Single-compartment Model Research Articles

Establishment of an Integrated Population Pharmacokinetic/Pharmacodynamics Model of Apixaban in Chinese Healthy Population Adjusting for Key Genetic Variants.

To improve the understanding of pharmacokinetic/pharmacodynamic (PK/PD) profiles of apixaban, supporting personalised drug prescriptions for future patients. Genetic as well as nongenetic factors can affect the predictable PK and PD characteristics of apixaban. Establish a integrated popPK/PD model that adjusts for critical genetic variant. The integrated PK/PD models was characterized on the basis of PK (apixaban blood concentration) and PD (prothrombin time (PT), activated partial thromboplastin time (APTT), and anti-FXa activity) data from 181 healthy Chinese volunteers. Other investigated covariate variables included: Meaningful intrinsic and extraneous determinants, correlated markers (ABCG2, F13A1, C3, etc.). A total of 2877 PK concentration observations were included in the modeling dataset. The PK model of apixaban is adopted by single compartment model with first-order oral absorption. The estimated values of total clearance rate (CL/F), apparent distribution volume (V/F), and absorption rate constant (KA) in the final model are 3.37 l/h, 28.2 l, and 0.781 l/h, respectively. The PK model includes significance covariates such as FOOD, RBC, WT, and gene (ABCG2). The PD model of apixaban is adopted by a linear direct effect model with additive error, which was used to describe the relationship between markers such as APTT, PT, anti-FXa, versus plasma concentration. PK simulation within the modelled dose range is similar to clinical real date, while PD simulation results also show that the simulated exposure parameters is within the range of the literature. We established a comprehensive PK/PD model and used it to simulate markers level such as APTT, PT, and anti-FXa of apixaban. Individual predictive values with a dose of 2.5 mg are basically within the expected recommended range.

Therapeutic drug monitoring of linezolid in Chinese premature neonates: a population pharmacokinetic analysis and dosage optimization.

This study aimed to develop a pharmacokinetic model of linezolid in premature neonates and evaluate and optimize the administration regimen. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used to detect the blood concentration data of 54 premature neonates after intravenous administration of linezolid, and the relevant clinical data were collected. The population pharmacokinetic (PPK) model was established by nonlinear mixed effects modeling. Based on the final model parameters, the optimal administration regimen of linezolid in premature neonates with different body surface areas (BSA) was simulated and evaluated. The pharmacokinetic properties of linezolid in premature neonates are best described by a single-compartment model with primary elimination. The population typical values for apparent volume of distribution and clearance were 0.783 L and 0.154 L/h, respectively. BSA was a statistically significant covariate with clearance (CL) and volume of distribution (Vd). Monte Carlo simulations showed that the optimal administration regimen for linezolid in premature neonates was 6 mg/kg q8h for BSA 0.11 m2, 7 mg/kg q8h for BSA 0.13 m2, and 9 mg/kg q8h for BSA 0.15 m2 with minimum inhibitory concentration (MIC) ≤1 mg/L, 7 mg/kg q8h for BSA 0.11 m2, 8 mg/kg q8h for BSA 0.13 m2, and 10 mg/kg q8h for BSA 0.15 m2 with MIC = 2 mg/L. A pharmacokinetic model was developed to predict the blood concentration on linezolid in premature neonates. Based on this model, the optimal administration regimen of linezolid in premature neonates needs to be individualized according to different BSA levels.

A blood-free modeling approach for the quantification of the blood-to-brain tracer exchange in TSPO PET imaging.

