HillTau: A fast, compact abstraction for model reduction in biochemical signaling networks

Signaling networks mediate many aspects of cellular function. The conventional, mechanistically motivated approach to modeling such networks is through mass-action chemistry, which maps directly to biological entities and facilitates experimental tests and predictions. However such models are complex, need many parameters, and are computationally costly. Here we introduce the HillTau form for signaling models. HillTau retains the direct mapping to biological observables, but it uses far fewer parameters, and is 100 to over 1000 times faster than ODE-based methods. In the HillTau formalism, the steady-state concentration of signaling molecules is approximated by the Hill equation, and the dynamics by a time-course tau. We demonstrate its use in implementing several biochemical motifs, including association, inhibition, feedforward and feedback inhibition, bistability, oscillations, and a synaptic switch obeying the BCM rule. The major use-cases for HillTau are system abstraction, model reduction, scaffolds for data-driven optimization, and fast approximations to complex cellular signaling.

Catalytic Prebiotic Formation of Glycerol Phosphate Esters and an Estimation of Their Steady State Abundance under Plausible Early Earth Conditions

The emergence of biological phosphate esters of glycerol could have been a crucial step in the origin and evolution of life on the early Earth as glycerol phosphates today play a central role in biochemistry. We investigate here the formation of the glycerol phosphates by employing various rock samples, salts, and minerals as potential catalysts to aid the phosphorylation process. We report the synthesis of various phosphate esters of glycerol including glycerol-1-phosphate, glycerol-2-phosphate, cyclic glycerol-monophosphate as well as various diphosphate esters. Furthermore, the decomposition rates of glycerol phosphate under mild heating were also studied while keeping the pH constant. It was observed that glycerol phosphate starts decomposing quickly under mild heating conditions into inorganic orthophosphate and pyrophosphate, and a steady state concentration of ~0.5 M of glycerol phosphate may have been reasonable in ponds with abundant glycerol, phosphate, urea, and catalytic minerals.

A Review of the Effect of Irradiation on the Corrosion of Copper-Coated Used Fuel Containers

Radiation induced corrosion is one of the possible modes of materials degradation in the concept of long-term management of used nuclear fuel. Depending on the environmental conditions surrounding the used fuel container, a range of radiolysis products are expected to form that could impact the corrosion of the copper coating. For instance, γ-radiolysis of pure water produces molecular oxidants such as H2O2 and the radiolysis of humid air produces compounds such as NOx and HNO3. This review is confined to a discussion of the effect of γ-radiation on the corrosion of copper-coated containers. A simplified mixed-potential model is also presented to calculate the extent of copper corrosion by using the steady-state concentration of H2O2 generated during the first 300 years of emplacement, when the radiation field is significant.

Possible inhibitory effects of terbinafine on aripiprazole metabolism: Two case reports

Aripiprazole, an atypical antipsychotic, is a metabolic substrate for cytochrome P450 (CYP)3A4 and 2D6. Terbinafine, an antifungal agent used for onychomycosis, is a CYP2D6 inhibitor and could theoretically reduce the metabolism of aripiprazole. However, there are no published reports describing this interaction. We present 2 female patients hospitalized in a psychiatric unit who were both taking aripiprazole 15 mg daily and terbinafine 250 mg daily prior to admission. The first patient was a 58-year-old female who was prescribed aripiprazole and terbinafine concomitantly for approximately 5 months prior to admission. A commercial pharmacogenetic testing platform classified this patient as a normal metabolizer for CYP3A4 and 2D6. The first patient's serum trough aripiprazole concentration at steady-state concentration (Css) was 207.5 ng/mL. The second patient was a 43-year-old female who was taking aripiprazole and terbinafine concomitantly for approximately 2 weeks prior to admission who had a Css aripiprazole concentration of 278.9 ng/mL. Aripiprazole has a wide therapeutic range (100 to 350 ng/mL) and a reference dose-related drug concentration of 11.7 (mean) ± 5.6 (SD) ng/mL/mg/d. Our patients had Css aripiprazole concentrations 18% and 59% higher than guideline-supported dose-related drug concentrations. Through the use of therapeutic drug monitoring, pharmacogenetic data, electronic pharmaceutical claims data, and the Drug Interaction Probability Scale, we suggest terbinafine possibly increases aripiprazole concentrations 18% to 59%. Further reports are needed to confirm these findings prior to using this information in clinical practice.

