Growing a list

It is easy to find expert knowledge on the Internet on almost any topic, but obtaining a complete overview of a given topic is not always easy: Information can be scattered across many sources and must be aggregated to be useful. We introduce a method for intelligently growing a list of relevant items, starting from a small seed of examples. Our algorithm takes advantage of the wisdom of the crowd, in the sense that there are many experts who post lists of things on the Internet. We use a collection of simple machine learning components to find these experts and aggregate their lists to produce a single complete and meaningful list. We use experiments with gold standards and open-ended experiments without gold standards to show that our method significantly outperforms the state of the art. Our method uses the clustering algorithm Bayesian Sets even when its underlying independence assumption is violated, and we provide a theoretical generalization bound to motivate its use.

Molecular crowding defines a common origin for the Warburg effect in proliferating cells and the lactate threshold in muscle physiology

Aerobic glycolysis is a seemingly wasteful mode of ATP production that is seen both in rapidly proliferating mammalian cells and highly active contracting muscles, but whether there is a common origin for its presence in these widely different systems is unknown. To study this issue, here we develop a model of human central metabolism that incorporates a solvent capacity constraint of metabolic enzymes and mitochondria, accounting for their occupied volume densities, while assuming glucose and/or fatty acid utilization. The model demonstrates that activation of aerobic glycolysis is favored above a threshold metabolic rate in both rapidly proliferating cells and heavily contracting muscles, because it provides higher ATP yield per volume density than mitochondrial oxidative phosphorylation. In the case of muscle physiology, the model also predicts that before the lactate switch, fatty acid oxidation increases, reaches a maximum, and then decreases to zero with concomitant increase in glucose utilization, in agreement with the empirical evidence. These results are further corroborated by a larger scale model, including biosynthesis of major cell biomass components. The larger scale model also predicts that in proliferating cells the lactate switch is accompanied by activation of glutaminolysis, another distinctive feature of the Warburg effect. In conclusion, intracellular molecular crowding is a fundamental constraint for cell metabolism in both rapidly proliferating- and non-proliferating cells with high metabolic demand. Addition of this constraint to metabolic flux balance models can explain several observations of mammalian cell metabolism under steady state conditions

Coordination of opposing sex-specific and core muscle groups regulates male tail posture during Caenorhabditis elegans male mating behavior

Background To survive and reproduce, animals must be able to modify their motor behavior in response to changes in the environment. We studied a complex behavior of Caenorhabditis elegans, male mating behavior, which provided a model for understanding motor behaviors at the genetic, molecular as well as circuit level. C. elegans male mating behavior consists of a series of six sub-steps: response to contact, backing, turning, vulva location, spicule insertion, and sperm transfer. The male tail contains most of the sensory structures required for mating, in addition to the copulatory structures, and thus to carry out the steps of mating behavior, the male must keep his tail in contact with the hermaphrodite. However, because the hermaphrodite does not play an active role in mating and continues moving, the male must modify his tail posture to maintain contact. We provide a better understanding of the molecular and neuro-muscular pathways that regulate male tail posture during mating. Results Genetic and laser ablation analysis, in conjunction with behavioral assays were used to determine neurotransmitters, receptors, neurons and muscles required for the regulation of male tail posture. We showed that proper male tail posture is maintained by the coordinated activity of opposing muscle groups that curl the tail ventrally and dorsally. Specifically, acetylcholine regulates both ventral and dorsal curling of the male tail, partially through anthelmintic levamisole-sensitive, nicotinic receptor subunits. Male-specific muscles are required for acetylcholine-driven ventral curling of the male tail but dorsal curling requires the dorsal body wall muscles shared by males and hermaphrodites. Gamma-aminobutyric acid activity is required for both dorsal and ventral acetylcholine-induced curling of the male tail and an inhibitory gamma-aminobutyric acid receptor, UNC-49, prevents over-curling of the male tail during mating, suggesting that cross-inhibition of muscle groups helps maintain proper tail posture. Conclusion Our results demonstrated that coordination of opposing sex-specific and core muscle groups, through the activity of multiple neurotransmitters, is required for regulation of male tail posture during mating. We have provided a simple model for regulation of male tail posture that provides a foundation for studies of how genes, molecular pathways, and neural circuits contribute to sensory regulation of this motor behavior

