partial equilibrium modeling
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Living organisms interact with various chemical compounds via receptors, which is described by the receptor theory. The affinity of the biologically active compounds toward receptors and their ability to trigger a biological or toxic signal vary substantially. In this work, we describe a new insight into understanding of the mode of action of receptor partial agonists and the receptor theory using a Full Logistic Model (FLM) of mixture toxicology. We describe the hypothesis that the effect of a partial agonist can be mathematically described via separation of agonistic and antagonistic behavior of the partial agonist where the antagonistic effect is described as an action of the compound producing zero effect. In this way, a competitive antagonist can be considered as an agonist with zero effect. This idea is also placed into a context with classical concepts, e.g., Gaddum's equation. Using the assumption that competitive antagonists are agonists with no effect, equations describing the microscopic and macroscopic equilibrium constants have been derived. Accordingly, we show that the constants could be calculated from the measured partial agonistic dose-response curve. As a consequence, we provide a simple mathematical tool for comparison of dose-response curves of drugs according to their affinities and efficacies.
Cíl práce: Zjistit vliv kombinace částečné kapalinové ventilace (PLV) a vysokofrekvenční oscilační ventilace (HFO) na výměnu krevních plynů na modelu ARDS (syndromu akutní respirační tísně). Typ studie: Laboratorní experiment na zvířecím modelu. Místo: Laboratoř katedry experimentální patofyziologie lékařské fakulty Masarykovy univerzity Brno. Subjekty: 18 laboratorních zvířat - králíků. Metoda: Po premedikaci byla zvířatům provedena tracheostomie, monitorováno EKG, centrální žilní tlak a arteriální tlak. Po úvodní konvenční mechanické ventilaci byli králíci rozděleni do 2 skupin: 1. skupina s nepoškozenými plícemi a 2. skupina s experimentálním ARDS. U 1. skupiny proběhla úvodní HFO a následně PLV s HFO. Potom byl perfluorokarbon (PFC) odsát a králíci byli napojeni opět na HFO. U 2. skupiny byl po úvodní HFO navození ARDS opakovanou laváží plic fyziologickým roztokem, následovala PLV s HFO a nakonec po odsátí PFC pouze HFO. Každá fáze trvala 60 minut. V 5minutových intervalech jsme zaznamenávali acidobazickou rovnováhu, krevní plyny a střední tlak v dýchacích cestách; srovnány byly hodnoty ke konci každého období. Výsledky: Skupina 1: pokles pH během PLV a postupný návrat k normě není statisticky významný, stejně jako vzestup PaCO2 během PLV a pokles během HFO. PaO2/FiO2 v úvodu PLV klesl, ale ke konci PLV stoupl a byl dokonce vyšší, než během úvodní HFO. Nicméně po skončení PLV, během HFO, je patrný pokles. Téměř beze změn v průběhu experimentu zůstává střední tlak v dýchacích cestách (Paw). Skupina 2: pokles pH během laváže plic je statisticky významný, ale během PLV se postupně zvyšoval a vracel se k normě. PaCO2 narůstal během laváže i v úvodu PLV, ale během PLV a dále při HFO klesal k původním hodnotám. PaO2/FiO2 prudce klesal po laváži a již v úvodu PLV narůstal s nejvyšší hodnotou ke konci PLV. Během následující HFO opět klesal. Paw v průběhu experimentu nevykazoval významné změny. Závěr: Kombinací PLV a HFO u experimentálního ARDS je možné dosáhnout výrazné zlepšení oxygenace, které po skončení PLV nepokračuje. Ventilace se udržuje v mezích normálních hodnot, přechodnou acidózu kombinace PLV a HFO upravuje k normě. U nepoškozených plic je kombinací PLV a HFO také dosaženo zlepření oxygenace, které bez PLV není možné. Změny pH a ventilace nejsou statisticky významné. Během PLV s HFO je možné udržovat krevní plyny v uspokojivých hodnotách s minimálním Paw.
