Metabolic Futile Cycles and Their Functions: A Systems Analysis of Energy and Control

It has long been hypothesized that futile cycles in cellular metabolism are involved in the regulation of biochemical pathways. Following the work of Newsholme and Crabtree, we develop a quantitative theory for this idea based on open-system thermodynamics and metabolic control analysis. It is shown that the {\it stoichiometric sensitivity} of an intermediary metabolite concentration with respect to changes in steady-state flux is governed by the effective equilibrium constant of the intermediate formation, and the equilibrium can be regulated by a futile cycle. The direction of the shift in the effective equilibrium constant depends on the direction of operation of the futile cycle. High stoichiometric sensitivity corresponds to ultrasensitivity of an intermediate concentration to net flow through a pathway; low stoichiometric sensitivity corresponds to super-robustness of concentration with respect to changes in flux. Both cases potentially play important roles in metabolic regulation. Futile cycles actively shift the effective equilibrium by expending energy; the magnitude of changes in effective equilibria and sensitivities is a function of the amount of energy used by a futile cycle. This proposed mechanism for control by futile cycles works remarkably similarly to kinetic proofreading in biosynthesis. The sensitivity of the system is also intimately related to the rate of concentration fluctuations of intermediate metabolites. The possibly different roles of the two major mechanisms for cellular biochemical regulation, namely reversible chemical modifications via futile cycles and shifting equilibrium by macromolecular binding, are discussed.Comment: 11 pages, 5 figure

Fluctuating Elastic Rings: Statics and Dynamics

We study the effects of thermal fluctuations on elastic rings. Analytical expressions are derived for correlation functions of Euler angles, mean square distance between points on the ring contour, radius of gyration, and probability distribution of writhe fluctuations. Since fluctuation amplitudes diverge in the limit of vanishing twist rigidity, twist elasticity is essential for the description of fluctuating rings. We find a crossover from a small scale regime in which the filament behaves as a straight rod, to a large scale regime in which spontaneous curvature is important and twist rigidity affects the spatial configurations of the ring. The fluctuation-dissipation relation between correlation functions of Euler angles and response functions, is used to study the deformation of the ring by external forces. The effects of inertia and dissipation on the relaxation of temporal correlations of writhe fluctuations, are analyzed using Langevin dynamics.Comment: 43 pages, 9 Figure

Signatures of Spin and Charge Energy Scales in the Local Moment and Specific Heat of the Two-Dimensional Hubbard Model

Local moment formation driven by the on--site repulsion $U$ is one of the most fundamental features in the Hubbard model. At the simplest level, the temperature dependence of the local moment is expected to have a single structure at $T \sim U$, reflecting the suppression of the double occupancy. In this paper we show new low temperature Quantum Monte Carlo data which emphasize that the local moment also has a signature at a lower energy scale which previously had been thought to characterize only the temperatures below which moments on {\it different} sites begin to correlate locally. We discuss implications of these results for the structure of the specific heat, and connections to quasiparticle resonance and pseudogap formation in the density of states.Comment: 13 pages, 19 figure

Growing Environmental Activists: Developing Environmental Agency and Engagement Through Children’s Fiction.

We explore how story has the potential to encourage environmental engagement and a sense of agency provided that critical discussion takes place. We illuminate this with reference to the philosophies of John Macmurray on personal agency and social relations; of John Dewey on the primacy of experience for philosophy; and of Paul Ricoeur on hermeneutics, dialogue, dialectics and narrative. We view the use of fiction for environmental understanding as hermeneutic, a form of conceptualising place which interprets experience and perception. The four writers for young people discussed are Ernest Thompson Seton, Kenneth Grahame, Michelle Paver and Philip Pullman. We develop the concept of critical dialogue, and link this to Crick's demand for active democratic citizenship. We illustrate the educational potential for environmental discussions based on literature leading to deeper understanding of place and environment, encouraging the belief in young people that they can be and become agents for change. We develop from Zimbardo the key concept of heroic resister to encourage young people to overcome peer pressure. We conclude with a call to develop a greater awareness of the potential of fiction for learning, and for writers to produce more focused stories engaging with environmental responsibility and activism

