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  • Aerospace Medicine  (173)
  • Cell Line  (173)
  • 2005-2009  (346)
  • 2009  (346)
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  • 2005-2009  (346)
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  • 1
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    A Biomechanical Approach to Assessing Hip Fracture Risk (2009)
    In:  Other Sources
    Details
    Publication Date: 2019-07-19
    Description: Bone loss in microgravity is well documented, but it is difficult to quantify how declines in bone mineral density (BMD) contribute to an astronaut's overall risk of fracture upon return. This study uses a biomechanical approach to assessing hip fracture risk, or Factor of Risk (Phi), which is defined as the ratio of applied load to bone strength. All long-duration NASA astronauts from Expeditions 1-18 were included in this study (n=25), while crewmembers who flew twice (n=2) were treated as separate subjects. Bone strength was estimated based on an empirical relationship between areal BMD at the hip, as measured by DXA, and failure load, as determined by mechanical testing of cadaver femora. Fall load during a sideways fall was calculated from a previously developed biomechanical model, which takes into account body weight, height, gender, and soft tissue thickness overlying the lateral aspect of the hip that serves to attenuate the impact force. While no statistical analyses have been performed yet, preliminary results show that males in this population have a higher FOR than females, with a post- flight Phi of 0.87 and 0.36, respectively. FOR increases 5.1% from preflight to postflight, while only one subject crossed the fracture "threshold" of Phi = 1, for a total of 2 subjects with a postflight Phi 〉 1. These results suggest that men may be at greater risk for hip fracture due largely in part to their relatively thin soft tissue padding as compared to women, since soft tissue thickness has the highest correlation (R(exp 2)= .53) with FOR of all subject-specific parameters. Future work will investigate changes in FOR during recovery to see if baseline risk levels are restored upon return to 1-g activity. While dual x-ray absorptiometry (DXA) is the most commonly used clinical measure of bone health, it fails to provide compartment-specific information that is useful in assessing changes to bone quality as a result of microgravity exposure. Peripheral quantitative computed tomography (pQCT) accomplishes this by imaging transverse "slices" of the long bones. This project was a re-analysis of a 90 day bed rest study to determine if changes to cortical and trabecular compartments could be detected in the distal tibia with statistical significance using a new pQCT image analysis method. Nearly all changes in bone mineral density (BMD) and cross sectional area (CSA) measures were seen with statistical significance, with the exception of a change in cortical BMD. Total bone CSA increased by 1.1 % (p =0.01), cortical CSA decreased by - 5.6% (p〈0.001) and trabecular CSA increased by 1.76% (p=0.007); the combination of which suggests bone resorption occurred at the endocortical surface in response to mechanical unloading by bed rest. Furthermore, total BMD and trabecular BMD decreased (-3.8%, p=0.001 and -2.8%, p =0.007, respectively), while decreases in cortical BMD failed to reach significance (-1.2%, p=0.07). Given that compartment-specific changes are seen with significance and are likely to influence bone strength, it is recommended that pQCT remain a standard measure used in bed rest because it provides a unique measure by which to better evaluate the efficacy of countermeasures to microgravity-induced bone loss.
    Keywords: Aerospace Medicine
    Type: JSC-CN-18725 , SK Student Presentations; Aug 12, 2009; Houston, TX; United States
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  • 2
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    A Cell Kinetic Model of Granulocytopoiesis Under Radiation Exposure: Extension from Murines to Canines and Humans (2009)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: Space radiation poses significant challenges to space travel, and it is essential to understand the possible adverse effects from space radiation exposure to the radiosensitive organ systems that are important for immediate survival of human, e.g., the hematopoietic system. In this presentation a biomathematical model of granulocytopoiesis is described and used to analyze the blood granulocyte changes seen in the blood of mammalians under continuous and acute radiation exposure. This is one of a set of hematopoietic models that have been successfully utilized to simulate and interpret the experimental data of acute and chronic radiation on rodents. We discuss the underlying implicit regulation mechanism and the biological relevance of the kinetic parameters estimation method. Extension of the model to predictions in dogs and humans systems indicates that the modeling results are consistent with the cumulative experimental and empirical data from various sources. This implies the potential to integrate the models into one united system for monitoring the hematopoietic response of various species under irradiation. Based on the evidence of threshold responses of dogs to extended periods of low daily dose exposures, we discuss the potential health risks of the space traveler under chronic stress of low-dose irradiation and the possibly encountered Solar Particle Events.
