell

    2008  Volume 3, Issue 5, Page(s) 484–492

    Abstract: Physiological interactions between the nervous and immune systems with components of the local microenvironment are needed to maintain homeostasis throughout the body. Dynamic regulation of bone remodeling, hematopoietic stem cells, and their evolving ... ...

    Abstract Physiological interactions between the nervous and immune systems with components of the local microenvironment are needed to maintain homeostasis throughout the body. Dynamic regulation of bone remodeling, hematopoietic stem cells, and their evolving niches via neurotransmitter signaling are part of the host defense and repair mechanisms. This crosstalk links activated leukocytes, neuronal, and stromal cells, which combine to directly and indirectly regulate hematopoietic stem cells. Together, interactions between diverse systems create a regulatory "brain-bone-blood triad," contributing an additional dimension to the concept of the hematopoietic stem cell niche.
    MeSH term(s) Animals ; Cell Differentiation ; Cell Movement ; Circadian Rhythm/physiology ; Hematopoietic Stem Cell Mobilization ; Hematopoietic Stem Cells/cytology ; Hematopoietic Stem Cells/immunology ; Hematopoietic Stem Cells/metabolism ; Homeostasis/physiology ; Humans ; Neuroimmunomodulation/physiology ; Paracrine Communication/physiology ; Stem Cell Niche/physiology ; Stress, Physiological
    Language English
    Publishing date 2008-11-06
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2375354-7
    ISSN 1875-9777 ; 1934-5909
    ISSN (online) 1875-9777
    ISSN 1934-5909
    DOI 10.1016/j.stem.2008.10.006
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  6. Article ; Online: Blood-forming stem cells are nervous: direct and indirect regulation of immature human CD34+ cells by the nervous system.

    Kalinkovich, Alexander / Spiegel, Asaf / Shivtiel, Shoham / Kollet, Orit / Jordaney, Noela / Piacibello, Wanda / Lapidot, Tsvee

    Brain, behavior, and immunity

    2009  Volume 23, Issue 8, Page(s) 1059–1065

    Abstract: The nervous system regulates immunity through hormonal and neuronal routes as part of host defense and repair mechanism. Here, we review the emerging evidence for regulation of human hematopoietic stem and progenitor cells (HSPC) by the nervous system ... ...

    Abstract The nervous system regulates immunity through hormonal and neuronal routes as part of host defense and repair mechanism. Here, we review the emerging evidence for regulation of human hematopoietic stem and progenitor cells (HSPC) by the nervous system both directly and indirectly via their bone marrow (BM) niche-supporting stromal cells. Functional expression of several neurotransmitter receptors was demonstrated on HSPC, mainly on the more primitive CD34(+)/CD38(-/low) fraction. The myeloid cytokines, G-CSF and GM-CSF, dynamically upregulate neuronal receptor expression on human HSPC. This is followed by an increased response to neurotransmitters, leading to enhanced proliferation and motility of human CD34(+) progenitors, repopulation of the murine BM and their egress to the circulation. Importantly, recent observations showed rapid mobilization of human HSPC to high SDF-1 expressing ischemic tissues of stroke individuals followed by neoangiogenesis, neurological and functional recovery. Along with decreased levels of circulating immature CD34(+) cells and SDF-1 blood levels found in patients with early-stage Alzheimer's disease, these findings suggest a possible involvement of human HSPC in brain homeostasis and thus their potential clinical applications in neuropathology.
    MeSH term(s) Antigens, CD34/metabolism ; Bone Marrow/metabolism ; Hematopoiesis ; Hematopoietic Stem Cells/metabolism ; Humans ; Nervous System/metabolism ; Neurotransmitter Agents/metabolism ; Receptors, Neurotransmitter/metabolism ; Stromal Cells/metabolism
    Chemical Substances Antigens, CD34 ; Neurotransmitter Agents ; Receptors, Neurotransmitter
    Language English
    Publishing date 2009-11
    Publishing country Netherlands
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 639219-2
    ISSN 1090-2139 ; 0889-1591
    ISSN (online) 1090-2139
    ISSN 0889-1591
    DOI 10.1016/j.bbi.2009.03.008
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  7. Article: Mechanisms of long-distance seed dispersal.

