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  • Oxford University Press  (41)
  • Institute of Physics  (40)
  • American Association for the Advancement of Science (AAAS)
  • 2020-2022  (8)
  • 2010-2014  (57)
  • 1985-1989  (16)
  • 1975-1979  (3)
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  • 1
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    S/MAR-containing DNA nanoparticles promote persistent RPE gene expression and improvement in RPE65-associated LCA (2013)
    Oxford University Press
    Details
    Publication Date: 2013-03-23
    Description: Mutations in genes in the retinal pigment epithelium (RPE) cause or contribute to debilitating ocular diseases, including Leber's congenital amaurosis (LCA). Genetic therapies, particularly adeno-associated viruses (AAVs), are a popular choice for monogenic diseases; however, the limited payload capacity of AAVs combined with the large number of retinal disease genes exceeding that capacity make the development of alternative delivery methods critical. Here, we test the ability of compacted DNA nanoparticles (NPs) containing a plasmid with a scaffold matrix attachment region (S/MAR) and vitelliform macular dystrophy 2 (VMD2) promoter to target the RPE, drive long-term, tissue-specific gene expression and mediate proof-of-principle rescue in the rpe65 –/– model of LCA. We show that the S/MAR-containing plasmid exhibited reporter gene expression levels several fold higher than plasmid or NPs without S/MARs. Importantly, this expression was highly persistent, lasting up to 2 years (last timepoint studied). We therefore selected this plasmid for testing in the rpe65 –/– mouse model and observe that NP or plasmid VMD2-hRPE65-S/MAR led to structural and functional improvements in the LCA disease phenotype. These results indicate that the non-viral delivery of hRPE65 vectors can result in persistent, therapeutically efficacious gene expression in the RPE.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 2
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    Exploring the DNA mimicry of the Ocr protein of phage T7 (2012)
    Oxford University Press
    Details
    Publication Date: 2012-09-13
    Description: DNA mimic proteins have evolved to control DNA-binding proteins by competing with the target DNA for binding to the protein. The Ocr protein of bacteriophage T7 is the most studied DNA mimic and functions to block the DNA-binding groove of Type I DNA restriction/modification enzymes. This binding prevents the enzyme from cleaving invading phage DNA. Each 116 amino acid monomer of the Ocr dimer has an unusual amino acid composition with 34 negatively charged side chains but only 6 positively charged side chains. Extensive mutagenesis of the charges of Ocr revealed a regression of Ocr activity from wild-type activity to partial activity then to variants inactive in antirestriction but deleterious for cell viability and lastly to totally inactive variants with no deleterious effect on cell viability. Throughout the mutagenesis the Ocr mutant proteins retained their folding. Our results show that the extreme bias in charged amino acids is not necessary for antirestriction activity but that less charged variants can affect cell viability by leading to restriction proficient but modification deficient cell phenotypes.
    Print ISSN: 0305-1048
    Electronic ISSN: 1362-4962
    Topics: Biology
    Published by Oxford University Press
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  • 3
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    regSNPs: a strategy for prioritizing regulatory single nucleotide substitutions (2012)
    Oxford University Press
    Details
    Publication Date: 2012-07-06
    Description: Motivation: One of the fundamental questions in genetics study is to identify functional DNA variants that are responsible to a disease or phenotype of interest. Results from large-scale genetics studies, such as genome-wide association studies (GWAS), and the availability of high-throughput sequencing technologies provide opportunities in identifying causal variants. Despite the technical advances, informatics methodologies need to be developed to prioritize thousands of variants for potential causative effects. Results: We present regSNPs , an informatics strategy that integrates several established bioinformatics tools, for prioritizing regulatory SNPs, i.e. the SNPs in the promoter regions that potentially affect phenotype through changing transcription of downstream genes. Comparing to existing tools, regSNPs has two distinct features. It considers degenerative features of binding motifs by calculating the differences on the binding affinity caused by the candidate variants and integrates potential phenotypic effects of various transcription factors. When tested by using the disease-causing variants documented in the Human Gene Mutation Database, regSNPs showed mixed performance on various diseases. regSNPs predicted three SNPs that can potentially affect bone density in a region detected in an earlier linkage study. Potential effects of one of the variants were validated using luciferase reporter assay. Contact: yunliu@iupui.edu Supplementary information: Supplementary data are available at Bioinformatics online