Sign patterns for chemical reaction networks

Most differential equations found in chemical reaction networks (CRNs) have the form $dx/dt=f(x)= Sv(x)$, where $x$ lies in the nonnegative orthant, where $S$ is a real matrix (the stoichiometric matrix) and $v$ is a column vector consisting of real-valued functions having a special relationship to $S$. Our main interest will be in the Jacobian matrix, $f'(x)$, of $f(x)$, in particular in whether or not each entry $f'(x)_{ij}$ has the same sign for all $x$ in the orthant, i.e., the Jacobian respects a sign pattern. In other words species $x_j$ always acts on species $x_i$ in an inhibitory way or its action is always excitatory. In Helton, Klep, Gomez we gave necessary and sufficient conditions on the species-reaction graph naturally associated to $S$ which guarantee that the Jacobian of the associated CRN has a sign pattern. In this paper, given $S$ we give a construction which adds certain rows and columns to $S$, thereby producing a stoichiometric matrix $\widehat S$ corresponding to a new CRN with some added species and reactions. The Jacobian for this CRN based on $\hat S$ has a sign pattern. The equilibria for the $S$ and the $\hat S$ based CRN are in exact one to one correspondence with each equilibrium $e$ for the original CRN gotten from an equilibrium $\hat e$ for the new CRN by removing its added species. In our construction of a new CRN we are allowed to choose rate constants for the added reactions and if we choose them large enough the equilibrium $\hat e$ is locally asymptotically stable if and only if the equilibrium $e$ is locally asymptotically stable. Further properties of the construction are shown, such as those pertaining to conserved quantities and to how the deficiencies of the two CRNs compare.Comment: 23 page

Quantification of myocardial creatine and triglyceride content in the human heart: precision and accuracy of in vivo proton magnetic resonance spectroscopy

Background Proton magnetic resonance spectroscopy (H-1-MRS) of the human heart is deemed to be a quantitative method to investigate myocardial metabolite content, but thorough validations of in vivo measurements against invasive techniques are lacking.Purpose To determine measurement precision and accuracy for quantifications of myocardial total creatine and triglyceride content with localized H-1-MRS.Study type Test-retest repeatability and measurement validation study.Subjects Sixteen volunteers and 22 patients scheduled for open-heart aortic valve replacement or septal myectomy.Field Strength/Sequence Prospectively ECG-triggered respiratory-gated free-breathing single-voxel point-resolved spectroscopy (PRESS) sequence at 3 T.Assessment Myocardial total creatine and triglyceride content were quantified relative to the total water content by fitting the H-1-MR spectra. Precision was assessed with measurement repeatability. Accuracy was assessed by validating in vivo H-1-MRS measurements against biochemical assays in myocardial tissue from the same subjects.Statistical Tests Intrasession and intersession repeatability was assessed using Bland-Altman analyses. Agreement between H-1-MRS measurements and biochemical assay was tested with regression analyses.Results The intersession repeatability coefficient for myocardial total creatine content was 41.8% with a mean value of 0.083% +/- 0.020% of the total water signal, and 36.7% for myocardial triglyceride content with a mean value of 0.35% +/- 0.13% of the total water signal. Ex vivo myocardial total creatine concentrations in tissue samples correlated with the in vivo myocardial total creatine content measured with H-1-MRS: n = 22, r = 0.44; P < 0.05. Likewise, ex vivo myocardial triglyceride concentrations correlated with the in vivo myocardial triglyceride content: n = 20, r = 0.50; P < 0.05.Data Conclusion We validated the use of localized H-1-MRS of the human heart at 3 T for quantitative assessments of in vivo myocardial tissue metabolite content by estimating the measurement precision and accuracy.Level of Evidence 2Technical Efficacy Stage 2Cardiovascular Aspects of Radiolog

In search of disorders: internalizing symptom networks in a large clinical sample.

Background The co‐occurrence of internalizing disorders is a common form of psychiatric comorbidity, raising questions about the boundaries between these diagnostic categories. We employ network psychometrics in order to: (a) determine whether internalizing symptoms cluster in a manner reflecting DSM diagnostic criteria, (b) gauge how distinct these diagnostic clusters are and (c) examine whether this network structure changes from childhood to early and then late adolescence. Method Symptom‐level data were obtained for service users in publicly funded mental health services in England between 2011 and 2015 (N = 37,162). A symptom network (i.e. Gaussian graphical model) was estimated, and a community detection algorithm was used to explore the clustering of symptoms. Results The estimated network was densely connected and characterized by a multitude of weak associations between symptoms. Six communities of symptoms were identified; however, they were weakly demarcated. Two of these communities corresponded to social phobia and panic disorder, and four did not clearly correspond with DSM diagnostic categories. The network structure was largely consistent by sex and across three age groups (8–11, 12–14 and 15–18 years). Symptom connectivity in the two older age groups was significantly greater compared to the youngest group and there were differences in centrality across the age groups, highlighting the age‐specific relevance of certain symptoms. Conclusions These findings clearly demonstrate the interconnected nature of internalizing symptoms, challenging the view that such pathology takes the form of distinct disorders