Recent evidence suggests the blood-to-brain influx rate (K1 ) in TSPO PET imaging as a promising biomarker of blood-brain barrier (BBB) permeability alterations commonly associated with peripheral inflammation and heightened immune activity in the brain. However, standard compartmental modeling quantification is limited by the requirement of invasive and laborious procedures for extracting an arterial blood input function. In this study, we validate a simplified blood-free methodologic framework for K1 estimation by fitting the early phase tracer dynamics using a single irreversible compartment model and an image-derived input function (1T1K-IDIF). The method is tested on a multi-site dataset containing 177 PET studies from two TSPO tracers ([11C]PBR28 and [18F]DPA714). Firstly, 1T1K-IDIF K1 estimates were compared in terms of both bias and correlation with standard kinetic methodology. Then, the method was tested on an independent sample of [11C]PBR28 scans before and after inflammatory interferon-α challenge, and on test-retest dataset of [18F]DPA714 scans. Comparison with standard kinetic methodology showed good-to-excellent intra-subject correlation for regional 1T1K-IDIF-K1 (ρintra = 0.93 ± 0.08), although the bias was variable depending on IDIF ability to approximate blood input functions (0.03-0.39 mL/cm3/min). 1T1K-IDIF-K1 unveiled a significant reduction of BBB permeability after inflammatory interferon-α challenge, replicating results from standard quantification. High intra-subject correlation (ρ = 0.97 ± 0.01) was reported between K1 estimates of test and retest scans. This evidence supports 1T1K-IDIF as blood-free alternative to assess TSPO tracers' unidirectional blood brain clearance. K1 investigation could complement more traditional measures in TSPO studies, and even allow further mechanistic insight in the interpretation of TSPO signal.

Model-Informed individualized dosage regimen of sirolimus in pediatric patients with intractable lymphatic malformations

Intractable lymphatic malformations (iLM) pose a significant threat to affected children, demonstrating limited responses to conventional treatments. Sirolimus, effectively inhibiting endothelial cell proliferation in lymphatic vessels, plays a crucial role in iLM treatment. However, the drug's narrow therapeutic window and substantial interindividual variability necessitate customized dosing strategies. This study aims to establish a Population Pharmacokinetic Model (PopPK model) for sirolimus in pediatric iLM patients, identifying quantitative relationships between covariates and sirolimus clearance and volume of distribution. Initial dosages are recommended based on a target concentration range of 5–15 ng/mL. Retrospective data from our institution, encompassing 53 pediatric patients with 275 blood concentration results over the past five years (average age: 4.64 ± 4.19 years), constituted the foundation of this analysis. The final model, adopting a first-order absorption and elimination single-compartment model, retained age as the sole covariate. Results indicated a robust correlation between apparent clearance (CL/F) at 5.56 L/h, apparent volume of distribution (V/F) at 292.57 L, and age. Monte Carlo simulation guided initial dosages for patients aged 0–18 years within the target concentration range. This study presents the first PopPK model using a large Therapeutic Drug Monitoring (TDM) database to describe personalized sirolimus dosing for pediatric iLM patients, contributing to pharmacokinetic guidance and potentially improving long-term clinical outcomes.

Computational modeling to study the impact of changes in Nav1.8 sodium channel on neuropathic pain.

Nav1.8 expression is restricted to sensory neurons; it was hypothesized that aberrant expression and function of this channel at the site of injury contributed to pathological pain. However, the specific contributions of Nav1.8 to neuropathic pain are not as clear as its role in inflammatory pain. The aim of this study is to understand how Nav1.8 present in peripheral sensory neurons regulate neuronal excitability and induce various electrophysiological features on neuropathic pain. To study the effect of changes in sodium channel Nav1.8 kinetics, Hodgkin-Huxley type conductance-based models of spiking neurons were constructed using the NEURON v8.2 simulation software. We constructed a single-compartment model of neuronal soma that contained Nav1.8 channels with the ionic mechanisms adapted from some existing small DRG neuron models. We then validated and compared the model with our experimental data from in vivo recordings on soma of small dorsal root ganglion (DRG) sensory neurons in animal models of neuropathic pain (NEP). We show that Nav1.8 is an important parameter for the generation and maintenance of abnormal neuronal electrogenesis and hyperexcitability. The typical increased excitability seen is dominated by a left shift in the steady state of activation of this channel and is further modulated by this channel's maximum conductance and steady state of inactivation. Therefore, modified action potential shape, decreased threshold, and increased repetitive firing of sensory neurons in our neuropathic animal models may be orchestrated by these modulations on Nav1.8. Computational modeling is a novel strategy to understand the generation of chronic pain. In this study, we highlight that changes to the channel functions of Nav1.8 within the small DRG neuron may contribute to neuropathic pain.