    Nathan, Ran / Schurr, Frank M / Spiegel, Orr / Steinitz, Ofer / Trakhtenbrot, Ana / Tsoar, Asaf

    Trends in ecology & evolution

    2008  Volume 23, Issue 11, Page(s) 638–647

    Abstract: Growing recognition of the importance of long-distance dispersal (LDD) of plant seeds for various ecological and evolutionary processes has led to an upsurge of research into the mechanisms underlying LDD. We summarize these findings by formulating six ... ...

    Abstract Growing recognition of the importance of long-distance dispersal (LDD) of plant seeds for various ecological and evolutionary processes has led to an upsurge of research into the mechanisms underlying LDD. We summarize these findings by formulating six generalizations stating that LDD is generally more common in open terrestrial landscapes, and is typically driven by large and migratory animals, extreme meteorological phenomena, ocean currents and human transportation, each transporting a variety of seed morphologies. LDD is often associated with unusual behavior of the standard vector inferred from plant dispersal morphology, or mediated by nonstandard vectors. To advance our understanding of LDD, we advocate a vector-based research approach that identifies the significant LDD vectors and quantifies how environmental conditions modify their actions.
    MeSH term(s) Animal Migration ; Animals ; Biological Evolution ; Ecosystem ; Geography ; Humans ; Models, Biological ; Population Dynamics ; Seeds ; Water Movements ; Wind
    Language English
    Publishing date 2008-11
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 284965-3
    ISSN 1872-8383 ; 0169-5347
    ISSN (online) 1872-8383
    ISSN 0169-5347
    DOI 10.1016/j.tree.2008.08.003
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  8. Article ; Online: IL-1β inflammatory response driven by primary breast cancer prevents metastasis-initiating cell colonization.

    Castaño, Zafira / San Juan, Beatriz P / Spiegel, Asaf / Pant, Ayush / DeCristo, Molly J / Laszewski, Tyler / Ubellacker, Jessalyn M / Janssen, Susanne R / Dongre, Anushka / Reinhardt, Ferenc / Henderson, Ayana / Del Rio, Ana Garcia / Gifford, Ann M / Herbert, Zachary T / Hutchinson, John N / Weinberg, Robert A / Chaffer, Christine L / McAllister, Sandra S

    Nature cell biology

    2018  Volume 20, Issue 9, Page(s) 1084–1097

    Abstract: Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. ...

    Abstract Lack of insight into mechanisms governing breast cancer metastasis has precluded the development of curative therapies. Metastasis-initiating cancer cells (MICs) are uniquely equipped to establish metastases, causing recurrence and therapeutic resistance. Using various metastasis models, we discovered that certain primary tumours elicit a systemic inflammatory response involving interleukin-1β (IL-1β)-expressing innate immune cells that infiltrate distant MIC microenvironments. At the metastatic site, IL-1β maintains MICs in a ZEB1-positive differentiation state, preventing MICs from generating highly proliferative E-cadherin-positive progeny. Thus, when the inherent plasticity of MICs is impeded, overt metastases cannot be established. Ablation of the pro-inflammatory response or inhibition of the IL-1 receptor relieves the differentiation block and results in metastatic colonization. Among patients with lymph node-positive breast cancer, high primary tumour IL-1β expression is associated with better overall survival and distant metastasis-free survival. Our data reveal complex interactions that occur between primary tumours and disseminated MICs that could be exploited to improve patient survival.
    MeSH term(s) Animals ; Anti-Inflammatory Agents/pharmacology ; Antigens, CD/genetics ; Antigens, CD/metabolism ; Breast Neoplasms/drug therapy ; Breast Neoplasms/immunology ; Breast Neoplasms/metabolism ; Breast Neoplasms/pathology ; Cadherins/genetics ; Cadherins/metabolism ; Cell Communication ; Cell Differentiation ; Cell Line, Tumor ; Cell Plasticity ; Cell Proliferation ; Female ; Humans ; Inflammation/immunology ; Inflammation/metabolism ; Inflammation/pathology ; Inflammation/prevention & control ; Interleukin-1beta/genetics ; Interleukin-1beta/metabolism ; Interleukin-1beta/pharmacology ; Lung Neoplasms/immunology ; Lung Neoplasms/metabolism ; Lung Neoplasms/prevention & control ; Lung Neoplasms/secondary ; Lymphatic Metastasis ; Mice, Nude ; Myeloid Cells/drug effects ; Myeloid Cells/immunology ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; Signal Transduction ; Time Factors ; Tumor Microenvironment ; Xenograft Model Antitumor Assays ; Zinc Finger E-box-Binding Homeobox 1/genetics ; Zinc Finger E-box-Binding Homeobox 1/metabolism
    Chemical Substances Anti-Inflammatory Agents ; Antigens, CD ; CDH1 protein, human ; Cadherins ; IL1B protein, human ; IL1B protein, mouse ; Interleukin-1beta ; ZEB1 protein, human ; Zinc Finger E-box-Binding Homeobox 1
    Language English
    Publishing date 2018-08-27
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 1474722-4
    ISSN 1476-4679 ; 1465-7392
    ISSN (online) 1476-4679
    ISSN 1465-7392
    DOI 10.1038/s41556-018-0173-5
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  9. Article ; Online: Neutrophils Suppress Intraluminal NK Cell-Mediated Tumor Cell Clearance and Enhance Extravasation of Disseminated Carcinoma Cells.

