Adaptation and homeostasis are essential properties of all living systems. However, our knowledge about the reaction kinetic mechanisms leading to robust homeostatic behavior in the presence of environmental perturbations is still poor. Here, we describe, and provide physiological examples of, a set of two-component controller motifs that show robust homeostasis. This basic set of controller motifs, which can be considered as complete, divides into two operational work modes, termed as inflow and outflow control. We show how controller combinations within a cell can integrate uptake and metabolization of a homeostatic controlled species and how pathways can be activated and lead to the formation of alternative products, as observed, for example, in the change of fermentation products by microorganisms when the supply of the carbon source is altered. The antagonistic character of hormonal control systems can be understood by a combination of inflow and outflow controllers.

This paper reviews current knowledge on sources, spread and removal mechanisms of antibiotic resistance genes (ARGs) in microbial communities of wastewaters, treatment plants and downstream recipients. Antibiotic is the most important tool to cure bacterial infections in humans and animals. The over- and misuse of antibiotics have played a major role in the development, spread, and prevalence of antibiotic resistance (AR) in the microbiomes of humans and animals, and microbial ecosystems worldwide. AR can be transferred and spread amongst bacteria via intra- and interspecies horizontal gene transfer (HGT). Wastewater treatment plants (WWTPs) receive wastewater containing an enormous variety of pollutants, including antibiotics, and chemicals from different sources. They contain large and diverse communities of microorganisms and provide a favorable environment for the spread and reproduction of AR. Existing WWTPs are not designed to remove micropollutants, antibiotic resistant bacteria (ARB) and ARGs, which therefore remain present in the effluent. Studies have shown that raw and treated wastewaters carry a higher amount of ARB in comparison to surface water, and such reports have led to further studies on more advanced treatment processes. This review summarizes what is known about AR removal efficiencies of different wastewater treatment methods, and it shows the variations among different methods. Results vary, but the trend is that conventional activated sludge treatment, with aerobic and/or anaerobic reactors alone or in series, followed by advanced post treatment methods like UV, ozonation, and oxidation removes considerably more ARGs and ARB than activated sludge treatment alone. In addition to AR levels in treated wastewater, it examines AR levels in biosolids, settled by-product from wastewater treatment, and discusses AR removal efficiency of different biosolids treatment procedures. Finally, it puts forward key-points and suggestions for dealing with and preventing further increase of AR in WWTPs and other aquatic environments, together with a discussion on the use of mathematical models to quantify and simulate the spread of ARGs in WWTPs. Mathematical models already play a role in the analysis and development of WWTPs, but they do not consider AR and challenges remain before models can be used to reliably study the dynamics and reduction of AR in such systems.

Robust homeostatic mechanisms are essential for the protection and adaptation of organisms in a changing and challenging environment. Integral feedback is a control-engineering concept that leads to robust, i.e., perturbation-independent, adaptation and homeostatic behavior in the controlled variable. Addressing two-component negative feedback loops of a controlled variable A and a controller molecule E, we have shown that integral control is closely related to the presence of zero-order fluxes in the removal of the manipulated variable E. Here we show that autocatalysis is an alternative mechanism to obtain integral control. Although the conservative and marginal stability of the Lotka-Volterra oscillator (LVO) with autocatalysis in both A and E is often considered as a major inadequacy, homeostasis in the average concentrations of both A and E ( and ) is observed. Thus, autocatalysis does not only represent a mere driving force, but may also have regulatory roles.

Thorsen K, Drengstig T, Ruoff P. Transepithelial glucose transport and Na ϩ /K ϩ homeostasis in enterocytes: an integrative model. Am J Physiol Cell Physiol 307: C320 -C337, 2014. First published June 4, 2014; doi:10.1152/ajpcell.00068.2013.-The uptake of glucose and the nutrient coupled transcellular sodium traffic across epithelial cells in the small intestine has been an ongoing topic in physiological research for over half a century. Driving the uptake of nutrients like glucose, enterocytes must have regulatory mechanisms that respond to the considerable changes in the inflow of sodium during absorption. The Na-K-ATPase membrane protein plays a major role in this regulation. We propose the hypothesis that the amount of active Na-K-ATPase in enterocytes is directly regulated by the concentration of intracellular Na ϩ and that this regulation together with a regulation of basolateral K permeability by intracellular ATP gives the enterocyte the ability to maintain ionic Na ϩ /K ϩ homeostasis. To explore these regulatory mechanisms, we present a mathematical model of the sodium coupled uptake of glucose in epithelial enterocytes. Our model integrates knowledge about individual transporter proteins including apical SGLT1, basolateral Na-K-ATPase, and GLUT2, together with diffusion and membrane potentials. The intracellular concentrations of glucose, sodium, potassium, and chloride are modeled by nonlinear differential equations, and molecular flows are calculated based on experimental kinetic data from the literature, including substrate saturation, product inhibition, and modulation by membrane potential. Simulation results of the model without the addition of regulatory mechanisms fit well with published short-term observations, including cell depolarization and increased concentration of intracellular glucose and sodium during increased concentration of luminal glucose/sodium. Adding regulatory mechanisms for regulation of Na-K-ATPase and K permeability to the model show that our hypothesis predicts observed long-term ionic homeostasis.enterocytes; epithelial transport; homeostasis; mathematical modeling; ionic regulation THE UPTAKE AND TRANSPORT OF glucose by the epithelial enterocytes in the small intestine are essential steps in all higher animals. Much of the glucose uptake in the small intestine is coupled to transport of sodium, and the different transporter proteins involved in the sodium coupled glucose uptake are well known (23,61,67,97). Although the electrochemical kinetics of the individual transporter proteins responsible for glucose and nutrient uptake are fairly elucidated (19,54,67,82,97), the combined function in which these transporters drive a net inflow of nutrients from the intestinal lumen to the serosal blood has not yet been modeled in detail.We have developed a mathematical model of an enterocyte that incorporates the available kinetic data from studies on individual transporter proteins. The model includes apical SGLT1 (the glucose sodium cotransporter), coupled apical flow of Na ϩ an...

Whole cell and surface proteomes were analyzed together with adhesive properties of the probiotic bacterium Lactobacillus acidophilus NCFM (NCFM) grown on the emerging prebiotic raffinose, exemplifying a synbiotic. Adhesion of NCFM to mucin and intestinal HT-29 cells increased three-fold after culture with raffinose versus glucose, as also visualized by scanning electron microscopy. Comparative proteomics using 2D-DIGE showed 43 unique proteins to change in relative abundance in whole cell lysates from NCFM grown on raffinose compared to glucose. Furthermore, 14 unique proteins in 18 spots of the surface subproteome underwent changes identified by differential 2DE, including elongation factor G, thermostable pullulanase, and phosphate starvation inducible stress-related protein increasing in a range of +2.1 - +4.7 fold. By contrast five known moonlighting proteins decreased in relative abundance by up to -2.4 fold. Enzymes involved in raffinose catabolism were elevated in the whole cell proteome; α-galactosidase (+13.9 fold); sucrose phosphorylase (+5.4 fold) together with metabolic enzymes from the Leloir pathway for galactose utilization and the glycolysis; β-galactosidase (+5.7 fold); galactose (+2.9/+3.1 fold) and fructose (+2.8 fold) kinases. The insights at the molecular and cellular levels contributed to the understanding of the interplay of a synbiotic composed of NCFM and raffinose with the host.