Statistical mechanics for metabolic networks during steady-state growth

Which properties of metabolic networks can be derived solely from stoichiometric information about the network's constituent reactions? Predictive results have been obtained by Flux Balance Analysis (FBA), by postulating that cells set metabolic fluxes within the allowed stoichiometry so as to maximize their growth. Here, we generalize this framework to single cell level using maximum entropy models from statistical physics. We define and compute, for the core metabolism of Escherichia coli, a joint distribution over all fluxes that yields the experimentally observed growth rate. This solution, containing FBA as a limiting case, provides a better match to the measured fluxes in the wild type and several mutants. We find that E. coli metabolism is close to, but not at, the optimality assumed by FBA. Moreover, our model makes a wide range of predictions: (i) on flux variability, its regulation, and flux correlations across individual cells; (ii) on the relative importance of stoichiometric constraints vs. growth rate optimization; (iii) on quantitative scaling relations for singe-cell growth rate distributions. We validate these scaling predictions using data from individual bacterial cells grown in a microfluidic device at different sub-inhibitory antibiotic concentrations. Under mild dynamical assumptions, fluctuation-response relations further predict the autocorrelation timescale in growth data and growth rate adaptation times following an environmental perturbation.Comment: 12 pages, 4 figure

A far UV study of interstellar gas towards HD34078: high excitation H2 and small scale structure - Based on observations performed by the FUSE mission and at the CFHT telescope

To investigate the presence of small scale structure in the spatial distribution of H2 molecules we have undertaken repeated FUSE UV observations of the runaway O9.5V star, HD34078. In this paper we present five spectra obtained between January 2000 and October 2002. These observations reveal an unexpectedly large amount of highly excited H2. Column densities for H2 levels from (v = 0, J = 0) up to (v = 0, J = 11) and for several v = 1 and v = 2 levels are determined. These results are interpreted in the frame of a model involving essentially two components: i) a foreground cloud (unaffected by HD34078) responsible for the H2 (J = 0, 1), CI, CH, CH+ and CO absorptions; ii) a dense layer of gas (n = 10E4 cm-3) close to the O star and strongly illuminated by its UV flux which accounts for the presence of highly excited H2. Our model successfully reproduces the H2 excitation, the CI fine-structure level populations as well as the CH, CH+ and CO column densities. We also examine the time variability of H2 absorption lines tracing each of these two components. From the stability of the J = 0, 1 and 2 damped H2 profiles we infer a 3 sigma upper limit on column density variations Delta(N(H2))/N(H2) of 5% over scales ranging from 5 to 50 AU. This result clearly rules out any pronounced ubiquitous small scale "density" structure of the kind apparently seen in HI. The lines from highly excited gas are also quite stable (equivalent to Delta(N)/N <= 30%) indicating i) that the ambient gas through which HD34078 is moving is relatively uniform and ii) that the gas flow along the shocked layer is not subject to marked instabilitie

Chronic musculoskeletal pain predicted hospitalisation due to serious medical conditions in a 10 year follow up study

BACKGROUND: The aim was to examine if self reported chronic regional pain (CRP) and chronic widespread pain (CWP) predicted inpatient care due to serious medical conditions such as cerebrovascular diseases, ischemic heart diseases, neoplasms and infectious diseases in a general population cohort over a ten year follow-up period.METHODS: A ten-year follow up of a cohort from the general adult population in two health care districts with mixed urban and rural population in the south of Sweden, that in 1995 participated in a survey on health and musculoskeletal pain experience. Information on hospitalisation for each subject was taken from the regional health care register. Multiple logistic regression analyses were used to study the associations between chronic musculoskeletal pain and different medical conditions as causes of hospitalisation.RESULTS: A report of CRP (OR = 1.6; p < 0.001) or CWP ( OR = 2.1; p < 0.001) predicted at least one episode of inpatient care over a ten year period, with an increased risk in almost all diagnostic subgroups, including cerebrovascular diseases, ischemic heart diseases, and infectious diseases. There was however no increased risk of hospitalisation due to neoplasms.CONCLUSIONS: The presence of especially CWP was associated with hospital inpatient care due to several serious medical disorders. This may imply a general vulnerability to different medical conditions that has to be addressed in the assessment and management of subjects with chronic musculoskeletal pain

The genetic basis of the fitness costs of antimicrobial resistance : : a meta-analysis approach

Peer reviewedPublisher PD

Coupling of alpha(1)-Adrenoceptors to ERK1/2 in the Human Prostate

Introduction: alpha(1)-Adrenoceptors are considered critical for the regulation of prostatic smooth muscle tone. However, previous studies suggested further alpha(1)-adrenoceptor functions besides contraction. Here, we investigated whether alpha(1)-adrenoceptors in the human prostate may activate extracellular signal-regulated kinases (ERK1/2). Methods: Prostate tissues from patients undergoing radical prostatectomy were stimulated in vitro. Activation of ERK1/2 was assessed by Western blot analysis. Expression of ERK1/2 was studied by immunohistochemistry. The effect of ERK1/2 inhibition by U0126 on phenylephrine-induced contraction was studied in organ-bath experiments. Results: Stimulation of human prostate tissue with noradrenaline (30 mu M) or phenylephrine (10 mu M) resulted in ERK activation. This was reflected by increased levels of phosphorylated ERK1/2. Expression of ERK1/2 in the prostate was observed in smooth muscle cells. Incubation of prostate tissue with U0126 (30 mu M) resulted in ERK1/2 inhibition. Dose-dependent phenylephrine-induced contraction of prostate tissue was not modulated by U0126. Conclusions: alpha(1)-Adrenoceptors in the human prostate are coupled to ERK1/2. This may partially explain previous observations suggesting a role of alpha(1)-adrenoceptors in the regulation of prostate growth. Copyright (C) 2011 S. Karger AG, Base