    Print ISSN: 1367-4803
    Electronic ISSN: 1460-2059
    Topics: Biology , Computer Science , Medicine
    Published by Oxford University Press
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  • 4
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    Magma Evolution in the Primitive, Intra-oceanic Tonga Arc: Petrogenesis of Basaltic Andesites at Tofua Volcano (2012)
    Oxford University Press
    Details
    Publication Date: 2012-05-25
    Description: Tofua volcano is situated midway along the Tonga oceanic arc and has undergone two phases of ignimbrite-forming activity. The eruptive products are almost entirely basaltic andesites (52·5–57 wt % SiO 2 ) with the exception of a volumetrically minor pre-caldera dacite. The suite displays a strong tholeiitic trend with K 2 O 〈1 wt %. Phenocryst assemblages typically comprise plagioclase + clinopyroxene ± orthopyroxene with microlites of Ti-magnetite. Olivine (Fo 83 – 88 ) is rare and believed to be dominantly antecrystic. An increase in the extent and frequency of reverse zoning in phenocrysts, sieve-textured plagioclase and the occurrence of antecrystic phases in post-caldera lavas record a shift to dynamic conditions, allowing the interaction of magma batches that were previously distinct. Pyroxene thermobarometry suggests crystallization at 950–1200°C and 0·8–1·8 kbar. Volatile measurements of glassy melt inclusions indicate a maximum H 2 O content of 4·16 wt % H 2 O, and CO 2 –H 2 O saturation curves indicate that crystallization occurred at two levels, at depths of 4–5·5 km and 1·5–2·5 km. Major and trace element models suggest that the compositions of the majority of the samples represent a differentiation trend whereby the dacite was produced by 65% fractional crystallization of the most primitive basaltic andesite. Trace element models suggest that the sub-arc mantle source is the residuum of depleted Indian mid-ocean ridge basalt mantle (IDMM-1% melt), whereas radiogenic isotope data imply addition of 0·2% average Tongan sediment melt and a fluid component derived from the subducted altered Pacific oceanic crust. A horizontal array on the U–Th equiline diagram and Ra excesses of up to 500% suggest fluid addition to the mantle wedge within the last few thousand years. Time-integrated ( 226 Ra/ 230 Th) vs Sr/Th and Ba/Th fractionation models imply differentiation timescales of up to 4500 years for the dacitic magma compositions at Tofua.
    Print ISSN: 0022-3530
    Electronic ISSN: 1460-2415
    Topics: Geosciences
    Published by Oxford University Press
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  • 5
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    A genome-wide association study and biological pathway analysis of epilepsy prognosis in a prospective cohort of newly treated epilepsy (2013)
    Oxford University Press
    Details
    Publication Date: 2013-12-11
    Description: We present the analysis of a prospective multicentre study to investigate genetic effects on the prognosis of newly treated epilepsy. Patients with a new clinical diagnosis of epilepsy requiring medication were recruited and followed up prospectively. The clinical outcome was defined as freedom from seizures for a minimum of 12 months in accordance with the consensus statement from the International League Against Epilepsy (ILAE). Genetic effects on remission of seizures after starting treatment were analysed with and without adjustment for significant clinical prognostic factors, and the results from each cohort were combined using a fixed-effects meta-analysis. After quality control (QC), we analysed 889 newly treated epilepsy patients using 472 450 genotyped and 6.9 x 10 6 imputed single-nucleotide polymorphisms. Suggestive evidence for association (defined as P meta 〈 5.0 x 10 –7 ) with remission of seizures after starting treatment was observed at three loci: 6p12.2 (rs492146, P meta = 2.1 x 10 –7 , OR[G] = 0.57), 9p23 (rs72700966, P meta = 3.1 x 10 –7 , OR[C] = 2.70) and 15q13.2 (rs143536437, P meta = 3.2 x 10 –7 , OR[C] = 1.92). Genes of biological interest at these loci include PTPRD and ARHGAP11B (encoding functions implicated in neuronal development) and GSTA4 (a phase II biotransformation enzyme). Pathway analysis using two independent methods implicated a number of pathways in the prognosis of epilepsy, including KEGG categories ‘calcium signaling pathway’ and ‘phosphatidylinositol signaling pathway’. Through a series of power curves, we conclude that it is unlikely any single common variant explains 〉4.4% of the variation in the outcome of newly treated epilepsy.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 6