    Keywords: Aerospace Medicine
    Type: JSC-CN-19109 , 15th International Symposium on Microdosimetry (MICROS 2009); Oct 25, 2009 - Oct 30, 2009; Verona; Italy
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  • 3
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    A Comprehensive Characterization of Microorganisms and Allergens in Spacecraft Environment (2009)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: The determination of risk from infectious disease during long-duration missions is composed of several factors including the concentration and the characteristics of the infectious agent. Thus, a thorough knowledge of the microorganisms aboard spacecraft is essential in mitigating infectious disease risk to the crew. While stringent steps are taken to minimize the transfer of potential pathogens to spacecraft, several medically significant organisms have been isolated from both the Mir and International Space Station (ISS). Historically, the method for isolation and identification of microorganisms from spacecraft environmental samples depended upon their growth on culture media. Unfortunately, only a fraction of the organisms may grow on a culture medium, potentially omitting those microorganisms whose nutritional and physical requirements for growth are not met. Thus, several pathogens may not have been detected, such as Legionella pneumophila, the etiological agent of Legionnaire s disease. We hypothesize that environmental analysis using non-culture-based technologies will reveal microorganisms, allergens, and microbial toxins not previously reported in spacecraft, allowing for a more complete health assessment. The development of techniques for this flight experiment, operationally named SWAB, has already provided advances in NASA laboratory processes and beneficial information toward human health risk assessment. The translation of 16S ribosomal DNA sequencing for the identification of bacteria from the SWAB experiment to nominal operations has increased bacterial speciation of environmental isolates from previous flights three fold compared to previous conventional methodology. The incorporation of molecular-based DNA fingerprinting using repetitive sequence-based polymerase chain reaction (rep-PCR) into the capabilities of the laboratory has provided a methodology to track microorganisms between crewmembers and their environment. Both 16S ribosomal DNA identification and bacterial fingerprinting have improved NASA s capability to better understand spacecraft environments and determine the source of contamination events. Preflight sampling has been completed for air, surface, and water samples. In-flight sample collection has been completed for a total of 8 air and surface sample collection sessions. In-flight hardware has performed well and the surface sampling device received positive feedback from the crew for its ease of use. While processing and analysis continue for these samples, early results have begun to provide information on the spacecraft environment. Using a method called Denaturing Gradient Gel Electrophoresis (DGGE), several air and samples were evaluated to determine the types of organisms that were present. Using only molecular techniques, DGGE does not depend on any microbial growth on culture media, allowing a more comprehensive assessment of the spacecraft interior. Preliminary results have identified several microorganisms that would not have been isolated using current technology, though none of these organisms would be considered medically significant. Interestingly, the isolation of Gram negative organisms is greater using DGGE than conventional media based isolation. The cause of this finding is unclear, though it may be the result of the technique s ability to isolate both viable and non-viable bacteria. The next phase of the SWAB sample analysis is the use of quantitative polymerase chain reaction (QPCR) to look for specific medically significant organisms. While not as broad as DGGE, QPCR is much more sensitive and may reveal findings that were not seen during the initial evaluation. Together, this information will lead toward an accurate microbial risk assessment to help set flight requirements to protect the safety, health, and performance of the crew.