CYP2C19 Genotyping May Provide a Better Treatment Strategy when Administering Escitalopram in Chinese Population

Depression disorder is one of the most serious mental illnesses in the world. Escitalopram is the essential first-line medication for depression disorder. It is the substrate of hepatic cytochrome P450 (CYP) enzyme CYP2C19 with high polymorphism. The effect of CYP2C19 on pharmacokinetics and pharmacodynamics on Caucasian population has been studied. The Clinical Pharmacogenetics Implementation Consortium Guideline provides dosing recommendations for escitalopram on CYP2C19 genotypes on the basis of the studies on Caucasian population. However, the gene frequency of the alleles of CYP2C19 showed racial differences between Chinese and Caucasian populations. Representatively, the frequency of the *2 and *3 allele, which were considered as poor metabolizer, has been shown to be three times higher in Chinese than in Caucasians. In addition, the environments might also lead to different degrees of impacts on genotypes. Therefore, the guidelines based on the Caucasians may not be applicable to the Chinese, which induced the establishment of a guideline in China. It is necessary to provide the evidence of individual treatment of escitalopram in Chinese by studying the effect of CYP2C19 genotypes on the pharmacokinetics parameters and steady-state concentration on Chinese. In this study, single-center, randomized, open-label, two-period, two-treatment crossover studies were performed. Ninety healthy Chinese subjects finished the trials, and they were included in the statistical analysis. The pharmacokinetics characteristics of different genotypes in Chinese were obtained. The results indicate that the poor metabolizer had higher exposure, and increased half-life than the extensive metabolizer and intermediate metabolite. The prediction of steady-state concentration based on the single dose trial on escitalopram shows that the poor metabolizer might have a higher steady-state concentration than the extensive metabolizer and intermediate metabolite in Chinese. The results indicate that the genetic testing before medication and the adjustment of escitalopram in the poor metabolizer should be considered in the clinical treatments in Chinese. The results provide the evidence of individual treatment of escitalopram in Chinese, which will be beneficial for the safer and more effective application of escitalopram in the Chinese population.Clinical Trial Registration: identifier ChiCTR1900027226.

Diffusion coefficient calculated by time-lag using the film-roll method

A method for determining the diffusion coefficient by time-lag using the film-roll method for the sublimation diffusion of disperse dye was proposed. A polyethylene terephthalate film-roll coated with dye paste was treated at 170–190°C for various times. A solution consisting of the sum of a steady-state solution and a transient solution was obtained by the homogeneous boundary value problem from a trigonometrical series. The boundary conditions of the steady-state first layer and the steady-state first layer amount of dye were determined from the steady-state concentration distribution. For various diffusion times, the steady-state first layer-passed total amounts of dye that passed through the first layer in the steady-state condition were obtained by subtracting the steady-state first layer amounts from the total amounts. The time-lag was calculated from the linear regression line for the plot of the steady-state first layer-passed total number(X) of positive values against time. The diffusion coefficient was calculated by the boundary conditions of the steady-state first layer and the time-lag. For diffusion at 170°C, 180°C, and 190°C, the correlations of the steady-state first layer-passed total amounts with respect to time were very linear and the reliability of the diffusion coefficients obtained by the time-lag was proved by the good linearity of the Arrhenius plot. The activation energy obtained was 36.8 kcal[Formula: see text]mol−1.