Objective: To evaluate the effect of combination of partial liquid ventilation (PLV) and high frequency oscillatory ventilation (HFO) on blood gases exchange in acute respiratory distress syndrome (ARDS) model. Type of study: Laboratory experiment on animal model. Setting: The laboratory of experimental pathophysiology, Medical Faculty, Masaryk University, Brno. Subjects: 18 laboratory animals – rabbits. Method: After premedication, tracheostomy was performed in all animals. ECG, central venous pressure and arterial pressure were monitored. After initial conventional mechanical ventilation, rabbits were randomly allocated into two groups: 1st group with intact lungs and 2nd group with experimental ARDS. The animals in the 1st group were ventilated with HFO, followed by PLV with HFO. Subsequently, perfluorocarbon (PFC) was removed b y suction and rabbits were ventilated in HFO. ARDS was induced by repeated wash-out of lungs with normal saline in the animals in the 2nd group; PLV with HFO followed, after PFC removal replaced with HFO. All phases of the experiment lasted 60 minutes. We monitored acid-base balance, blood gases and mean airway pressure in 5 minutes interval; the values were compared at the end of each period. Results: Group 1: Decrease in pH during PLV and gradual return to normal values is not statistically significant, as well as paCO2 rise during PLV and decrease during HFO. paO2/FiO2 during the initial phase of PLV decreases, in the late phase increases and is even higher compared to initial HFO. Nevertheless, after PLV termination, during HFO, decrease can be observed. Almost no changes can be detected in mean airway pressure (Paw). Group 2: decrease in pH during lung lavage is statistically significant, during PLV gradually increases and returns to normal values. paCO2 increases during lavage and initial phase of PLV, but during PLV and during HFO decreases to original levels. paO2/FiO2 steeply decreases after lavage and even in the initial phase of PLV increases, peaking at the end of PLV. In the following period of HFO decreases again. Paw during experiment does not change significantly. Conclusion: Using combination of PLV and HFO in experimental ARDS model, significant improvement of oxygenation could be achieved; this improvement is restricted to the PLV and HFO period only, not extending beyond PLV termination. Ventilation is kept within normal limits, transitory acidosis is controlled with PLV and HFO. In intact lungs, PLV and HFO combination also leads to improvement in oxygenation which is not possible without PLV. Changes in pH and ventilation are not statistically significant. Blood gases could be maintained within normal limits during PLV and HFO with minimal Paw.
- MeSH
- acidobazická rovnováha MeSH
- analýza krevních plynů MeSH
- hyperbarická oxygenace MeSH
- králíci MeSH
- modely nemocí na zvířatech MeSH
- plicní ventilace metody MeSH
- syndrom respirační tísně novorozenců terapie MeSH
- vysokofrekvenční ventilace MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- přehledy MeSH
- srovnávací studie MeSH
Artificial soil (AS) is used in soil ecotoxicology as a test medium or reference matrix. AS is prepared according to standard OECD/ISO protocols and components of local sources are usually used by laboratories. This may result in significant inter-laboratory variations in AS properties and, consequently, in the fate and bioavailability of tested chemicals. In order to reveal the extent and sources of variations, the batch equilibrium method was applied to measure the sorption of 2 model compounds (phenanthrene and cadmium) to 21 artificial soils from different laboratories. The distribution coefficients (Kd) of phenanthrene and cadmium varied over one order of magnitude: from 5.3 to 61.5L/kg for phenanthrene and from 17.9 to 190L/kg for cadmium. Variations in phenanthrene sorption could not be reliably explained by measured soil properties; not even by the total organic carbon (TOC) content which was expected. Cadmium logKd values significantly correlated with cation exchange capacity (CEC), pHH2O and pHKCl, with Pearson correlation coefficients of 0.62, 0.80, and 0.79, respectively. CEC and pHH2O together were able to explain 72% of cadmium logKd variability in the following model: logKd=0.29pHH2O+0.0032 CEC -0.53. Similarly, 66% of cadmium logKd variability could be explained by CEC and pHKCl in the model: logKd=0.27pHKCl+0.0028 CEC -0.23. Variable cadmium sorption in differing ASs could be partially treated with these models. However, considering the unpredictable variability of phenanthrene sorption, a more reliable solution for reducing the variability of ASs from different laboratories would be better harmonization of AS preparation and composition.