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    Coding variants in TREM2 increase risk for Alzheimer's disease (2014)
    Oxford University Press
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    Publication Date: 2014-10-09
    Description: The triggering receptor expressed on myeloid 2 ( TREM2 ) is an immune phagocytic receptor expressed on brain microglia known to trigger phagocytosis and regulate the inflammatory response. Homozygous mutations in TREM2 cause Nasu–Hakola disease, a rare recessive form of dementia. A heterozygous TREM2 variant, p.R47H, was recently shown to increase Alzheimer’'s disease (AD) risk. We hypothesized that if TREM2 is truly an AD risk gene, there would be additional rare variants in TREM2 that substantially affect AD risk. To test this hypothesis, we performed pooled sequencing of TREM2 coding regions in 2082 AD cases and 1648 cognitively normal elderly controls of European American descent. We identified 16 non-synonymous variants, six of which were not identified in previous AD studies. Two variants, p.R47H [ P = 9.17 x 10 –4 , odds ratio (OR) = 2.63 (1.44–4.81)] and p.R62H [ P = 2.36 x 10 –4 , OR = 2.36 (1.47–3.80)] were significantly associated with disease risk in single-variant analyses. Gene-based tests demonstrate variants in TREM2 are genome-wide significantly associated with AD [ P SKAT-O = 5.37 x 10 –7 ; OR = 2.55 (1.80–3.67)]. The association of TREM2 variants with AD is still highly significant after excluding p.R47H [ P SKAT-O = 7.72 x 10 –5 ; OR = 2.47 (1.62–3.87)], indicating that additional TREM2 variants affect AD risk. Genotyping in available family members of probands suggested that p.R47H ( P = 4.65 x 10 –2 ) and p.R62H ( P = 6.87 x 10 –3 ) were more frequently seen in AD cases versus controls within these families. Gel electrophoresis analysis confirms that at least three TREM2 transcripts are expressed in human brains, including one encoding a soluble form of TREM2.
    Print ISSN: 0964-6906
    Electronic ISSN: 1460-2083
    Topics: Biology , Medicine
    Published by Oxford University Press
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  • 7
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    The flush early and avoid the rush hypothesis holds after accounting for spontaneous behavior (2014)
    Oxford University Press
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    Publication Date: 2014-09-12
    Description: When approached by a predator, prey make economic decisions between remaining where they are and obtaining benefits from their current activity or leaving and enhancing their safety. The "flush early and avoid the rush" hypothesis suggests that animals that flee to escape approaching threats flee soon after they become alert to an approaching predator so as to reduce any costs incurred by ongoing monitoring of the predator. This hypothesis has been supported by several studies, but some researchers argue the relationship may be partially or entirely a consequence of bouts of spontaneous vigilance and/or bouts of spontaneous locomotion (vigilance or locomotion that occur when the animal is unaffected by a predator), rather than an economic decision related to the approaching predator. If this were true, spontaneous vigilance might incorrectly be recorded as alert distance (predator–prey distance when the prey becomes aware of and begins to monitor the predator) and spontaneous locomotion might be incorrectly recorded as flight initiation distance (predator–prey distance when escape begins). To evaluate these potential effects, we recorded the intervals between bouts of spontaneous vigilance and locomotion by yellow-bellied marmots ( Marmota flaviventris ). We used these baseline rates to conduct a series of alert distance–flight initiation distance regressions after removing potentially spurious observations recorded as alert distance or flight initiation distance. Although spontaneous vigilance and spontaneous locomotion may lead to artifactual increases in flight initiation distance as alert distance increases, the fundamental relationship remains after effects of spontaneous movements have been removed, supporting the flush early and avoid the rush hypothesis. We tested a key challenge of the "flush early and avoid the rush" (FEAR) hypothesis; our results provide strong support for the hypothesis.