The Effect of Zinc Concentration on Bioaccumulation in Milkfish <i>(Chanos chanos)</i> Use of <sup>65</sup>Zn as a Radioactive Tracer

Bioaccumulation studies of zinc (Zn) in milkfish (Chanos chanos) have been carried out in the laboratory using a 65Zn radiotracer. The research was conducted to determine the effect of Zn concentration on the ability of Chanos chanos to accumulate and release these contaminants. Zn absorption follows the single-compartment model, and experiments were carried out until stable conditions were achieved. The stages of research were biota collection, acclimatization, bioaccumulation, and elimination. Acclimatization was carried out for biota adaptation in the experimental environment. Bioaccumulation was carried out for 7 days by placing the biota in an aquarium filled with seawater added with 65Zn radiotracer contaminants. The elimination process involves the release of contaminants from the biota by placing them in contaminant-free seawater for 7 days. The results of the bioaccumulation experiment showed that the concentration factor (CF) ranged from 0.67 - 18.18 mLgr-1 at a concentration of ZnCl2 of 1.5 ppm, and the absorption constant (ku) 1.878 - 3.267d-1 and R2 was 0.0276. The release of contaminants in depuration experiments was highest at ZnCl2 2 ppm concentrations. The percentage of retention during depuration was between 14.61 - 79.91 %, the elimination constant (ke) was 8.681, and R2 was 0.7213.

A biochemical description of postsynaptic plasticity—with timescales ranging from milliseconds to seconds

Synaptic plasticity [long-term potentiation/depression (LTP/D)], is a cellular mechanism underlying learning. Two distinct types of early LTP/D (E-LTP/D), acting on very different time scales, have been observed experimentally-spike timing dependent plasticity (STDP), on time scales of tens of ms; and behavioral time scale synaptic plasticity (BTSP), on time scales of seconds. BTSP is a candidate for a mechanism underlying rapid learning of spatial location by place cells. Here, a computational model of the induction of E-LTP/D at a spine head of a synapse of a hippocampal pyramidal neuron is developed. The single-compartment model represents two interacting biochemical pathways for the activation (phosphorylation) of the kinase (CaMKII) with a phosphatase, with ion inflow through channels (NMDAR, CaV1,Na). The biochemical reactions are represented by a deterministic system of differential equations, with a detailed description of the activation of CaMKII that includes the opening of the compact state of CaMKII. This single model captures realistic responses (temporal profiles with the differing timescales) of STDP and BTSP and their asymmetries. The simulations distinguish several mechanisms underlying STDP vs. BTSP, including i) the flow of [Formula: see text] through NMDAR vs. CaV1 channels, and ii) the origin of several time scales in the activation of CaMKII. The model also realizes a priming mechanism for E-LTP that is induced by [Formula: see text] flow through CaV1.3 channels. Once in the spine head, this small additional [Formula: see text] opens the compact state of CaMKII, placing CaMKII ready for subsequent induction of LTP.

How teacher behaviors and perceptions, air change rates, and portable air purifiers affect indoor air quality in naturally ventilated schools.

