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This study aimed to develop a rapid, 1 mm3 isotropic resolution, whole-brain MRI technique for automatic lesion segmentation and multi-parametric mapping without using contrast by continuously applying balanced steady-state free precession with inversion pulses throughout incomplete inversion recovery in a single 6 min scan. Modified k-means clustering was performed for automatic brain tissue and lesion segmentation using distinct signal evolutions that contained mixed T1/T2/magnetization transfer properties. Multi-compartment modeling was used to derive quantitative multi-parametric maps for tissue characterization. Fourteen patients with contrast-enhancing gliomas were scanned with this sequence prior to the injection of a contrast agent, and their segmented lesions were compared to conventionally defined manual segmentations of T2-hyperintense and contrast-enhancing lesions. Simultaneous T1, T2, and macromolecular proton fraction maps were generated and compared to conventional 2D T1 and T2 mapping and myelination water fraction mapping acquired with MAGiC. The lesion volumes defined with the new method were comparable to the manual segmentations (r = 0.70, p < 0.01; t-test p > 0.05). The T1, T2, and macromolecular proton fraction mapping values of the whole brain were comparable to the reference values and could distinguish different brain tissues and lesion types (p < 0.05), including infiltrating tumor regions within the T2-lesion. Highly efficient, whole-brain, multi-contrast imaging facilitated automatic lesion segmentation and quantitative multi-parametric mapping without contrast, highlighting its potential value in the clinic when gadolinium is contraindicated.

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications. [ABSTRACT FROM AUTHOR]

Copyright of Journal of Xinyang Normal University Natural Science Edition is the property of Journal of Xinyang Normal University Editorial Office and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Currently, lung cancer is treated by the highest number of therapeutic options and the benefits are based on multiple large‐scale sequencing studies, translational research and new drug development, which has promoted our understanding of the molecular pathology of lung cancer. According to the driver alterations, different characteristics have been revealed, such as differences in ethnic prevalence, median age and alteration patterns. Consequently, beyond traditional chemoradiotherapy, molecular‐targeted therapy and treatment with immune check‐point inhibitors (ICI) also became available major therapeutic options. Interestingly, clinical results suggest that the recently established therapies target distinct lung cancer proportions, particularly between the EGFR/ALK and PD‐1/PD‐L1‐positive subsets, e.g. the kinase inhibitors target driver mutation‐positive tumours, whereas driver mutation‐negative tumours respond to ICI treatment. These therapeutic efficacy‐related differences might be explained by the molecular pathogenesis of lung cancer. Addictive driver mutations promote tumour formation with powerful transformation performance, resulting in a low tumour mutation burden, reduced immune surveillance, and subsequent poor response to ICIs. In contrast, regular tobacco smoke exposure repeatedly injures the proximal airway epithelium, leading to accumulated genetic alterations. In the latter pathway, overgrowth due to alteration and immunological exclusion against neoantigens is initially balanced. However, tumours could be generated from certain clones that outcompete immunological exclusion and outgrow the others. Consequently, this cancer type responds to immune check‐point treatment. These pathogenic differences are explained well by the two‐compartment model, focusing upon the anatomical and functional composition of distinct cellular components between the terminal respiratory unit and the air‐conducting system. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies are commonly engineered with an introduction of Met428Leu and Asn434Ser, known as the LS mutation, in the fragment crystallizable region to improve pharmacokinetic profiles. The LS mutation delays antibody clearance by enhancing binding affinity to the neonatal fragment crystallizable receptor found on endothelial cells. To characterize the LS mutation for monoclonal antibodies targeting HIV, we compared pharmacokinetic parameters between parental versus LS variants for five pairs of anti-HIV immunoglobin G1 monoclonal antibodies (VRC01/LS/VRC07-523LS, 3BNC117/LS, PGDM1400/LS PGT121/LS, 10-1074/LS), analyzing data from 16 clinical trials of 583 participants without HIV. We described serum concentrations of these monoclonal antibodies following intravenous or subcutaneous administration by an open two-compartment disposition, with first-order elimination from the central compartment using non-linear mixed effects pharmacokinetic models. We compared estimated pharmacokinetic parameters using the targeted maximum likelihood estimation method, accounting for participant differences. We observed lower clearance rate, central volume, and peripheral volume of distribution for all LS variants compared to parental monoclonal antibodies. LS monoclonal antibodies showed several improvements in pharmacokinetic parameters, including increases in the elimination half-life by 2.7- to 4.1-fold, the dose-normalized area-under-the-curve by 4.1- to 9.5-fold, and the predicted concentration at 4 weeks post-administration by 3.4- to 7.6-fold. Results suggest a favorable pharmacokinetic profile of LS variants regardless of HIV epitope specificity. Insights support lower dosages and/or less frequent dosing of LS variants to achieve similar levels of antibody exposure in future clinical applications.

Copyright of Acta Scientiarum Naturalium Universitatis Sunyatseni / Zhongshan Daxue Xuebao is the property of Sun-Yat-Sen University and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (ka) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the ka values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (kmax). The accuracy of the direct method in ka estimation was determined using the setting parameters (k12, k21, and k10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of ka estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the ka values of these drugs were accurately estimated using the direct method based on good correlations between the ka values and other PK parameters that reflected the absorption properties of drugs in vivo (Tmax, Cmax, and Cmax/AUC0-t). This novelmethod can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment. [ABSTRACT FROM AUTHOR]

