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  • 1
    In: Nature, Springer Science and Business Media LLC, Vol. 609, No. 7928 ( 2022-09-22), p. 754-760
    Abstract: Identifying the host genetic factors underlying severe COVID-19 is an emerging challenge 1–5 . Here we conducted a genome-wide association study (GWAS) involving 2,393 cases of COVID-19 in a cohort of Japanese individuals collected during the initial waves of the pandemic, with 3,289 unaffected controls. We identified a variant on chromosome 5 at 5q35 (rs60200309-A), close to the dedicator of cytokinesis 2 gene ( DOCK2 ), which was associated with severe COVID-19 in patients less than 65 years of age. This risk allele was prevalent in East Asian individuals but rare in Europeans, highlighting the value of genome-wide association studies in non-European populations. RNA-sequencing analysis of 473 bulk peripheral blood samples identified decreased expression of DOCK2 associated with the risk allele in these younger patients. DOCK2 expression was suppressed in patients with severe cases of COVID-19. Single-cell RNA-sequencing analysis ( n  = 61 individuals) identified cell-type-specific downregulation of DOCK2 and a COVID-19-specific decreasing effect of the risk allele on DOCK2 expression in non-classical monocytes. Immunohistochemistry of lung specimens from patients with severe COVID-19 pneumonia showed suppressed DOCK2 expression. Moreover, inhibition of DOCK2 function with CPYPP increased the severity of pneumonia in a Syrian hamster model of SARS-CoV-2 infection, characterized by weight loss, lung oedema, enhanced viral loads, impaired macrophage recruitment and dysregulated type I interferon responses. We conclude that DOCK2 has an important role in the host immune response to SARS-CoV-2 infection and the development of severe COVID-19, and could be further explored as a potential biomarker and/or therapeutic target.
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2022
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  • 2
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: The Hayabusa2 spacecraft retrieved surface and subsurface samples from the carbonaceous near-Earth asteroid (162173) Ryugu, which was expected to be enriched in volatile species. The samples were collected from two locations, one undisturbed surface and the other including material excavated by an artificial impact. Unlike meteorites, these samples have experienced minimal alteration by Earth’s atmosphere. Ryugu is thought to have formed from material ejected (by an impact) from a parent body, which had experienced aqueous alteration (reactions with liquid water) ~4.56 billion years (Gyr) ago. Ryugu’s orbit later migrated from the main asteroid belt to become a near-Earth asteroid. RATIONALE Noble gases and nitrogen isotopes in Ryugu grains are inherited from Ryugu’s parent body and potentially provide information about the source of Earth’s volatile elements. Noble gas isotopes can also be used to assess the orbital evolution and recent surface activities of Ryugu. We pelletized ~0.8-mm-diameter Ryugu grains and investigated their mineralogy before carrying out isotope measurements. We measured the concentrations and isotopic compositions of noble gases and nitrogen, extracted by stepped heating, with mass spectrometers. RESULTS The mineralogy of the Ryugu grains is similar to Ivuna-type carbonaceous (CI) chondrite meteorites. Fine-grained hydrous silicates (phyllosilicates), produced through aqueous alteration of primary minerals, compose the major fraction of the samples. This is consistent with infrared spectroscopic observations of the asteroid. Iron oxide, iron sulfides, and carbonates are also found within the matrix. Noble gas isotopes are dominated by primordially trapped gases. Their abundances are mostly similar to the highest found in a CI chondrite, with some grains having several times higher concentrations than the highest CI value. Isotopic compositions and concentrations of nitrogen vary between the Ryugu grains, with divergence from the CI chondrite composition. The nitrogen concentrations in four Ryugu grains are one-half to one-third the CI values, and the 15 N/ 14 N ratio is also lower. The Ryugu grains with compositions farthest from the CI values are similar to the composition of a dehydrated CI chondrite. Only two surface samples, out of the 16 Ryugu grains measured, have clear signs of noble gases derived from solar wind (SW). Their abundances correspond to SW exposure durations of ≳3500 and ≳250 years at the current orbit, whereas most of the grains were exposed for ≳1 to ≳50 years. Cosmic ray–produced 21 Ne concentrations vary, with no systematic difference between the sample collection sites. The estimated cosmic ray exposure (CRE) ages for the surface and subsurface samples are 5.3 ± 0.9 and 5.2 ± 0.8 million years (Myr), assuming irradiations at 2 to 5 g cm −2 and 150 g cm −2 , respectively. This is consistent with the expected surface residence time under near-Earth impact rates. We infer that Ryugu’s orbit migrated from the main asteroid belt to the near-Earth region ~5 Myr ago. About 30% of cosmogenic 21 Ne, corresponding to a CRE age of ~1 Myr, was released in gas-extraction steps at 100°C, indicating that the Ryugu samples have not experienced heating above 100°C within the past 1 Myr. Previous studies have suggested that Ryugu experienced an orbital excursion much closer to the Sun. If this is the case, this excursion must have occurred ≳1 Myr ago. CONCLUSION The mineralogical and noble gas measurements show that the Ryugu samples are similar to CI chondrites. The nitrogen data indicate a heterogeneous distribution of nitrogen-carrying materials with different compositions, one of which has been lost from Ryugu grains to varying degrees. The CRE age of ~5 Myr and the implanted SW are records of the recent irradiation at the current near-Earth orbit of Ryugu. Inferred formation and history of Ryugu. Ryugu’s parent body formed in the early Solar System, incorporating primordial noble gases and nitrogen, followed by aqueous alteration ~4.56 Gyr ago. Ryugu formed from the accumulation of fragments of the parent body ejected by an impact, at an unknown date. Ryugu migrated to its current near-Earth orbit ~5 Myr ago. Ryugu might have experienced another change in orbit, bringing it closer to the Sun (“Path A”), or remained in the same near-Earth orbit (“Path B”).