Many school buildings have inadequate ventilation, rudimentary if any air filtration, and aging and poorly maintained mechanical systems, all of which can lead to poor indoor air quality (IAQ). These issues are especially acute in environmental justice (EJ) communities where schools are located in polluted areas. This community-based participatory research examines how IAQ in naturally ventilated school buildings is affected by the use of air purifiers, air change rates, outdoor pollution levels, and teacher and staff behavior. IAQ assessments were performed at two schools in Detroit, Michigan, which included building walk-through inspections and continuous indoor and outdoor measurements of black carbon (BC), particulate matter (PM10 and PM2.5), carbon dioxide (CO2), air change rates (ACRs), temperature, humidity, and sound pressure levels. Air purifiers with usage monitors were then installed, and the IAQ assessments were repeated. Teachers were surveyed before and after purifier deployment. At baseline, classrooms had low ACRs (0.58-1.38 h-1), moderate PM2.5 levels (2.8-8.9 μg/m3), highly variable PM10 concentrations (4.7-37.5 μg/m3), and elevated BC levels (0.3-0.7 μg/m3), reflecting emissions from local traffic, industry and other sources. The installation and use of purifiers reduced pollutant levels and the overall performance matched the predictions of a single compartment model. However, daily reductions varied widely among classrooms, reflecting differences in teacher behavior regarding the frequency of opening windows and the operation of purifiers, including differences in purifier fan speed settings and whether purifiers were used at night. Survey responses indicated that many teachers were aware of IAQ problems. The higher rates reported for health symptoms and dissatisfaction at one school may have lowered the teachers' tolerance to noise and reduced purifier use. The study helps explain the variation reported in prior studies using purifiers, and it reinforces the need to monitor IAQ and purifier use, use enhanced filtration and increase ventilation, and engage with teachers and school staff to support and maintain IAQ programs in schools.

Dynamic Contrast-enhanced CT Lymphangiography to Quantify Thoracic Duct Lymphatic Flow.

Background CT lymphangiography has been used to image the lymphatic anatomy and assess lymphatic abnormalities. There is, however, a need to develop a method for quantification of lymphatic flow rate in the thoracic duct (TD). Purpose To develop and validate a TD lymphatic flow measurement technique using dynamic contrast-enhanced CT lymphangiography. Materials and Methods Lymphatic flow rate was measured with two techniques: a first-pass analysis technique based on a single compartment model and a thresholding technique distinguishing between opacified and nonopacified voxels within the TD. The measurements were validated in a swine animal model between November 2021 and September 2022. CT images were acquired at 100 kV and 200 mA using a fast-pitched helical scan mode covering the entire TD following contrast material injection into the bilateral inguinal lymph nodes. Two helical CT scans, acquired at the base and peak contrast enhancement of the TD, were used to measure lymphatic flow rate. A US flow probe surgically placed around the TD provided the reference standard measurement. CT lymphatic flow measurements were compared with the reference US flow probe measurements using regression and Bland-Altman analysis. Repeatability was determined using repeated flow measurements within approximately 10 minutes of each other. Results Eleven swine (10 male; mean weight, 43.6 kg ± 2.6 [SD]) were evaluated with 71 dynamic CT acquisitions. The lymphatic flow rates measured using the first-pass analysis and thresholding techniques were highly correlated with the reference US flow probe measurements (r = 0.99 and 0.91, respectively) and showed good agreement with the reference standard, with Bland-Altman analysis showing small mean differences of 0.04 and 0.05 mL/min, respectively. The first-pass analysis and thresholding techniques also showed good agreement for repeated flow measurements (r = 0.94 and 0.90, respectively), with small mean differences of 0.09 and 0.03 mL/min, respectively. Conclusion The first-pass analysis and thresholding techniques could be used to accurately and noninvasively quantify TD lymphatic flow using dynamic contrast-enhanced CT lymphangiography. © RSNA, 2023 See also the editorial by Choyke in this issue.

Single-compartment model of a pyramidal neuron, fitted to recordings with current and conductance injection.

