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21.
T.E. Warnecke M.D. Lynch A. Karimpour-Fard M.L. Lipscomb P. Handke T. Mills C.J. Ramey T. Hoang R.T. Gill 《Metabolic engineering》2010,12(3):241-250
The understanding and engineering of complex phenotypes is a critical issue in biotechnology. Conventional approaches for engineering such phenotypes are often resource intensive, marginally effective, and unable to generate the level of biological understanding desired. Here, we report a new approach for rapidly dissecting a complex phenotype that is based upon the combination of genome-scale growth phenotype data, precisely targeted growth selections, and informatic strategies for abstracting and summarizing data onto coherent biological processes. We measured at high resolution (125 NT) and for the entire genome the effect of increased gene copy number on overall biological fitness corresponding to the expression of a complex phenotype (tolerance to 3-hydroxypropionic acid (3-HP) in Escherichia coli). Genetic level fitness data were then mapped according to various definitions of gene–gene interaction in order to generate network-level fitness data. When metabolic pathways were used to define interactions, we observed that genes within the chorismate and threonine super-pathways were disproportionately enriched throughout selections for 3-HP tolerance. Biochemical and genetic studies demonstrated that alleviation of inhibition of either of these super-pathways was sufficient to mitigate 3-HP toxicity. These data enabled the design of combinatorial modifications that almost completely offset 3-HP toxicity in minimal medium resulting in a 20 g/L and 25-fold increase in tolerance and specific growth, respectively. 相似文献
22.
Several studies have shown that in vertebrate mtDNAs the nucleotide content at fourfold degenerate sites is well correlated
with the site’s time of exposure to the single-strand state, as predicted from the asymmetrical model of mtDNA replication.
Here we examine whether the same explanation may hold for the regional variation in nucleotide content in the maternal and
paternal mtDNAs of the mussel Mytilus galloprovincialis. The origin of replication of the heavy strand (OH) of these genomes has been previously established. A systematic search of the two genomes for sequences that are likely to
act as the origin of replication of the light strand (OL) suggested that the most probable site lies within the ND3 gene. By adopting this OL position we calculated times of exposure for 0FD (nondegenerate), 2FD (twofold degenerate), and 4FD (fourfold degenerate) sites of the protein-coding part of the genome and for the rRNA, tRNA and noncoding parts. The presence
of thymine and absence of guanine at 4FD sites was highly correlated with the presumed time of exposure. Such an effect was not found for the 2FD sites, the rRNA, the tRNA, or the noncoding parts. There was a trend for a small increase in cytosine at 0FD sites with exposure time, which is explicable as the result of biased usage of 4FD codons. The same analysis was applied to a recently sequenced mitochondrial genome of Mytilus trossulus and produced similar results. These results are consistent with the asymmetrical model of replication and suggest that guanine
oxidation due to single-strand exposure is the main cause of regional variation of nucleotide content in Mytilus mitochondrial genomes.
Electronic Supplementary Material The online version of this article (doi:) contains supplementary material, which is available to authorized users.
[Reviewing Editor: Dr. David Pollock] 相似文献
23.
Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer 总被引:1,自引:0,他引:1
Fernandes C Oliveira C Gano L Bourkoula A Pirmettis I Santos I 《Bioorganic & medicinal chemistry》2007,15(12):3974-3980
In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-bromopropionamide, a novel EGFR-TK inhibitor synthesised in our laboratory, was accomplished via halogen exchange. Purification by RP-HPLC gave [125I]-N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide with a radiochemical purity higher than 95% and a high specific activity. In vitro studies indicate that both iodinated quinazoline and its bromo precursor inhibit A431 cell growth and also possess higher potency than the parent quinazoline to inhibit the EGFR autophosphorylation. In vivo stability studies suggest metabolization of the radioiodinated quinazoline indicating a short biological half-life. The in vitro results point out that these quinazoline derivatives could be promising candidates for SPECT imaging of EGFR positive tumours provided that they are selectively modified in order to achieve better in vivo radiochemical stability. 相似文献
24.
Waterborne Cryptosporidium has been responsible for drinking water-associated disease outbreaks in a number of developed countries. As a result of the resistance of Cryptosporidium to chlorine, which is typically applied as a final barrier to protect the quality of distributed drinking water, current management practices are focused on source-water management and water treatment as ways of preventing Cryptosporidium from entering drinking-water supplies. In the event that treatment barriers fail, surprisingly little is known of the fate of oocysts once they enter a distribution system. To assess properly the risks of waterborne Cryptosporidium, a more thorough understanding of the fate of oocysts in water distribution systems, with emphasis on Cryptosporidium-biofilm interactions, is required. 相似文献
25.
26.
Auxotrophy and intrapopulation complementary in the ‘interactome’ of a cultivated freshwater model community
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Sarahi L. Garcia Moritz Buck Katherine D. McMahon Hans‐Peter Grossart Alexander Eiler Falk Warnecke 《Molecular ecology》2015,24(17):4449-4459
Microorganisms are usually studied either in highly complex natural communities or in isolation as monoclonal model populations that we manage to grow in the laboratory. Here, we uncover the biology of some of the most common and yet‐uncultured bacteria in freshwater environments using a mixed culture from Lake Grosse Fuchskuhle. From a single shotgun metagenome of a freshwater mixed culture of low complexity, we recovered four high‐quality metagenome‐assembled genomes (MAGs) for metabolic reconstruction. This analysis revealed the metabolic interconnectedness and niche partitioning of these naturally dominant bacteria. In particular, vitamin‐ and amino acid biosynthetic pathways were distributed unequally with a member of Crenarchaeota most likely being the sole producer of vitamin B12 in the mixed culture. Using coverage‐based partitioning of the genes recovered from a single MAG intrapopulation metabolic complementarity was revealed pointing to ‘social’ interactions for the common good of populations dominating freshwater plankton. As such, our MAGs highlight the power of mixed cultures to extract naturally occurring ‘interactomes’ and to overcome our inability to isolate and grow the microbes dominating in nature. 相似文献
27.
