In silico modeling for ex vivo placenta perfusion of nicotine.

Nicotine readily crosses the placenta to reach fetuses. However, membrane transporters, e.g., organic cation transporters (OCTs) play a role in the clearance of nicotine from the fetal to the maternal side, and this is rarely investigated clinically. In this work, we use an in silico model to simulate an ex vivo placenta perfusion experiment, which is the gold standard for measuring the transplacental permeability of compounds, including nicotine. The model consists of a system of seven ordinary differential equations (ODEs), where each equation represents the nicotine concentration in compartments that emulate the ex vivo experiment setup. The transport role of OCTs is simulated bi-directionally at the placenta's basal membrane (the fetal side). We show that the model can not only reproduce the actual ex vivo experiment results, but also predict the likely maternal and fetal nicotine concentrations when the OCT transporters are inhibited, which leads to a ∼12% increase in fetal nicotine concentration after 2 hours of OCT modulated nicotine perfusion. In conclusion, a first in silico model is proposed in this paper that can be used to simulate some subtle features of trans-placental properties of nicotine.

In silico modeling for the hepatic circulation and transport: From the liver organ to lobules.

The function of the liver depends critically on its blood supply. Numerous in silico models have been developed to study various aspects of the hepatic circulation, including not only the macro-hemodynamics at the organ level, but also the microcirculation at the lobular level. In addition, computational models of blood flow and bile flow have been used to study the transport, metabolism, and clearance of drugs in pharmacokinetic studies. These in silico models aim to provide insights into the liver organ function under both healthy and diseased states, and to assist quantitative analysis for surgical planning and postsurgery treatment. The purpose of this review is to provide an update on state-of-the-art in silico models of the hepatic circulation and transport processes. We introduce the numerical methods and the physiological background of these models. We also discuss multiscale frameworks that have been proposed for the liver, and their linkage with the large context of systems biology, systems pharmacology, and the Physiome project. This article is categorized under: Metabolic Diseases > Computational Models Metabolic Diseases > Biomedical Engineering Cardiovascular Diseases > Computational Models.

In Silico Modeling for Ex Vivo Placental Transfer of Morphine.

Morphine may be administered in pregnant women as an analgesic agent. The transplacental pharmacokinetics (PK) of morphine varies during pregnancy because of physiological and metabolic changes. In this work, we use a multi-compartment model to simulate ex vivo human placental transfer studies of morphine. The computational model is based on a recently published model for metformin with both passive and active transport kinetics. Modifications were made to incorporate morphine-specific transfer parameters. Parameters for the PK models were determined via the nonlinear regression method. In addition, the Latin hypercube sampling (LHS) method was used for the global parameter analysis of the model. Simulation results show good agreement between the model and observed fetal and maternal morphine concentrations. In addition, the lower efflux of morphine from fetal to maternal plasma reflects reduced P-glycoprotein (P-gp) transport as pregnancy progresses, which leads to slower clearance of morphine in the maternal plasma. The LHS analysis also indicates the more significant roles played by the passive diffusion parameters than the active transport parameter on the fetal/maternal morphine concentrations. In conclusion, we used an in silico model to investigate the transplacental properties of morphine and to predict the in vivo transplacental properties of morphine when PK parameters change.

Clinical genetic testing in four highly suspected pediatric restrictive cardiomyopathy cases.

BACKGROUND: Restrictive cardiomyopathy (RCM) presents a high risk for sudden cardiac death in pediatric patients. Constrictive pericarditis (CP) exhibits a similar clinical presentation to RCM and requires differential diagnosis. While mutations of genes that encode sarcomeric and cytoskeletal proteins may lead to RCM, infection, rather than gene mutation, is the main cause of CP. Genetic testing may be helpful in the clinical diagnosis of RCM. METHODS: In this case series study, we screened for TNNI3, TNNT2, and DES gene mutations that are known to be etiologically linked to RCM in four pediatric patients with suspected RCM. RESULTS: We identified one novel heterozygous mutation, c.517C>T (substitution, position 517 C → T) (amino acid conversion, p.Leu173Phe), and two already known heterozygous mutations, c.508C>T (substitution, position 508, C → T) (amino acid conversion, p.Arg170Trp) and c.575G>A (substitution, position 575, G → A) (amino acid conversion, p.Arg192His), in the TNNI3 gene in three of the four patients. CONCLUSION: Our findings support the notion that genetic testing may be helpful in the clinical diagnosis of RCM.