    Spiegel, Asaf / Brooks, Mary W / Houshyar, Samin / Reinhardt, Ferenc / Ardolino, Michele / Fessler, Evelyn / Chen, Michelle B / Krall, Jordan A / DeCock, Jasmine / Zervantonakis, Ioannis K / Iannello, Alexandre / Iwamoto, Yoshiko / Cortez-Retamozo, Virna / Kamm, Roger D / Pittet, Mikael J / Raulet, David H / Weinberg, Robert A

    Cancer discovery

    2016  Volume 6, Issue 6, Page(s) 630–649

    Abstract: Unlabelled: Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression ... ...

    Abstract Unlabelled: Immune cells promote the initial metastatic dissemination of carcinoma cells from primary tumors. In contrast to their well-studied functions in the initial stages of metastasis, the specific roles of immunocytes in facilitating progression through the critical later steps of the invasion-metastasis cascade remain poorly understood. Here, we define novel functions of neutrophils in promoting intraluminal survival and extravasation at sites of metastatic dissemination. We show that CD11b(+)/Ly6G(+) neutrophils enhance metastasis formation via two distinct mechanisms. First, neutrophils inhibit natural killer cell function, which leads to a significant increase in the intraluminal survival time of tumor cells. Thereafter, neutrophils operate to facilitate extravasation of tumor cells through the secretion of IL1β and matrix metalloproteinases. These results identify neutrophils as key regulators of intraluminal survival and extravasation through their cross-talk with host cells and disseminating carcinoma cells.
    Significance: This study provides important insights into the systemic contributions of neutrophils to cancer metastasis by identifying how neutrophils facilitate intermediate steps of the invasion-metastasis cascade. We demonstrate that neutrophils suppress natural killer cell activity and increase extravasation of tumor cells. Cancer Discov; 6(6); 630-49. ©2016 AACR.This article is highlighted in the In This Issue feature, p. 561.
    MeSH term(s) Adoptive Transfer ; Animals ; Biomarkers ; Carcinoma/genetics ; Carcinoma/immunology ; Carcinoma/metabolism ; Carcinoma/pathology ; Cell Communication ; Cell Line, Tumor ; Cell Movement ; Cell Survival ; Cytokines/biosynthesis ; Disease Models, Animal ; Endothelial Cells/metabolism ; Heterografts ; Humans ; Immunity, Innate ; Immunophenotyping ; Killer Cells, Natural/immunology ; Killer Cells, Natural/metabolism ; Matrix Metalloproteinases/metabolism ; Mice ; Mice, Knockout ; Neoplasm Invasiveness ; Neoplasm Metastasis ; Neutrophils/immunology ; Neutrophils/metabolism ; Phenotype
    Chemical Substances Biomarkers ; Cytokines ; Matrix Metalloproteinases (EC 3.4.24.-)
    Language English
    Publishing date 2016
    Publishing country United States
    Document type Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
    ZDB-ID 2625242-9
    ISSN 2159-8290 ; 2159-8274
    ISSN (online) 2159-8290
    ISSN 2159-8274
    DOI 10.1158/2159-8290.CD-15-1157
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  10. Article ; Online: Infantile cerebellar-retinal degeneration associated with a mutation in mitochondrial aconitase, ACO2.