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 3
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: Organic compounds in asteroids and comets contain information about the early history of the Solar System. They could also have delivered organic material to early Earth. The Hayabusa2 spacecraft visited the carbonaceous asteroid Ryugu and collected samples of its surface materials, which were brought to Earth in December 2020. RATIONALE We investigated the macromolecular organic matter in the Ryugu samples, measuring its elemental, isotopic, and functional group compositions along with its small-scale structures and morphologies. Analytical methods used included spectro-microscopies, electron microscopy, and isotopic microscopy. We examined intact Ryugu grains and insoluble carbonaceous residues isolated by acid treatment of the Ryugu samples. RESULTS Organic matter is abundant in the Ryugu grains, distributed as submicrometer-sized organic grains and as organic matter dispersed in matrix. The Ryugu organic matter consists of aromatic carbons, aliphatic carbons, ketones, and carboxyls. The functional group compositions are consistent with those of insoluble organic matter (IOM) from primitive carbonaceous CI (Ivuna-type) and CM (Mighei-type) chondritic meteorites. Those meteorites experienced aqueous alteration (reactions with liquid water) on their parent bodies, which implies that the Ryugu organic material was also modified by aqueous alteration on the asteroid parent body. The functional group distributions of the Ryugu organic matter vary on submicrometer scales in ways that relate to the morphologies: nanoparticulate and/or nanoglobular regions are aromatic-rich, whereas organic matter associated with Mg-rich phyllosilicate matrix and carbonates is IOM-like or occurs as diffuse carbon. The observed macromolecular diversity provides further evidence that the organics were modified by aqueous alteration on Ryugu’s parent body. The diffuse carbon is similar to clay-bound organic matter that occurs in CI chondrites and the ungrouped C2-type meteorite Tagish Lake. No graphite-like material was found, which indicates that the Ryugu organic matter was not subjected to heating events on the parent body. The bulk hydrogen and nitrogen isotopic ratios of the Ryugu grains are between the bulk values of CI chondrites and the IOM in CI chondrites. Some carbonaceous grains showed extreme deuterium (D) and/or nitrogen-15 ( 15 N) enrichments or depletions. These indicate an origin in the interstellar medium or presolar nebula. The bulk hydrogen isotopic ratios of insoluble carbonaceous residues from the Ryugu samples are lower than those in CI and CM chondrites. The range of D enrichments are consistent with the ranges of CI, CM, and Tagish Lake chondrites. The nitrogen isotopic ratios of the IOM from Ryugu samples were close to those in CI chondrites. CONCLUSION The organic matter in Ryugu probably consists of primordial materials that formed during (or before) the early stages of the Solar System’s formation, which were later modified by heterogeneous aqueous alteration on Ryugu’s parent body asteroid. Although the surface of Ryugu is exposed to solar wind, impacts, and heating by sunlight, the macromolecular organics in the surface grains of Ryugu are similar in their chemical, isotopic, and morphological compositions to those seen in primitive carbonaceous chondrites. The properties of Ryugu’s organic matter could explain the low albedo of the asteroid’s surface. Chemical evolution of macromolecular organic matter in samples of asteroid Ryugu. Organic matter formed in the interstellar medium or in the outer region of the protoplanetary disk that formed the Solar System. It was then incorporated into a planetesimal—Ryugu’s parent body—where it experienced varying degrees of reactions with liquid water. An impact ejected material from the parent body, which reassembled to form Ryugu. Samples were brought to Earth by Hayabusa2. CREDIT: HIROSHIMA UNIVERSITY, JAXA, UNIVERSITY OF TOKYO, KOCHI UNIVERSITY, RIKKYO UNIVERSITY, NAGOYA UNIVERSITY, CHIBA INSTITUTE OF TECHNOLOGY, MEIJI UNIVERSITY, UNIVERSITY OF AIZU, AIST
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 4