Fatty Acid Production and Direct Acyl Transfer through Polar Lipids Control TAG Biosynthesis during Nitrogen Deprivation in the Halotolerant Alga Dunaliella tertiolecta

The aims of this work were to evaluate the contribution of the free fatty acid (FA) pool to triacylglyceride (TAG) biosynthesis and to try to characterize the mechanism by which FA are assimilated into TAG in the green alga Dunaliella tertiolecta. A time-resolved lipidomic analysis showed that nitrogen (N) deprivation induces a redistribution of total lipidome, particularly of free FA and major polar lipid (PL), in parallel to enhanced accumulation of polyunsaturated TAG. The steady-state concentration of the FA pool, measured by prolonged 14C-bicarbonate pre-labeling, showed that N deprivation induced a 50% decrease in total FA level within the first 24 h and up to 85% after 96 h. The abundance of oleic acid increased from 50 to 70% of total free FA while polyunsaturated FA (PUFA) disappeared under N deprivation. The FA flux, measured by the rate of incorporation of 14C-palmitic acid (PlA), suggests partial suppression of phosphatidylcholine (PC) acyl editing and an enhanced turnover of the FA pool and of total digalactosyl-diacylglycerol (DGDG) during N deprivation. Taken together, these results imply that FA biosynthesis is a major rate-controlling stage in TAG biosynthesis in D. tertiolecta and that acyl transfer through PL such as PC and DGDG is the major FA assimilation pathway into TAG in that alga and possibly in other green microalgae. Increasing the availability of FA could lead to enhanced TAG biosynthesis and to improved production of high-value products from microalgae.

Win, Lose, or Tie: Mathematical Modeling of Ligand Competition at the Cell–Extracellular Matrix Interface

Integrin transmembrane proteins conduct mechanotransduction at the cell–extracellular matrix (ECM) interface. This process is central to cellular homeostasis and therefore is particularly important when designing instructive biomaterials and organoid culture systems. Previous studies suggest that fine-tuning the ECM composition and mechanical properties can improve organoid development. Toward the bigger goal of fully functional organoid development, we hypothesize that resolving the dynamics of ECM–integrin interactions will be highly instructive. To this end, we developed a mathematical model that enabled us to simulate three main interactions, namely integrin activation, ligand binding, and integrin clustering. Different from previously published computational models, we account for the binding of more than one type of ligand to the integrin. This competition between ligands defines the fate of the system. We have demonstrated that an increase in the initial concentration of ligands does not ensure an increase in the steady state concentration of ligand-bound integrins. The ligand with higher binding rate occupies more integrins at the steady state than does the competing ligand. With cell type specific, quantitative input on integrin-ligand binding rates, this model can be used to develop instructive cell culture systems.

Population pharmacokinetics and outcomes of critically ill pediatric patients treated with intravenous colistin at higher than recommended doses

Limited pharmacokinetic (PK) data suggest that currently recommended pediatric dosages of colistimethate sodium (CMS) by the Food and Drug Administration and European Medicines Agency may lead to suboptimal exposure, resulting in plasma colistin concentrations frequently <2 mg/L. We conducted a population PK study in 17 critically ill patients 3 months-13.75 years (median 3.3 years) old, who received CMS for infections caused by carbapenem-resistant Gram-negative bacteria. CMS was dosed at 200,000 IU/kg/d [6.6 mg colistin base activity (CBA)/kg/d, 6 patients], 300,000 IU/kg/d (9.9 mg CBA/kg/d, 10 patients) and 350,000 IU/kg/d (11.6 mg CBA/kg/d, 1 patient). Plasma colistin concentrations were determined using ultra-performance liquid chromatography combined with electrospray ionization tandem mass spectrometry. Colistin PK was described by a one-compartment disposition model including creatinine clearance, body weight and the presence or absence of systemic inflammatory response syndrome (SIRS) as covariates (p<0.05 for each). The average colistin plasma steady-state concentration (Css,avg) ranged from 1.11-8.47 mg/L (median 2.92 mg/L). Ten patients had Css,avg ≥2 mg/L. The presence of SIRS was associated with decreased apparent clearance of colistin (47.8% of that without SIRS). The relationship between the mg/day of CBA to achieve each 1 mg/L of plasma colistin Css,avg and creatinine clearance (mL/min) was described by linear regression with different slopes for patients with and without SIRS. Nephrotoxicity, probably colistin-unrelated, was observed in one patient. In conclusion, administration of CMS at the above doses improved exposure and was well tolerated. Apparent clearance of colistin was influenced by creatinine clearance and the presence or absence of SIRS.