Synergistic effect of preheating and different power output high-intensity ultrasound on the physicochemical, structural, and gelling properties of myofibrillar protein from chicken wooden breast.

The effects of preheating to 50 ℃ and the subsequent application of high-intensity ultrasound (HIU, 20 kHz) at 200, 400, 600, and 800 W on the physicochemical, structural, and gelling properties of wooden breast myofibrillar protein (WBMP) were studied. Results suggested that the WBMP structure expanded to the balanced state at 600 W, and rheological properties exhibit that 600 W HIU (P < 0.05) significantly improved the storage modulus (G') of WBMP. Notably, the WBMP gel (600 W) had the best hardness (65.428 ± 0.33 g), springiness (0.582 ± 0.01), and water-holding capacity (86.11 ± 0.83%). Raman spectra and low-field NMR indicated that 600 W HIU increased the ß-fold content (37.94 ± 0.04%) and enlarged the immobilized-water proportion (93.87 ± 0.46%). Scanning electron micrographs confirmed that the gel was uniform and dense at 600 W. Therefore, preheating to 50 ℃ followed by HIU (600 W) helped form a superior WBMP gel.

Improving physicochemical properties of myofibrillar proteins from wooden breast of broiler by diverse glycation strategies.

The effect of diverse glycation strategies on the physicochemical and structural properties of wooden breast myofibrillar protein (WBMP) were studied. The WBMP was mixed with D-ribose (RI), sodium alginate (SA), and glucosamine (GH) respectively in a weight ratio of 1:2 (w/w) at 70 °C, and was heated for 6 h. Atomic force microscopy and particle size results showed that the glycation reaction in the presence of RI made WBMP to be more evenly dispersed in the solution and had a significantly smaller particle size (78-955 nm, average 361.06 nm) (P < 0.05). There was an increase in WBMP-RI solubility (76.23 ± 0.56%) and α-helix content (51.23 ± 1.1%) than other groups. Compared with WBMP-RI, WBMP-SA and WBMP-GH have poor performance in particle distribution, solubility and emulsification. This study clarified the aldehyde group in aldose was more suitable for the glycation modification of WBMP than the ketone group in ketose.

Effect of Anastomosis Angles on Retrograde Perfusion and Hemodynamics of Hybrid Treatment for Thoracoabdominal Aortic Aneurysm.

BACKGROUND: Hemodynamic effects on the retrograde visceral reconstruction (RVR) for thoracoabdominal aortic aneurysms treatment by anastomotic angle remains unclear. This study aims to qualitatively and quantitatively investigate the effects of different anastomotic angles on hemodynamics and patency. METHODS: Three RVR models with 45°, 60° and 90° anastomotic angles were reconstructed respectively by manipulating apostoperative patient-specific model. The manipulated models of the RVRs were numerically simulated and analyzed in terms of hemodynamics including theinstant and cumulative patency, flow pattern and indicators based on wall shear stress (WSS). RESULTS: Although a smaller anastomotic angle may decrease the patency rate of common iliac arteries, it can improve the visceral perfusion during a cardiac cycle. More importantly, RVR with the smallest anastomotic angle experienced a minimal low time-averaged wall shear stress, high oscillatory shear index and relative residence time in the anastomosis region, whereas the largest anastomotic angle can introduce more unfavorable WSS in the graft trunk. Furthermore, a spiral flow pattern was observed in the proximal graft trunk of all three models, where no high-risk shear distribution was detected in this region. CONCLUSION: A smaller anastomotic angle may have more benefits of hemodynamic environment in RVR, especially the WSS distribution and flow pattern in the graft trunk. We may also suggest that additional stents or an extended cuff for the graft can be used to induce spiral flow intentionally, which can further improve local hemodynamic environment and long-term prognosis.

Global sensitivity analysis of a single-cell HBV model for viral dynamics in the liver.

