Identifying quantitative operation principles in metabolic pathways: a systematic method for searching feasible enzyme activity patterns leading to cellular adaptive responses

<p>Abstract</p> <p>Background</p> <p>Optimization methods allow designing changes in a system so that specific goals are attained. These techniques are fundamental for metabolic engineering. However, they are not directly applicable for investigating the evolution of metabolic adaptation to environmental changes. Although biological systems have evolved by natural selection and result in well-adapted systems, we can hardly expect that actual metabolic processes are at the theoretical optimum that could result from an optimization analysis. More likely, natural systems are to be found in a feasible region compatible with global physiological requirements.</p> <p>Results</p> <p>We first present a new method for globally optimizing nonlinear models of metabolic pathways that are based on the Generalized Mass Action (GMA) representation. The optimization task is posed as a nonconvex nonlinear programming (NLP) problem that is solved by an outer-approximation algorithm. This method relies on solving iteratively reduced NLP slave subproblems and mixed-integer linear programming (MILP) master problems that provide valid upper and lower bounds, respectively, on the global solution to the original NLP. The capabilities of this method are illustrated through its application to the anaerobic fermentation pathway in <it>Saccharomyces cerevisiae</it>. We next introduce a method to identify the feasibility parametric regions that allow a system to meet a set of physiological constraints that can be represented in mathematical terms through algebraic equations. This technique is based on applying the outer-approximation based algorithm iteratively over a reduced search space in order to identify regions that contain feasible solutions to the problem and discard others in which no feasible solution exists. As an example, we characterize the feasible enzyme activity changes that are compatible with an appropriate adaptive response of yeast <it>Saccharomyces cerevisiae </it>to heat shock</p> <p>Conclusion</p> <p>Our results show the utility of the suggested approach for investigating the evolution of adaptive responses to environmental changes. The proposed method can be used in other important applications such as the evaluation of parameter changes that are compatible with health and disease states.</p

Differential Role of Human Choline Kinase α and β Enzymes in Lipid Metabolism: Implications in Cancer Onset and Treatment

11 pages, 6 figures, 1 table.Background The Kennedy pathway generates phosphocoline and phosphoethanolamine through its two branches. Choline Kinase (ChoK) is the first enzyme of the Kennedy branch of synthesis of 1phosphocholine, the major component of the plasma membrane. ChoK family of proteins is composed by ChoKα and ChoKβ isoforms, the first one with two different variants of splicing. Recently ChoKα has been implicated in the carcinogenic process, since it is over-expressed in a variety of human cancers. However, no evidence for a role of ChoKβ in carcinogenesis has been reported. Methodology/Principal Findings Here we compare the in vitro and in vivo properties of ChoKα1 and ChoKβ in lipid metabolism, and their potential role in carcinogenesis. Both ChoKα1 and ChoKβ showed choline and ethanolamine kinase activities when assayed in cell extracts, though with different affinity for their substrates. However, they behave differentially when overexpressed in whole cells. Whereas ChoKβ display an ethanolamine kinase role, ChoKα1 present a dual choline/ethanolamine kinase role, suggesting the involvement of each ChoK isoform in distinct biochemical pathways under in vivo conditions. In addition, while overexpression of ChoKα1 is oncogenic when overexpressed in HEK293T or MDCK cells, ChoKβ overexpression is not sufficient to induce in vitro cell transformation nor in vivo tumor growth. Furthermore, a significant upregulation of ChoKα1 mRNA levels in a panel of breast and lung cancer cell lines was found, but no changes in ChoKβ mRNA levels were observed. Finally, MN58b, a previously described potent inhibitor of ChoK with in vivo antitumoral activity, shows more than 20-fold higher efficiency towards ChoKα1 than ChoKβ. Conclusion/Significance This study represents the first evidence of the distinct metabolic role of ChoKα and ChoKβ isoforms, suggesting different physiological roles and implications in human carcinogenesis. These findings constitute a step forward in the design of an antitumoral strategy based on ChoK inhibition.This work has been supported by grants to JCL from Comunidad de Madrid (GR-SAL-0821-2004), Ministerio de Ciencia e Innovación (SAF2008-03750, RD06/0020/0016), Fundación Mutua Madrileña, and by a grant to ARM from Fundación Mutua Madrileña.Peer reviewe

The role of receptivity in the courtship behavior of Podocnemis erythrocephala in captivity