    Print ISSN: 1045-2249
    Electronic ISSN: 1465-7279
    Topics: Biology
    Published by Oxford University Press
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  • 8
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    Specific expression of nuclear proto-oncogenes before entry into meiotic prophase of spermatogenesis (1989)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 1989-08-18
    Description: The expression of proto-oncogenes representative of several functional categories has been investigated during development of mouse male germ cells. The c-raf proto-oncogene and three members of the c-ras gene family were expressed in mitotically active stem cells, throughout the prophase of meiosis and to varying extents in post-meiotic cell types. In contrast, the nuclear proto-oncogenes c-fos, c-jun, and c-myc were specifically expressed at high levels in type B spermatogonia. High levels of c-myc and c-jun RNAs were also detected in spermatocytes early in the prophase of meiosis. The type B spermatogonia represent the last mitotic cell division before entry into meiotic prophase; therefore, these nuclear proto-oncogenes may be involved in altering programs of gene expression at this developmental transition.〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Wolfes, H -- Kogawa, K -- Millette, C F -- Cooper, G M -- CA 21082/CA/NCI NIH HHS/ -- CA 28946/CA/NCI NIH HHS/ -- HD 15269/HD/NICHD NIH HHS/ -- New York, N.Y. -- Science. 1989 Aug 18;245(4919):740-3.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Dana-Farber Cancer Institute, Boston, MA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/2475907" target="_blank"〉PubMed〈/a〉
    Keywords: Animals ; Cell Nucleus/*metabolism ; DNA-Binding Proteins/genetics ; *Gene Expression Regulation ; Male ; *Meiosis ; Mice ; Nucleic Acid Hybridization ; Proto-Oncogene Proteins/genetics ; Proto-Oncogene Proteins c-fos ; Proto-Oncogene Proteins c-jun ; Proto-Oncogene Proteins c-myc ; Proto-Oncogene Proteins c-raf ; Proto-Oncogene Proteins p21(ras) ; *Proto-Oncogenes ; RNA/analysis ; Spermatids/metabolism ; Spermatocytes/metabolism ; *Spermatogenesis ; Spermatogonia/metabolism ; Spermatozoa/analysis/metabolism/*ultrastructure ; Transcription Factors/genetics ; Transcription, Genetic
    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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  • 9
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    Specifying and sustaining pigmentation patterns in domestic and wild cats (2012)
    American Association for the Advancement of Science (AAAS)
    Details
    Publication Date: 2012-09-22
    Description: Color markings among felid species display both a remarkable diversity and a common underlying periodicity. A similar range of patterns in domestic cats suggests a conserved mechanism whose appearance can be altered by selection. We identified the gene responsible for tabby pattern variation in domestic cats as Transmembrane aminopeptidase Q (Taqpep), which encodes a membrane-bound metalloprotease. Analyzing 31 other felid species, we identified Taqpep as the cause of the rare king cheetah phenotype, in which spots coalesce into blotches and stripes. Histologic, genomic expression, and transgenic mouse studies indicate that paracrine expression of Endothelin3 (Edn3) coordinates localized color differences. We propose a two-stage model in which Taqpep helps to establish a periodic pre-pattern during skin development that is later implemented by differential expression of Edn3.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3709578/" 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/PMC3709578/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Kaelin, Christopher B -- Xu, Xiao -- Hong, Lewis Z -- David, Victor A -- McGowan, Kelly A -- Schmidt-Kuntzel, Anne -- Roelke, Melody E -- Pino, Javier -- Pontius, Joan -- Cooper, Gregory M -- Manuel, Hermogenes -- Swanson, William F -- Marker, Laurie -- Harper, Cindy K -- van Dyk, Ann -- Yue, Bisong -- Mullikin, James C -- Warren, Wesley C -- Eizirik, Eduardo -- Kos, Lidia -- O'Brien, Stephen J -- Barsh, Gregory S -- Menotti-Raymond, Marilyn -- N01-CO-12400/CO/NCI NIH HHS/ -- U54 HG003079/HG/NHGRI NIH HHS/ -- Intramural NIH HHS/ -- New York, N.Y. -- Science. 2012 Sep 21;337(6101):1536-41.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉HudsonAlpha Institute for Biotechnology, Huntsville, AL 35806, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22997338" target="_blank"〉PubMed〈/a〉