The predictive accuracy of mathematical models representing anything ranging from the meteorological to the biological system profoundly depends on the quality of model parameters derived from experimental data. Hence, robust sensitivity analysis (SA) of these critical model parameters aids in sifting the influential from the negligible out of typically vast parameter regimes, thus illuminating key components of the system under study. We here move beyond traditional local sensitivity analysis to the adoption of global SA techniques. Partial rank correlation coefficient (PRCC) based on Latin hypercube sampling is compared with the variance-based Sobol method. We selected for this SA investigation an infection model for the hepatitis-B virus (HBV) that describes infection dynamics and clearance of HBV in the liver [Murray & Goyal, 2015]. The model tracks viral particles such as the tenacious and nearly ineradicable covalently closed circular DNA (cccDNA) embedded in infected nuclei and an HBV protein known as p36. Our application of these SA methods to the HBV model illuminates, especially over time, the quantitative relationships between cccDNA synthesis rate and p36 synthesis and export. Our results reinforce previous observations that the viral protein, p36, is by far the most influential factor for cccDNA replication. Moreover, both methods are capable of finding crucial parameters of the model. Though the Sobol method is independent of model structure (e.g., linearity and monotonicity) and well suited for SA, our results ensure that LHS-PRCC suffices for SA of a non-linear model if it is monotonic.

Physiologically Based Pharmacokinetic Modelling for Nicotine and Cotinine Clearance in Pregnant Women.

Introduction: Physiologically based pharmacokinetic (PBPK) models for the absorption, disposition, metabolism and excretion (ADME) of nicotine and its major metabolite cotinine in pregnant women (p-PBPK) are rare. The aim of this short research report is to present a p-PBPK model and its simulations for nicotine and cotinine clearance. Methods: The maternal-placental-fetal compartments of the p-PBPK model contain a total of 16 compartments representing major maternal and fetal organs and tissue groups. Qualitative and quantitative data of nicotine and cotinine disposition and clearance have been incorporated into pharmacokinetic parameters. Results: The p-PBPK model reproduced the higher clearance rates of nicotine and cotinine in pregnant women than non-pregnant women. Temporal profiles for their disposition in organs such as the brain were also simulated. Nicotine concentration reaches its maximum value within 2 min after an intravenous injection. Conclusion: The proposed p-PBPK model produces results consistent with available data sources. Further pharmacokinetic experiments are required to calibrate clearance parameters for individual organs, and for the fetus.

Distribution and variation in proteins of casein micellar fractions response to heat-treatment from five dairy species.

Casein micelles (CMs) contribute to the physicochemical properties and stability of milk. However, how the proteome of CMs changes following heat treatment has not been elucidated. Here, changes in the proteins of CMs in samples of Holstein, buffalo, yak, goat, and camel milk following heat treatment were investigated using a LC-MS/MS approach. According to the hierarchical clustering results, Holstein, yak, and buffalo milk samples had similar CMs protein components, followed by goat and camel milk samples. Changes in lipoprotein lipase and α-lactalbumin in CMs were dependent on the intensity of heat treatment and were similar among the studied species, whereas changes in κ-casein, lactoferrin, and apolipoprotein A-I differed among different types of milk. These results provide information on the distribution and variations of the proteomes of CMs following heat treatment, which will assist in the identification of proteins that are dissociated and attached to CMs from different dairy species during heat treatment.

Prevalence, Drug Resistance, and Virulence Genes of Potential Pathogenic Bacteria in Pasteurized Milk of Chinese Fresh Milk Bar.

Fresh Milk Bar (FMB), an emerging dairy retail franchise, is used to instantly produce and sell pasteurized milk and other dairy products in China. However, the quality and safety of pasteurized milk in FMB have received little attention. The objective of this study was to investigate the prevalence, antimicrobial resistance, and virulence genes of Escherichia coli, Staphylococcus aureus, and Streptococcus in 205 pasteurized milk samples collected from FMBs in China. Four (2.0%) isolates of E. coli, seven (3.4%) isolates of S. aureus, and three (1.5%) isolates of Streptococcus agalactiae were isolated and identified. The E. coli isolates were resistant to amikacin (100%), streptomycin (50%), and tetracycline (50%). Their detected resistance genes include aac(3)-III (75%), blaTEM (25%), aadA (25%), aac(3)-II (25%), catI (25%), and qnrB (25%). The S. aureus isolates were mainly resistant to penicillin G (71.4%), trimethoprim-sulfamethoxazole (71.4%), kanamycin (57.1%), gentamicin (57.1%), amikacin (57.1%), and clindamycin (57.1%). blaZ (42.9%), mecA (28.6%), ermB (14.3%), and ermC (14.3%) were detected as their resistance genes. The Streptococcus strains were mainly resistant to tetracycline (66.7%) and contained the resistance genes pbp2b (33.3%) and tetM (33.3%). The virulence genes eae and stx2 were only found in one E. coli strain (25%), sec was detected in two S. aureus strains (28.6%), and bca was detected in one S. agalactiae strain (33.3%). The results of this study indicate that bacteria with drug resistance and virulence genes isolated from the pasteurized milk of FMB are a potential risk to consumers' health.