With the aging population, osteoporosis has become an important public health issue. The purpose of this study was to establish a two-compartment model (TCM) to quantify the volumetric bone mineral density (vBMD) of the lumbar spine using abdominal computed tomography (CT) images. The TCM approach uses water as the bone marrow equivalent and K2HPO4 solution as the cortical bone equivalent. A phantom study was performed to evaluate the accuracy of vBMD estimation at 100 kVp and 120 kVp. The data of 180 patients who underwent abdominal CT imaging and dual-energy X-ray absorptiometry (DXA) within one month were retrospectively collected. vBMD of L1–L4 vertebrae were calculated, and the receiver-operating characteristic curve analysis was performed to establish the diagnostic thresholds for osteoporosis and osteopenia in terms of vBMD. The average difference between the measured vBMD following TCM and the theoretical vBMD of the self-made phantom was 0.2%, and the maximum difference was 0.5%. vBMD of lumbar vertebrae obtained from TCM and aBMD obtained by DXA had a significant positive correlation (r = 0.655 to 0.723). The average diagnostic threshold for osteoporosis was 0.116 g/cm3. The sensitivity, specificity, and accuracy were 95.7%, 75.6.5%, and 80.0%, respectively. The average diagnostic threshold for osteopenia was 0.126 g/cm3. The sensitivity, specificity, and accuracy were 81.3%, 82.5%, and 82.7%, respectively. The aforementioned threshold values were used to perform the diagnostics on a test cohort, and the performance was equivalent to that in the experimental cohort. From the perspective of preventive medicine, opportunistic screening of bone mineral density using abdominal CT images and the TCM approach can facilitate early detection of osteoporosis and osteopenia and, with in-time treatment, slow down their progression. [ABSTRACT FROM AUTHOR]

The propagation of slowly-varying firing rates has been proved significant for the development of the central nervous system. Recent reports have shown that the membrane passive properties of dendrites play a key role in the computation of the single neuron, which is of great importance to the function of neural networks. However, it is still unclear how dendritic passive properties affect the ability of cortical networks to propagate slowly-varying spiking activity. Here, we use two-compartment biophysical models to construct multilayered feedforward neural networks (FFNs) to investigate how dendritic passive properties affect the propagation of the slow-varying inputs. In the two-compartment biophysical models, one compartment represents apical dendrites, and the other compartment describes the soma plus the axon initial segment. Area proportion occupied by somatic compartment and coupling conductance between dendritic and somatic compartments are abstracted to capture the dendritic passive properties. A time-varying signal is injected into the first layer of the FFNs and the fidelity of the signal during propagation is used to qualify the ability of the FFN to transmit wave-like signals. Numerical results reveal an optimal value of coupling conductance between dendritic and somatic compartments to maximize the fidelity of the initial spiking activity. An increase of the dendritic area enhances the initial firing rate of neurons in the first layer by increasing the response of neurons to slow-varying wave-like input, resulting in a delay of attenuation of the firing rate, thus promoting the transmission of signals in FFN. Using a mean-field approach, we examine that changes in area proportion occupied by somatic compartment and coupling conductance between dendritic and somatic compartment affect the signal propagation ability of the FFN by adjusting the input–output transform of a single neuron. With the participation of external noise, a wide range of initial firing rates maintains a unique representation during propagation, which ensures the reliable transmission of slow-varying signals in FFNs. These findings are helpful to understand how passive properties of dendrites participate in the propagation of slowly varying signals in the cerebellum. [ABSTRACT FROM AUTHOR]

A large number of studies have shown that the correlation of spike trains in paired neurons is a key indicator of functional connectivity. Acting as the important components of neurons, dendrites affect the generation of spike train and the transmission of signals by changing the transfer function of neurons. However, it is not clear how the intrinsic properties of dendrites influence the degree of correlation of neuronal spike trains. This paper used a biophysically-based two-compartment model to simulate the firing output of neurons that receive correlated input currents, quantify the relationship between the active and passive properties of dendrites and the pairwise spike train correlations. We found that increasing the proportion of dendritic area or the coupling conductance between two compartments increases the output correlation. It is also shown that decreasing the intracellular calcium concentration and the conductance of calcium activated outward potassium channel or increasing the conductance of sodium and potassium channel in dendritic compartment increases the output correlation. This results from the increase of the number of dendritic spikes due to changing dendritic intrinsic properties, which causes more internal current flowing into the soma from dendrites, thereby leading to an increase of somatic firing rate. Our results reveal the influence of the intrinsic characteristics of dendrites on firing output of individual neuron, which further influences the correlation between the spike trains of a pairs or population of neurons. This study is of great significance for understanding how neuronal intrinsic properties affect neural network coding. [ABSTRACT FROM AUTHOR]

Background/Aim. Methotrexate (MTX) plays a significant role in the treatment of various diseases, but the toxicity remains the main issue of its use, especially when administered in high doses. Considering altered pharmacokinetics of MTX as a factor strongly implicated in the large interpatient variability and unexpected toxicity in certain patients, the accurate description of MTX pharmacokinetic behaviour of both low and high doses is of the utmost importance. Therefore, the objective of this study was to determine the pharmacokinetics of MTX after intravenous (iv) administration in ascending doses of 5, 40, 80 and 160 mg/kg in rats and to select the appropriate mathematical model describing MTX pharmacokinetics. Methods. Plasma concentrations of MTX were measured using the liquid chromatography - mass spectrometry (LC/MS) method. Pharmacokinetic parameters were calculated by non-compartmental and two-compartmental integer-order analyses. Results. MTX showed linear pharmacokinetics following iv administration up to the dose of 80 mg/kg. The administration of a high dose of MTX (160 mg/kg) resulted in the similar pharmacokinetic behaviour as when applied in the twice lower dose (80 mg/kg), which can be explained by dose-dependent changes in the expression of solute carrier (SLC) and ATP binding cassette (ABC) transport proteins and intracellular metabolism. Furthermore, the classical two-compartment model could not explain the pharmacokinetics of MTX in a small percentage of experimental animals, which opens up new strategies for the use of fractional order pharmacokinetic models in MTX therapy optimisation. Conclusion. These results of pharmacokinetic analyses may be helpful in adjusting the dosage regimen of MTX, but the application of novel pharmacokinetic models, such as those based on fractional calculus, is still needed in the process of MTX therapy optimisation.

