Effect of macromolecular crowding on the kinetics of glycolytic enzymes and the behaviour of glycolysis in yeast

Water is involved in all aspects of biological activity, both as a solvent and as a reactant. It is hypothesized that intracellular water is in a highly structured state due to the high concentrations of macromolecules in the cell and that this may change the activity of intracellular enzymes due to altered binding affinities and allosteric regulations. Here we first investigate the kinetics of two glycolytic enzymes in artificially crowded aqueous solutions and show that crowding does indeed change their kinetics. Based on our kinetic measurements we propose a new model of oscillating glycolysis that instead of Michaelis-Menten or Monod-Wyman-Changeux kinetics uses the Yang-Ling adsorption isotherm introduced by G. Ling in the frame of the Association-Induction (AI) hypothesis. Using this model, we can reproduce previous experimental observations of the coupling of glycolytic oscillations and intracellular water dynamics, e.g., (i) during the metabolic oscillations, the latter variable oscillates in phase with ATP activity, and (ii) the emergence of glycolytic oscillations largely depends on the extent of intracellular water dipolar relaxation in cells in the resting state. Our results support the view that the extent of intracellular water dipolar relaxation is regulated by the ability of cytoplasmic proteins to polarize intracellular water with the assistance of ATP, as suggested in the AI hypothesis. This hypothesis may be relevant to the interpretation of many other biological oscillators, including cell signalling processes.Fil: Thoke, Henrik S.. University Of Southern Denmark; DinamarcaFil: Bagatolli, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Olsen, Lars F.. University Of Southern Denmark; Dinamarc

Coupled response of membrane hydration with oscillating metabolism in live cells: An alternative way to modulate structural aspects of biological membranes?

We propose that active metabolic processes may regulate structural changes in biological membranes via the physical state of cell water. This proposition is based on recent results obtained from our group in yeast cells displaying glycolytic oscillations, where we demonstrated that there is a tight coupling between the oscillatory behavior of glycolytic metabolites (ATP, NADH) and the extent of the dipolar relaxation of intracellular water, which oscillates synchronously. The mechanism we suggest involves the active participation of a polarized intracellular water network whose degree of polarization is dynamically modulated by temporal ATP fluctuations caused by metabolism with intervention of a functional cytoskeleton, as conceived in the long overlooked association-induction hypothesis (AIH) of Gilbert Ling. Our results show that the polarized state of intracellular water can be propagated from the cytosol to regions containing membranes. Since changes in the extent of the polarization of water impinge on its chemical activity, we hypothesize that metabolism dynamically controls the local structure of cellular membranes via lyotropic effects. This hypothesis offers an alternative way to interpret membrane related phenomena (e.g., changes in local curvature pertinent to endo/exocytosis or dynamical changes in membranous organelle structure, among others) by integrating relevant but mostly overlooked physicochemical characteristics of the cellular milieu.Fil: Bagatolli, Luis Alberto. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra. Universidad Nacional de Córdoba. Instituto de Investigación Médica Mercedes y Martín Ferreyra; ArgentinaFil: Stock, Roberto P.. International and Interdisciplinary Research Network; DinamarcaFil: Olsen, Lars F.. University Of Southern Denmark; Dinamarc

Lessons learned from the commercial exploitation of marine battery energy storage systems

Large, reliable, and economically viable battery energy storage systems (BESSs) play a crucial role in electrifying the maritime industry. In this paper, we draw from the experiences of over 750 recent commercial marine BESS installations to bridge the gap between research findings and industrial needs in four key areas: (i) Decision-making for installations: We introduce a go/no-go-decision matrix for assessing the feasibility of installations in a maritime context. (ii) Safe and cost-effective installations: This study evaluates the risks and expenses associated with these BESS installations, including retrofitting a 500 kWh BESS (total costs: 1.3 million euros; 2600 euros per kWh), installing a 4.5 MWh BESS (5 million euros; 1100 euros per kWh), and an unsuccessful attempt to retrofit an 800 kWh BESS. (iii) Operation analysis: We delve into the operational outcomes of BESSs deployed on 47 offshore supply vessels (OSVs) (ranging from 452 to 1424 kWh) and a large 4.5 MWh BESS on a newly constructed cruise ship. The application of the equivalent full cycle (EFC) method reveals that the operational EFCs were notably lower than the designed EFCs. The proposed two new evaluation criteria assess the annual fuel saving resulting from BESS installed per kWh and per EFC. Over a two-year period, the 4.5 MWh BESS demonstrated fuel saving of 1–2 % as compared to the 5 % target. Addressing converter losses during low-power BESS operation modes necessitates further investigation. (iv) Further development: This study advocates for research aimed at enhancing safety measures, exploring onshore/offshore power supply and charging, optimizing multi-objective operations, and progressing towards zero emissions. The insights gathered in this paper can serve as a valuable resource for ship support ship owners and operators seeking to kick-off faster or to install more BESSs on their vessels and optimize their operational effectiveness

