scholarly journals As potential biomarkers, kinetic network features may be more predictive than molecule abundances

2021 ◽  
Author(s):  
Alexander Hoffmann ◽  
Paul Loriaux ◽  
Ying Tang

The identification of prognostic biomarkers fuels personalized medicine. Here we tested two underlying, but often overlooked assumptions: 1) measurements at the steady state are sufficient for predicting the response to drug action, and 2) specifically, measurements of molecule abundances are sufficient. It is not clear that these are justified, as 1) the response results from non-linear molecular relationships, and 2) the steady state is defined by both abundance and orthogonal flux information. An experimentally validated mathematical model of the cellular response to the anti-cancer agent TRAIL was our test case. We developed a mathematical representation in which abundances and fluxes (static and kinetic network features) are largely independent, and simulated heterogeneous drug responses. Machine learning revealed predictive power, but that kinetic, not static network features were most informative. Analytical treatment of the underlying network motif identified kinetic buffering as the relevant circuit design principle. Our work suggests that network topology considerations ought to guide biomarker discovery efforts.

1990 ◽  
Vol 10 (1) ◽  
pp. 391-396
Author(s):  
L Hu ◽  
L J Gudas

Retinoic acid (RA) receptor alpha (RAR alpha) and RAR gamma steady-state mRNA levels remained relatively constant over time after the addition of RA to F9 teratocarcinoma stem cells. In contrast, the steady-state RAR beta mRNA level started to increase within 12 h after the addition of RA and reached a 20-fold-higher level by 48 h. This RA-associated RAR beta mRNA increase was not prevented by protein synthesis inhibitors but was prevented by the addition of cyclic AMP analogs. In the presence of RA, cyclic AMP analogs also greatly reduced the RAR alpha and RAR gamma mRNA levels, even though cyclic AMP analogs alone did not alter these mRNA levels. The addition of either RA or RA plus cyclic AMP analogs did not result in changes in the three RAR mRNA half-lives. These results suggest that agents which elevate the internal cyclic AMP concentration may also affect the cellular response to RA by altering the expression of the RARs.


1988 ◽  
Vol 34 (12) ◽  
pp. 2486-2489 ◽  
Author(s):  
F Keller ◽  
C Emde ◽  
A Schwarz

Abstract Enzyme kinetics are usually described by the Michaelis-Menten equation, where the time-dependent decrease of substrate (-dS/dt) is a hyperbolic function of maximal velocity (Vmax), Michaelis constant (Km), and amount of substrate (S). Because the Michaelis-Menten function in its most general meaning requires an assumption of steady-state, it is less curvilinear than true enzyme kinetics. A saturation-type exponential function is more curvilinear than the hyperbolic function and more closely approximates enzyme kinetics: -dS/dt = Vmax [1 - exp(-S/Km)]. The mathematical representation of enzyme kinetics can be further improved by introducing a deceleration term (Vdec), to make the assumption of a steady state unnecessary. For the action of chymotrypsin on N-acetyltyrosylethylester, the Michaelis-Menten equation yields the following: Vmax = 3.74 mumol/min and Km = 833 mumol. According to decelerated enzyme kinetics, the values Vmax = 4.80 mumol/min, Vdec = 0.0118 mumol/min, and the association constant (Ka) = 0.00111/mumol are more nearly accurate for this reaction (where 1/Ka = 901 mumol approximately Km).


2015 ◽  
Vol 19 (10) ◽  
pp. 4377-4396 ◽  
Author(s):  
C. Duku ◽  
H. Rathjens ◽  
S. J. Zwart ◽  
L. Hein

Abstract. Ecosystem accounting is an emerging field that aims to provide a consistent approach to analysing environment–economy interactions. One of the specific features of ecosystem accounting is the distinction between the capacity and the flow of ecosystem services. Ecohydrological modelling to support ecosystem accounting requires considering among others physical and mathematical representation of ecohydrological processes, spatial heterogeneity of the ecosystem, temporal resolution, and required model accuracy. This study examines how a spatially explicit ecohydrological model can be used to analyse multiple hydrological ecosystem services in line with the ecosystem accounting framework. We use the Upper Ouémé watershed in Benin as a test case to demonstrate our approach. The Soil Water and Assessment Tool (SWAT), which has been configured with a grid-based landscape discretization and further enhanced to simulate water flow across the discretized landscape units, is used to simulate the ecohydrology of the Upper Ouémé watershed. Indicators consistent with the ecosystem accounting framework are used to map and quantify the capacities and the flows of multiple hydrological ecosystem services based on the model outputs. Biophysical ecosystem accounts are subsequently set up based on the spatial estimates of hydrological ecosystem services. In addition, we conduct trend analysis statistical tests on biophysical ecosystem accounts to identify trends in changes in the capacity of the watershed ecosystems to provide service flows. We show that the integration of hydrological ecosystem services into an ecosystem accounting framework provides relevant information on ecosystems and hydrological ecosystem services at appropriate scales suitable for decision-making.


