Mechanistic modeling
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Effects of chemicals are, in most cases, caused by internal concentrations within organisms which rely on uptake and elimination kinetics. These processes might be key components for assessing the effects of time-variable exposure of chemicals which regularly occur in aquatic systems. However, the knowledge of toxicokinetic patterns caused by time-variable exposure is limited, and gaining such information is complex. In this work, a previously developed mechanistic growth model of Myriophyllum spicatum is coupled with a newly developed toxicokinetic part, providing a model that is able to predict uptake and elimination of chemicals, as well as distribution processes between plant compartments (leaves, stems, roots) of M. spicatum. It is shown, that toxicokinetic patterns, at least for most of the investigated chemicals, can be calculated in agreement with experimental observations, by only calibrating two chemical- specific parameters, the cuticular permeability and a plant/water partition coefficient. Through the model-based determination of the cuticular permeabilities of Isoproturon, Iofensulfuron, Fluridone, Imazamox and Penoxsulam, their toxicokinetic pattern can be described with the model approach. For the use of the model for predicting toxicokinetics of other chemicals, where experimental data is not available, equations are presented that are based on the log (P oct/wat) of a chemical and estimate parameters that are necessary to run the model. In general, a method is presented to analyze time-variable exposure of chemicals more in detail without conducting time and labour intensive experiments.
Chromosome numbers have been widely used to describe the most fundamental genomic attribute of an organism or a lineage. Although providing strong phylogenetic signal, chromosome numbers vary remarkably among eukaryotes at all levels of taxonomic resolution. Changes in chromosome numbers regularly serve as indication of major genomic events, most notably polyploidy and dysploidy. Here, we review recent advancements in our ability to make inferences regarding historical events that led to alterations in the number of chromosomes of a lineage. We first describe the mechanistic processes underlying changes in chromosome numbers, focusing on structural chromosomal rearrangements. Then, we focus on experimental procedures, encompassing comparative cytogenomics and genomics approaches, and on computational methodologies that are based on explicit models of chromosome-number evolution. Together, these tools offer valuable predictions regarding historical events that have changed chromosome numbers and genome structures, as well as their phylogenetic and temporal placements.
According to the Dobzhansky-Muller model, hybrid sterility is a consequence of the independent evolution of related taxa resulting in incompatible genomic interactions of their hybrids. The model implies that the incompatibilities evolve randomly, unless a particular gene or nongenic sequence diverges much faster than the rest of the genome. Here we propose that asynapsis of heterospecific chromosomes in meiotic prophase provides a recurrently evolving trigger for the meiotic arrest of interspecific F1 hybrids. We observed extensive asynapsis of chromosomes and disturbance of the sex body in >95% of pachynemas of Mus m. musculus × Mus m. domesticus sterile F1 males. Asynapsis was not preceded by a failure of double-strand break induction, and the rate of meiotic crossing over was not affected in synapsed chromosomes. DNA double-strand break repair was delayed or failed in unsynapsed autosomes, and misexpression of chromosome X and chromosome Y genes was detected in single pachynemas and by genome-wide expression profiling. Oocytes of F1 hybrid females showed the same kind of synaptic problems but with the incidence reduced to half. Most of the oocytes with pachytene asynapsis were eliminated before birth. We propose the heterospecific pairing of homologous chromosomes as a preexisting condition of asynapsis in interspecific hybrids. The asynapsis may represent a universal mechanistic basis of F1 hybrid sterility manifested by pachytene arrest. It is tempting to speculate that a fast-evolving subset of the noncoding genomic sequence important for chromosome pairing and synapsis may be the culprit.