For single neuron models, reproducing characteristics of neuronal activity such as the firing rate, amplitude of spikes, and threshold potentials as functions of both synaptic current and conductance is a challenging task. In the present work, we measure these characteristics of regular spiking cortical neurons using the dynamic patch-clamp technique, compare the data with predictions from the standard Hodgkin-Huxley and Izhikevich models, and propose a relatively simple five-dimensional dynamical system model, based on threshold criteria. The model contains a single sodium channel with slow inactivation, fast activation and moderate deactivation, as well as, two fast repolarizing and slow shunting potassium channels. The model quantitatively reproduces characteristics of steady-state activity that are typical for a cortical pyramidal neuron, namely firing rate not exceeding 30Hz; critical values of the stimulating current and conductance which induce the depolarization block not exceeding 80mV and 3, respectively (both values are scaled by the resting input conductance); extremum of hyperpolarization close to the midpoint between spikes. The analysis of the model reveals that the spiking regime appears through a saddle-node-on-invariant-circle bifurcation, and the depolarization block is reached through a saddle-node bifurcation of cycles. The model can be used for realistic network simulations, and it can also be implemented within the so-called mean-field, refractory density framework.

Tumour status prediction by means of carbon-ion beam irradiation: comparison of washout rates between in-beam PET and DCE-MRI in rats

Objective. Tumour response to radiation therapy appears as changes in tumour vascular condition. There are several methods for analysing tumour blood circulatory changes one of which is dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI), but there is no method that can observe the tumour vascular condition and physiological changes at the site of radiation therapy. Positron emission tomography (PET) has been applied for treatment verification in charged particle therapy, which is based on the detection of positron emitters produced through nuclear fragmentation reactions in a patient’s body. However, the produced positron emitters are washed out biologically depending on the tumour vascular condition. This means that measuring the biological washout rate may allow evaluation of the tumour radiation response, in a similar manner to DCE-MRI. Therefore, this study compared the washout rates in rats between in-beam PET during 12C ion beam irradiation and DCE-MRI. Approach. Different vascular conditions of the tumour model were prepared for six nude rats. The tumour of each nude rat was irradiated by a 12C ion beam with simultaneous in-beam PET measurement. In 10–12 h, the DCE-MRI experiment was performed for the same six nude rats. The biological washout rate of the produced positron emitters (k 2,1st) and the MRI contrast agent (k 2a) were derived using the single tissue compartment model. Main results. A linear correlation was observed between k 2,1st and k 2a, and they were inversely related to fractional necrotic volume. Significance. This is the first animal study which confirmed the biological washout rate of in-beam PET correlates closely with tumour vascular condition measured with the MRI contrast agent administrated intravenously.

A deuterium tracer experiment for simulating accumulation and elimination of organically bound tritium in an edible flatfish, olive flounder

Tritium (3H, T) is discharged by nuclear facilities into coastal oceans as tritiated water (HTO). When the concentration of HTO in seawater increases, the accumulation of organically bound tritium (OBT) in edible fish becomes a concern because of its longer residence time than HTO. To evaluate the accumulation potential of OBT in olive flounder (Paralichthys olivaceus), a commercially important edible fish in northeast Asia, we experimentally exposed the fish to seawater enriched with deuterium (2H, D) as a substitute for tritium. Progressive increases and decreases in the concentration of organically bound deuterium (OBD) were observed in the edible part (i.e., muscle) of the fish during the period of exposure to 2H (161 days) and the subsequent period of elimination of OBD (196 days). The measured concentration of OBD was analyzed using a newly developed single-compartment model to describe the metabolism of OBD in muscle via the following three transfer pathways: formation of OBD from 2H in water, elimination of OBD by catabolism, and ingestion of feed with natural abundance of OBD. The model estimates were in good agreement with the measured muscle OBD concentrations. The formation and elimination rate constants for OBD in the muscle were estimated by fitting our model to the measured data. The biological half-life of OBT in the muscle, estimated from the elimination rate constant, was 133 days, which was far longer than that of HTO in the free water of the muscle. Our model facilitates the estimation of OBT accumulation potential in olive flounder inhabiting coastal areas near nuclear facilities, and thus, will help to assess the radiation dose that humans are exposed to from ingesting seafood.

