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See detailA genome-wide network model capturing seed germination reveals co-ordinated regulation of plant cellular phase transitions
Bassel, George W.; Lanc, Hui; Glaab, Enrico UL et al

in Proceedings of the National Academy of Sciences of the United States of America (2011), 108(23), 9709-9714

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See detailCorrect biological timing in Arabidopsis requires multiple light-signaling pathways.
Dalchau, N.; Hubbard, K. E.; Robertson, F. C. et al

in Proceedings of the National Academy of Sciences of the United States of America (2010), 107(29), 13171-13176

Circadian oscillators provide rhythmic temporal cues for a range of biological processes in plants and animals, enabling anticipation of the day/night cycle and enhancing fitness-associated traits. We ... [more ▼]

Circadian oscillators provide rhythmic temporal cues for a range of biological processes in plants and animals, enabling anticipation of the day/night cycle and enhancing fitness-associated traits. We have used engineering models to understand the control principles of a plant's response to seasonal variation. We show that the seasonal changes in the timing of circadian outputs require light regulation via feed-forward loops, combining rapid light-signaling pathways with entrained circadian oscillators. Linear time-invariant models of circadian rhythms were computed for 3,503 circadian-regulated genes and for the concentration of cytosolic-free calcium to quantify the magnitude and timing of regulation by circadian oscillators and light-signaling pathways. Bioinformatic and experimental analysis show that rapid light-induced regulation of circadian outputs is associated with seasonal rephasing of the output rhythm. We identify that external coincidence is required for rephasing of multiple output rhythms, and is therefore important in general phase control in addition to specific photoperiod-dependent processes such as flowering and hypocotyl elongation. Our findings uncover a fundamental design principle of circadian regulation, and identify the importance of rapid light-signaling pathways in temporal control. [less ▲]

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See detailProteogenomic basis for ecological divergence of closely related bacteria in natural acidophilic microbial communities
Denef, Vincent J.; Kalnejais, Linda H.; Mueller, Ryan S. et al

in Proceedings of the National Academy of Sciences of the United States of America (2010), 107(6), 2383-2390

Bacterial species concepts are controversial. More widely accepted is the need to understand how differences in gene content and sequence lead to ecological divergence. To address this relationship in ... [more ▼]

Bacterial species concepts are controversial. More widely accepted is the need to understand how differences in gene content and sequence lead to ecological divergence. To address this relationship in ecosystem context, we investigated links between genotype and ecology of two genotypic groups of Leptospirillum group II bacteria in comprehensively characterized, natural acidophilic biofilm communities. These groups share 99.7% 16S rRNA gene sequence identity and 95% average amino acid identity between their orthologs. One genotypic group predominates during early colonization, and the other group typically proliferates in later successional stages, forming distinct patches tens to hundreds of micrometers in diameter. Among early colonizing populations, we observed dominance of five genotypes that differed from each other by the extent of recombination with the late colonizing type. Our analyses suggest that the specific recombinant variant within the early colonizing group is selected for by environmental parameters such as temperature, consistent with recombination as a mechanism for ecological fine tuning. Evolutionary signatures, and strain-resolved expression patterns measured via mass spectrometry-based proteomics, indicate increased cobalamin biosynthesis, (de) methylation, and glycine cleavage in the late colonizer. This may suggest environmental changes within the biofilm during development, accompanied by redirection of compatible solutes from osmoprotectants toward metabolism. Across 27 communities, comparative proteo-genomic analyses show that differential regulation of shared genes and expression of a small subset of the similar to 15% of genes unique to each genotype are involved in niche partitioning. In summary, the results show how subtle genetic variations can lead to distinct ecological strategies. [less ▲]

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See detailCompetition between collective and individual dynamics
Grauwin, Sebastian; Bertin, Eric; Lemoy, Rémi UL et al

in PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA (2009), 106(49), 20622-20626

Linking microscopic and macroscopic behavior is at the heart of many natural and social sciences. This apparent similarity conceals essential differences across disciplines: Although physical particles ... [more ▼]