The objective was to explore variations of temperature distribution and coagulation zone size computed by a two-compartment radiofrequency ablation (RFA) model when including simultaneously reversible changes in the tissue electrical conductivity (σ) due to temperature and irreversible changes due to thermal coagulation. Two-compartment (tumor and healthy tissue) models were built and simulated. Reversible change of σ was modeled by a piecewise function characterized by increments of +1.5%/℃ up to 100 ℃, and a 100 times smaller value from 100 ℃ onwards. Irreversible changes of σ were modeled using an Arrhenius model. We assumed that both tumor and healthy tissue had a different initial σ value (as suggested by the experimental data in the literature) and tended towards a common value as thermal damage progressed (necrotized tissue). We modeled a constant impedance protocol based on 90 V pulses voltage and three tumor diameters (2, 3 and 4 cm). Computer simulations showed that the differences between both models were only 0.1 and 0.2 cm for axial and transverse diameters, respectively, and this small difference was reflected in the similar temperature distributions computed by both models. In view of the available experimental data on changes of electrical conductivity in tumors and healthy tissue during heating, our results suggest that irreversible changes in electrical conductivity do not have a significant impact on coagulation zone size in two-compartment RFA models.

With the aging population, osteoporosis has become an important public health issue. The purpose of this study was to establish a two-compartment model (TCM) to quantify the volumetric bone mineral density (vBMD) of the lumbar spine using abdominal computed tomography (CT) images. The TCM approach uses water as the bone marrow equivalent and K2HPO4 solution as the cortical bone equivalent. A phantom study was performed to evaluate the accuracy of vBMD estimation at 100 kVp and 120 kVp. The data of 180 patients who underwent abdominal CT imaging and dual-energy X-ray absorptiometry (DXA) within one month were retrospectively collected. vBMD of L1–L4 vertebrae were calculated, and the receiver-operating characteristic curve analysis was performed to establish the diagnostic thresholds for osteoporosis and osteopenia in terms of vBMD. The average difference between the measured vBMD following TCM and the theoretical vBMD of the self-made phantom was 0.2%, and the maximum difference was 0.5%. vBMD of lumbar vertebrae obtained from TCM and aBMD obtained by DXA had a significant positive correlation (r = 0.655 to 0.723). The average diagnostic threshold for osteoporosis was 0.116 g/cm3. The sensitivity, specificity, and accuracy were 95.7%, 75.6.5%, and 80.0%, respectively. The average diagnostic threshold for osteopenia was 0.126 g/cm3. The sensitivity, specificity, and accuracy were 81.3%, 82.5%, and 82.7%, respectively. The aforementioned threshold values were used to perform the diagnostics on a test cohort, and the performance was equivalent to that in the experimental cohort. From the perspective of preventive medicine, opportunistic screening of bone mineral density using abdominal CT images and the TCM approach can facilitate early detection of osteoporosis and osteopenia and, with in-time treatment, slow down their progression.

The most aggressive tumor cells, which often reside in a hypoxic environment, can release vast amounts of lactate and protons via monocarboxylate transporters (MCTs). This additional proton efflux exacerbates extracellular acidification and supports the formation of a hostile environment. In the present study we propose a novel, data-based model for this proton-coupled lactate transport in cancer cells. The mathematical settings involve systems coupling nonlinear ordinary and stochastic differential equations describing the dynamics of intra- and extracellular proton and lactate concentrations. The data involve time series of intracellular proton concentrations of normoxic and hypoxic MCF-7 breast cancer cells. The good agreement of our final model with the data suggests the existence of proton pools near the cell membrane, which can be controlled by intracellular and extracellular carbonic anhydrases to drive proton-coupled lactate transport across the plasma membrane of hypoxic cancer cells.

Copyright of Journal of Agro-Environment Science is the property of Journal of Agro-Environment Science Editorial Board and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Abstract Background The large potential of the soil organic carbon (SOC) pool to sequester CO2 from the atmosphere could greatly ameliorate the effect of future climate change. However, the quantity of carbon stored in terrestrial soils largely depends upon the magnitude of SOC mineralization. SOC mineralization constitutes an important part of the carbon cycle, and is driven by many biophysical variables, such as temperature and moisture. Methods Soil samples of a pine forest, an oak forest, and a pine and oak mixed forest were incubated for 387 days under conditions with six temperature settings (5 °C, 10 °C, 15 °C, 20 °C, 25 °C, 30 °C) and three levels of soil moisture content (SMC, 30%, 60%, 90%). The instantaneous rate of mineralized SOC was periodically and automatically measured using a Li-Cor CO2 analyzer. Based on the measured amount of mineralized SOC, carbon fractions were estimated separately via first-order kinetic one- and two-compartment models. Results During the 387 day incubation experiment, accumulative mineralized carbon ranged from 22.89 mg carbon (C) ·g− 1 SOC at 30 °C and 30% SMC for the mixed forest to 109.20 mg C·g− 1 SOC at 15 °C and 90% SMC for the oak forest. Mineralized recalcitrant carbon varied from 18.48 mg C·g− 1 SOC at 30 °C and 30% SMC for the mixed forest to 104.98 mg C·g− 1 SOC at 15 °C and 90% SMC for the oak forest, and contributed at least 80% to total mineralized carbon. Conclusions Based on the results of this experiment, the soil organic matter of the pure broadleaved forest is more vulnerable to soil microbial degradation in northern China; most of the amount of the mineralized SOC derived from the recalcitrant carbon pool. Labile carbon fraction constitutes on average 0.4% of SOC across the three forest types and was rapidly digested by soil microbes in the early incubation stage. SOC mineralization markedly increased with soil moisture content, and correlated parabolically to temperature with the highest value at 15 °C. No significant interaction was detected among these variables in the present study.