Quantification of P-glycoprotein function at the human blood-brain barrier using [18F]MC225 and PET

IntroductionP-glycoprotein (P-gp) is one of the most studied efflux transporters at the blood-brain barrier. It plays an important role in brain homeostasis by protecting the brain from a variety of endogenous and exogeneous substances. Changes in P-gp function are associated both with the onset of neuropsychiatric diseases, including Alzheimer’s disease and Parkinson’s disease, and with drug-resistance, for example in treatment-resistant depression. The most widely used approach to measure P-gp function in vivo is (R)-[11C]verapamil PET. (R)-[11C]verapamil is, however, an avid P-gp substrate, which complicates the use of this tracer to measure an increase in P-gp function as its baseline uptake is already very low. [18F]MC225 was developed to measure both increases and decreases in P-gp function.AimThe aim of this study was (1) to identify the pharmacokinetic model that best describes [18F]MC225 kinetics in the human brain and (2) to determine test-retest variability.MethodsFive (2 male, 3 female) of fourteen healthy subjects (8 male, 6 female, age 67 ± 5 years) were scanned twice (injected dose 201 ± 47 MBq) with a minimum interval of 2 weeks between scans. Each scanning session consisted of a 60-min dynamic [18F]MC225 scan with continuous arterial sampling. Whole brain grey matter data were fitted to a single tissue compartment model, and to reversible and irreversible two tissue-compartment models to obtain various outcome parameters (in particular the volume of distribution (VT), Ki, and the rate constants K1 and k2). In addition, a reversible two-tissue compartment model with fixed k3/k4 was included. The preferred model was selected based on the weighted Akaike Information Criterion (AIC) score. Test-retest variability (TRTV) was determined to assess reproducibility.ResultsSixty minutes post-injection, the parent fraction was 63.8 ± 4.0%. The reversible two tissue compartment model corrected for plasma metabolites with an estimated blood volume (VB) showed the highest AIC weight score of 34.3 ± 17.6%. The TRVT of the VT for [18F]MC225 PET scans was 28.3 ± 20.4% for the whole brain grey matter region using this preferred model.Conclusion[18F]MC225 VT, derived using a reversible two-tissue compartment model, is the preferred parameter to describe P-gp function in the human BBB. This outcome parameter has an average test-retest variability of 28%.Trial registrationEudraCT 2020-001564-28. Registered 25 May 2020.