Occurrence, Antimicrobial Resistance Patterns, and Genetic Characterization of Staphylococcus aureus Isolated from Raw Milk in the Dairy Farms over Two Seasons in China.

This study investigated the occurrence and resistance rates of Staphylococcus aureus strains isolated from raw milk in the dairy farms over two seasons (spring and autumn) and across four regions that included 11 provinces in China. In total, 750 raw milk samples from the 405 dairy farms were collected. Fifteen antimicrobial agents were tested for antimicrobial resistance via disk diffusion tests, and PCR tests were performed to identify drug resistance genes of S. aureus isolates. Out of 750 samples, 276 (36.8%) were positive for S. aureus, with 150 (41.1%) being positive in spring and 126 (32.7%) being positive in autumn. The occurrence rate of S. aureus in northeastern China (45%) was higher than that in western China (33%) and southern China (31.9%), respectively, and the rate significantly (p < 0.05) differed from those of western China and southern China. Of 276 isolates, 261 (94.6%) strains were resistant to more than 1 antimicrobial drug, and 193 (69.9%) strains were multidrug resistant. The blaZ (46.3%), dfrG (35.5%), and tetM (27.2%) genes were detected at a high frequency in the S. aureus strains. Our data revealed a variation (p < 0.05) in the resistance patterns in the different regions and across the two seasons. The occurrence and drug resistance rates of S. aureus isolated from raw milk obtained from dairy farms may still cause severe problems in China.

Survey of Aflatoxin M1 in Commercial Liquid Milk Products in China.

ABSTRACT: The objective of this study was to investigate the occurrence of aflatoxin M1 (AFM1) in Chinese liquid milk products. A total of 190 liquid milk samples, including 168 ultrahigh-temperature-treated milk samples and 22 pasteurized milk (PM) samples, were collected in August 2019. A screening assay with the Charm rapid test kit and a confirmation method with high-performance liquid chromatography were used for AFM1 analysis. Nine (4.74%) samples were screened positive, of which 5 (2.11%) samples were confirmed with concentration levels of 0.022 to 0.049 µg/kg. The AFM1 levels confirmed were all below the maximum residue levels set by China, the European Union, the United States, and the Codex Alimentarius Commission. The detection rate of AFM1 in domestic milk samples was 3.39%, while no AFM1 was detected in samples of imported milk. The prevalences of AFM1 detected in three groups of brands were as follows: group I, the major brands of China, 2.70%; group II, the local city domestic brands, 4.55%; and group III, the brands imported into China, 0. The detection rate of AFM1 was significantly higher in PM samples (9.09%) than in ultrahigh-temperature-treated samples (1.19%) (P < 0.05). Although the residue level of AFM1 did not exceed the maximum residue levels in any of the samples, the higher detection rate in local Chinese brands, especially in PM samples, deserves the attention of the Chinese government and consumers.

A Pilot Study on Secondhand Smoke Exposure Among Pregnant Women in Chongqing, China: A Combined Questionnaire, Saliva Cotinine Test, and Ultrasound Flow Index Analysis.

Objective: The aim of the study was to gain updated data on SHS exposure among pregnant women in Chongqing city, one of the four municipalities of China. Study Design and Setting: Pregnant women attending routine ultrasound checks at an obstetrics and gynecology center voluntarily participated in the survey of SHS exposure. Some participants were also invited to have saliva cotinine tests using a NicAlert kit. The pulsatility index (PI) of the umbilical artery was compared between the SHS and non-SHS groups. Results: A total of 548 pregnant women (74.82 and 25.18% at 12 and 24 weeks' gestation, respectively) participated in the survey from July to November 2019. SHS exposure was reported by 29.44% of participants. "Workplace" was listed as the top location for SHS exposure. Twenty-three of the 31 participants who tested cotinine-negative in their saliva samples self-reported SHS exposure in the survey questionnaire. However, two of the eight participants who tested cotinine-positive in their saliva samples self-reported SHS-exposure negative. The mean PI in the SHS group is higher than that in the non-SHS group (1.10 vs. 1.02) in fetuses at 24 weeks' gestation. However, the PI may not be suitable as an index for SHS exposure at 12 weeks' gestation due to frequent absent or reversed diastolic flow. Conclusion: The first survey on SHS exposure in pregnant women that combines a questionnaire, saliva cotinine tests, and ultrasound flow index analysis has been performed in China and provided valuable data for ensuing studies.