Some elements for a history of the dynamical systems theory

Leon Glass would like to thank the Natural Sciences and Engineering Research Council (Canada) for its continuous support of curiosity-driven research for over 40 years starting with the events recounted here. He also thanks his colleagues and collaborators including Stuart Kauffman, Rafael Perez, Ronald Shymko, Michael Mackey for their wonderful insights and collaborations during the times recounted here. R.G. is endebted to the following friends and colleagues, listed in the order encountered on the road described: F. T. Arecchi, L. M. Narducci, J. R. Tredicce, H. G. Solari, E. Eschenazi, G. B. Mindlin, J. L. Birman, J. S. Birman, P. Glorieux, M. Lefranc, C. Letellier, V. Messager, O. E. Rössler, R. Williams. U.P. would like to thank the following friends and colleagues who accompanied his first steps into the world of nonlinear phenomena: U. Dressler, I. Eick, V. Englisch, K. Geist, J. Holzfuss, T. Klinker, W. Knop, A. Kramer, T. Kurz, W. Lauterborn, W. Meyer-Ilse, C. Scheffczyk, E. Suchla and M. Wisenfeldt. The work by L. Pecora and T. Carroll was supported directly by the Office of Naval Research (ONR) and by ONR through the Naval Research Laboratory’s Basic Research Program. C.L. would like to thank Jürgen Kurths for his support to this project.Peer reviewedPostprintPublisher PD

Impact of blinding on estimated treatment effects in randomised clinical trials:meta-epidemiological study

International audienceAbstract Objectives To study the impact of blinding on estimated treatment effects, and their variation between trials; differentiating between blinding of patients, healthcare providers, and observers; detection bias and performance bias; and types of outcome (the MetaBLIND study). Design Meta-epidemiological study. Data source Cochrane Database of Systematic Reviews (2013-14). Eligibility criteria for selecting studies Meta-analyses with both blinded and non-blinded trials on any topic. Review methods Blinding status was retrieved from trial publications and authors, and results retrieved automatically from the Cochrane Database of Systematic Reviews. Bayesian hierarchical models estimated the average ratio of odds ratios (ROR), and estimated the increases in heterogeneity between trials, for non-blinded trials (or of unclear status) versus blinded trials. Secondary analyses adjusted for adequacy of concealment of allocation, attrition, and trial size, and explored the association between outcome subjectivity (high, moderate, low) and average bias. An ROR lower than 1 indicated exaggerated effect estimates in trials without blinding. Results The study included 142 meta-analyses (1153 trials). The ROR for lack of blinding of patients was 0.91 (95% credible interval 0.61 to 1.34) in 18 meta-analyses with patient reported outcomes, and 0.98 (0.69 to 1.39) in 14 meta-analyses with outcomes reported by blinded observers. The ROR for lack of blinding of healthcare providers was 1.01 (0.84 to 1.19) in 29 meta-analyses with healthcare provider decision outcomes (eg, readmissions), and 0.97 (0.64 to 1.45) in 13 meta-analyses with outcomes reported by blinded patients or observers. The ROR for lack of blinding of observers was 1.01 (0.86 to 1.18) in 46 meta-analyses with subjective observer reported outcomes, with no clear impact of degree of subjectivity. Information was insufficient to determine whether lack of blinding was associated with increased heterogeneity between trials. The ROR for trials not reported as double blind versus those that were double blind was 1.02 (0.90 to 1.13) in 74 meta-analyses. Conclusion No evidence was found for an average difference in estimated treatment effect between trials with and without blinded patients, healthcare providers, or outcome assessors. These results could reflect that blinding is less important than often believed or meta-epidemiological study limitations, such as residual confounding or imprecision. At this stage, replication of this study is suggested and blinding should remain a methodological safeguard in trials