#5710 CHARACTERIZATION OF RESPONSE TO TREATMENT WITH RITUXIMAB IN PATIENTS WITH PRIMARY GLOMERULOPATIES

Abstract Background and Aims Rituximab (RTX) is an anti-CD20 monoclonal antibody used in renal diseases with glomerular involvement, which usually present with proteinuria. The doses used in this pathologies are extrapolated from other diseases such as rheumatoid arthritis, but the optimal regimen in this population has not been well defined. Objective To describe the behaviuor of RITUXIMAB in patients with primary glomerulopathies in whom its use is indicated. Method Descriptive low-intervention single-center clinical trial approved by the Spanish Medicines Agency (NEFRTX, EUDRACT 2020-000484-23. Patients treated with rituximab were included according to medical criteria, prior approval by the Pharmacy Commission. The regimen used was 1g every 15 days, or only 1gr dose with premedication according to clinical practice guidelines. 24-hour blood and urine samples were collected on days 1 (post-rituximab), 7, 15 (pre and post-rituximab), 28, and 45. Serum rituximab was determined using ELISA (Lisa-Traker®-Rituximab, Theraradiag®). Clinical and pharmacokinetic data analyzes were performed considering a single compartment model by non-linear regression with Winnolin® to obtain clearance (Cl), half-life (t1/2), maximum concentration (Cmax) and volume of distribution (Vd). Some quantitative results are expressed as mean ± standard deviation. Linear regression was used to establish correlations. Results The results of 5 patients were analyzed, 2 women and 3 men, with a mean age of 68.8 ± 17.02 years of 72 years and a diagnosis of membranous GN (3), ANCA MPO GN (1), focal and segmental GN (1). Renal function CKD EPI: GFR between 45- 60 ml/min N = 2 GFR >60 ml/min N = 3. According to clinical practice guidelines, patients received 1g doses, 2/5 patients received a second dose on day 15. The evaluation parameters were: proteinuria, CD 19+ lymphocyte depletion, Antibodies titers and histological characteristics as appropriate. levels of rituximab in urine samples after the rituximab administration (15, 30, 180, 365 days after) were determinate. All the patients presented proteinuria, with a mean of 11±14.6 g in 24 h urine. Mean Rituximab clearance was 0.676±0.431 ml/h/kg, distribution volume was 222.35±140.52 mL/Kg and Cmax 69.66±26.14 mcg/mL and t1/2 269.66± 229.71 h (11 days approximately). There is a correlation between proteinuria and rituximab half-life (p = 0.077), as well as between proteinuria and clearance creatinine (p = 0.975) suggesting that half life of rituximab is lower if proteinuria increases (Fig. 1). All presented lymphocyte depletion of CD 19 at 45 days. However, those with more proteinuria >2.5 g (N = 3) in those 45 days, after 6 months of exposure to RTX, progressive repopulation of CD19 was observed, which persisted in the year of follow-up. Conclusion In patients with high proteinuria, rituximab has a t1/2 lower than the 21–28 days described in the data sheet, which may suggest that patients with nephrotic syndrome may require higher doses to ensure the effectiveness of treatment with rituximab. Repopulation of CD19 in 45 days could be a reliable indicator of non response in patients with nephrotic proteinuria.

Mathematical Modeling of Brain Swelling in Electroencephalography and Magnetoencephalography

In the present paper, the forward problem of EEG and MEG is discussed, where the head is modeled by a spherical two-shell piecewise-homogeneous conductor with a neuronal current source positioned in the exterior shell area representing the brain tissue, while the interior shell portrays a cerebral edema. We consider constant conductivity, which assumes different values in each compartment, where the expansions of the electric potential and the magnetic field are represented via spherical harmonics. Furthermore, we demonstrate the reduction of our analytical results to the single-compartment model while it is shown that the magnetic field in the exterior of the conductor is a function only of the dipole moment and its position. Consequently, it does not depend on the inhomogeneity dictated by the interior shell, a fact that verifies the efficiency of the model.

Competitive, multi-objective, and compartmented Flux Balance Analysis for addressing tissue-specific inborn errors of metabolism.

The inborn error of metabolism phenylketonuria (PKU, OMIM 261600) is most often due to inactivation of phenylalanine hydroxylase (PAH), which converts phenylalanine (Phe) into tyrosine (Tyr). The reduced PAH activity increases blood concentration of phenylalanine and urine levels of phenylpyruvate. Flux balance analysis (FBA) of a single-compartment model of PKU predicts that maximum growth rate should be reduced unless Tyr is supplemented. However, the PKU phenotype is lack of development of brain function specifically, and Phe reduction rather than Tyr supplementation cures the disease. Phe and Tyr cross the blood-brain barrier (BBB) through the aromatic amino acid transporter implying that the two transport reactions interact. However, FBA does not accommodate such competitive interactions. We here report on an extension to FBA that enables it to deal with such interactions. We built a three-compartment model, made the common transport across the BBB explicit, and included dopamine and serotonin synthesis as parts of the brain function to be delivered by FBA. With these ramifications, FBA of the genome-scale metabolic model extended to three compartments does explain that (i) the disease is brain specific, (ii) phenylpyruvate in urine is a biomarker, (iii) excess of blood-phenylalanine rather than shortage of blood-tyrosine causes brain pathology, and (iv) Phe deprivation is the better therapy. The new approach also suggests (v) explanations for differences in pathology between individuals with the same PAH inactivation, and (vi) interference of disease and therapy with the functioning of other neurotransmitters.