    Keywords: Aerospace Medicine
    Type: JSC-17776 , Human Research Program Investigators Workshop; Feb 02, 2009 - Feb 04, 2009; Texas; United States
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  • 4
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    A dimerization-dependent mechanism drives RAF catalytic activation (2009)
    Nature Publishing Group (NPG)
    Details
    Publication Date: 2009-09-04
    Description: The ERK (extracellular signal-regulated kinase) pathway is an evolutionarily conserved signal transduction module that controls cellular growth, differentiation and survival. Activation of receptor tyrosine kinases (RTKs) by the binding of growth factors initiates GTP loading of RAS, which triggers the initial steps in the activation of the ERK pathway by modulating RAF family kinase function. Once activated, RAF participates in a sequential cascade of phosphorylation events that activate MEK, and in turn ERK. Unbridled signalling through the ERK pathway caused by activating mutations in RTKs, RAS or RAF has been linked to several human cancers. Of note, one member of the RAF family, BRAF, is the most frequently mutated oncogene in the kinase superfamily. Not surprisingly, there has been a colossal effort to understand the underlying regulation of this family of kinases. In particular, the process by which the RAF kinase domain becomes activated towards its substrate MEK remains of topical interest. Here, using Drosophila Schneider S2 cells, we demonstrate that RAF catalytic function is regulated in response to a specific mode of dimerization of its kinase domain, which we term the side-to-side dimer. Moreover, we find that the RAF-related pseudo-kinase KSR (kinase suppressor of Ras) also participates in forming side-to-side heterodimers with RAF and can thereby trigger RAF activation. This mechanism provides an elegant explanation for the longstanding conundrum about RAF catalytic activation, and also provides an explanation for the capacity of KSR, despite lacking catalytic function, to directly mediate RAF activation. We also show that RAF side-to-side dimer formation is essential for aberrant signalling by oncogenic BRAF mutants, and identify an oncogenic mutation that acts specifically by promoting side-to-side dimerization. Together, our data identify the side-to-side dimer interface of RAF as a potential therapeutic target for intervention in BRAF-dependent tumorigenesis.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Rajakulendran, Thanashan -- Sahmi, Malha -- Lefrancois, Martin -- Sicheri, Frank -- Therrien, Marc -- England -- Nature. 2009 Sep 24;461(7263):542-5. doi: 10.1038/nature08314. Epub 2009 Sep 2.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Centre for Systems Biology, Samuel Lunenfeld Research Institute, Toronto, Ontario M5G 1X5, Canada.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19727074" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Binding Sites ; Biocatalysis ; Cell Line ; Drosophila Proteins/*chemistry/genetics/*metabolism ; Drosophila melanogaster/*enzymology ; Enzyme Activation ; Humans ; Models, Molecular ; Protein Kinases/chemistry/metabolism ; *Protein Multimerization ; Protein Structure, Quaternary ; Protein Structure, Tertiary ; Proto-Oncogene Proteins B-raf/chemistry/genetics/metabolism ; Proto-Oncogene Proteins c-raf/*chemistry/genetics/*metabolism ; Structure-Activity Relationship
    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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  • 5
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    A genetically encoded photoactivatable Rac controls the motility of living cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-08-21
    Description: The precise spatio-temporal dynamics of protein activity are often critical in determining cell behaviour, yet for most proteins they remain poorly understood; it remains difficult to manipulate protein activity at precise times and places within living cells. Protein activity has been controlled by light, through protein derivatization with photocleavable moieties or using photoreactive small-molecule ligands. However, this requires use of toxic ultraviolet wavelengths, activation is irreversible, and/or cell loading is accomplished via disruption of the cell membrane (for example, through microinjection). Here we have developed a new approach to produce genetically encoded photoactivatable derivatives of Rac1, a key GTPase regulating actin cytoskeletal dynamics in metazoan cells. Rac1 mutants were fused to the photoreactive LOV (light oxygen voltage) domain from phototropin, sterically blocking Rac1 interactions until irradiation unwound a helix linking LOV to Rac1. Photoactivatable Rac1 (PA-Rac1) could be reversibly and