Systems biology of energetic and atomic costs in the yeast transcriptome, proteome, and metabolome

Proteins vary in their cost to the cell and natural selection may favour the use of proteins that are cheaper to produce. We develop a novel approach to estimate the amino acid biosynthetic cost based on genome-scale metabolic models, and directly investigate the effects of biosynthetic cost on transcriptomic, proteomic and metabolomic data in _Saccharomyces cerevisiae_. We find that our systems approach to formulating biosynthetic cost produces a novel measure that explains similar levels of variation in gene expression compared with previously reported cost measures. Regardless of the measure used, the cost of amino acid synthesis is weakly associated with transcript and protein levels, independent of codon usage bias. In contrast, energetic costs explain a large proportion of variation in levels of free amino acids. In the economy of the yeast cell, there appears to be no single currency to compute the cost of amino acid synthesis, and thus a systems approach is necessary to uncover the full effects of amino acid biosynthetic cost in complex biological systems that vary with cellular and environmental conditions

String Junctions for Arbitrary Lie Algebra Representations

We consider string junctions with endpoints on a set of branes of IIB string theory defining an ADE-type gauge Lie algebra. We show how to characterize uniquely equivalence classes of junctions related by string/brane crossing through invariant charges that count the effective number of prongs ending on each brane. Each equivalence class defines a point on a lattice of junctions. We define a metric on this lattice arising from the intersection pairing of junctions, and use self-intersection to identify junctions in the adjoint and fundamental representations of all ADE algebras. This information suffices to determine the relation between junction lattices and the Lie-algebra weight lattices. Arbitrary representations are built by allowing junctions with asymptotic (p,q) charges, on which the group of conjugacy classes of representations is represented additively. One can view the (p,q) asymptotic charges as Dynkin labels associated to two new fundamental weight vectors.Comment: 60 pages, 17 figures, BoxedEPS.te

Constraints on the BPS Spectrum of N = 2, D = 4 Theories with A-D-E Flavor Symmetry

BPS states of N=2, D=4 Super Yang-Mills theories with ADE flavor symmetry arise as junctions joining a D3-brane to a set of 7-branes defining the enhanced flavor algebra. We show that the familiar BPS spectrum of SU(2) theories with N_f <= 4 is simply given by the set of junctions whose self-intersection is bounded below as required by supersymmetry. This constraint, together with the relations between junction and weight lattices, is used to establish the appearance of arbitrarily large flavor representations for the case of D_{n>=5} and E_n symmetries. Such representations are required by consistency with decoupling down to smaller flavor symmetries.Comment: 15 pages, LaTeX, 1 eps figure; references adde

Evolutionary Systems Biology of Amino Acid Biosynthetic Cost in Yeast

Every protein has a biosynthetic cost to the cell based on the synthesis of its constituent amino acids. In order to optimise growth and reproduction, natural selection is expected, where possible, to favour the use of proteins whose constituents are cheaper to produce, as reduced biosynthetic cost may confer a fitness advantage to the organism. Quantifying the cost of amino acid biosynthesis presents challenges, since energetic requirements may change across different cellular and environmental conditions. We developed a systems biology approach to estimate the cost of amino acid synthesis based on genome-scale metabolic models and investigated the effects of the cost of amino acid synthesis on Saccharomyces cerevisiae gene expression and protein evolution. First, we used our two new and six previously reported measures of amino acid cost in conjunction with codon usage bias, tRNA gene number and atomic composition to identify which of these factors best predict transcript and protein levels. Second, we compared amino acid cost with rates of amino acid substitution across four species in the genus Saccharomyces. Regardless of which cost measure is used, amino acid biosynthetic cost is weakly associated with transcript and protein levels. In contrast, we find that biosynthetic cost and amino acid substitution rates show a negative correlation, but for only a subset of cost measures. In the economy of the yeast cell, we find that the cost of amino acid synthesis plays a limited role in shaping transcript and protein expression levels compared to that of translational optimisation. Biosynthetic cost does, however, appear to affect rates of amino acid evolution in Saccharomyces, suggesting that expensive amino acids may only be used when they have specific structural or functional roles in protein sequences. However, as there appears to be no single currency to compute the cost of amino acid synthesis across all cellular and environmental conditions, we conclude that a systems approach is necessary to unravel the full effects of amino acid biosynthetic cost in complex biological systems

