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Berlin Brandenburg

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  • Meyer, M  (47)
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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, 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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  • 3
    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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  • 4
    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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  • 5
    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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  • 6
    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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  • 7
    Language: English
    In: Population health management, December 2017, Vol.20(6), pp.475-485
    Description: The need for population health management expertise has increased as the health care industry shifts toward value-based care. However, many organizations report hiring gaps as they seek to fill positions. The purpose of this study was to analyze the types of population health management positions for which health care organizations are hiring, including qualifications and competencies required for these positions. A content analysis was conducted on 271 job postings collected during a 2-month period. A typology of qualifications and competencies was developed based on the content analysis. Profiles were generated for the top 5 job title classifications: directors, coordinators, care managers, analysts, and specialists. This study highlights the investment health care organizations are making in population health management and the prominent role these positions are playing in the health care environment today. Many organizations are building out population health management teams resulting in multiple positions at different levels being added. As the market demands competent candidates who are equipped with specialized population health expertise as well as practical experience in program development, technology applications, care management, and analytics, professional education programs will need to adapt curricula to address the required areas. Competencies for specific job title classifications may need further evaluation and refinement over time. Study results can be used by organizations for strategic planning, by educators to target needed qualifications and competencies, and by researchers and policy advisors to assess progress toward value-based care.
    Keywords: Population Health Management Job Competencies ; Population Health Management Job Content Analysis ; Population Health Management Job Qualifications ; Delivery of Health Care ; Personnel Management ; Population Health
    ISSN: 19427891
    E-ISSN: 1942-7905
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  • 8
    Language: English
    In: Journal of the American Chemical Society, 06 October 2010, Vol.132(39), pp.13733-41
    Description: The diprotonated form of a fluorinated free base porphyrin, namely 5-(p-aminophenyl)-10,15,20-tris(pentafluorophenyl)porphyrin (H(2)FAP), can catalyze the reduction of oxygen by a weak electron donor, namely ferrocene (Fc). At a water/1,2-dichloroethane interface, the interfacial formation of H(4)FAP(2+) is observed by UV-vis spectroscopy and ion-transfer voltammetry, due to the double protonation of H(2)FAP at the imino nitrogen atoms in the tetrapyrrole ring. H(4)FAP(2+) is shown to bind oxygen, and the complex in the organic phase can easily be reduced by Fc to produce hydrogen peroxide as studied by two-phase reactions with the Galvani potential difference between the two phases being controlled by the partition of a common ion. Spectrophotometric measurements performed in 1,2-dichloroethane solutions clearly evidence that reduction of oxygen by Fc catalyzed by H(4)FAP(2+) only occurs in the presence of the tetrakis(pentafluorophenyl)borate (TB(-)) counteranion in the organic phase. Finally, ab initio computations support the catalytic activation of H(4)FAP(2+) on oxygen.
    Keywords: Ethylene Dichlorides -- Chemistry ; Oxygen -- Chemistry ; Porphyrins -- Chemistry ; Water -- Chemistry
    ISSN: 00027863
    E-ISSN: 1520-5126
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  • 9
    Language: English
    In: Proceedings of the National Academy of Sciences of the United States of America, 05 December 2017, Vol.114(49), pp.12934-12939
    Description: Ribosomal RNAs (rRNAs) are main effectors of messenger RNA (mRNA) decoding, peptide-bond formation, and ribosome dynamics during translation. Ribose 2'-O-methylation (2'-O-Me) is the most abundant rRNA chemical modification, and displays a complex pattern in rRNA. 2'-O-Me was shown to be essential for accurate and efficient protein synthesis in eukaryotic cells. However, whether rRNA 2'-O-Me is an adjustable feature of the human ribosome and a means of regulating ribosome function remains to be determined. Here we challenged rRNA 2'-O-Me globally by inhibiting the rRNA methyl-transferase fibrillarin in human cells. Using RiboMethSeq, a nonbiased quantitative mapping of 2'-O-Me, we identified a repertoire of 2'-O-Me sites subjected to variation and demonstrate that functional domains of ribosomes are targets of 2'-O-Me plasticity. Using the cricket paralysis virus internal ribosome entry site element, coupled to in vitro translation, we show that the intrinsic capability of ribosomes to translate mRNAs is modulated through a 2'-O-Me pattern and not by nonribosomal actors of the translational machinery. Our data establish rRNA 2'-O-Me plasticity as a mechanism providing functional specificity to human ribosomes.