Linking microscopic and macroscopic behavior is at the heart of many natural and social sciences. This apparent similarity conceals essential differences across disciplines: Although physical particles are assumed to optimize the global energy, economic agents maximize their own utility. Here, we solve exactly a Schelling-like segregation model, which interpolates continuously between cooperative and individual dynamics. We show that increasing the degree of cooperativity induces a qualitative transition from a segregated phase of low utility toward a mixed phase of high utility. By introducing a simple function that links the individual and global levels, we pave the way to a rigorous approach of a wide class of systems, where dynamics are governed by individual strategies. [less ▲]

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See detailGlobal reconstruction of the human metabolic network based on genomic and bibliomic data.
Duarte, Natalie C.; Becker, Scott A.; Jamshidi, Neema et al

in Proceedings of the National Academy of Sciences of the United States of America (2007), 104(6), 1777-82

Metabolism is a vital cellular process, and its malfunction is a major contributor to human disease. Metabolic networks are complex and highly interconnected, and thus systems-level computational ... [more ▼]

Metabolism is a vital cellular process, and its malfunction is a major contributor to human disease. Metabolic networks are complex and highly interconnected, and thus systems-level computational approaches are required to elucidate and understand metabolic genotype-phenotype relationships. We have manually reconstructed the global human metabolic network based on Build 35 of the genome annotation and a comprehensive evaluation of >50 years of legacy data (i.e., bibliomic data). Herein we describe the reconstruction process and demonstrate how the resulting genome-scale (or global) network can be used (i) for the discovery of missing information, (ii) for the formulation of an in silico model, and (iii) as a structured context for analyzing high-throughput biological data sets. Our comprehensive evaluation of the literature revealed many gaps in the current understanding of human metabolism that require future experimental investigation. Mathematical analysis of network structure elucidated the implications of intracellular compartmentalization and the potential use of correlated reaction sets for alternative drug target identification. Integrated analysis of high-throughput data sets within the context of the reconstruction enabled a global assessment of functional metabolic states. These results highlight some of the applications enabled by the reconstructed human metabolic network. The establishment of this network represents an important step toward genome-scale human systems biology. [less ▲]

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See detailThe Notch ligand Jagged1 is required for inner ear sensory development.
Kiernan, A. E.; Ahituv, N.; Fuchs, H. et al

in Proceedings of the National Academy of Sciences of the United States of America (2001), 98(7), 3873-8

Within the mammalian inner ear there are six separate sensory regions that subserve the functions of hearing and balance, although how these sensory regions become specified remains unknown. Each sensory ... [more ▼]

Within the mammalian inner ear there are six separate sensory regions that subserve the functions of hearing and balance, although how these sensory regions become specified remains unknown. Each sensory region is populated by two cell types, the mechanosensory hair cell and the supporting cell, which are arranged in a mosaic in which each hair cell is surrounded by supporting cells. The proposed mechanism for creating the sensory mosaic is lateral inhibition mediated by the Notch signaling pathway. However, one of the Notch ligands, Jagged1 (Jag1), does not show an expression pattern wholly consistent with a role in lateral inhibition, as it marks the sensory patches from very early in their development--presumably long before cells make their final fate decisions. It has been proposed that Jag1 has a role in specifying sensory versus nonsensory epithelium within the ear [Adam, J., Myat, A., Roux, I. L., Eddison, M., Henrique, D., Ish-Horowicz, D. & Lewis, J. (1998) Development (Cambridge, U.K.) 125, 4645--4654]. Here we provide experimental evidence that Notch signaling may be involved in specifying sensory regions by showing that a dominant mouse mutant headturner (Htu) contains a missense mutation in the Jag1 gene and displays missing posterior and sometimes anterior ampullae, structures that house the sensory cristae. Htu/+ mutants also demonstrate a significant reduction in the numbers of outer hair cells in the organ of Corti. Because lateral inhibition mediated by Notch predicts that disruptions in this pathway would lead to an increase in hair cells, we believe these data indicate an earlier role for Notch within the inner ear. [less ▲]