Lean production and manufacturing performance improvement in Japan, the US and UK 1994-2001

This paper reports the findings of a longitudinal study into manufacturing performance, lean production principles and buyer supplier relations in the Japanese, US and UK automotive industries. A total of 26 first tier component makers in the three countries were subject to detailed benchmarking exercises in 1994 and in 1999-2001. In each exercise data on labour productivity and quality performance were obtained, along with a series of quantitative measures indicating the extent to which each plant conformed to ‘lean production’ principles. The results show that the Japanese plants improved their labour productivity by around 20 per cent between 1994 and 2001, whilst productivity in the US plants remained flat over the same period. All plants improved their quality performance during the period, but the Japanese plants retained their lead with an average external defect rate of 81 parts per million (ppm), compared to 111 ppm for the US plants and 416 ppm in the case of the UK plants. Measures of leanness in the supply chain (inventory levels, delivery frequencies and so on) should be sensitive to any weakening of the inter-firm relationships that have historically characterized the Japanese auto industry. These measures showed no evidence of such weakening, although qualitative evidence suggested that a polarization of the Japanese auto industry may be occurring under the influence of foreign capital, with independent firms such as Toyota and Honda (and their suppliers) retaining a stronger ‘Japanese’ character than their counterparts who have entered into equity relationships with non-Japanese companies

Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis

Objective: Biologic drug therapies represent a huge advance in the treatment of rheumatoid arthritis (RA). However, very good disease control is achieved in only 30% of patients, making identification of biomarkers of response a research priority. We undertook this study to test our hypothesis that differential DNA methylation patterns may provide biomarkers predictive of response to tumor necrosis factor inhibitor (TNFi) therapy in patients with RA. Methods: An epigenome-wide association study was performed on pretreatment whole blood DNA from patients with RA. Patients who displayed good response (n = 36) or no response (n = 36) to etanercept therapy at 3 months were selected. Differentially methylated positions were identified using linear regression. Variance of methylation at differentially methylated positions was assessed for correlation with cis-acting single-nucleotide polymorphisms (SNPs). A replication experiment for prioritized SNPs was performed in an independent cohort of 1,204 RA patients. Results: Five positions that were differentially methylated between responder groups were identified, with a false discovery rate of <5%. The top 2 differentially methylated positions mapped to exon 7 of the LRPAP1 gene on chromosome 4 (cg04857395, P = 1.39 × 10−8 and cg26401028, P = 1.69 × 10−8). The A allele of the SNP rs3468 was correlated with higher levels of methylation for both of the top 2 differentially methylated positions (P = 2.63 × 10−7 and P = 1.05 × 10−6, respectively). Furthermore, the A allele of rs3468 was correlated with European League Against Rheumatism nonresponse in the discovery cohort (P = 0.03; n = 56) and in the independent replication cohort (P = 0.003; n = 1,204). Conclusion: We identify DNA methylation as a potential biomarker of response to TNFi therapy, and we report the association between response and the LRPAP1 gene, which encodes a chaperone of low-density lipoprotein receptor–related protein 1. Additional replication experiments in independent sample collections are now needed

The Victorian Newsletter (Fall 2004)

The Victorian Newsletter is sponsored for the Victorian Group of the Modern Language Association by Western Kentucky University and is published twice annually."Eternal honour to his name": Tennyson's Ode on the Death of the Duke of Wellington and Victorian Memorial Aesthetics / Anna Jane Barton -- Deviance in The Law and the Lady: The Uneasy Positioning of Mr. Dexter / Mary Rosner -- Sympathy and Discipline in Mary Barton / Melissa Schaub -- Victorian Sisterhoods and Female Religious Vocation in Margaret Oliphant's Chronicles of Carlingford / Oliver Lovesey -- Catharsis in George Meredith's Essay on Comedy / Jacob Korg -- Books Receive