    Keywords: Acinonyx/genetics/metabolism ; Alleles ; Aminopeptidases/chemistry/*genetics/metabolism ; Animals ; Cats/embryology/*genetics/growth & development/metabolism ; Endothelin-3/*genetics/metabolism ; Epistasis, Genetic ; Felidae/*genetics/growth & development/metabolism ; Gene Expression Regulation ; Gene Frequency ; Genetic Variation ; Hair/embryology/growth & development ; Hair Color/*genetics ; Hair Follicle/embryology ; Haplotypes ; Metalloproteases/chemistry/*genetics/metabolism ; Mice ; Mice, Transgenic ; Panthera/genetics/metabolism ; Phenotype ; Polymorphism, Single Nucleotide ; Skin/anatomy & histology/embryology/*metabolism ; Species Specificity
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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  • 10
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    Total synthesis of a functional designer eukaryotic chromosome (2014)
    American Association for the Advancement of Science (AAAS)
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    Publication Date: 2014-03-29
    Description: Rapid advances in DNA synthesis techniques have made it possible to engineer viruses, biochemical pathways and assemble bacterial genomes. Here, we report the synthesis of a functional 272,871-base pair designer eukaryotic chromosome, synIII, which is based on the 316,617-base pair native Saccharomyces cerevisiae chromosome III. Changes to synIII include TAG/TAA stop-codon replacements, deletion of subtelomeric regions, introns, transfer RNAs, transposons, and silent mating loci as well as insertion of loxPsym sites to enable genome scrambling. SynIII is functional in S. cerevisiae. Scrambling of the chromosome in a heterozygous diploid reveals a large increase in a-mater derivatives resulting from loss of the MATalpha allele on synIII. The complete design and synthesis of synIII establishes S. cerevisiae as the basis for designer eukaryotic genome biology.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4033833/" 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/PMC4033833/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Annaluru, Narayana -- Muller, Heloise -- Mitchell, Leslie A -- Ramalingam, Sivaprakash -- Stracquadanio, Giovanni -- Richardson, Sarah M -- Dymond, Jessica S -- Kuang, Zheng -- Scheifele, Lisa Z -- Cooper, Eric M -- Cai, Yizhi -- Zeller, Karen -- Agmon, Neta -- Han, Jeffrey S -- Hadjithomas, Michalis -- Tullman, Jennifer -- Caravelli, Katrina -- Cirelli, Kimberly -- Guo, Zheyuan -- London, Viktoriya -- Yeluru, Apurva -- Murugan, Sindurathy -- Kandavelou, Karthikeyan -- Agier, Nicolas -- Fischer, Gilles -- Yang, Kun -- Martin, J Andrew -- Bilgel, Murat -- Bohutski, Pavlo -- Boulier, Kristin M -- Capaldo, Brian J -- Chang, Joy -- Charoen, Kristie -- Choi, Woo Jin -- Deng, Peter -- DiCarlo, James E -- Doong, Judy -- Dunn, Jessilyn -- Feinberg, Jason I -- Fernandez, Christopher -- Floria, Charlotte E -- Gladowski, David -- Hadidi, Pasha -- Ishizuka, Isabel -- Jabbari, Javaneh -- Lau, Calvin Y L -- Lee, Pablo A -- Li, Sean -- Lin, Denise -- Linder, Matthias E -- Ling, Jonathan -- Liu, Jaime -- Liu, Jonathan -- London, Mariya -- Ma, Henry -- Mao, Jessica -- McDade, Jessica E -- McMillan, Alexandra -- Moore, Aaron M -- Oh, Won Chan -- Ouyang, Yu -- Patel, Ruchi -- Paul, Marina -- Paulsen, Laura C -- Qiu, Judy -- Rhee, Alex -- Rubashkin, Matthew G -- Soh, Ina Y -- Sotuyo, Nathaniel E -- Srinivas, Venkatesh -- Suarez, Allison -- Wong, Andy -- Wong, Remus -- Xie, Wei Rose -- Xu, Yijie -- Yu, Allen T -- Koszul, Romain -- Bader, Joel S -- Boeke, Jef D -- Chandrasegaran, Srinivasan -- 092076/Wellcome Trust/United Kingdom -- GM077291/GM/NIGMS NIH HHS/ -- R01 GM077291/GM/NIGMS NIH HHS/ -- R01 GM090192/GM/NIGMS NIH HHS/ -- New York, N.Y. -- Science. 2014 Apr 4;344(6179):55-8. doi: 10.1126/science.1249252. Epub 2014 Mar 27.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Environmental Health Sciences, Johns Hopkins University (JHU) School of Public Health, Baltimore, MD 21205, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24674868" target="_blank"〉PubMed〈/a〉
    Keywords: Base Sequence ; *Chromosomes, Fungal/genetics/metabolism ; DNA, Fungal/genetics ; Genes, Fungal ; Genetic Fitness ; Genome, Fungal ; Genomic Instability ; Introns ; Molecular Sequence Data ; Mutation ; Polymerase Chain Reaction ; RNA, Fungal/genetics ; RNA, Transfer/genetics ; Saccharomyces cerevisiae/cytology/*genetics/physiology ; Sequence Analysis, DNA ; Sequence Deletion ; Synthetic Biology/*methods ; Transformation, Genetic
    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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