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See detailTargeted disruption of Pax1 defines its null phenotype and proves haploinsufficiency.
Wilm, B.; Dahl, E.; Peters, H. et al

in Proceedings of the National Academy of Sciences of the United States of America (1998), 95(15), 8692-7

The murine paired box-containing gene Pax1 is required for normal development of the vertebral column, the sternum, and the scapula. Previous studies have shown that three natural Pax1 mouse mutants, the ... [more ▼]

The murine paired box-containing gene Pax1 is required for normal development of the vertebral column, the sternum, and the scapula. Previous studies have shown that three natural Pax1 mouse mutants, the undulated alleles, exhibit phenotypes of different severity in these skeletal elements. Nevertheless, these analyses have not clarified whether the semidominant Undulated short-tail (Uns) mutation, in which the complete Pax1 locus is deleted, represents a null allele. Moreover, the analyses of the classical undulated mutants did not allow a conclusion with respect to haploinsufficiency of Pax1. To address both questions we have created a Pax1 null allele in mice by gene targeting. Surprisingly, the phenotype of this defined mutation exhibits clear differences to that of Uns. This result strongly indicates the contribution of additional gene(s) to the Uns mutant phenotype. Furthermore, the phenotype of mice heterozygous for the null allele demonstrates that Pax1 is haploinsufficient in some though not all skeletal elements which express Pax1 during embryonic development. [less ▲]

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See detailThe biosynthetic cluster for the polyketide immunosuppressant rapamycin
Schwecke, T.; Aparicio, J. F.; Molnár, I. et al

in Proceedings of the National Academy of Sciences of the United States of America (1995), 92(17), 7839-7843

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and ... [more ▼]

The macrocyclic polyketides rapamycin and FK506 are potent immunosuppressants that prevent T-cell proliferation through specific binding to intracellular protein receptors (immunophilins). The cloning and specific alteration of the biosynthetic genes for these polyketides might allow the biosynthesis of clinically valuable analogues. We report here that three clustered polyketide synthase genes responsible for rapamycin biosynthesis in Streptomyces hygroscopicus together encode 14 homologous sets of enzyme activities (modules), each catalyzing a specific round of chain elongation. An adjacent gene encodes a pipecolate-incorporating enzyme, which completes the macrocycle. The total of 70 constituent active sites makes this the most complex multienzyme system identified so far. The DNA region sequenced (107.3 kbp) contains 24 additional open reading frames, some of which code for proteins governing other key steps in rapamycin biosynthesis. [less ▲]

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See detailInsertion of a bacterial gene into the mouse germ line using an infectious retrovirus vector.
Huszar, D.; Balling, Rudi UL; Kothary, R. et al

in Proceedings of the National Academy of Sciences of the United States of America (1985), 82(24), 8587-91

Using a Moloney leukemia virus vector containing the bacterial neo gene, we demonstrate that retrovirus vectors can be used to introduce genes into the mouse germ line. Infection of preimplantation ... [more ▼]

Using a Moloney leukemia virus vector containing the bacterial neo gene, we demonstrate that retrovirus vectors can be used to introduce genes into the mouse germ line. Infection of preimplantation embryos with the vector MLV-NEO.1 resulted in integration of neo sequences in approximately equal to 10% of the progeny mice. One of these animals, mouse F.2, contained approximately six MLV-NEO.1 proviruses at independent integration sites, each present at less than a single copy per cell. This mosaic mouse transmitted one of these proviruses to her offspring, producing a line of transgenic mice carrying a full-length, unrearranged MLV.NEO.1 provirus at a single chromosomal integration site. Mice homozygous at this MLV-NEO.1 locus have also been produced. No expression of the neo gene has been detected in the transgenic mice, either by screening of primary bone marrow or lung cells for resistance to G418 or by RNA transfer blot analysis of RNA from several tissues. In addition, the neo gene was found to be extensively methylated in the transgenic mice; however, treatment of primary cells with 5-azacytidine did not induce G418 resistance. The inactivity of the MLV-NEO.1 provirus in transgenic mice and potential means of eliciting neo expression under these conditions are discussed. [less ▲]

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