repeatedly activated using 458- or 473-nm light to generate precisely localized cell protrusions and ruffling. Localized Rac activation or inactivation was sufficient to produce cell motility and control the direction of cell movement. Myosin was involved in Rac control of directionality but not in Rac-induced protrusion, whereas PAK was required for Rac-induced protrusion. PA-Rac1 was used to elucidate Rac regulation of RhoA in cell motility. Rac and Rho coordinate cytoskeletal behaviours with seconds and submicrometre precision. Their mutual regulation remains controversial, with data indicating that Rac inhibits and/or activates Rho. Rac was shown to inhibit RhoA in mouse embryonic fibroblasts, with inhibition modulated at protrusions and ruffles. A PA-Rac crystal structure and modelling revealed LOV-Rac interactions that will facilitate extension of this photoactivation approach to other proteins.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2766670/" 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/PMC2766670/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wu, Yi I -- Frey, Daniel -- Lungu, Oana I -- Jaehrig, Angelika -- Schlichting, Ilme -- Kuhlman, Brian -- Hahn, Klaus M -- GM057464/GM/NIGMS NIH HHS/ -- GM64346/GM/NIGMS NIH HHS/ -- R01 GM057464/GM/NIGMS NIH HHS/ -- R01 GM057464-09/GM/NIGMS NIH HHS/ -- U54 GM064346/GM/NIGMS NIH HHS/ -- U54 GM064346-089026/GM/NIGMS NIH HHS/ -- England -- Nature. 2009 Sep 3;461(7260):104-8. doi: 10.1038/nature08241. Epub 2009 Aug 19.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Pharmacology, University of North Carolina, Chapel Hill, North Carolina 27599, USA. yiwu@med.unc.edu〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19693014" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Avena/genetics ; Cell Line ; *Cell Movement/radiation effects ; Cell Surface Extensions ; Cell Survival ; Cryptochromes ; Crystallization ; Crystallography, X-Ray ; Embryo, Mammalian/cytology ; Enzyme Activation/radiation effects ; Fibroblasts ; Flavoproteins/chemistry/genetics/metabolism ; Fluorescence Recovery After Photobleaching ; Genetic Engineering/*methods ; HeLa Cells ; Humans ; Mice ; Models, Molecular ; Myosins/metabolism ; Protein Conformation ; rac1 GTP-Binding Protein/chemistry/*genetics/*metabolism/radiation effects ; rho GTP-Binding Proteins/antagonists & inhibitors/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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  • 6
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    A History of Space Toxicology Mishaps: Lessons Learned and Risk Management (2009)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: After several decades of human spaceflight, the community of space-faring nations has accumulated a diverse and sometimes harrowing history of toxicological events that have plagued human space endeavors almost from the very beginning. Lessons have been learned in ground-based test beds and others were discovered the hard way - when human lives were at stake in space. From such lessons one can build a risk-management framework for toxicological events to minimize the probability of a harmful exposure, while recognizing that we cannot foresee all events. Space toxicologists have learned that relatively harmless compounds can be converted by air revitalization systems into compounds that cause serious harm to the crew. Our toxic risk management strategy now includes an assessment of the fate of any compound that might be released into the atmosphere. Propellants are highly toxic compounds, yet we have not always been able to thoroughly isolate the crew from exposure to these toxicants. Leakage of fluids from systems has resulted in hazardous conditions at times, and the behavior of such compounds inside a spacecraft has taught us how to manage potentially harmful escapes should they occur. Potential combustion events are an ever-present threat to the wellbeing of the crew. Such events have been sufficiently common that we have learned that one cannot judge the health threat of a given fire by the magnitude of the event. Management of such risks demands monitoring of combustion products. In the category of unpredictable toxic events, if one assumes that fires are predictable, we can place experience with toxic microbial metabolites, upsets during repair operations, and discharges from filters that have accumulated a substantial load of pollutants in their absorption beds. Management of such events requires a broad-spectrum, real-time analytical capability to discern the identity and concentrations of pollutants if they enter the atmosphere. Adverse events are an integral part of any human activity, and the spacefaring community must learn as much as possible from mistakes and near misses.