Background: Short imaging protocol to quantify myocardial blood flow (MBF) and myocardial flow reserve (MFR) may enhance the clinical application of 13N-ammonia cardiac PET. We assessed the flow quantitation of 13N-ammonia PET implementing simple retention model and two-compartment model.Methods: Fourteen healthy volunteers (HVT) and twenty-three clinical patients received 13N-ammonia PET/CT. The simple retention model used the first 7-minute image to quantify MBF. Global and regional MBF and MFR of the two models were compared.Results: Global and regional MBF and MFR of these two models were highly correlated with mildly inferior correlation in RCA territory (global R2: rest MBF = 0.79, stress MBF = 0.65, MFR = 0.77; regional R2: rest MBF ≥ 0.72, stress MBF ≥ 0.52, MFR ≥ 0.68). There were significant differences for MFR (4.04 ± 0.72, 3.66 ± 0.48, p = .02) and rest MBF (0.69 ± 0.12, 0.78 ± 0.12, p = .02) between the two models in the HVT group.Conclusions: 13N-ammonia global and regional MBF and MFR from the simple retention model demonstrate strong correlations with that from the two-compartment model. Significant differences of MFR and rest MBF are noted in the HVT group, with a proposed normal reference value for the 13N-ammonia short simple retention protocol. [ABSTRACT FROM AUTHOR]

Accurate prediction of blood toxin concentration during and after dialysis will greatly contribute to the determination of dialysis treatment conditions. Conventional models, namely single-compartment model and two-compartment model, have advantages and disadvantages in terms of accuracy and practical application. In this study, we attempted to derive the mathematical model that predicts blood toxin concentrations during and after dialysis, which has both accuracy and practicality. To propose the accurate model, a new two-compartment model was mathematically derived by adapting volume-averaging theory to the mass transfer around peripheral tissues. Subsequently, to propose a practical model for predicting the blood toxin concentration during dialysis, an analytical solution expressed as algebraic expression was derived by adopting variable transformation. Furthermore, the other analytical solution that predicts rebound phenomena after dialysis was also derived through similar steps. The comparisons with the clinical data revealed that the proposed analytical solutions can reproduce the behavior of the measured blood urea concentration during and after dialysis. The analytical solutions proposed as algebraic expressions will allow a doctor to estimate the blood toxin concentration of a patient during and after dialysis. The proposed analytical solutions may be useful to consider the treatment conditions for dialysis, including the rebound phenomenon.

We study a nonlinear age‐structured model of locust population dynamics with variable time of egg incubation that describes the phase shifting and behavior of desert locust, Schistocerca gregaria. The model is based on the 2‐compartment system of transport equations with nonlinear density‐dependent fertility rates with time delay in boundary conditions. It describes the dynamics of the density of 2 phases of locust's population—solitarious and gregarious. Such system is studied both theoretically and numerically. The analysis of asymptotical stability of the trivial and nontrivial equilibria of the autonomous system allows to understand the conditions and the particularities of bidirectional phase shifts between solitarious and gregarious S gregaria. We found that the parameter of maturation age was very important in the 2‐phase dynamics. We extrapolate that a rapid change in environmental conditions that may trigger the maturation process of dormant solitarious population may also decrease, overall, the maturation age and hence destabilize the solitarious subpopulation from a near zero population size towards much larger populations and hence initiate quickly good conditions for gregarization. We also observed that the most realistic population dynamics of locusts was when the attraction point of a stable solitarious population size was above the gregarization threshold. This means that solitarious populations may last through time only near a zero size, but as soon as environmental conditions become favorable to population increase, the gregarization may happen. This outlines the intrinsic character of outbreaking dynamics that a species such as desert locust displays. [ABSTRACT FROM AUTHOR]

Objectives: The purpose of this study was to develop a quantitative method for myocardial blood flow (MBF) measurement using contrast-enhanced multidetector computed tomography (MDCT) images with bolus tracking and helical scanning. Materials and Methods: Nine canine models of left anterior descending artery stenosis were prepared and underwent MDCT perfusion imaging during adenosine infusion to study a wide range of flow parameters. Neutron-activated microspheres were injected to document MBF during adenosine infusion. Six animals underwent dynamic MDCT perfusion imaging, and K1 and k2 (which represent the first-order transfer constants from left ventricular blood to myocardium and from myocardium to the vascular system, respectively) were measured using a two-compartment model. The results were compared against microsphere MBF measurements, and the extraction fraction (E) of contrast agent and the mean value of k1/k2 were calculated. Six animals then underwent helical CT perfusion imaging, and neutron-activated microspheres were injected to document MBF during adenosine infusion. For each animal, based on E, K1/k2, time-registered helical CT myocardial data, and arterial input function data, tables of myocardial CT values versus MBF were simulated for various MBF values to create look-up tables from the myocardial CT value to MBF. The CT-derived MBF values were compared against the microsphere MBF measurements. Results: A strong linear correlation was observed between the MDCT-derived MBF and the microsphere MBF (y = 1.065x – 0.616, R2 = 0.838). Conclusions: Regional MBF can be measured accurately using a combination of bolus tracking and time-registered helical CT data from contrast-enhanced MDCT scanning during adenosine stress.

