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Berlin Brandenburg

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  • 1
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 24 August 2010, Vol.107(34), pp.15022-6
    Description: Gene targeting by homologous recombination in embryonic stem cells is extensively used to generate specific mouse mutants. However, most mammalian species lack tools for targeted gene manipulation. Since double-strand breaks strongly increase the rate of homologous recombination at genomic loci, we explored whether gene targeting can be directly performed in zygotes by the use of zinc-finger nucleases. Here we report that gene targeting is achieved in 1.7-4.5% of murine one-cell embryos upon the coinjection of targeting vectors with zinc-finger nucleases, without preselection. These findings enable the manipulation of the mammalian germ line in a single step in zygotes, independent of ES cells.
    Keywords: Endonucleases -- Metabolism ; Gene Targeting -- Methods ; Zygote -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 2
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 2012, Vol.109(24), pp.9354-9359
    Description: Gene targeting by zinc-finger nucleases in one-cell embryos provides an expedite mutagenesis approach in mice, rats, and rabbits. This technology has been recently used to create knockout and knockin mutants through the deletion or insertion of nucleotides. Here we apply zinc-finger nucleases in one-cell mouse embryos to generate disease-related mutants harboring single nucleotide or codon replacements. Using a gene-targeting vector or a synthetic oligodesoxynucleotide as template for homologous recombination, we introduced missense and silent mutations into the Rab38 gene, encoding a small GTPase that regulates intracellular vesicle trafficking. These results demonstrate the feasibility of seamless gene editing in one-cell embryos to create genetic disease models and establish synthetic oligodesoxynucleotides as a simplified mutagenesis tool. ; p. 9354-9359.
    Keywords: Nucleases ; Mice ; Physiological Transport ; Gene Targeting ; Rabbits ; Genes ; Disease Models ; Mutagenesis ; Genetic Disorders ; Nucleotides ; Homologous Recombination ; Guanosinetriphosphatase ; Rats ; Mutants
    ISSN: 0027-8424
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  • 3
    Language: English
    In: Trends in Neurosciences, October 2015, Vol.38(10), pp.659-668
    Description: Several recent genome-wide association studies (GWAS) in patients with neurodegenerative disorders have shed new light on the brain immune system, suggesting that it plays a pivotal role in disease pathogenesis. Mononuclear phagocytes are blatantly involved in Alzheimer's disease (AD) of the central nervous system (CNS), but the specific functions of resident microglia, perivascular or meningeal macrophages, and circulating myeloid cells have not yet been fully resolved. Next-generation sequencing, high-throughput immune profiling technologies, and novel genetic tools have recently revolutionized the characterization of innate immune responses during AD. These studies advocate selective and non-redundant roles for myeloid subsets, which could be a target for novel disease-modifying therapies in AD. Myeloid cells differ in their kinetics (long-lived versus short-lived) and localization. This should be taken into account when targeting myeloid cells during neurodegenerative diseases. Microglia are recruited to and cluster around newly formed Aβ plaques, indicating that they are not directly involved in the initial stages of amyloid plaque formation. Microglia are phagocytic cells in the brain equipped with several receptors that play a role in the clearance of Aβ. Downregulation of these immune-receptors results in compromised phagocytotic capacity of microglia. Morphological alterations such as dystrophic (senescent) microglia have been observed in the aged human and AD brain. Emerging data suggest that microglia deteriorate with age and are dysfunctional during AD.
    Keywords: Microglia ; Yolk Sac ; Neurodegeneration ; Cx3cr1 ; Macrophage ; Alzheimer'S Disease ; Medicine ; Anatomy & Physiology
    ISSN: 0166-2236
    E-ISSN: 1878-108X
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  • 4
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 March 2013, Vol.110(10), pp.3782-7
    Description: The study of genetic disease mechanisms relies mostly on targeted mouse mutants that are derived from engineered embryonic stem (ES) cells. Nevertheless, the establishment of mutant ES cells is laborious and time-consuming, restricting the study of the increasing number of human disease mutations discovered by high-throughput genomic analysis. Here, we present an advanced approach for the production of mouse disease models by microinjection of transcription activator-like effector nucleases (TALENs) and synthetic oligodeoxynucleotides into one-cell embryos. Within 2 d of embryo injection, we created and corrected chocolate missense mutations in the small GTPase RAB38; a regulator of intracellular vesicle trafficking and phenotypic model of Hermansky-Pudlak syndrome. Because ES cell cultures and targeting vectors are not required, this technology enables instant germline modifications, making heterozygous mutants available within 18 wk. The key features of direct mutagenesis by TALENs and oligodeoxynucleotides, minimal effort and high speed, catalyze the generation of future in vivo models for the study of human disease mechanisms and interventions.