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: The Hayabusa2 spacecraft made two landings on the asteroid (162173) Ryugu in 2019, during which it collected samples of the surface material. Those samples were delivered to Earth in December 2020. The colors, shapes, and morphologies of the returned samples are consistent with those observed on Ryugu by Hayabusa2, indicating that they are representative of the asteroid. Laboratory analysis of the samples can determine the chemical composition of Ryugu and provide information on its formation and history. RATIONALE We used laboratory analysis to inform the following questions: (i) What are the elemental abundances of Ryugu? (ii) What are the isotopic compositions of Ryugu? (iii) Does Ryugu consist of primary materials produced in the disk from which the Solar System formed or of secondary materials produced in the asteroid or on a parent asteroid? (iv) When were Ryugu’s constituent materials formed? (v) What, if any, relationship does Ryugu have with meteorites? RESULTS We quantified the abundances of 66 elements in the Ryugu samples: H, Li, Be, C, O, Na, Mg, Al, Si, P, S, Cl, K, Ca, Sc, Ti, V, Cr, Mn, Fe, Co, Ni, Cu, Zn, Ga, Ge, As, Se, Rb, Sr, Y, Zr, Nb, Mo, Ru, Rh, Pd, Ag, Cd, In, Sn, Te, Cs, Ba, La, Ce, Pr, Nd, Sm, Eu, Gd, Tb, Dy, Ho, Er, Tm, Yb, Lu, Hf, Ta, W, Tl, Pb, Bi, Th, and U. There is a slight variation in chemical compositions between samples from the first and second touchdown sites, but the variations could be due to heterogeneity among the samples that were analyzed. The Cr-Ti isotopes and abundance of volatile elements are similar to those of carbonaceous meteorites in the CI (Ivuna-like) chondrite group. The Ryugu samples consist of the minerals magnetite, breunnerite, dolomite, and pyrrhotite as grains embedded in a matrix composed of serpentine and saponite. This mineral assemblage and the texture are also similar to those of CI meteorites. Anhydrous silicates are almost absent, which indicates extensive liquid water–rock reactions (aqueous alteration) in the material. We conclude that the samples mainly consist of secondary materials that were formed by aqueous alteration in a parent body, from which Ryugu later formed. The oxygen isotopes in the bulk Ryugu samples are also similar to those in CI chondrites. We used oxygen isotope thermometry to determine the temperature at which the dolomite and magnetite precipitated from an aqueous solution, which we found to be 37° ± 10°C. The 53 Mn- 53 Cr isotopes date the aqueous alteration at 5.2 − 0.7 + 0.8 million (statistical) or 5.2 − 2.1 + 1.6 million (systematic) years after the birth of the Solar System. Phyllosilicate minerals are the main host of water in the Ryugu samples. The amount of structural water in Ryugu is similar to that in CI chondrites, but interlayer water is largely absent in Ryugu, which suggests a loss of interlayer water to space. The abundance of structural water and results from dehydration experiments indicate that the Ryugu samples remained below ~100°C from the time of aqueous alteration until the present. We ascribe the removal of interlayer water to a combination of impact heating, solar heating, solar wind irradiation, and long-term exposure to the ultrahigh vacuum of space. The loss of interlayer water from phyllosilicates could be responsible for the comet-like activity of some carbonaceous asteroids and the ejection of solid material from the surface of asteroid Bennu. CONCLUSION The Ryugu samples are most similar to CI chondrite meteorites but are more chemically pristine. The chemical composition of the Ryugu samples is a closer match to the Sun’s photosphere than to the composition of any other natural samples studied in laboratories. CI chondrites appear to have been modified on Earth or during atmospheric entry. Such modification of CI chondrites could have included the alteration of the structures of organics and phyllosilicates, the adsorption of terrestrial water, and the formation of sulfates and ferrihydrites. Those issues do not affect the Ryugu samples. Those modifications might have changed the albedo, porosity, and density of the CI chondrites, causing the observed differences between CI meteorites, Hayabusa2 measurements of Ryugu’s surface, and the Ryugu samples returned to Earth. Representative petrography of a Ryugu sample, designated C0002-C1001. Colors indicate elemental abundances determined from x-ray spectroscopy. Lines of iron, sulfur, and calcium are shown as red, green, and blue (RGB) color channels in that order. Combinations of these elements are assigned to specific minerals, as indicated in the legend. All visible minerals were formed by aqueous alteration on Ryugu’s parent body.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 5