This paper proposes that modified two-compartment Pinsky–Rinzel (PR) neural model can be used to develop the simple form of central pattern generator (CPG). The CPG is called as ‘half-central oscillator’, which constructed by two inhibitory chemical coupled PR neurons with time delay. Some key properties of PR neural model related to CPG are studied and proved to meet the requirements of CPG. Using the simple CPG network, we first study the relationship between rhythmical output and key factors, including ambient noise, sensory feedback signals, morphological character of single neuron as well as the coupling delay time. We demonstrate that, appropriate intensity noise can enhance synchronization between two coupled neurons. Different output rhythm of CPG network can be entrained by sensory feedback signals. We also show that the morphology of single neuron has strong effect on the output rhythm. The phase synchronization indexes decrease with the increase of morphology parameter’s difference. Through adjusting coupled delay time, we can get absolutely phase synchronization and antiphase state of CPG. Those results of simulation show the feasibility of PR neural model as a valid CPG as well as the emergent behaviors of the particularly CPG. [ABSTRACT FROM AUTHOR]

Neural computation is performed by transforming input signals into sequences of action potentials (APs), which is metabolically expensive and limited by the energy available to the brain. The metabolic efficiency of single AP has important consequences for the computational power of the cell, which is determined by its biophysical properties and morphologies. Here we adopt biophysically-based two-compartment models to investigate how dendrites affect energy efficiency of APs in cortical pyramidal neurons. We measure the Na+ entry during the spike and examine how it is efficiently used for generating AP depolarization. We show that increasing the proportion of dendritic area or coupling conductance between two chambers decreases Na+ entry efficiency of somatic AP. Activating inward Ca2+ current in dendrites results in dendritic spike, which increases AP efficiency. Activating Ca2+-activated outward K+ current in dendrites, however, decreases Na+ entry efficiency. We demonstrate that the active and passive dendrites take effects by altering the overlap between Na+ influx and internal current flowing from soma to dendrite. We explain a fundamental link between dendritic properties and AP efficiency, which is essential to interpret how neural computation consumes metabolic energy and how biophysics and morphologies contribute to such consumption.

Purpose: Due to variations in biological half-life, accurate thyroid dosimetry for I-131 therapy is not trivial in clinical practice. In recent publications, systems are described to measure the uptake of I-131 in the thyroid repeatedly over time. In this work, we present a method to calculate patient specific pharmacokinetics and absorbed dose using such a collar detector system (CoTI) in combination with a SPECT acquisition and a two-compartment model fit. Methods: For three patients receiving I-131 therapy for benign thyroid conditions, the complete uptake profile is measured over a period of 15 to 25 days after administration. A SPECT measurement is performed to assess the functional volume of the thyroid and the amount of I-131 in the thyroid. The uptake profile measured in counts-per-second is converted to absolute activity in MBq using the absolute quantification of the SPECT. A two-compartment model is used as a fit to the uptake data of the thyroid and to estimate the activity in the blood-pool. The estimated absorbed dose to the thyroid is then calculated from the integral of the activity. The assessed parameters from the method (6- and 24-h uptake, thyroid volume and I-131 uptake concentration) are compared with the values as determined in clinical practice. Furthermore, the convergence of the calculated absorbed dose as a function of measurement series duration is determined to assess the required measurement duration of the uptake profile. Results: The two-compartment model fit shows a good agreement with the measured data points. Resulting dynamic uptake profiles of the three patients differ from each other. The uptake percentages differ from the pretherapy I-123 uptake measurements that are used in usual clinical practice, which shows the potential added value of the proposed method. The duration of the required measurement series appears to be patient dependent and therefore needs to be determined for each patient individually. The proposed method allows for a basic investigation of the individual dynamic uptake profile of I-131 in the thyroid and the calculation of the absorbed dose. Conclusions: The proposed measurement method is feasible and easily implementable given a system that can measure the uptake of I-131 in the thyroid repeatedly over time. The observed differences in dynamic uptake profiles and the differences in the absorbed thyroid dose as calculated with our method and the parameters of the usual clinical care support the relevance of the proposed method. In future studies, this approach may possibly be used for outcome prediction and therapeutic activity optimization. [ABSTRACT FROM AUTHOR]

Objective To simplify the calculation of T>MIC and evaluate meropenem regimens based on the simple mathematical model of T>MIC reported in literature for two-compartment model. Methods Six meropenem regimens were designed according to the recommended dose with the infusion duration of 0.5 h and 3 h. Four different MIC susceptibility breakpoint of meropenem against clinical microbiologic flora were used to formulate different T>MIC. Each T>MIC was calculated by both the simple and two-compartment model of T>MIC.Meropenem regimens were evaluated for different bacterial infections based on the simple model of T>MIC with 40%~100% of the T>MIC% as the target. The t-test suggested no significant difference between the pairs of T>MIC calculated by the two models. Results and Conclusion Simple model of T>MIC can replace the two-compartment model. Meropenem regimens can be optimized based on this simple model of T>MIC conveniently and quickly. [ABSTRACT FROM AUTHOR]

Given that the traditional methods of estimating pharmacokinetic parameters are constrained by the sensitivity of their initial value and incapability of evolutionary algorithm to determine search range, this paper proposes a hybrid invasive weed optimization (HIWO) algorithm by combining the Hooke-Jeeves (HJ) and invasive weed optimization (IWO) algorithm. Using the HIWO algorithm for the parameter optimization by the experiment of extravascular administration two-compartment model, we can see that the proposed method is not only better than traditional feathering method (FM) in terms of numerical stability, but also better than HJ and IWO in terms of error minimization. The experimental results show that HIWO algorithm is a feasible method to optimize the pharmacokinetic parameters, which has higher precision and stronger robustness than the other techniques. [ABSTRACT FROM AUTHOR]