Klasický Siggaard-Andersenův nomogram, široce využívaný v klinické praxi pro vyhodnocování acidobazické rovnováhy, byl původně experimentálně získán při teplotě 38°C a za předpokladu normální koncentrace plazmatických bílkovin. V klinické praxi je však nomogram (dnes většinou v počítačové podobě) používán k výpočtům z měřených dat ze vzorků krve temperovaných na standardní teplotu 37°C. Provedli jsme simulační přepočet výchozích experimentálních dat na teplotu 37°C a sestavili nový nomogram pro 37°C. Při porovnání s původním nomogramem nejsou zásadní odchylky, pokud se BE neodchyluje více než 10 mmol/l, při odchylkách větších než 15 mmol/l jsou však výsledky rozdílné. Navrhli jsme algoritmus a program, který z hodnot pH a pCO2 počítá BE dle původního i korigovaného nomogramu. Nicméně data, z nichž nomogram vycházel, počítají s normální hodnotou plazmatických bílkovin. Dále jsme kombinovali model acidobazické rovnováhy plazmy dle Figgeho a Fencla s daty, vycházejícími z dat Siggaard-Andersenova nomogramu, korigovaného na 37°C. Definovali jsme pak BE v závislosti nejen na koncentraci hemoglobinu, ale též i v závislosti na koncentraci plazmatických bílkovin a fosfátů. Pak je BE v podstatě totožné se změnou SID dle tzv. “moderní koncepce” acidobazické rovnováhy dle Stewarta. Model mimo jiné jasně ukazuje, že v případě uvažování plné krve zcela neplatí nezávislost SID a PCO2. Model je jádrem širšího modelu acidobazické rovnováhy organismu, na kterém je možné realizovat patogenezu poruch acidobazické rovnováhy v souladu s naším dříve publikovaným bilančním přístupem k interpretaci poruch ABR.
Carbon dioxide (CO₂) availability strongly affects the productivity of algal photobioreactors, where it is dynamically exchanged between different compartments, phases, and chemical forms. To understand the underlying processes, we constructed a nonequilibrium mathematical model of CO₂ dynamics in a flat-panel algal photobioreactor. The model includes mass transfer to the algal suspension from a stream of bubbles of CO₂-enriched air and from the photobioreactor headspace. Also included are the hydration of dissolved CO₂ to bicarbonate ion (HCO₃⁻) as well as uptake and/or cycling of these two chemical forms by the cells. The model was validated in experiments using a laboratory-scale flat-panel photobioreactor that controls light, temperature, and pH and where the concentration of dissolved CO₂, and partial pressure of CO₂ in the photobioreactor exhaust are measured. First, the model prediction was compared with measured CO₂ dynamics that occurred in response to a stepwise change in the CO₂ partial pressure in the gas sparger. Furthermore, the model was used to predict CO₂ dynamics in photobioreactors with unicellular, nitrogen-fixing cyanobacterium Cyanothece sp. The metabolism changes dramatically during a day, and the distribution of CO₂ is expected to exhibit a pronounced diurnal modulation that significantly deviates from chemical equilibrium.
Frozen aqueous solutions are an important subject of study in numerous scientific branches including the pharmaceutical and food industry, atmospheric chemistry, biology, and medicine. Here, we present an advanced environmental scanning electron microscope methodology for research of ice samples at environmentally relevant subzero temperatures, thus under conditions in which it is extremely challenging to maintain the thermodynamic equilibrium of the specimen. The methodology opens possibilities to observe intact ice samples at close to natural conditions. Based on the results of ANSYS software simulations of the surface temperature of a frozen sample, and knowledge of the partial pressure of water vapor in the gas mixture near the sample, we monitored static ice samples over several minutes. We also discuss possible artifacts that can arise from unwanted surface ice formation on, or ice sublimation from, the sample, as a consequence of shifting conditions away from thermodynamic equilibrium in the specimen chamber. To demonstrate the applicability of the methodology, we characterized how the true morphology of ice spheres containing salt changed upon aging and the morphology of ice spheres containing bovine serum albumin. After combining static observations with the dynamic process of ice sublimation from the sample, we can attain images with nanometer resolution.