    In: Science, American Association for the Advancement of Science (AAAS), Vol. 379, No. 6634 ( 2023-02-24)
    Abstract: Surface material from the near-Earth carbonaceous (C-type) asteroid (162173) Ryugu was collected and brought to Earth by the Hayabusa2 spacecraft. Ryugu is a dark, primitive asteroid containing hydrous minerals that are similar to the most hydrated carbonaceous meteorites. C-type asteroids are common in the asteroid belt and have been proposed as the parent bodies of carbonaceous meteorites. The samples of Ryugu provide an opportunity to investigate organic compounds for comparison with those from carbonaceous meteorites. Unlike meteorites, the Ryugu samples were collected and delivered for study under controlled conditions, reducing terrestrial contamination and the effects of atmospheric entry. RATIONALE Primitive carbonaceous chondrite meteorites are known to contain a variety of soluble organic molecules (SOMs), including prebiotic molecules such as amino acids. Meteorites might have delivered amino acids and other prebiotic organic molecules to the early Earth and other rocky planets. Organic matter in the Ryugu samples is the product of physical and chemical processes that occurred in the interstellar medium, the protosolar nebula, and/or on the planetesimal that became Ryugu’s parent body. We investigated SOMs in Ryugu samples principally using mass spectrometry coupled with liquid or gas chromatography. RESULTS We identified numerous organic molecules in the Ryugu samples. Mass spectroscopy detected hundreds of thousands of ion signals, which we assigned to ~20,000 elementary compositions consisting of carbon, hydrogen, nitrogen, oxygen, and/or sulfur. Fifteen amino acids, including glycine, alanine, and α-aminobutyric acid, were identified. These were present as racemic mixtures (equal right- and left-handed abundances), consistent with an abiotic origin. Aliphatic amines (such as methylamine) and carboxylic acids (such as acetic acid) were also detected, likely retained on Ryugu as organic salts. The presence of aromatic hydrocarbons, including alkylbenzenes, fluoranthene, and pyrene, implies hydrothermal processing on Ryugu’s parent body and/or presolar synthesis in the interstellar medium. Nitrogen-containing heterocyclic compounds were identified as their alkylated homologs, which could have been synthesized from simple aldehydes and ammonia. In situ analysis of a grain surface showed heterogeneous spatial distribution of alkylated homologs of nitrogen- and/or oxygen-containing compounds. CONCLUSION The wide variety of molecules identified indicates that prolonged chemical processes contributed to the synthesis of soluble organics on Ryugu or its parent body. The highly diverse mixture of SOMs in the samples resembles that seen in some carbonaceous chondrites. However, the SOM concentration in Ryugu is less than that in moderately aqueously altered CM (Mighei-type) chondrites, being more similar to that seen in warm aqueously altered CI (Ivuna-type) chondrites. The chemical diversity with low SOM concentration in Ryugu is consistent with aqueous organic chemistry at modest temperatures on Ryugu’s parent asteroid. The samples collected from the surface of Ryugu were exposed to the hard vacuum of space, energetic particle irradiation, heating by sunlight, and micrometeoroid impacts, but the SOM is still preserved, likely by being associated with minerals. The presence of prebiotic molecules on the asteroid surface suggests that these molecules can be transported throughout the Solar System. SOMs detected in surface samples of asteroid Ryugu. Chemical structural models are shown for example molecules from several classes identified in the Ryugu samples. Gray balls are carbon, white are hydrogen, red are oxygen, and blue are nitrogen. Clockwise from top: amines (represented by ethylamine), nitrogen-containing heterocycles (pyridine), a photograph of the sample vials for analysis, polycyclic aromatic hydrocarbons (PAHs) (pyrene), carboxylic acids (acetic acid), and amino acids (β-alanine). The central hexagon shows a photograph of the Ryugu sample in the sample collector of the Hayabusa2 spacecraft. The background image shows Ryugu in a photograph taken by Hayabusa2. CREDIT: JAXA, University of Tokyo, Kochi University, Rikkyo University, Nagoya University, Chiba Institute of Technology, Meiji University, University of Aizu, AIST, NASA, Dan Gallagher.