1. The number of developed therapeutic monoclonal antibodies (mAbs) has increased in this decade. This study aims to predict their pharmacokinetic profiles after intravenous (iv) injection using only the data taken after subcutaneous (sc) injection in cynomolgus monkey. 2. Two-compartment model parameters, Q, Vc and Vp, were collected from the published data after iv injection in cynomolgus monkey for 21 mAbs (Group A). Bioavailability after sc injection (F), CL and serum/plasma concentration after iv injection of other published 19 mAbs (Group B) were predicted using the estimated geometric means of Q, Vc and Vp in Group A and the serum/plasma concentration after sc injection in Group B. 3. F and CL of 18 out of 19 mAbs in Group B were successfully predicted within 30% difference of observed value. Moreover, most of the observed serum/plasma concentrations after iv injection of mAbs in Group B were successfully predicted within 2-fold difference. Our approach suggests that iv injection might not be required to evaluate absorption of mAbs after sc injection in cynomolgus monkey. Therefore, our approach might reduce the time and cost of drug development, reduce the burden on resources, and also contribute to animal welfare. [ABSTRACT FROM AUTHOR]

Background Direct current stimulation (DCS) affects both neuronal firing rate and synaptic efficacy. The neuronal input/output (I/O) function determines the likelihood that a neuron elicits an action potential in response to synaptic input of a given strength. Changes of the neuronal I/O function by DCS may underlie previous observations in animal models and human testing, yet have not been directly assessed. Objective Test if the neuronal input/output function is affected by DCS Methods Using rat hippocampal brain slices and computational modeling, we provide evidence for how DCS modulates the neuronal I/O function. Results We show for the first time that DCS modulates the likelihood of neuronal firing for a given and fixed synaptic input. Opposing polarization of soma and dendrite may have a synergistic effect for anodal stimulation, increasing the driving force of synaptic activity while simultaneously increasing spiking probability at the soma. For cathodal stimulation, however, the opposing effects tend to cancel. This results in an asymmetry in the strength of the effects of stimulation for opposite polarities. Conclusions Our results may explain the asymmetries observed in acute and long term effects of transcranial direct current stimulation. [ABSTRACT FROM AUTHOR]

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Disentangling the tissue microstructural information from the diffusion magnetic resonance imaging (dMRI) measurements is quite important for extracting brain tissue specific measures. The autocorrelation function of diffusing spins is key for understanding the relation between dMRI signals and the acquisition gradient sequences. In this paper, we demonstrate that the autocorrelation of diffusion in restricted or bounded spaces can be well approximated by exponential functions. To this end, we propose to use the multivariate Ornstein-Uhlenbeck (OU) process to model the matrix-valued exponential autocorrelation function of three-dimensional diffusion processes with bounded trajectories. We present detailed analysis on the relation between the model parameters and the time-dependent apparent axon radius and provide a general model for dMRI signals from the frequency domain perspective. For our experimental setup, we model the diffusion signal as a mixture of two compartments that correspond to diffusing spins with bounded and unbounded trajectories, and analyze the corpus-callosum in an ex-vivo data set of a monkey brain.

The in vivo performances of most drugs after extravascular administration are fitted well with the two-compartment pharmacokinetic (PK) model, but the estimation of absorption rate constant (k a ) for these drugs becomes difficult during unavailability of intravenous PK data. Herein, we developed a novel method, called the direct method, for estimating the k a values of drugs without using intravenous PK data, by proposing a new PK parameter, namely, maximum apparent rate constant of disposition (k max ). The accuracy of the direct method in k a estimation was determined using the setting parameters (k 12 , k 21 , and k 10 values at high, medium, and low levels, respectively) and clinical data. The results showed that the absolute relative error of k a estimated using the direct method was significantly lower than that obtained using both the Loo-Riegelman method and the statistical moment method for the setting parameters. Human PK studies of telmisartan, candesartan cilexetil, and tenofovir disoproxil fumarate indicated that the k a values of these drugs were accurately estimated using the direct method based on good correlations between the k a values and other PK parameters that reflected the absorption properties of drugs in vivo (T max , C max , and C max /AUC 0-t ). This novel method can be applied in situations where intravenous PK data cannot be obtained and is expected to provide valuable support for PK evaluation and in vitro-in vivo correlation establishment., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Liu, Yi, Wang, Cheng and Zhang.)

Govaniadine (GOV) is an alkaloid isolated from Corydalis govaniana Wall. It has been reported to show a different number of biological activities including anti-urease, leishmanicidal and antinociceptive. The present study aims to characterize the GOV in vitro metabolism after incubation with rat and human liver microsomes (RLM and HLM, respectively) and to evaluate its pharmacokinetic properties. The identification of GOV metabolites was conducted by different mass analyzers: a micrOTOF II—ESI-ToF Bruker Daltonics ® and an amaZon-SL ion trap (IT) Bruker Daltonics ® . For the pharmacokinetic study of GOV in rats after intravenous administration, a LC–MS/MS method was developed and applied to. The analyses were performed using an Acquity UPLC ® coupled to an Acquity TQD detector equipped with an ESI interface. The liver microsomal incubation resulted in new O-demethylated, di-hydroxylated and mono-hydroxylated compounds. Regarding the method validation, the calibration curve was linear over the concentration range of 2.5–3150.0 ng mL −1 , with a lower limit of quantitation (LLOQ) of 2.5 ng mL −1 . This method was successfully applied to a pharmacokinetic study. The profile was best fitted to a two-compartment model, the first phase with a high distribution rate constant (α) 0.139 ± 0.086 min −1 , reflected by the short distribution half-life (t1/2α) 9.2 ± 8.9 min and the later one, with an elimination half-life (t1/2β) 55.1 ± 37.9 min. The main plasma protein binding was 96.1%. This is a first report in this field and it will be useful for further development of govaniadine as a drug candidate. [ABSTRACT FROM AUTHOR]

We consider the optimal design of pharmacokinetic studies in patients that receive intermittent hemodialysis and intravenous antibiotic. Hemodialysis perturbs the pharmacokinetic system, providing additional opportunity for study. Designs that allocate measurements to occur exclusively during hemodialysis are shown to be viable alternatives to conventional designs, where all measurements occur outside of hemodialysis. Furthermore, hybrid designs with both conventional and intradialytic measurements have nearly double the efficiency of conventional designs. Convex optimal design and Monte Carlo techniques were used to simultaneously optimize hemodialysis event characteristics and sampling times, accounting for population pharmacokinetic heterogeneity. We also present several related methodological innovations. [ABSTRACT FROM AUTHOR]