- MeSH
- apoptóza genetika MeSH
- biologická evoluce MeSH
- biologické modely MeSH
- druhová specificita MeSH
- dvouřetězcové zlomy DNA MeSH
- inbrední kmeny myší klasifikace genetika fyziologie MeSH
- infertilita genetika patologie patofyziologie MeSH
- křížení genetické MeSH
- meióza genetika MeSH
- myši inbrední BALB C MeSH
- myši inbrední C57BL MeSH
- myši MeSH
- oocyty patologie MeSH
- párování chromozomů genetika MeSH
- rekombinace genetická MeSH
- spermatocyty patologie MeSH
- spermatogeneze genetika MeSH
- těhotenství MeSH
- transkriptom MeSH
- vznik druhů (genetika) MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- myši MeSH
- těhotenství MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Metabolic pathways are complex dynamic systems whose response to perturbations and environmental challenges are governed by multiple interdependencies between enzyme properties, reactions rates, and substrate levels. Understanding the dynamics arising from such a network can be greatly enhanced by the construction of a computational model that embodies the properties of the respective system. Such models aim to incorporate mechanistic details of cellular interactions to mimic the temporal behavior of the biochemical reaction system and usually require substantial knowledge of kinetic parameters to allow meaningful conclusions. Several approaches have been suggested to overcome the severe data requirements of kinetic modeling, including the use of approximative kinetics and Monte-Carlo sampling of reaction parameters. In this work, we employ a probabilistic approach to study the response of a complex metabolic system, the central metabolism of the lactic acid bacterium Lactococcus lactis, subject to perturbations and brief periods of starvation. Supplementing existing methodologies, we show that it is possible to acquire a detailed understanding of the control properties of a corresponding metabolic pathway model that is directly based on experimental observations. In particular, we delineate the role of enzymatic regulation to maintain metabolic stability and metabolic recovery after periods of starvation. It is shown that the feedforward activation of the pyruvate kinase by fructose-1,6-bisphosphate qualitatively alters the bifurcation structure of the corresponding pathway model, indicating a crucial role of enzymatic regulation to prevent metabolic collapse for low external concentrations of glucose. We argue that similar probabilistic methodologies will help our understanding of dynamic properties of small-, medium- and large-scale metabolic networks models.
- MeSH
- adenosintrifosfát metabolismus MeSH
- biologické modely MeSH
- fruktosadifosfáty metabolismus MeSH
- Lactococcus lactis metabolismus MeSH
- metabolické sítě a dráhy MeSH
- metabolismus sacharidů * MeSH
- metoda Monte Carlo MeSH
- počítačová simulace MeSH
- statistické modely MeSH
- zpětná vazba fyziologická MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Butyryl cholinesterase (BChE) has been seen as a key enzyme in the search for new strategies in the treatment of poisoning by organophosphates (OPs), since human BChE (HssBChE), complexed with the appropriate oxime, can be a suitable scavenger and deactivator for OPs in the blood stream. However, the efficacy of HssBChE is limited by its strict stoichiometric scavenging, slow reactivation, and propensity for aging. The improvement of the reactivation rate by new and more efficient oximes could contribute to mitigate this problem and increase the HssBChE efficiency as scavenger. Several oximes have been synthesized and tested with this goal, some with promising results, but the mechanistic aspects of the reactivation reaction are not fully understood yet. In order to better investigate this mechanism, docking and mixed quantum and molecular mechanics combined with principal components analysis were performed here to evaluate the capacity of reactivation and determine the preferred route for the reactivation reaction of two new oximes on HssBChE inhibited by the neurotoxic agents cyclosarin and sarin. Plots of potential energies were calculated and all the transition states of the reactional mechanism were determined. Our results showed a good correlation with experimental data and pointed to the most efficient oxime with both OPs. The protocol used could be a suitable tool for a preliminary evaluation of the HssBChE reactivation rates by new oximes.
- MeSH
- butyrylcholinesterasa chemie MeSH
- chemické modely MeSH
- cholinesterasové inhibitory chemie farmakologie MeSH
- lidé MeSH
- molekulární modely MeSH
- organofosforové sloučeniny chemie farmakologie MeSH
- oximy chemie farmakologie MeSH
- reaktivátory cholinesterasy chemie farmakologie MeSH
- sarin chemie farmakologie MeSH
- vazba proteinů MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Mammalian cell perfusion cultures are gaining renewed interest as an alternative to traditional fed-batch processes for the production of therapeutic proteins, such as monoclonal antibodies (mAb). The steady state operation at high viable cell density allows the continuous delivery of antibody product with increased space-time yield and reduced in-process variability of critical product quality attributes (CQA). In particular, the production of a confined mAb N-linked glycosylation pattern has the potential to increase therapeutic efficacy and bioactivity. In this study, we show that accurate control of flow rates, media composition and cell density of a Chinese hamster ovary (CHO) cell perfusion bioreactor allowed the production of a constant glycosylation profile for over 20 days. Steady state was reached after an initial transition phase of 6 days required for the stabilization of extra- and intracellular processes. The possibility to modulate the glycosylation profile was further investigated in a Design of Experiment (DoE), at different viable cell density and media supplement concentrations. This strategy was implemented in a sequential screening approach, where various steady states were achieved sequentially during one culture. It was found that, whereas high ammonia levels reached at high viable cell densities (VCD) values inhibited the processing to complex glycan structures, the supplementation of either galactose, or manganese as well as their synergy significantly increased the proportion of complex forms. The obtained experimental data set was used to compare the reliability of a statistical response surface model (RSM) to a mechanistic model of N-linked glycosylation. The latter outperformed the response surface predictions with respect to its capability and reliability in predicting the system behavior (i.e., glycosylation pattern) outside the experimental space covered by the DoE design used for the model parameter estimation. Therefore, we can conclude that the modulation of glycosylation in a sequential steady state approach in combination with mechanistic model represents an efficient and rational strategy to develop continuous processes with desired N-linked glycosylation patterns. Biotechnol. Bioeng. 2017;114: 1978-1990. © 2017 Wiley Periodicals, Inc.
