A physical model of cell metabolism

Cell metabolism is characterized by three fundamental energy demands: to sustain cell maintenance, to trigger aerobic fermentation and to achieve maximum metabolic rate. The transition to aerobic fermentation and the maximum metabolic rate are currently understood based on enzymatic cost constraints. Yet, we are lacking a theory explaining the maintenance energy demand. Here we report a physical model of cell metabolism that explains the origin of these three energy scales. Our key hypothesis is that the maintenance energy demand is rooted on the energy expended by molecular motors to fluidize the cytoplasm and counteract molecular crowding. Using this model and independent parameter estimates we make predictions for the three energy scales that are in quantitative agreement with experimental values. The model also recapitulates the dependencies of cell growth with extracellular osmolarity and temperature. This theory brings together biophysics and cell biology in a tractable model that can be applied to understand key principles of cell metabolism

Limits of aerobic metabolism in cancer cells

Cancer cells exhibit high rates of glycolysis and glutaminolysis. Glycolysis can provide energy and glutaminolysis can provide carbon for anaplerosis and reductive carboxylation to citrate. However, all these metabolic requirements could be in principle satisfied from glucose. Here we investigate why cancer cells do not satisfy their metabolic demands using aerobic biosynthesis from glucose. Based on the typical composition of a mammalian cell we quantify the energy demand and the OxPhos burden of cell biosynthesis from glucose. Our calculation demonstrates that aerobic growth from glucose is feasible up to a minimum doubling time that is proportional to the OxPhos burden and inversely proportional to the mitochondria OxPhos capacity. To grow faster cancer cells must activate aerobic glycolysis for energy generation and uncouple NADH generation from biosynthesis. To uncouple biosynthesis from NADH generation cancer cells can synthesize lipids from carbon sources that do not produce NADH in their catabolism, including acetate and the amino acids glutamate, glutamine, phenylalanine and tyrosine. Finally, we show that cancer cell lines have an OxPhos capacity that is insufficient to support aerobic biosynthesis from glucose. We conclude that selection for high rate of biosynthesis implies a selection for aerobic glycolysis and uncoupling biosynthesis from NADH generation

Impact of limited solvent capacity on metabolic rate, enzyme activities, and metabolite concentrations of S. cerevisiae glycolysis

The cell's cytoplasm is crowded by its various molecular components, resulting in a limited solvent capacity for the allocation of new proteins, thus constraining various cellular processes such as metabolism. Here we study the impact of the limited solvent capacity constraint on the metabolic rate, enzyme activities, and metabolite concentrations using a computational model of Saccharomyces cerevisiae glycolysis as a case study. We show that given the limited solvent capacity constraint, the optimal enzyme activities and the metabolite concentrations necessary to achieve a maximum rate of glycolysis are in agreement with their experimentally measured values. Furthermore, the predicted maximum glycolytic rate determined by the solvent capacity constraint is close to that measured in vivo. These results indicate that the limited solvent capacity is a relevant constraint acting on S. cerevisiae at physiological growth conditions, and that a full kinetic model together with the limited solvent capacity constraint can be used to predict both metabolite concentrations and enzyme activities in vivo. © 2008 Vazquez et al

A fractional porous medium equation

We develop a theory of existence, uniqueness and regularity for a porous medium equation with fractional diffusion, $\frac{\partial u}{\partial t} + (-\Delta)^{1/2} (|u|^{m-1}u)=0$ in $\mathbb{R}^N$, with $m>m_*=(N-1)/N$, $N\ge1$ and $f\in L^1(\mathbb{R}^N)$. An $L^1$-contraction semigroup is constructed and the continuous dependence on data and exponent is established. Nonnegative solutions are proved to be continuous and strictly positive for all $x\in\mathbb{R}^N$, $t>0$

From Zn to Mn: the study of novel manganese-binding groups in the search for new drugs against tuberculosis.

In most eubacteria, apicomplexans, and most plants, including the causal agents for diseases such as malaria, leprosy, and tuberculosis, the methylerythritol phosphate pathway is the route for the biosynthesis of the C(5) precursors to the essential isoprenoid class of compounds. Owing to their absence in humans, the enzymes of the methylerythritol phosphate pathway have become attractive targets for drug discovery. This work investigates a new class of inhibitors against the second enzyme of the pathway, 1-deoxy-D-xylulose 5-phosphate reductoisomerase. Inhibition of this enzyme may involve the chelation of a crucial active site Mn ion, and the metal-chelating moieties studied here have previously been shown to be successful in application to the zinc-dependent metalloproteinases. Quantum mechanics and docking calculations presented in this work suggest the transferability of these metal-chelating compounds to Mn-containing 1-deoxy-D-xylulose 5-phosphate reductoisomerase enzyme, as a promising starting point to the development of potent inhibitors

ELEMENTS INVOLVED IN THE TERRITORY BRAND FROM RESIDENTS’ PERCEPTION: THE CITY OF MÁLAGA

The brand might create a position of the territory that could be useful for the development of geographical spaces. It could also become a solid basis upon which to make decisions about the tourism planning of a city. This paper deals with the features, which are recognized by residents as those that are involved in the creation of Málaga brand. In order to achieve the goals set in this research, a descriptive methodology has been used. This study has been carried out using a questionnaire in which 1230 residents have participated. The findings have corroborated the hypotheses. Indeed, the results show that Málaga brand is being built under the concept of culture and that some places of the city are vital in the making of the territory image. This also encourages economic growth and hence employment. This paper offers important implications and tools to both public and private institutions insofar as they promote tourism promotion campaigns

Evaluation of wave loads on a new type of perforated caisson

Permission is granted by ICE Publishing to print one copy for personal use. Any other use of these PDF files is subject to reprint fees.A new type of perforated breakwater has been tested combining the advantages of cylindrical geometry with stepped wave energy dissipation. Thus, the new type of caisson implies a significant reduction of maximum wave forces, as well as loads transmitted to the foundation in comparison with conventional vertical breakwater and other types of perforated caissons. Starting from a brief description of the model and test results, this paper describes the development of a methodology for the estimation of maximum wave loads on this type of breakwater, in order to become a generalisable tool for predesign purposes. Construction and installation constraints of this new type of caisson are also assessed. These need to be taken into account in order to keep some advantages from the proposed design, while noting the key factors from a practical point of view.Peer ReviewedPostprint (published version