    Keywords: Aerospace Medicine
    Type: ICES Meeting; Jul 13, 2009 - Jul 16, 2009; Savannah, GA; United States
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  • 7
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    A mechanosensitive transcriptional mechanism that controls angiogenesis (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-02-27
    Description: Angiogenesis is controlled by physical interactions between cells and extracellular matrix as well as soluble angiogenic factors, such as VEGF. However, the mechanism by which mechanical signals integrate with other microenvironmental cues to regulate neovascularization remains unknown. Here we show that the Rho inhibitor, p190RhoGAP (also known as GRLF1), controls capillary network formation in vitro in human microvascular endothelial cells and retinal angiogenesis in vivo by modulating the balance of activities between two antagonistic transcription factors, TFII-I (also known as GTF2I) and GATA2, that govern gene expression of the VEGF receptor VEGFR2 (also known as KDR). Moreover, this new angiogenesis signalling pathway is sensitive to extracellular matrix elasticity as well as soluble VEGF. This is, to our knowledge, the first known functional cross-antagonism between transcription factors that controls tissue morphogenesis, and that responds to both mechanical and chemical cues.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2708674/" 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/PMC2708674/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Mammoto, Akiko -- Connor, Kip M -- Mammoto, Tadanori -- Yung, Chong Wing -- Huh, Dongeun -- Aderman, Christopher M -- Mostoslavsky, Gustavo -- Smith, Lois E H -- Ingber, Donald E -- P01 CA045548/CA/NCI NIH HHS/ -- P01 CA045548-22/CA/NCI NIH HHS/ -- England -- Nature. 2009 Feb 26;457(7233):1103-8. doi: 10.1038/nature07765.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Vascular Biology Program, Department of Pathology & Surgery, Children's Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19242469" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Animals, Newborn ; Cell Line ; Endothelial Cells/metabolism ; Endothelium, Vascular/cytology/growth & development ; Extracellular Matrix/metabolism ; GATA2 Transcription Factor/metabolism ; Gene Knockdown Techniques ; Guanine Nucleotide Exchange Factors/deficiency/genetics/metabolism ; Humans ; Mice ; Mice, Inbred C57BL ; Neovascularization, Physiologic/*genetics/physiology ; Repressor Proteins/genetics/metabolism ; Retinal Vessels/growth & development/metabolism ; Signal Transduction ; Transcription Factors/deficiency/genetics/*metabolism ; Transcription Factors, TFII/metabolism ; *Transcription, Genetic ; Up-Regulation ; Vascular Endothelial Growth Factor A/metabolism ; Vascular Endothelial Growth Factor Receptor-2/biosynthesis/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 8
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    A New Approach to Defining Human Touch Temperature Standards (2009)
    In:  Other Sources
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    Publication Date: 2019-07-19
    Description: Defining touch temperature limits for skin contact with both hot and cold objects is important to prevent pain and skin damage, which may affect task performance or become a safety concern. Pain and skin damage depend on the resulting skin temperature during contact, which depends on the object s initial temperature, its material properties and its ability to transfer heat. However, previous spacecraft standards have incorrectly defined touch temperature limits in terms of a single object temperature value for all materials, or have provided limited material-specific values which do not cover the gamut of most designs. A new approach is being used in new NASA standards, which defines touch temperature limits in terms of skin temperature at pain onset for bare skin contact with hot and cold objects. The authors have developed an analytical verification method for safe hot and cold object temperatures for contact times from 1 second to infinity.
    Keywords: Aerospace Medicine
    Type: JSC-CN-19209 , 40th International Conference on Environmental Systems (ICES); Jul 11, 2010 - Jul 15, 2010; Barcelona; Spain
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  • 9
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    A parallel circuit of LIF signalling pathways maintains pluripotency of mouse ES cells (2009)
    Nature Publishing Group (NPG)
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    Publication Date: 2009-07-03