    Spiegel, Ronen / Pines, Ophry / Ta-Shma, Asaf / Burak, Efrat / Shaag, Avraham / Halvardson, Jonatan / Edvardson, Shimon / Mahajna, Muhammad / Zenvirt, Shamir / Saada, Ann / Shalev, Stavit / Feuk, Lars / Elpeleg, Orly

    American journal of human genetics

    2012  Volume 90, Issue 3, Page(s) 518–523

    Abstract: Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied ... ...

    Abstract Degeneration of the cerebrum, cerebellum, and retina in infancy is part of the clinical spectrum of lysosomal storage disorders, mitochondrial respiratory chain defects, carbohydrate glycosylation defects, and infantile neuroaxonal dystrophy. We studied eight individuals from two unrelated families who presented at 2-6 months of age with truncal hypotonia and athetosis, seizure disorder, and ophthalmologic abnormalities. Their course was characterized by failure to acquire developmental milestones and culminated in profound psychomotor retardation and progressive visual loss, including optic nerve and retinal atrophy. Despite their debilitating state, the disease was compatible with survival of up to 18 years. Laboratory investigations were normal, but the oxidation of glutamate by muscle mitochondria was slightly reduced. Serial brain MRI displayed progressive, prominent cerebellar atrophy accompanied by thinning of the corpus callosum, dysmyelination, and frontal and temporal cortical atrophy. Homozygosity mapping followed by whole-exome sequencing disclosed a Ser112Arg mutation in ACO2, encoding mitochondrial aconitase, a component of the Krebs cycle. Specific aconitase activity in the individuals' lymphoblasts was severely reduced. Under restrictive conditions, the mutant human ACO2 failed to complement a yeast ACO1 deletion strain, whereas the wild-type human ACO2 succeeded, indicating that this mutation is pathogenic. Thus, a defect in mitochondrial aconitase is associated with an infantile neurodegenerative disorder affecting mainly the cerebellum and retina. In the absence of noninvasive biomarkers, determination of the ACO2 sequence or of aconitase activity in lymphoblasts are warranted in similarly affected individuals, based on clinical and neuroradiologic grounds.
    MeSH term(s) Aconitate Hydratase/genetics ; Adolescent ; Atrophy/enzymology ; Atrophy/genetics ; Cerebellum/abnormalities ; Cerebellum/enzymology ; Child ; Child, Preschool ; Exome ; Exons ; Female ; Genotype ; Glutamic Acid/metabolism ; Heterozygote ; Homozygote ; Humans ; Infant ; Magnetic Resonance Imaging/methods ; Male ; Mitochondria/enzymology ; Mitochondria/genetics ; Mutation ; Neurodegenerative Diseases/enzymology ; Neurodegenerative Diseases/genetics ; Oxidation-Reduction ; Polymorphism, Single Nucleotide ; Retina/abnormalities ; Retina/enzymology
    Chemical Substances Glutamic Acid (3KX376GY7L) ; ACO2 protein, human (EC 4.2.1.3) ; Aconitate Hydratase (EC 4.2.1.3)
    Language English
    Publishing date 2012-03-10
    Publishing country United States
    Document type Journal Article
    ZDB-ID 219384-x
    ISSN 1537-6605 ; 0002-9297
    ISSN (online) 1537-6605
    ISSN 0002-9297
    DOI 10.1016/j.ajhg.2012.01.009
    Database MEDical Literature Analysis and Retrieval System OnLINE

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