    Keywords: 2′-O-Methylation ; RNA Epigenetics ; Fibrillarin ; Ribosomal RNA ; Translational Control ; Protein Biosynthesis ; RNA, Ribosomal -- Metabolism
    ISSN: 00278424
    E-ISSN: 1091-6490
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  • 10
    Language: English
    In: Gondwana Research, August 2015, Vol.28(1), pp.1-25
    Description: The study of subduction-related high-pressure- and ultra-high-pressure metamorphic rocks exposed in orogenic belts is critical for unraveling the tectonothermal evolution of an orogen. The South Tianshan Orogen of the southwestern Central Asian Orogenic Belt, one of the world's largest accretionary orogens, contains several Paleozoic (ultra-)high-pressure ((U)HP) metamorphic terranes. (U)HP eclogites, blueschists and associated (U)HP metasedimentary rocks of continental and oceanic origin were reported from two localities in the Northern Tianshan (NTS) of Kazakhstan and Kyrgyzstan, namely from the Ordovician Aktyuz and Makbal metamorphic terranes. Furthermore Lower Carboniferous (U)HP eclogites and blueschists of oceanic origin are located in the Southern Tianshan Accretionary Complex (STAC) of southern Kyrgyzstan (Atbashi) and northwestern China (Akeyazi). The continentally-derived Aktyuz eclogite is considered to have experienced a continuous clockwise prograde P–T path with peak metamorphic conditions of ca. 1.6–2.1 GPa at 610–670 °C, corresponding to a burial depth of about 70 km. A peak metamorphic Lu–Hf garnet isochron age of 474 ± 2 Ma for the retrogressed eclogite of continental origin is in accordance with a Sm–Nd garnet isochron age of 462 ± 7 Ma interpreted as time of cooling and decompression of the metamorphic rock assemblage below 650 to 600 °C. Quantitative P–T pseudosection modeling for peripheral Makbal HP garnet amphibolites of continental origin also revealed a continuous clockwise P–T path with peak-metamorphic conditions of ca. 1.4 GPa at ca. 620 °C followed by an isothermal uplift to ca. 0.7 GPa. Furthermore, prograde P–T paths of oceanically-derived central Makbal high-pressure metabasic rocks revealed peak metamorphic conditions between 520 °C and 560 °C at 2.2 GPa to 2.5 GPa with subsequent isothermal decompressions. The metamorphic (P–T) evolution of a garnet–chloritoid–talc schist is exhibited by a P–T trajectory starting ca. 480 °C at 2.5 GPa, followed by peak pressures of ca. 2.85 GPa at 525 °C and peak temperatures of ca. 580 °C at 2.4 GPa. A Lu–Hf peak metamorphic age of 470.1 ± 2.5 Ma for a peripheral garnet amphibolite is in accordance with a garnet-growth Sm–Nd age of 475 ± 4 Ma of the UHP garnet–chloritoid–talc schist. Different and variable P–T paths show that former oceanic and continental crust at Makbal was subducted to different maximum depths (HP versus UHP conditions). The (U)HP metamorphism of oceanic and continental mafic rocks from the Aktyuz and Makbal metamorphic terranes is assumed to have occurred in a similar time frame of between 500 and 460 Ma. The proposed geodynamic model for the HP Aktyuz metamorphic terrane incorporates the deep northeast-directed subduction of NTS continental crust under the Ankrakhai block of Paleo-Kazakhstan subsequent to the closure of the Djalair–Naiman Basin. At Makbal the final consumption of the oceanic crust of the Terskey Ocean to the northeast was immediately followed by the deep subduction of a (thinned) passive continental margin of the Central Tianshan Arc Terrane (CTA). Both scenarios are in accordance with continental-type subduction geodynamics producing the subduction-related (U)HP rocks during continental–continental collision processes. The exhumation of detached oceanic material by channel flow may have been initiated by the transient subduction of oceanic and subsequent continental crust. The Lower Carboniferous (U)HP metamorphic terranes (Atbashi and Akeyazi) in the Southern Tianshan Accretionary Complex are mainly composed of metasediments which host some lenses and boudins of oceanically-derived blueschists and eclogites. Most eclogites, blueschists and metasediments have experienced peak high-pressure metamorphism (480–580 °C at 1.4–2.1 GPa), while some slices display UHP-conditions (2.7–3.3 GPa at 570–630 °C). Multi-point Lu–Hf and Sm–Nd isochrons from several eclogite and blueschist samples from the Atbashi and Akeyazi metamorphic terranes revealed consistent ages of ca. 320–315 Ma for the peak of metamorphism, thereby confirming that (U)HP metamorphism occurred during a single subduction event. The highly variable peak metamorphic conditions displayed by the (U)HP rocks imply that metamorphism of the metasediments and the various metabasic rocks occurred in different depths of the subduction zone. (U)HP metabasites and metasediments exhibit different P–T paths, which is consistent with the chaotic incorporation in a subduction channel resulting in the eventual exhumation as a mélange. This scenario is much in agreement with initial subduction of oceanic crust and accretionary wedge sediment removal by subduction erosion and thus is similar to accretionary-type subduction terranes, although, with higher peak P–T conditions than previously recorded. The absence of significant melting, in combination with the variable peak pressure metamorphic conditions and the intimate interlayering of high- and ultrahigh-pressure rocks, suggests that the (U)HP rocks were derived from varying depths within the subduction zone and then juxtaposed during exhumation in the subduction channel. This is in accordance with exhumation of the (U)HP rocks by channel flow.
    Keywords: South Tianshan Orogen ; (Ultra-)High-Pressure Metamorphism ; Geochronology ; Accretionary- and Continental-Type Subductions ; Channel Flow Exhumation ; Geology
    ISSN: 1342-937X
    E-ISSN: 1878-0571
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