The courtship behavior of Podocnemis erythrocephala (Red-headed Amazon River Turtle) in captivity was studied to examine female receptivity and male response to female rejection. We observed 20 females and 39 males in 150 sessions (3–6 h/day for a total of 450 h). In 36% of the trials, there was no interaction between males and females, and 20% of the trials resulted in copulations. All males introduced into tanks approached females, and eventually there was aggression among the males. In 48% of the experiments, females also searched for or approached males. When males initially approached females, they either accepted the male’s advances (14%), rejected the male passively (38%), or rejected the male aggressively (48%). In 86% of the cases where males were rejected, 4% attempted to approach females again, and in 51% they were ultimately successful

Metabolic assessment of the action of targeted cancer therapeutics using magnetic resonance spectroscopy

Developing rational targeted cancer drugs requires the implementation of pharmacodynamic (PD), preferably non-invasive, biomarkers to aid response assessment and patient follow-up. Magnetic resonance spectroscopy (MRS) allows the non-invasive study of tumour metabolism. We describe the MRS-detectable PD biomarkers resulting from the action of targeted therapeutics, and discuss their biological significance and future translation into clinical use

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Evaluation of serum CEA, CYFRA21-1 and CA125 for the early detection of colorectal cancer using longitudinal preclinical samples

Blood-borne biomarkers for early detection of colorectal cancer (CRC) could markedly increase screening uptake. The aim of this study was to evaluate serum carcinoembryonic antigen (CEA), CYFRA21-1 and CA125 for the early detection of CRC in an asymptomatic cohort

Latest Miocene restriction of the Mediterranean Outflow Water:a perspective from the Gulf of Cádiz

The Mediterranean-Atlantic water mass exchange provides the ideal setting for deciphering the role of gateway evolution in ocean circulation. However, the dynamics of Mediterranean Outflow Water (MOW) during the closure of the Late Miocene Mediterranean-Atlantic gateways are poorly understood. Here, we define the sedimentary evolution of Neogene basins from the Gulf of Cádiz to the West Iberian margin to investigate MOW circulation during the latest Miocene. Seismic interpretation highlights a middle to upper Messinian seismic unit of transparent facies, whose base predates the onset of the Messinian salinity crisis (MSC). Its facies and distribution imply a predominantly hemipelagic environment along the Atlantic margins, suggesting an absence or intermittence of MOW preceding evaporite precipitation in the Mediterranean, simultaneous to progressive gateway restriction. The removal of MOW from the Mediterranean-Atlantic water mass exchange reorganized the Atlantic water masses and is correlated to a severe weakening of the Atlantic Meridional Overturning Circulation (AMOC) and a period of further cooling in the North Atlantic during the latest Miocene

Prognostic value of metabolic response in breast cancer patients receiving neoadjuvant chemotherapy

<p>Abstract</p> <p>Background</p> <p>Today's clinical diagnostic tools are insufficient for giving accurate prognosis to breast cancer patients. The aim of our study was to examine the tumor metabolic changes in patients with locally advanced breast cancer caused by neoadjuvant chemotherapy (NAC), relating these changes to clinical treatment response and long-term survival.</p> <p>Methods</p> <p>Patients (n = 89) participating in a randomized open-label multicenter study were allocated to receive either NAC as epirubicin or paclitaxel monotherapy. Biopsies were excised pre- and post-treatment, and analyzed by high resolution magic angle spinning magnetic resonance spectroscopy (HR MAS MRS). The metabolite profiles were examined by paired and unpaired multivariate methods and findings of important metabolites were confirmed by spectral integration of the metabolite peaks.</p> <p>Results</p> <p>All patients had a significant metabolic response to NAC, and pre- and post-treatment spectra could be discriminated with 87.9%/68.9% classification accuracy by paired/unpaired partial least squares discriminant analysis (PLS-DA) (<it>p </it>< 0.001). Similar metabolic responses were observed for the two chemotherapeutic agents. The metabolic responses were related to patient outcome. Non-survivors (< 5 years) had increased tumor levels of lactate (<it>p </it>= 0.004) after treatment, while survivors (≥ 5 years) experienced a decrease in the levels of glycine (<it>p </it>= 0.047) and choline-containing compounds (<it>p </it>≤ 0.013) and an increase in glucose (<it>p </it>= 0.002) levels. The metabolic responses were not related to clinical treatment response.</p> <p>Conclusions</p> <p>The differences in tumor metabolic response to NAC were associated with breast cancer survival, but not to clinical response. Monitoring metabolic responses to NAC by HR MAS MRS may provide information about tumor biology related to individual prognosis.</p