Impact of the solvent capacity constraint on E. coli metabolism

<p>Abstract</p> <p>Background</p> <p>Obtaining quantitative predictions for cellular metabolic activities requires the identification and modeling of the physicochemical constraints that are relevant at physiological growth conditions. Molecular crowding in a cell's cytoplasm is one such potential constraint, as it limits the solvent capacity available to metabolic enzymes.</p> <p>Results</p> <p>Using a recently introduced flux balance modeling framework (FBAwMC) here we demonstrate that this constraint determines a metabolic switch in <it>E. coli </it>cells when they are shifted from low to high growth rates. The switch is characterized by a change in effective optimization strategy, the excretion of acetate at high growth rates, and a global reorganization of <it>E. coli </it>metabolic fluxes, the latter being partially confirmed by flux measurements of central metabolic reactions.</p> <p>Conclusion</p> <p>These results implicate the solvent capacity as an important physiological constraint acting on <it>E. coli </it>cells operating at high metabolic rates and for the activation of a metabolic switch when they are shifted from low to high growth rates. The relevance of this constraint in the context of both the aerobic ethanol excretion seen in fast growing yeast cells (Crabtree effect) and the aerobic glycolysis observed in rapidly dividing cancer cells (Warburg effect) should be addressed in the future.</p

Biomechanics-informed Neural Networks for Myocardial Motion Tracking in MRI

Image registration is an ill-posed inverse problem which often requires regularisation on the solution space. In contrast to most of the current approaches which impose explicit regularisation terms such as smoothness, in this paper we propose a novel method that can implicitly learn biomechanics-informed regularisation. Such an approach can incorporate application-specific prior knowledge into deep learning based registration. Particularly, the proposed biomechanics-informed regularisation leverages a variational autoencoder (VAE) to learn a manifold for biomechanically plausible deformations and to implicitly capture their underlying properties via reconstructing biomechanical simulations. The learnt VAE regulariser then can be coupled with any deep learning based registration network to regularise the solution space to be biomechanically plausible. The proposed method is validated in the context of myocardial motion tracking on 2D stacks of cardiac MRI data from two different datasets. The results show that it can achieve better performance against other competing methods in terms of motion tracking accuracy and has the ability to learn biomechanical properties such as incompressibility and strains. The method has also been shown to have better generalisability to unseen domains compared with commonly used L2 regularisation schemes.Comment: The paper is early accepted by MICCAI 202

PH wave-front propagation in the urea-urease reaction

The urease-catalyzed hydrolysis of urea displays feedback that results in a switch from acid (pH ∼3) to base (pH ∼9) after a controllable period of time (from 10 to \u3e5000 s). Here we show that the spatially distributed reaction can support pH wave fronts propagating with a speed of the order of 0.1-1 mm min-1. The experimental results were reproduced qualitatively in reaction-diffusion simulations including a Michaelis-Menten expression for the urease reaction with a bell-shaped rate-pH dependence. However, this model fails to predict that at lower enzyme concentrations, the unstirred reaction does not always support fronts when the well-stirred reaction still rapidly switches to high pH. © 2012 by the Biophysical Society

Catabolic efficiency of aerobic glycolysis: The Warburg effect revisited

<p>Abstract</p> <p>Background</p> <p>Cancer cells simultaneously exhibit glycolysis with lactate secretion and mitochondrial respiration even in the presence of oxygen, a phenomenon known as the Warburg effect. The maintenance of this mixed metabolic phenotype is seemingly counterintuitive given that aerobic glycolysis is far less efficient in terms of ATP yield per moles of glucose than mitochondrial respiration.</p> <p>Results</p> <p>Here, we resolve this apparent contradiction by expanding the notion of metabolic efficiency. We study a reduced flux balance model of ATP production that is constrained by the glucose uptake capacity and by the solvent capacity of the cell's cytoplasm, the latter quantifying the maximum amount of macromolecules that can occupy the intracellular space. At low glucose uptake rates we find that mitochondrial respiration is indeed the most efficient pathway for ATP generation. Above a threshold glucose uptake rate, however, a gradual activation of aerobic glycolysis and slight decrease of mitochondrial respiration results in the highest rate of ATP production.</p> <p>Conclusions</p> <p>Our analyses indicate that the Warburg effect is a favorable catabolic state for all rapidly proliferating mammalian cells with high glucose uptake capacity. It arises because while aerobic glycolysis is less efficient than mitochondrial respiration in terms of ATP yield per glucose uptake, it is more efficient in terms of the required solvent capacity. These results may have direct relevance to chemotherapeutic strategies attempting to target cancer metabolism.</p