Identifying Energy Extraction Optimisation Strategies of Actinobacillus succinogenes

A. succinogenes is well known for utilising various catabolic pathways. A multitude of batch fermentation studies confirm flux shifts in the catabolism as time proceeds. It has also been shown that continuous cultures exhibit flux variation as a function of dilution rate. This indicates a direct influence of the external environment on the proteome of the organism. In this work, ATP production efficiency was explored to evaluate the extent of bio-available energy on the production behaviour of A. succinogenes. It was found that the microbe successively utilised its most-to-least efficient energy extraction pathways, providing evidence of an energy optimisation survival strategy. Moreover, data from this study suggest a pyruvate overflow mechanism as a means to throttle acetic and formic acid production, indicating a scenario in which the external concentration of these acids play a role in the energy extraction capabilities of the organism. Data also indicates a fleeting regime where A. succinogenes utilises an oxidised environment to its advantage for ATP production. Here it is postulated that the energy gain and excretion cost of catabolites coupled to the changing environment is a likely mechanism responsible for the proteome alteration and its ensuing carbon flux variation. This offers valuable insights into the microbe’s metabolic logic gates, providing a foundation to understand how to exploit the system.

Computational study on ratio-sensing in yeast galactose utilization pathway

Metabolic networks undergo gene expression regulation in response to external nutrient signals. In microbes, the synthesis of enzymes that are used to transport and catabolize less preferred carbon sources is repressed in the presence of a preferred carbon source. For most microbes, glucose is a preferred carbon source, and it has long been believed that as long as glucose is present in the environment, the expression of genes related to the metabolism of alternative carbon sources is shut down, due to catabolite repression. However, recent studies have shown that the induction of the galactose (GAL) metabolic network does not solely depend on the exhaustion of glucose. Instead, the GAL genes respond to the external concentration ratio of galactose to glucose, a phenomenon of unknown mechanism that we termed ratio-sensing. Using mathematical modeling, we found that ratio-sensing is a general phenomenon that can arise from competition between two carbon sources for shared transporters, between transcription factors for binding to communal regulatory sequences of the target genes, or a combination of the aforementioned two levels of competition. We analyzed how the parameters describing the competitive interaction influenced ratio-sensing behaviors in each scenario and found that the concatenation of both layers of signal integration can expand the dynamical range of ratio-sensing. Finally, we investigated the influence of circuit topology on ratio-sensing and found that incorporating negative auto-regulation and/or coherent feedforward loop motifs to the basic signal integration unit can tune the sensitivity of the response to the external nutrient signals. Our study not only deepened our understanding of how ratio-sensing is achieved in yeast GAL metabolic regulation, but also elucidated design principles for ratio-sensing signal processing that can be used in other biological settings, such as being introduced into circuit designs for synthetic biology applications.Author summaryMicrobes make sophisticated choices about the uptake and metabolism of nutrients depending on the variety of nutrient choices available to them in their environment. In the well-studied yeast galactose utilization network, a recent study has shown that galactose metabolic genes respond to the external concentration ratio of galactose to glucose. Using computational models, we showed that this type of phenomenon could arise from a competition between galactose and glucose for transporters, a competition between transcription factors for promoters, or a combination of these two mechanisms. We further revealed the controlling parameters that determined the system sensitivity towards competing input signals and that determined the concentration ratio required to induce the metabolic network in each scenario. Combining competition inhibition at both the transporter level and the transcriptional level can enlarge the ratio-sensing regime, resulting a robust signal integration module. We suspect that modules of this kind may be common in many areas of biology.

Qualitative analysis of a free boundary problem for tumor growth under the action of periodic external inhibitors

In this paper, a free boundary problem for a solid avascular tumor growth under the action of periodic external inhibitors with time delays in proliferation is studied. Sufficient conditions for the global stability of tumor-free equilibrium are given. Moreover, if external concentration of nutrients is large, we also prove that the tumor will not disappear and determine the conditions under which there exist periodic solutions to the model. The results show that the periodicity of the inhibitor may imply periodicity of the size of the tumor. More precisely, if [Formula: see text] (the concentration of external nutrients) is greater than [Formula: see text], where [Formula: see text] are two constants; [Formula: see text]; [Formula: see text] is a periodic function which can be interpreted as a treatment and [Formula: see text] is the period of [Formula: see text]. Results are illustrated by computer simulations.

Length-dependent Ca2+ activation in skeletal muscle fibers from mammalians

We tested the hypotheses that 1) a decrease in activation of skeletal muscles at short sarcomere lengths (SLs) is caused by an inhibition of Ca2+ release from the sarcoplasmic reticulum (SR), and 2) the decrease in Ca2+ would be caused by an inhibition of action potential conduction from the periphery to the core of the fibers. Intact, single fibers dissected from the flexor digitorum brevis from mice were activated at different SLs, and intracellular Ca2+ was imaged with confocal microscopy. Force decreased at SLs shorter than 2.1 μm, while Ca2+ concentration decreased at SLs below 1.9 μm. The concentration of Ca2+ at short SL was lower at the core than at the peripheries of the fiber. When the external concentration of Na+ was decreased in the experimental media, impairing action potential conduction, Ca2+ gradients were observed in all SLs. When caffeine was used in the experimental media, the gradients of Ca2+ were abolished. We concluded that there is an inhibition of Ca2+ release from the sarcoplasmic reticulum (SR) at short SLs, which results from a decreased conduction of action potential from the periphery to the core of the fibers.