    Description: The cytokine leukaemia inhibitory factor (LIF) integrates signals into mouse embryonic stem (ES) cells to maintain pluripotency. Although the Jak-Stat3 pathway is essential and sufficient to mediate LIF signals, it is still unclear how these signals are linked to the core circuitry of pluripotency-associated transcription factors, consisting of Oct3/4 (also called Pou5f1), Sox2 and Nanog. Here we show that two LIF signalling pathways are each connected to the core circuitry via different transcription factors. In mouse ES cells, Klf4 is mainly activated by the Jak-Stat3 pathway and preferentially activates Sox2, whereas Tbx3 is preferentially regulated by the phosphatidylinositol-3-OH kinase-Akt and mitogen-activated protein kinase pathways and predominantly stimulates Nanog. In the absence of LIF, artificial expression of Klf4 or Tbx3 is sufficient to maintain pluripotency while maintaining the expression of Oct3/4. Notably, overexpression of Nanog supports LIF-independent self-renewal of mouse ES cells in the absence of Klf4 and Tbx3 activity. Therefore, Klf4 and Tbx3 are involved in mediating LIF signalling to the core circuitry but are not directly associated with the maintenance of pluripotency, because ES cells keep pluripotency without their expression in the particular context.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Niwa, Hitoshi -- Ogawa, Kazuya -- Shimosato, Daisuke -- Adachi, Kenjiro -- England -- Nature. 2009 Jul 2;460(7251):118-22. doi: 10.1038/nature08113.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Laboratory for Pluripotent Cell Studies, RIKEN Center for Developmental Biology, 2-2-3 Minatojima-minamimachi, Chuo-ku, Kobe 6500047, Japan. niwa@cdb.riken.jp〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19571885" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Line ; Embryonic Stem Cells/*cytology/*metabolism ; Gene Expression Regulation ; Homeodomain Proteins/genetics/metabolism ; Janus Kinases/metabolism ; Kruppel-Like Transcription Factors/genetics/metabolism ; Leukemia Inhibitory Factor/*metabolism ; MAP Kinase Signaling System ; Mice ; Phosphatidylinositol 3-Kinases/metabolism ; Pluripotent Stem Cells/*cytology/*metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; STAT3 Transcription Factor/metabolism ; *Signal Transduction ; T-Box Domain Proteins/genetics/metabolism
    Print ISSN: 0028-0836
    Electronic ISSN: 1476-4687
    Topics: Biology , Chemistry and Pharmacology , Medicine , Natural Sciences in General , Physics
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  • 10
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    A recessive mutation in the APP gene with dominant-negative effect on amyloidogenesis (2009)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2009-03-17
    Description: beta-Amyloid precursor protein (APP) mutations cause familial Alzheimer's disease with nearly complete penetrance. We found an APP mutation [alanine-673--〉valine-673 (A673V)] that causes disease only in the homozygous state, whereas heterozygous carriers were unaffected, consistent with a recessive Mendelian trait of inheritance. The A673V mutation affected APP processing, resulting in enhanced beta-amyloid (Abeta) production and formation of amyloid fibrils in vitro. Co-incubation of mutated and wild-type peptides conferred instability on Abeta aggregates and inhibited amyloidogenesis and neurotoxicity. The highly amyloidogenic effect of the A673V mutation in the homozygous state and its anti-amyloidogenic effect in the heterozygous state account for the autosomal recessive pattern of inheritance and have implications for genetic screening and the potential treatment of Alzheimer's disease.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2728497/" 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/PMC2728497/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Di Fede, Giuseppe -- Catania, Marcella -- Morbin, Michela -- Rossi, Giacomina -- Suardi, Silvia -- Mazzoleni, Giulia -- Merlin, Marco -- Giovagnoli, Anna Rita -- Prioni, Sara -- Erbetta, Alessandra -- Falcone, Chiara -- Gobbi, Marco -- Colombo, Laura -- Bastone, Antonio -- Beeg, Marten -- Manzoni, Claudia -- Francescucci, Bruna -- Spagnoli, Alberto -- Cantu, Laura -- Del Favero, Elena -- Levy, Efrat -- Salmona, Mario -- Tagliavini, Fabrizio -- NS42029/NS/NINDS NIH HHS/ -- R01 NS042029/NS/NINDS NIH HHS/ -- R01 NS042029-01A1/NS/NINDS NIH HHS/ -- R01 NS042029-02/NS/NINDS NIH HHS/ -- R01 NS042029-03/NS/NINDS NIH HHS/ -- R01 NS042029-04/NS/NINDS NIH HHS/ -- R01 NS042029-05/NS/NINDS NIH HHS/ -- R01 NS042029-06/NS/NINDS NIH HHS/ -- New York, N.Y. -- Science. 2009 Mar 13;323(5920):1473-7. doi: 10.1126/science.1168979.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Division of Neurology and Neuropathology, "Carlo Besta" National Neurological Institute, 20133 Milan, Italy.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/19286555" target="_blank"〉PubMed〈/a〉
    Keywords: Adult ; Alzheimer Disease/*genetics/metabolism ; Amino Acid Substitution ; Amyloid/*metabolism ; Amyloid beta-Peptides/chemistry/metabolism ; Amyloid beta-Protein Precursor/*genetics/metabolism ; Cell Line ; Dementia/*genetics/metabolism ; Female ; *Genes, Recessive ; Heterozygote ; Homozygote ; Humans ; Kinetics ; Male ; *Mutation ; Pedigree ; Peptide Fragments/chemistry/metabolism ; Protein Binding ; Transfection
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
    Published by American Association for the Advancement of Science (AAAS)
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