Slow nonequilibrium dynamics: parallels between classical and quantum glasses and gently driven systems

We review an scenario for the non-equilibrium dynamics of glassy systems that has been motivated by the exact solution of simple models. This approach allows one to set on firmer grounds well-known phenomenological theories. The old ideas of entropy crisis, fictive temperatures, free-volume... have clear definitions within these models. Aging effects in the glass phase are also captured. One of the salient features of the analytic solution, the breakdown of the fluctuation-dissipation relations, provides a definition of a bonafide {\it effective temperature} that is measurable by a thermometer, controls heat flows, partial equilibrations, and the reaction to the external injection of heat. The effective temperature is an extremely robust concept that appears in non-equilibrium systems in the limit of small entropy production as, for instance, sheared fluids, glasses at low temperatures when quantum fluctuations are relevant, tapped or vibrated granular matter, etc. The emerging scenario is one of partial equilibrations, in which glassy systems arrange their internal degrees of freedom so that the slow ones select their own effective temperatures. It has been proven to be consistent within any perturbative resummation scheme (mode coupling, etc) and it can be challenged by experimental and numerical tests, some of which it has already passed.Comment: 15 pages, 8 figure

Muscarinic receptor subtypes and signalling involved in the attenuation of isoprenaline-induced rat urinary bladder relaxation

β-Adrenoceptors are important mediators of smooth muscle relaxation in the urinary bladder, but the concomitant presence of a muscarinic agonist, e.g., carbachol, can attenuate relaxation responses by reducing potency and/or efficacy of β-adrenoceptor agonists such as isoprenaline. Therefore, the present study was designed to explore the subtypes and signalling pathways of muscarinic receptors involved in the attenuation of isoprenaline-induced isolated rat detrusor preparations using novel subtype-selective receptor ligands. In radioligand binding studies, we characterized BZI to be a M3-sparing muscarinic agonist, providing selective M2 stimulation in rat bladder, and THRX-182087 as a highly M2-selective antagonist. The use of BZI and of THRX-182087 in the presence of carbachol enabled experimental conditions with a selective stimulation of only M2 or M3 receptors, respectively. Confirming previous findings, carbachol attenuated isoprenaline-induced detrusor relaxation. M2-selective stimulation partly mimicked this attenuation, indicating that both M2 and M3 receptors are involved. During M3-selective stimulation, the attenuation of isoprenaline responses was reduced by the phospholipase C inhibitor U 73,122 but not by the protein kinase C inhibitor chelerythrine. We conclude that both M2 and M3 receptors contribute to attenuation of β-adrenoceptor-mediated relaxation of rat urinary bladder; the signal transduction pathway involved in the M3 component of this attenuation differs from that mediating direct contractile effects of M3 receptors

Effect of pre-contraction on β-adrenoceptor-mediated relaxation of rat urinary bladder

Purpose The human physiological bladder contraction is largely mediated by acetylcholine acting on muscarinic receptors, but in pathophysiological settings the relative role of non-cholinergic stimuli gains importance. beta-Adrenoceptor agonists are currently in clinical development as treatments for the overactive bladder syndrome. Therefore, we have explored the ability of the beta-adrenoceptor agonist isoprenaline to induce rat isolated bladder strip relaxation on pre-contraction with the muscarinic agonist carbachol as compared to bladder tone induced by several non-cholinergic stimuli. Methods Bladder tone was induced by passive tension, receptor independently by KCl, carbachol, bradykinin or serotonin. Concentration-response curves were generated for relaxation by isoprenaline, and a single concentration of the receptor-independent relaxant forskolin was also tested. Results The various contractile stimuli induced different degrees of bladder tone, but the ability of isoprenaline or forskolin to relax rat bladder was not correlated with the degree of tone. Isoprenaline was significantly less potent and effective in causing relaxation against carbachol-induced tone than against any other stimulus, whereas no such relationship was observed for forskolin. Conclusions We conclude that beta-adrenoceptor agonists can induce rat bladder relaxation against a wide range of contractile stimuli and are more potent and/or effective against non-cholinergic stimuli than against muscarinic agonism. This profile appears desirable for agents intended for the treatment of overactive bladde

Sexual selection protects against extinction

Reproduction through sex carries substantial costs, mainly because only half of sexual adults produce offspring. It has been theorised that these costs could be countered if sex allows sexual selection to clear the universal fitness constraint of mutation load. Under sexual selection, competition between (usually) males, and mate choice by (usually) females create important intraspecific filters for reproductive success, so that only a subset of males gains paternity. If reproductive success under sexual selection is dependent on individual condition, which depends on mutation load, then sexually selected filtering through ‘genic capture’ could offset the costs of sex because it provides genetic benefits to populations. Here, we test this theory experimentally by comparing whether populations with histories of strong versus weak sexual selection purge mutation load and resist extinction differently. After evolving replicate populations of the flour beetle Tribolium castaneum for ~7 years under conditions that differed solely in the strengths of sexual selection, we revealed mutation load using inbreeding. Lineages from populations that had previously experienced strong sexual selection were resilient to extinction and maintained fitness under inbreeding, with some families continuing to survive after 20 generations of sib × sib mating. By contrast, lineages derived from populations that experienced weak or non-existent sexual selection showed rapid fitness declines under inbreeding, and all were extinct after generation 10. Multiple mutations across the genome with individually small effects can be difficult to clear, yet sum to a significant fitness load; our findings reveal that sexual selection reduces this load, improving population viability in the face of genetic stress