Natriuretic peptides and integrated risk assessment for cardiovascular disease. an individual-participant-data meta-analysis

BACKGROUND: Guidelines for primary prevention of cardiovascular diseases focus on prediction of coronary heart disease and stroke. We assessed whether or not measurement of N-terminal-pro-B-type natriuretic peptide (NT-proBNP) concentration could enable a more integrated approach than at present by predicting heart failure and enhancing coronary heart disease and stroke risk assessment. METHODS: In this individual-participant-data meta-analysis, we generated and harmonised individual-participant data from relevant prospective studies via both de-novo NT-proBNP concentration measurement of stored samples and collection of data from studies identified through a systematic search of the literature (PubMed, Scientific Citation Index Expanded, and Embase) for articles published up to Sept 4, 2014, using search terms related to natriuretic peptide family members and the primary outcomes, with no language restrictions. We calculated risk ratios and measures of risk discrimination and reclassification across predicted 10 year risk categories (ie, <5%, 5% to <7·5%, and ≥7·5%), adding assessment of NT-proBNP concentration to that of conventional risk factors (ie, age, sex, smoking status, systolic blood pressure, history of diabetes, and total and HDL cholesterol concentrations). Primary outcomes were the combination of coronary heart disease and stroke, and the combination of coronary heart disease, stroke, and heart failure. FINDINGS: We recorded 5500 coronary heart disease, 4002 stroke, and 2212 heart failure outcomes among 95 617 participants without a history of cardiovascular disease in 40 prospective studies. Risk ratios (for a comparison of the top third vs bottom third of NT-proBNP concentrations, adjusted for conventional risk factors) were 1·76 (95% CI 1·56-1·98) for the combination of coronary heart disease and stroke and 2·00 (1·77-2·26) for the combination of coronary heart disease, stroke, and heart failure. Addition of information about NT-proBNP concentration to a model containing conventional risk factors was associated with a C-index increase of 0·012 (0·010-0·014) and a net reclassification improvement of 0·027 (0·019-0·036) for the combination of coronary heart disease and stroke and a C-index increase of 0·019 (0·016-0·022) and a net reclassification improvement of 0·028 (0·019-0·038) for the combination of coronary heart disease, stroke, and heart failure. INTERPRETATION: In people without baseline cardiovascular disease, NT-proBNP concentration assessment strongly predicted first-onset heart failure and augmented coronary heart disease and stroke prediction, suggesting that NT-proBNP concentration assessment could be used to integrate heart failure into cardiovascular disease primary prevention

Serum concentrations of phthalate metabolites are related to abdominal fat distribution two years later in elderly women

BACKGROUND: Phthalates, commonly used to soften plastic goods, are known PPAR-agonists affecting lipid metabolism and adipocytes in the experimental setting. We evaluated if circulating concentrations of phthalates were related to different indices of obesity using data from the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS) study. Data from both dual-energy X-ray absorptiometry (DXA) and abdominal magnetic resonance imaging (MRI) were used. METHODS: 1,016 subjects aged 70 years were investigated in the PIVUS study. Four phthalate metabolites were detected in the serum of almost all subjects (&gt; 96%) by an API 4000 liquid chromatograph/tandem mass spectrometer. Abdominal MRI was performed in a representative subsample of 287 subjects (28%), and a dual-energy X-ray absorptiometry (DXA)-scan was obtained in 890 (88%) of the subjects two year following the phthalate measurements. RESULTS: In women, circulating concentrations of mono-isobutyl phthalate (MiBP) were positively related to waist circumference, total fat mass and trunk fat mass by DXA, as well as to subcutaneous adipose tissue by MRI following adjustment for serum cholesterol and triglycerides, education, smoking and exercise habits (all p &lt; 0.008). Mono-methyl phthalate (MMP) concentrations were related to trunk fat mass and the trunk/leg-ratio by DXA, but less powerful than MiBP. However, no such statistically significant relationships were seen in men. CONCLUSIONS: The present evaluation shows that especially the phthalate metabolite MiBP was related to increased fat amount in the subcutaneous abdominal region in women measured by DXA and MRI two years later