2021 ◽  
Author(s):  
Nitin Sai Beesabathuni ◽  
Priya S. Shah

AbstractAutophagy is a multistep degradative process that is essential for maintaining cellular homeostasis. Systematically quantifying flux through this pathway is critical for gaining fundamental insights and effectively modulating this process that is dysregulated during many diseases. Established methods to quantify flux use steady state measurements, which provide limited information about the perturbation and the cellular response. We present a theoretical and experimental framework to measure autophagic steps in the form of rates under non-steady state conditions. We use this approach to measure temporal responses to rapamycin and wortmannin treatments, two commonly used autophagy modulators. We quantified changes in autophagy rates in as little as 10 minutes, which can establish direct mechanisms for autophagy perturbation before feedback begins. We identified concentration-dependent effects of rapamycin on the initial and temporal progression of autophagy rates. We also found variable recovery time from wortmannin’s inhibition of autophagy, which is further accelerated by rapamycin. In summary, this new approach enables the quantification of autophagy flux with high sensitivity and temporal resolution and facilitates a comprehensive understanding of this process.


2017 ◽  
Author(s):  
Gosse Overal ◽  
Bas Teusink ◽  
Frank J. Bruggeman ◽  
Josephus Hulshof ◽  
Robert Planqué

AbstractIn microorganisms such as bacteria or yeasts, metabolic rates are tightly coupled to growth rate, and therefore to fitness. Although the topology of central pathways are largely conserved across organisms, the enzyme kinetics and their parameters generally vary. This prevents us to understand and predict (changes in) metabolic dynamics. The analytical treatment of metabolic pathways is generally restricted to small models, containing maybe two to four equations. Since such small core models involve much coarse graining, their biological interpretation is often hampered. In this paper we aim to bridge the gap between analytical, more in-depth treatment of small core models and biologically more realistic and detailed models by developing new methods. We illustrate these methods for a model of glycolysis in Saccharo-myces cerevisiae yeast, arguably the best characterised metabolic pathway in the literature. The model is more involved than in previous studies, and involves both ATP/ADP and NADH/NAD householding.A detailed analysis of the steady state equations sheds new light on two recently studied biological phenomena in yeast glycolysis: whether it is to be expected that fructose-1,6-biphosphate (FBP) parameterises all steady states, and the occurrence of bistability between a regular steady state and imbalanced steady state in which glycolytic intermediates keep accumulating.This work shows that the special structure of metabolic pathways does allow for more in-depth bifurcation analyses than is currently the norm. We especially emphasise which of the techniques developed here scale to larger pathways, and which do not.


2017 ◽  
Vol 10 (9) ◽  
pp. 3277-3295 ◽  
Author(s):  
Jin-Yun Tang ◽  
William J. Riley

Abstract. Several land biogeochemical models used for studying carbon–climate feedbacks have begun explicitly representing microbial dynamics. However, to our knowledge, there has been no theoretical work on how to achieve a consistent scaling of the complex biogeochemical reactions from microbial individuals to populations, communities, and interactions with plants and mineral soils. We focus here on developing a mathematical formulation of the substrate–consumer relationships for consumer-mediated redox reactions of the form A + BE→  products, where products could be, e.g., microbial biomass or bioproducts. Under the quasi-steady-state approximation, these substrate–consumer relationships can be formulated as the computationally difficult full equilibrium chemistry problem or approximated analytically with the dual Monod (DM) or synthesizing unit (SU) kinetics. We find that DM kinetics is scaling inconsistently for reaction networks because (1) substrate limitations are not considered, (2) contradictory assumptions are made regarding the substrate processing rate when transitioning from single- to multi-substrate redox reactions, and (3) the product generation rate cannot be scaled from one to multiple substrates. In contrast, SU kinetics consistently scales the product generation rate from one to multiple substrates but predicts unrealistic results as consumer abundances reach large values with respect to their substrates. We attribute this deficit to SU's failure to incorporate substrate limitation in its derivation. To address these issues, we propose SUPECA (SU plus the equilibrium chemistry approximation – ECA) kinetics, which consistently imposes substrate and consumer mass balance constraints. We show that SUPECA kinetics satisfies the partition principle, i.e., scaling invariance across a network of an arbitrary number of reactions (e.g., as in Newton's law of motion and Dalton's law of partial pressures). We tested SUPECA kinetics with the equilibrium chemistry solution for some simple problems and found SUPECA outperformed SU kinetics. As an example application, we show that a steady-state SUPECA-based approach predicted an aerobic soil respiration moisture response function that agreed well with laboratory observations. We conclude that, as an extension to SU and ECA kinetics, SUPECA provides a robust mathematical representation of complex soil substrate–consumer interactions and can be applied to improve Earth system model (ESM) land models.