    Keywords: Disease Models, Animal ; Germ-Line Mutation ; Genetic Diseases, Inborn -- Genetics ; Oligodeoxyribonucleotides -- Administration & Dosage
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 5
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 12 June 2012, Vol.109(24), pp.9354-9
    Description: Gene targeting by zinc-finger nucleases in one-cell embryos provides an expedite mutagenesis approach in mice, rats, and rabbits. This technology has been recently used to create knockout and knockin mutants through the deletion or insertion of nucleotides. Here we apply zinc-finger nucleases in one-cell mouse embryos to generate disease-related mutants harboring single nucleotide or codon replacements. Using a gene-targeting vector or a synthetic oligodesoxynucleotide as template for homologous recombination, we introduced missense and silent mutations into the Rab38 gene, encoding a small GTPase that regulates intracellular vesicle trafficking. These results demonstrate the feasibility of seamless gene editing in one-cell embryos to create genetic disease models and establish synthetic oligodesoxynucleotides as a simplified mutagenesis tool.
    Keywords: Embryo, Mammalian ; Gene Targeting ; Mutation
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 6
    Language: English
    In: LITHOS, Sept 1, 2013, Vol.177, p.207(19)
    Description: To link to full-text access for this article, visit this link: http://dx.doi.org/10.1016/j.lithos.2013.06.015 Byline: Melanie Meyer, Reiner Klemd, Dmitry Konopelko Abstract: The Makbal Complex in the western Tianshan Mountains of Kazakhstan and Kyrgyzstan consists of HP/UHP metasedimentary host rocks which enclose various HP mafic blocks or boudins. These mafic rocks comprise rare eclogites (sensu stricto and sensu lato), garnet amphibolites (retrograded eclogites) and a newly discovered glaucophanite (glaucophane-garnet-omphacite bearing rock). So far the Makbal Complex has been interpreted to predominantly consist of continental lithologies and the mafic rocks were considered as dismembered dikes intruding continental metasediments. This interpretation is mainly based on the geological relationship and bulk rock chemistry of the different rock types. It was further suggested that the continental lithologies of the Makbal Complex underwent eclogite-facies metamorphism in a former subduction zone. In the present study we combined conventional geothermometry, P-T pseudosection modeling and major and trace element whole rock geochemistry for different mafic samples (glaucophanite and eclogites (sensu lato)) in order to shed light on both the metamorphic evolution and the protoliths of the mafic HP rocks in the Makbal Complex. Prograde to peak-pressure clockwise P-T paths of glaucophanite and eclogites (sensu lato) were modeled using garnet isopleth thermobarometry. The results show that the glaucophanite and eclogite (sensu lato) samples experienced similar prograde P-T paths and slightly different peak metamorphic conditions at ~560[degrees]C at 2.4GPa for the former and between ~520[degrees]C at 2.2GPa and ~555[degrees]C at ~2.5GPa for the latter, corresponding to burial depths between 70 and 85km. Whole rock major and trace element analyses and petrological evidence imply that the various rock types at the Makbal Complex most likely originated from different precursor rocks. Eclogites (sensu lato) are believed to represent strongly retrogressed former eclogite-facies rocks that had never been eclogites (sensu stricto, i.e. 〉70 vol.% garnet and omphacite) due to an unfavorable alkali-poor bulk composition (Na.sub.2O 〈1wt.%). The four high-pressure mafic samples investigated in this study originated from oceanic crust (Zr/Hf ratio of 33 to 35) which contradicts all previous studies suggesting a continental protolith for all mafic HP/UHP rocks at Makbal. The present study indicates that the mafic high-pressure rocks represent incoherent segments of exhumed oceanic crust. Juxtaposition of different mafic oceanic (this study) and continental rocks is suggested to be due to buoyancy-driven exhumation of the metasedimentary host rock in the subduction channel where dismembered fragments of the subducted oceanic crust were captured in different depths. Article History: Received 26 February 2013; Accepted 21 June 2013
    Keywords: Metamorphism (Geology) -- Analysis ; Metamorphic Rocks -- Analysis
    ISSN: 0024-4937
    Source: Cengage Learning, Inc.
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  • 7
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 27 May 2014, Vol.111(21), pp.7659-64
    Description: The lariat-capping (LC) ribozyme is a natural ribozyme isolated from eukaryotic microorganisms. Despite apparent structural similarity to group I introns, the LC ribozyme catalyzes cleavage by a 2',5' branching reaction, leaving the 3' product with a 3-nt lariat cap that functionally substitutes for a conventional mRNA cap in the downstream pre-mRNA encoding a homing endonuclease. We describe the crystal structures of the precleavage and postcleavage LC ribozymes, which suggest that structural features inherited from group I ribozymes have undergone speciation due to profound changes in molecular selection pressure, ultimately giving rise to an original branching ribozyme family. The structures elucidate the role of key elements that regulate the activity of the LC ribozyme by conformational switching and suggest a mechanism by which the signal for branching is transmitted to the catalytic core. The structures also show how conserved interactions twist residues, forming the lariat to join chemical groups involved in branching.