The equilibrium dissociation constant of competitive antagonists represents the affinity of the receptor-ligand interaction, and it is a key characteristic of many therapeutic drugs or toxic compounds. Two commonly used methods by which the affinity of the antagonist can be estimated are Schild analysis and the Cheng-Prusoff method. However, both methods yield different results when applied to systems with slopes not equal to one. The Gaddum equation, which is fundamental for both methods, should be extended to incorporate the slope parameter of the dose-response curves and this extension should diminish the differences between the Schild and Cheng-Prusoff methods. In this study, we derived a novel form of the Gaddum equation with a slope parameter (Hill coefficient) of agonist dose-response curve. We also derived the subsequent equations for Schild and Cheng-Prusoff analysis and we validated the proposed model by the measurement of several known estrogen receptor competitive antagonists. Standardized in vitro yeast reporter gene assay (BMAEREluc/ERα) has been used for the measurements and the range of used antagonist concentrations was 1.37-46.03 μM. By applying our mathematical model, both Schild and Cheng-Prusoff methods provide more similar values of antagonist affinity than the original mathematical approach. The correctness of the model has also been demonstrated by the measurement of a partial agonist with a known receptor affinity. The presented mathematical model significantly reduces the differences in values calculated by the Cheng-Prusoff and Schild methods and yields more accurate estimations of antagonist affinity.
- MeSH
- alfa receptor estrogenů antagonisté a inhibitory metabolismus MeSH
- antagonisté estrogenového receptoru metabolismus farmakologie MeSH
- benzhydrylové sloučeniny metabolismus toxicita MeSH
- biologické modely * MeSH
- endokrinní disruptory metabolismus toxicita MeSH
- estradiol metabolismus farmakologie MeSH
- estrogeny metabolismus farmakologie MeSH
- fenoly metabolismus toxicita MeSH
- kompetitivní vazba MeSH
- lidé MeSH
- ligandy MeSH
- parciální agonismus léků MeSH
- reprodukovatelnost výsledků MeSH
- vazba proteinů MeSH
- vztah mezi dávkou a účinkem léčiva MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- MeSH
- acidobazická rovnováha MeSH
- králíci MeSH
- krevní tlak MeSH
- mechanické ventilátory MeSH
- modely nemocí na zvířatech MeSH
- syndrom respirační tísně novorozenců MeSH
- tracheostomie MeSH
- transkutánní měření krevních plynů MeSH
- zvířata MeSH
- Check Tag
- králíci MeSH
- zvířata MeSH
- Publikační typ
- srovnávací studie MeSH
The ALF transcription factor paralogs, AFF1, AFF2, AFF3, and AFF4, are components of the transcriptional super elongation complex that regulates expression of genes involved in neurogenesis and development. We describe an autosomal dominant disorder associated with de novo missense variants in the degron of AFF3, a nine amino acid sequence important for its binding to ubiquitin ligase, or with de novo deletions of this region. The sixteen affected individuals we identified, along with two previously reported individuals, present with a recognizable pattern of anomalies, which we named KINSSHIP syndrome (KI for horseshoe kidney, NS for Nievergelt/Savarirayan type of mesomelic dysplasia, S for seizures, H for hypertrichosis, I for intellectual disability, and P for pulmonary involvement), partially overlapping the AFF4-associated CHOPS syndrome. Whereas homozygous Aff3 knockout mice display skeletal anomalies, kidney defects, brain malformations, and neurological anomalies, knockin animals modeling one of the microdeletions and the most common of the missense variants identified in affected individuals presented with lower mesomelic limb deformities like KINSSHIP-affected individuals and early lethality, respectively. Overexpression of AFF3 in zebrafish resulted in body axis anomalies, providing some support for the pathological effect of increased amount of AFF3. The only partial phenotypic overlap of AFF3- and AFF4-associated syndromes and the previously published transcriptome analyses of ALF transcription factors suggest that these factors are not redundant and each contributes uniquely to proper development.
- MeSH
- dánio pruhované genetika MeSH
- dítě MeSH
- epilepsie komplikace genetika MeSH
- fenotyp MeSH
- frekvence genu MeSH
- fúze ledvin genetika MeSH
- jaderné proteiny chemie nedostatek genetika MeSH
- kojenec MeSH
- lidé MeSH
- mentální retardace genetika MeSH
- missense mutace * MeSH
- mladiství MeSH
- mladý dospělý MeSH
- molekulární evoluce MeSH
- molekulární modely MeSH
- myši MeSH
- nemoci mozku etiologie genetika MeSH
- osteochondrodysplazie genetika MeSH
- předškolní dítě MeSH
- sekvence aminokyselin MeSH
- stabilita proteinů MeSH
- syndrom MeSH
- transkripční elongační faktory chemie genetika MeSH
- zvířata MeSH
- Check Tag
- dítě MeSH
- kojenec MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- myši MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