2016 ◽  
Vol 21 (4) ◽  
pp. 805-826
Author(s):  
B. Fijałkowski

Abstract In this article, a new mathematical representation of the sinusoidal alternating velocity, force and power by means of some complex quantities, termed ‘holors’ is proposed. The word holor is a term to describe a mathematical entity that is made up of one or more independent quantities, and includes complex numbers, scalars, vectors, matrices, tensors and other hypernumbers. Holors, thus defined, have been known for centuries but each has been developed more or less independently, accompanied by separate nomenclature and theory.


1990 ◽  
Vol 10 (1) ◽  
pp. 391-396 ◽  
Author(s):  
L Hu ◽  
L J Gudas

Retinoic acid (RA) receptor alpha (RAR alpha) and RAR gamma steady-state mRNA levels remained relatively constant over time after the addition of RA to F9 teratocarcinoma stem cells. In contrast, the steady-state RAR beta mRNA level started to increase within 12 h after the addition of RA and reached a 20-fold-higher level by 48 h. This RA-associated RAR beta mRNA increase was not prevented by protein synthesis inhibitors but was prevented by the addition of cyclic AMP analogs. In the presence of RA, cyclic AMP analogs also greatly reduced the RAR alpha and RAR gamma mRNA levels, even though cyclic AMP analogs alone did not alter these mRNA levels. The addition of either RA or RA plus cyclic AMP analogs did not result in changes in the three RAR mRNA half-lives. These results suggest that agents which elevate the internal cyclic AMP concentration may also affect the cellular response to RA by altering the expression of the RARs.


Author(s):  
E Y K Ng ◽  
W L Siauw

An unsteady Navier-Stokes (N-S) solver based on the method of operator splitting and artificial compressibility has been studied for the moving boundary problem to simulate blood flow through a compliant vessel. Galerkin finite element analysis is used to discretize the governing equations. The model has been applied to a time-varying computational domain (two-dimensional tube) as a test case for validation. Consideration has been given to retaining the space conservation property. The same code is then applied to a hypothetical critical high-pressure gradient over a short length of blood vessel based on the spring and dashpot model. The governing equation for the blood vessel is based on two-dimensional dynamic thin-shell theory that takes into account the curvature of the stenotic portion of the vessel. Progressing the solution towards steady state is considered, as the main objective is to show the viability of the current technique for fluid/structure interactions. Preliminary results of the wall velocity and displacement based on steady state prediction agree well with data in the literature. Results, such as the streamlines, wall pressures and wall shear stress depict the possible progression of arterial disease.


2006 ◽  
Vol 134 (10) ◽  
pp. 2849-2856 ◽  
Author(s):  
Dave Broutman ◽  
Jun Ma ◽  
Stephen D. Eckermann ◽  
John Lindeman

Abstract The Fourier-ray method involves ray tracing in a Fourier-transform domain. The ray solutions are then Fourier synthesized to produce a spatial solution. Here previous steady-state developments of the Fourier-ray method are extended to include a transient source of mountain waves. The method is illustrated with an initial value problem in which the background flow is started abruptly from rest and then maintained at steady velocity. The resulting wave transience is modeled in a simple way. All rays that radiate from the mountain, including the initial rays, are assigned the full amplitude of the longtime steady-state solution. Time dependence comes in through the changing position of the initial rays. This is sufficient to account for wave transience in a test case, as demonstrated by comparison with simulations from a mesoscale numerical model.


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