    Keywords: Gir1 ; RNA Catalysis ; RNA Structure ; Saxs ; Crystallography ; Evolution, Molecular ; Models, Molecular ; Introns -- Genetics ; RNA, Catalytic -- Chemistry ; Signal Transduction -- Genetics
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 8
    Language: English
    In: LITHOS, 2011, Vol.126(3), pp.388-401
    Description: The trace element composition of rutile and Zr-in-rutile temperatures were determined for ultra-high temperature (UHT) metamorphic rocks from the Epembe Unit of the Epupa Complex in NW-Namibia. Ortho- and paragneisses record Mesoproterozoic peak metamorphic UHT conditions of 970 ± 40 °C at 9.5 ± 2 kbar, as estimated from conventional thermobarometry and constraints from pseudosection modeling. Rutile exhibits superchondritic concentrations of V, Zr, Nb, Hf, Ta, Th and U while rare earth elements (REE) are far less enriched. Zr and Hf correlate positively with two distinct trends. Nb and Ta as well as Cr and V show a positive correlation although with less clear trends. Only Hf correlates with Zr, suggesting a decoupling of Zr and Hf from the other high field-strength elements (HFSE) probably during retrogression. In general, the non-homogeneous HFSE distribution in rutile indicates that equilibrium trace element distribution achieved during UHT peak metamorphic conditions was either almost completely erased or had never been achieved as a common feature of all rutile grains. The retrograde metamorphic evolution of the UHT rocks is interpreted to be responsible for trace element redistribution under equilibrium conditions restricted to small domains. This has affected the trace element composition of the rutile grains investigated here thereby disturbing their UHT signature, which may cause problems for provenance studies involving such ‘disturbed’ grains. A systematic comparison of all available Zr-in-rutile thermometer calibrations shows that beside of one, all give similar temperature estimates for the studied samples. No systematic differences regarding the Zr content were observed between rutile grains in different textural positions (i.e. matrix grains, those shielded by host minerals or post-peak grains). However, calculations revealed a broad range of temperatures between 〈 400 °C and 〉 1000 °C. The large spread of calculated temperatures is interpreted to result from intergrain diffusion and trace element exchange by fluid-mediated recrystallization during the retrograde metamorphic evolution. This interpretation is supported by the presence of extensively formed retrograde reaction textures involving hydrous phases such as cordierite and biotite in the studied samples. In addition, tiny (≤ 5 μm) Zr-silica-rich phase separations which occur either homogeneously or heterogeneously distributed in single rutile grains may cause intergrain Zr variations. ► Three Zr-in-rutile calibrations give similar results independent of a P-correction. ► Re-equilibration of rutile during retrogression is likely =〉 loss of UHT information. ► Single rutile grains contain Zr-rich domains (here interpreted as exsolutions). ► Rutile trace element analysis shows a decoupling of Zr and Hf from the other HFSE. ► Protolithic signature of rutile might get lost during the metamorphic evolution.
    Keywords: Rutile Trace Element Composition ; La-Icp-MS ; Epupa Complex ; Uht Granulites ; Zr-in-Rutile Thermometry ; Engineering ; Geology
    ISSN: 0024-4937
    E-ISSN: 1872-6143
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  • 9
    Language: English
    In: Journal of Community Health, 2011, Vol.36(4), pp.669-674
    Description: To describe the participatory approach used to develop “Good For The Neighborhood” (GFTN), a community program to improve the health of four underserved communities. A core program was developed involving a “park and stay” approach to impact four underserved predominately minority communities (two predominately African American, 1 predominately Latino, and the Seneca Nation of Indians). The core program includes health screenings, risk assessments, health education, and exposure to health services. An extensive tracking and evaluation system was developed to determine participation and impact on the community. Multi-methods (key informant interviews, focus groups, surveys) were implemented to gain feedback from community partners and participants as to how to adopt the program to meet the needs of the community. GFTN has been sustained for over 3 years and has reached over 3,500 predominately minority individuals in four communities with 1/3 of participants engaging regularly in the program. The program has evolved in the four communities to meet specific needs. A “park and stay” approach in partnership with the community has led to a strong program that community partners and residents embrace. Community ownership and social networking, including word-of-mouth from residents is essential to establishing a successful program.
    Keywords: Community health ; Health disparities ; Evaluation ; Community based participatory research ; Minorities
    ISSN: 0094-5145
    E-ISSN: 1573-3610
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  • 10
    Language: English
    In: The Patient - Patient-Centered Outcomes Research, 2017, Vol.10(4), pp.381-387
    Description: Changes in economic conditions and healthcare delivery models have shifted more healthcare costs to patients, resulting in greater patient financial responsibilities. As a result, it is important to understand the potential impact of financial literacy on patients’ healthcare behavior. With the focus on delivering better health outcomes at lower costs, factors that influence patient behavior are important considerations for healthcare providers. Although researchers have proposed a variety of conceptual models that identify influential factors, those models do not fully address financial literacy and its potential impact patients’ healthcare decisions. This article examines existing models of patient healthcare decision-making and current research on factors affecting patient decision-making and behavior and then presents recommendations for closing the identified gap in our current knowledge.
    Keywords: Decision Making ; Financing, Personal ; Health Services -- Statistics & Numerical Data;
    ISSN: 1178-1653
    E-ISSN: 1178-1661
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