- MeSH
- analýza selhání vybavení MeSH
- biologické modely * MeSH
- bioreaktory * MeSH
- CHO buňky MeSH
- Cricetulus MeSH
- design s pomocí počítače MeSH
- design vybavení MeSH
- glykosylace MeSH
- monoklonální protilátky izolace a purifikace metabolismus MeSH
- perfuze přístrojové vybavení metody MeSH
- počítačová simulace MeSH
- polysacharidy metabolismus MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
For most patients, the HIV viral load can be made undetectable by highly active antiretroviral treatments highly active antiretroviral therapy: the virus, however, cannot be eradicated. Thus, the major problem is to try to reduce the side effects of the treatment that patients have to take during their life time. We tackle the problem of monitoring the treatment dose, with the aim of giving the minimum dose that yields an undetectable viral load. The approach is based on mechanistic models of the interaction between virus and the immune system. It is shown that the "activated cells model," allows making good predictions of the effect of dose changes and, thus, could be a good basis for treatment monitoring. Then, we use the fact that in dynamical models, there is a nontrivial equilibrium point, that is with a virus load larger than zero, only if the reproductive number R(0) is larger than one. For reducing side effects, we may give a dose just above the critical dose corresponding to R(0) equal to 1. A prior distribution of the parameters of the model can be taken as the posterior arising from the analysis of previous clinical trials. Then the observations for a given patient can be used to dynamically tune the dose so that there is a high probability that the reproductive number is below one. The advantage of the approach is that it does not depend on a cost function, weighing side effects and efficiency of the drug. It is shown that it is possible to approach the critical dose if the model is correct. A sensitivity analysis assesses the robustness of the approach.
- MeSH
- algoritmy MeSH
- biologické modely MeSH
- biometrie MeSH
- CD4-pozitivní T-lymfocyty účinky léků imunologie virologie MeSH
- HIV infekce farmakoterapie imunologie virologie MeSH
- klinické zkoušky jako téma statistika a číselné údaje MeSH
- látky proti HIV aplikace a dávkování škodlivé účinky MeSH
- lidé MeSH
- modely imunologické MeSH
- monitorování léčiv statistika a číselné údaje MeSH
- statistické modely * MeSH
- virová nálož účinky léků MeSH
- vysoce aktivní antiretrovirová terapie * škodlivé účinky MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
Layered double hydroxides have been proposed as effective sorbents for As(V), but studies investigating adsorption mechanisms usually lack a comprehensive mechanistic/modeling approach. In this work, we propose coupling surface complexation modeling with various spectroscopic techniques. To this end, a series of batch experiments at different pH values were performed. Kinetic data were well fitted by a pseudo-second order kinetic model, and the equilibrium data were fitted by the Freundlich model. Moreover, the pH-dependent As(V) sorption data were satisfactorily fitted by a diffuse layer model, which described the formation of >SOAsO3H(-) monodentate and >(SO)2AsO2(-) bidentate inner-sphere complexes (">S" represents a crystallographically-bound group on the surface). Additionally, XPS analyses confirmed the adsorption mechanisms. The sorption mechanisms were affected by anion exchange, which was responsible for the formation of outer sphere complexes, as identified by XRD and FTIR analyses. Furthermore, a homogenous distribution of As(V) was determined by HR-TEM with elemental mapping. Using low-temperature Mössbauer spectroscopy on isotope (57)Fe, a slight shift of the hyperfine parameters towards higher values following As(V) sorption was measured, indicating a higher degree of structural disorder. In general, mechanistic adsorption modeling coupled with solid state analyses presents a powerful approach for investigating the adsorption mechanism of As(V) on Mg-Fe LDH or other sorbents.
- MeSH
- adsorpce MeSH
- arseničnany chemie izolace a purifikace MeSH
- difrakce rentgenového záření MeSH
- hydroxid hořečnatý chemie MeSH
- kinetika MeSH
- koncentrace vodíkových iontů MeSH
- povrchové vlastnosti MeSH
- roztoky MeSH
- spektroskopie infračervená s Fourierovou transformací MeSH
- teoretické modely * MeSH
- železité sloučeniny chemie MeSH
- Publikační typ
- časopisecké články MeSH