Purpose Model fitting of dynamic contrast-enhanced-magnetic resonance imaging-MRI data with nonlinear least squares (NLLS) methods is slow and may be biased by the choice of initial values. The aim of this study was to develop and evaluate a linear least squares (LLS) method to fit the two-compartment exchange and -filtration models. Methods A second-order linear differential equation for the measured concentrations was derived where model parameters act as coefficients. Simulations of normal and pathological data were performed to determine calculation time, accuracy and precision under different noise levels and temporal resolutions. Performance of the LLS was evaluated by comparison against the NLLS. Results The LLS method is about 200 times faster, which reduces the calculation times for a 256 × 256 MR slice from 9 min to 3 s. For ideal data with low noise and high temporal resolution the LLS and NLLS were equally accurate and precise. The LLS was more accurate and precise than the NLLS at low temporal resolution, but less accurate at high noise levels. Conclusion The data show that the LLS leads to a significant reduction in calculation times, and more reliable results at low noise levels. At higher noise levels the LLS becomes exceedingly inaccurate compared to the NLLS, but this may be improved using a suitable weighting strategy. Magn Reson Med 76:998-1006, 2016. © 2015 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

This work is the first report on the dissipation and final residue of cloransulam-methyl on soybean plant at field conditions. A fast, simple, and reliable residue analytical method for determination of cloransulam-methyl in soybean matrices and soil was developed based on quick, easy, cheap, effective, rugged, and safe (QuEChERS) sample preparation and liquid chromatography-tandem mass spectrometry (LC-MS/MS) detection. The average recoveries of cloransulam-methyl in soybean matrices and soil ranged from 80 to 105 %, with RSDs between 3-11%. The limit of detection (LOD) was 0.001 mg kg-1 for soybean grain, plant, and soil and was 0.005 mg kg-1 for soybean straw. This method was then used to characterize dissipation of cloransulam-methyl in soybeans and soil from three locations in China for the first time. Cloransulam-methyl dissipated quickly in soybean plant with half-lives (T1/2) of 0.21-0.56 days. The dissipation dynamic in soil was characterized using both first-order kinetics model and two-compartment model, and the half-lives were similar, ranging from 0.44 to 5.53 days at three experimental sites in 2012 and 2013. The final residue data showed a very low level of cloransulam-methyl in soil (≤0.026 mg kg-1), soybean grain (≤0.001 mg kg-1), and straw (≤0.005 mg kg-1) samples at harvest time. With the faster and simple analytical method on soybean and soil, rapid dissipation of cloransulam-methyl was observed at three geospatial locations in China, and the terminal residue levels were negligible, so mammalian ingestion exposure is minimal. [ABSTRACT FROM AUTHOR]

The purpose of this study was to develop a method to determine time discrepancies between input and myocardial time–signal intensity (TSI) curves for accurate estimation of myocardial perfusion with first-pass contrast-enhanced MRI. Estimation of myocardial perfusion with contrast-enhanced MRI using kinetic models requires faithful recording of contrast content in the blood and myocardium. Typically, the arterial input function (AIF) is obtained by setting a region of interest in the left ventricular cavity. However, there is a small delay between the AIF and the myocardial curves, and such time discrepancies can lead to errors in flow estimation using Patlak plot analysis. In this study, the time discrepancies between the arterial TSI curve and the myocardial tissue TSI curve were estimated based on the compartment model. In the early phase after the arrival of the contrast agent in the myocardium, the relationship between rate constant K 1 and the concentrations of Gd-DTPA contrast agent in the myocardium and arterial blood (LV blood) can be described by the equation K 1 = {dC myo (t peak )/dt}/C a (t peak ), where C myo (t) and C a (t) are the relative concentrations of Gd-DTPA contrast agent in the myocardium and in the LV blood, respectively, and t peak is the time corresponding to the peak of C a (t). In the ideal case, the time corresponding to the maximum upslope of C myo (t), t max , is equal to t peak . In practice, however, there is a small difference in the arrival times of the contrast agent into the LV and into the myocardium. This difference was estimated to correspond to the difference between t peak and t max . The magnitudes of such time discrepancies and the effectiveness of the correction for these time discrepancies were measured in 18 subjects who underwent myocardial perfusion MRI under rest and stress conditions. The effects of the time discrepancies could be corrected effectively in the myocardial perfusion estimates. [ABSTRACT FROM AUTHOR]