Tulika Sarma Athanasia Koutsouris Jiang Zhu Yu Aleksandar Krbanjevic Thomas J. Hope Mark M. Rasenick 《The Journal of biological chemistry》2015,290(16):10045-10056
Signals that activate the G protein Gαs and promote neuronal differentiation evoke Gαs internalization in rat pheochromocytoma (PC12) cells. These agents also significantly increase Gαs association with microtubules, resulting in an increase in microtubule dynamics because of the activation of tubulin GTPase by Gαs. To determine the function of Gαs/microtubule association in neuronal development, we used real-time trafficking of a GFP-Gαs fusion protein. GFP-Gαs concentrates at the distal end of the neurites in differentiated living PC12 cells as well as in cultured hippocampal neurons. Gαs translocates to specialized membrane compartments at tips of growing neurites. A dominant-negative Gα chimera that interferes with Gαs binding to tubulin and activation of tubulin GTPase attenuates neurite elongation and neurite number both in PC12 cells and primary hippocampal neurons. This effect is greatest on differentiation induced by activated Gαs. Together, these data suggest that activated Gαs translocates from the plasma membrane and, through interaction with tubulin/microtubules in the cytosol, is important for neurite formation, development, and outgrowth. Characterization of neuronal G protein dynamics and their contribution to microtubule dynamics is important for understanding the molecular mechanisms by which G protein-coupled receptor signaling orchestrates neuronal growth and differentiation. 相似文献
28.
Tricyclic dyes with different mesoatoms such as xanthenes (fluorescein, eosin) anthracenes and acridines (proflavine) approved
by the Food and Drug Administration (FDA) for use in foods, pharmaceuticals and cosmetic preparations interact with DNA, and
some of them do so through intercalation. Hyperchem 7.5, Spartan 04, Yasara 10.5.14 program packages and molecular modeling,
molecular mechanics and dynamics techniques with the oligonucleotides d(CCGGCGCCGG)2 and d(CGCGAATTCGCG)2 were utilized in
order to examine the mode of binding to DNA of a range of tricyclic carboxamides bearing N,N-dimethylaminoethyl side chain,
i.e., 9-amino-DACA, anthracene, acridine-1-carboxamide, acridine-4-carboxamide (DACA), azacridine, phenazine, pyridoquinoxaline,
oxopyridoquinoxaline, phenoxazine and xanthenone or N,N-dimethylaminobutyl moiety, i.e., phenazine and acridine. The bicyclic
quinoline-8-carboxamide was also examined for comparison reasons. On the basis of our data, prerequisite for the interaction
between protonated N,N-dimethylaminoethyl moiety and guanine is the formation of only one internal hydrogen bond between carboxamide
and peri NH + in the case of 9-amino-DACA or peri N in the cases of DACA, azacridine, phenazine and pyridoquinoxaline. The presence of an additional internal hydrogen bond
between oxygen carboxamide and protonated N,N-dimethylamino group in the cases of tricyclic systems bearing peri NH (phenoxazine) or O (xanthenone) group, prevents the interaction between side chain and guanine. Also, the formation of
one internal hydrogen bond between oxygen carboxamide and protonated N,N-dimethylamino group inhibits the interaction between
side chain and guanine in the case of acridine-1-carboxamide. Our findings are in accordance with previously reported results
obtained from the kinetic studies of the binding of acridine and related tricyclic carboxamides to DNA. 相似文献
29.
30.
Conformation of 4.5S RNA in the signal recognition particle and on the 30S ribosomal subunit
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Gu SQ Jöckel J Beinker P Warnecke J Semenkov YP Rodnina MV Wintermeyer W 《RNA (New York, N.Y.)》2005,11(9):1374-1384
The signal recognition particle (SRP) from Escherichia coli consists of 4.5S RNA and protein Ffh. It is essential for targeting ribosomes that are translating integral membrane proteins to the translocation pore in the plasma membrane. Independently of Ffh, 4.5S RNA also interacts with elongation factor G (EF-G) and the 30S ribosomal subunit. Here we use a cross-linking approach to probe the conformation of 4.5S RNA in SRP and in the complex with the 30S ribosomal subunit and to map the binding site. The UV-activatable cross-linker p-azidophenacyl bromide (AzP) was attached to positions 1, 21, and 54 of wild-type or modified 4.5S RNA. In SRP, cross-links to Ffh were formed from AzP in all three positions in 4.5S RNA, indicating a strongly bent conformation in which the 5' end (position 1) and the tetraloop region (including position 54) of the molecule are close to one another and to Ffh. In ribosomal complexes of 4.5S RNA, AzP in both positions 1 and 54 formed cross-links to the 30S ribosomal subunit, independently of the presence of Ffh. The major cross-linking target on the ribosome was protein S7; minor cross-links were formed to S2, S18, and S21. There were no cross-links from 4.5S RNA to the 50S subunit, where the primary binding site of SRP is located close to the peptide exit. The functional role of 4.5S RNA binding to the 30S subunit is unclear, as the RNA had no effect on translation or tRNA translocation on the ribosome. 相似文献