    Type of Medium: Online Resource
    ISSN: 0036-8075 , 1095-9203
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    Language: English
    Publisher: American Association for the Advancement of Science (AAAS)
    Publication Date: 2023
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  • 6
    In: Nature, Springer Science and Business Media LLC, Vol. 595, No. 7868 ( 2021-07-22), p. 511-515
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2021
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  • 7
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 107, No. 28 ( 2010-07-13), p. 12704-12709
    Abstract: Various types of induced pluripotent stem (iPS) cells have been established by different methods, and each type exhibits different biological properties. Before iPS cell-based clinical applications can be initiated, detailed evaluations of the cells, including their differentiation potentials and tumorigenic activities in different contexts, should be investigated to establish their safety and effectiveness for cell transplantation therapies. Here we show the directed neural differentiation of murine iPS cells and examine their therapeutic potential in a mouse spinal cord injury (SCI) model. “Safe” iPS-derived neurospheres, which had been pre-evaluated as nontumorigenic by their transplantation into nonobese diabetic/severe combined immunodeficiency (NOD/SCID) mouse brain, produced electrophysiologically functional neurons, astrocytes, and oligodendrocytes in vitro. Furthermore, when the safe iPS-derived neurospheres were transplanted into the spinal cord 9 d after contusive injury, they differentiated into all three neural lineages without forming teratomas or other tumors. They also participated in remyelination and induced the axonal regrowth of host 5HT + serotonergic fibers, promoting locomotor function recovery. However, the transplantation of iPS-derived neurospheres pre-evaluated as “unsafe” showed robust teratoma formation and sudden locomotor functional loss after functional recovery in the SCI model. These findings suggest that pre-evaluated safe iPS clone-derived neural stem/progenitor cells may be a promising cell source for transplantation therapy for SCI.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2010
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  • 8
    In: Proceedings of the National Academy of Sciences, Proceedings of the National Academy of Sciences, Vol. 105, No. 35 ( 2008-09-02), p. 12921-12926
    Abstract: Membrane fusion is an essential step in the encounter of two nuclei from sex cells—sperm and egg—in fertilization. However, aside from the involvement of two molecules, CD9 and Izumo, the mechanism of fusion remains unclear. Here, we show that sperm–egg fusion is mediated by vesicles containing CD9 that are released from the egg and interact with sperm. We demonstrate that the CD9 −/− eggs, which have a defective sperm-fusing ability, have impaired release of CD9-containing vesicles. We investigate the fusion-facilitating activity of CD9-containing vesicles by examining the fusion of sperm to CD9 −/− eggs with the aid of exogenous CD9-containing vesicles. Moreover, we show, by examining the fusion of sperm to CD9 −/− eggs, that hamster eggs have a similar fusing ability as mouse eggs. The CD9-containing vesicle release from unfertilized eggs provides insight into the mechanism required for fusion with sperm.
    Type of Medium: Online Resource
    ISSN: 0027-8424 , 1091-6490
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    Language: English
    Publisher: Proceedings of the National Academy of Sciences
    Publication Date: 2008
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  • 9
    In: Nature, Springer Science and Business Media LLC, Vol. 460, No. 7258 ( 2009-8), p. 1021-1025
    Type of Medium: Online Resource
    ISSN: 0028-0836 , 1476-4687
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    Language: English
    Publisher: Springer Science and Business Media LLC
    Publication Date: 2009
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  • 10
    In: Annals of the New York Academy of Sciences, Wiley, Vol. 1010, No. 1 ( 2003-12), p. 481-485
    Abstract: A bstract : The mechanism underlying space flight‐induced osteopenia is unknown. In osteoblasts, the inducible nitric oxide (NO) synthase (iNOS) is involved in the early response to mechanical strain and induction of apoptosis. GTP cyclohydrolase I (GTPCH) is a key enzyme that is essential for iNOS activity. The coordinate expression of GTPCH prevents apoptosis that is induced by iNOS/NO. The purpose of this study was to investigate the effects of space flight on the expression of apoptotic/anti‐apoptotic molecules iNOS and GTPCH in rat osteoblasts. Rat osteoblasts were cultured aboard a space shuttle and solubilized on the 4th and 5th days of the mission. The mRNA levels for iNOS and GTPCH in the flight cultures were increased to at least 120‐fold and threefold higher than the ground (1 × g) controls, respectively. The amount of cellular DNA per flight culture vessel was 53% and 58% of the ground controls on the 4th and 5th days, respectively. However, the increasing rate of the DNA amount from the 4th to the 5th day was not different between the flight cultures and the ground controls. Morphologically, the cells grew in space as well as on the ground. Co‐expression of GTPCH and iNOS may indicate a self‐protective mode of action in osteoblasts against the harmful stress under microgravity.
    Type of Medium: Online Resource
    ISSN: 0077-8923 , 1749-6632
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    Language: English
    Publisher: Wiley
    Publication Date: 2003
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