Purpose This study demonstrates how to quantify the tumor blood volume fraction (BVf) using the dynamic Rapid-Steady-State-T1 (RSST1)-MRI method despite contrast agent (CA) leakage and without arterial input function (AIF) determination. Methods For vasculature impermeable to CAs, the BVf is directly quantified from the RSST1 signal amplitude. In case of CA extravasation, we propose a two-compartment model to describe the dynamic RSST1 signal increase. We applied the mathematical model in a pilot-study on a RG2-glioma model to compare extravasation of two Gd-based CAs. The BVf quantification using the mathematical model in a C6-glioma model (n = 8) with the clinical CA Gd-DOTA was validated using a ΔR2*-steady-state MRI method with an USPIO and by immunohistochemical staining of perfused vessels labeled with Hoechst-33342 dye in the same rats. Results BVf in tumor and in healthy brain tissues (0.034 ± 0.005 and 0.026 ± 0.004, respectively) derived from the dynamic RSST1 signal were confirmed by ΔR2*-steady-state MRI (0.036 ± 0.003 and 0.027 ± 0.002, respectively, correlation coefficient rS = 0.74) and by histology (0.036 ± 0.003 and 0.025 ± 0.004 respectively, rS = 0.87). Conclusion Straightforward tumor BVf quantification without AIF determination is demonstrated in presence of CA leakage. The method will facilitate angiogenesis assessment in longitudinal neuro-oncologic studies in particular when monitoring the response to antiangiogenic therapies. Magn Reson Med 73:1005-1014, 2015. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: This paper proposes a new numerical modelling to examine environmental chemodynamics of a gaseous material exchanged between the air and turbulent water phases across a gas–liquid interface, followed by an aquarium chemical reaction. This study uses an extended concept of a two-compartment model, and assumes two physicochemical substeps to approximate the gas exchange processes. The first substep is the gas–liquid equilibrium between the air and water phases, , with Henry's law constant H. The second is a first-order irreversible chemical reaction in turbulent water, with a chemical reaction rate . A direct numerical simulation (DNS) technique has been employed to obtain details of the gas exchange mechanisms and the chemical reaction in the water compartment, while zero velocity and uniform concentration of A is considered in the air compartment. The study uses the different Schmidt numbers between 1 and 8, and six nondimensional chemical reaction rates between to 101 at a fixed Reynolds number. It focuses on the effects of the Schmidt number and the chemical reaction rate on fundamental mechanisms of the gas exchange processes across the interface. [Copyright &y& Elsevier]

Purpose To map the intra-to-extracellular water exchange rate constant in rat xenografts using a two-compartment model of relaxation with water exchange and a range of contrast agent concentrations and compare with histology. Methods MDA-MB-231 cells were xenografted into six nude rats. Three bolus injections of gadodiamide were administered. When uptake in the tumor demonstrated a steady-state, T1 data were acquired by spoiled gradient recalled acquisitions at four flip angles. A global fit of data to a two-compartment model incorporating exchange was performed, assuming a distribution volume of 20% of the rat. Results Voxels that did not reach steady-state and were excluded from parametric maps tended to be in large necrotic areas. TUNEL-negative (nonapoptotic) regions tended to have well-defined error bounds, with an average intra-to-extracellular exchange rate constant of 0.6 s−1. Apoptotic regions had higher exchange, but poorly determined upper bounds, with goodness of fit similar to that for a model assuming infinitely fast exchange. A lower bound of >3 s−1 was used to establish voxels where the exchange rate constant was fast despite a large upper bound. Conclusion Water exchange rates were higher in apoptotic regions, but examination of statistical errors was an important step in the mapping process. Magn Reson Med 71:1874-1887, 2014. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Recent studies show that naïve T cells bearing identical T cell receptors experience heterogeneous differentiation and clonal expansion processes. The factors controlling this outcome are not well characterized, and their contributions to immune cell dynamics are similarly poorly understood. In this study, we develop a computational model to elaborate mechanisms occurring within and between two important physiological compartments, lymph nodes and blood, to determine how immune cell dynamics are controlled. Our multi-organ (multi-compartment) model integrates cellular and tissue level events and allows us to examine the heterogeneous differentiation of individual precursor cognate naïve T cells to generate both effector and memory T lymphocytes. Using this model, we simulate a hypothetical immune response and reproduce both primary and recall responses to infection. Increased numbers of antigen-bearing dendritic cells (DCs) are predicted to raise production of both effector and memory T cells, and distinct "sweet spots" of peptide-MHC levels on those DCs exist that favor CD4+ or CD8+ T cell differentiation toward either effector or memory cell phenotypes. This has important implications for vaccine development and immunotherapy. [ABSTRACT FROM AUTHOR]

Abstract: This paper proposes a new numerical modelling to examine environmental chemodynamics of a gaseous material exchanged between the air and turbulent water phases across a gas–liquid interface, followed by an aquarium chemical reaction. This study uses an extended concept of a two-compartment model, and assumes two physicochemical substeps to approximate the gas exchange processes. The first substep is the gas–liquid equilibrium between the air and water phases, , with Henryʼs law constant H. The second is a first-order irreversible chemical reaction in turbulent water, with a chemical reaction rate . A direct numerical simulation (DNS) technique has been employed to obtain details of the gas exchange mechanisms and the chemical reaction in the water compartment, while zero velocity and uniform concentration of A is considered in the air compartment. The study uses the different Schmidt numbers between 1 and 8, and six nondimensional chemical reaction rates between to 101 at a fixed Reynolds number. It focuses on the effects of the Schmidt number and the chemical reaction rate on fundamental mechanisms of the gas exchange processes across the interface. [Copyright &y& Elsevier]

Purpose To identify the optimal tracer-kinetic modeling strategy for dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) data acquired at low temporal resolution. Materials and Methods DCE-MRI was performed on 13 patients with rheumatoid arthritis of the hand before and after anti-tumor necrosis factor alpha (TNFα) therapy, using a 3D sequence with a temporal resolution of 13 seconds, imaging for 4 minutes postcontrast injection. Concentration-time curves were extracted from regions of interest (ROIs) in enhancing synovium and fitted to the 3-parameter modified Tofts model (MT) and the 4-parameter two-compartment exchange model (2CXM). To assist the interpretation of the data, the same analysis was applied to simulated data with similar characteristics. Results Both models fitted the data closely, and showed similar therapy effects. The MT plasma volume was significantly lower than with 2CXM, but the differences in permeability and interstitial volume were not significant. 2CXM was less precise than MT, with larger standard deviations relative to the mean in most parameters. The additional perfusion parameter determined with 2CXM did not provide a statistically significant trend due to low precision. Conclusion The standard MT model is the optimal modeling strategy at low temporal resolution. Advanced models improve the accuracy and generate an additional parameter, but these benefits are offset by low precision. J. Magn. Reson. Imaging 2013;38:1554-1563. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]