Synergies between synaptic and HCN channel plasticity dictates firing rate homeostasis and mutual information transfer in hippocampal model neuron.

Homeostasis is a precondition for any physiological system of any living organism. Nonetheless, models of learning and memory that are based on processes of synaptic plasticity are unstable by nature according to Hebbian rules, and it is not fully clear how homeostasis is maintained during these processes. This is where theoretical and computational frameworks can help in gaining a deeper understanding of the various cellular processes that enable homeostasis in the face of plasticity. A previous simplistic single compartmental model with a single synapse showed that maintaining input/output response homeostasis and stable synaptic learning could be enabled by introducing a linear relationship between synaptic plasticity and HCN conductance plasticity. In this study, we aimed to examine whether this approach could be extended to a more morphologically realistic model that entails multiple synapses and gradients of various VGICs. In doing so, we found that a linear relationship between synaptic plasticity and HCN conductance plasticity was able to maintain input/output response homeostasis in our morphologically realistic model, where the slope of the linear relationship was dependent on baseline HCN conductance and synaptic permeability values. An increase in either baseline HCN conductance or synaptic permeability value led to a decrease in the slope of the linear relationship. We further show that in striking contrast to the single compartment model, here linear relationship was insufficient in maintaining stable synaptic learning despite maintaining input/output response homeostasis. Additionally, we showed that homeostasis of input/output response profiles was at the expense of decreasing the mutual information transfer due to the increase in noise entropy, which could not be fully rescued by optimizing the linear relationship between synaptic and HCN conductance plasticity. Finally, we generated a place cell model based on theta oscillations and show that synaptic plasticity disrupts place cell activity. Whereas synaptic plasticity accompanied by HCN conductance plasticity through linear relationship maintains the stability of place cell activity. Our study establishes potential differences between a single compartmental model and a morphologically realistic model.

Reduced oriens-lacunosum/moleculare cell model identifies biophysical current balances for in vivo theta frequency spiking resonance.

Conductance-based models have played an important role in the development of modern neuroscience. These mathematical models are powerful "tools" that enable theoretical explorations in experimentally untenable situations, and can lead to the development of novel hypotheses and predictions. With advances in cell imaging and computational power, multi-compartment models with morphological accuracy are becoming common practice. However, as more biological details are added, they make extensive explorations and analyses more challenging largely due to their huge computational expense. Here, we focus on oriens-lacunosum/moleculare (OLM) cell models. OLM cells can contribute to functionally relevant theta rhythms in the hippocampus by virtue of their ability to express spiking resonance at theta frequencies, but what characteristics underlie this is far from clear. We converted a previously developed detailed multi-compartment OLM cell model into a reduced single compartment model that retained biophysical fidelity with its underlying ion currents. We showed that the reduced OLM cell model can capture complex output that includes spiking resonance in in vivo-like scenarios as previously obtained with the multi-compartment model. Using the reduced model, we were able to greatly expand our in vivo-like scenarios. Applying spike-triggered average analyses, we were able to to determine that it is a combination of hyperpolarization-activated cation and muscarinic type potassium currents that specifically allow OLM cells to exhibit spiking resonance at theta frequencies. Further, we developed a robust Kalman Filtering (KF) method to estimate parameters of the reduced model in real-time. We showed that it may be possible to directly estimate conductance parameters from experiments since this KF method can reliably extract parameter values from model voltage recordings. Overall, our work showcases how the contribution of cellular biophysical current details could be determined and assessed for spiking resonance. As well, our work shows that it may be possible to directly extract these parameters from current clamp voltage recordings.

Preparation, Characterization, and In Vivo Evaluation of Gentiopicroside-Phospholipid Complex (GTP-PC) and Its Self-Nanoemulsion Drug Delivery System (GTP-PC-SNEDDS)

The objective of the present study was to develop a gentiopicroside-phospholipid complex (GTP-PC) and its self-nanoemulsion drug delivery system (GTP-PC-SNEDDS) to increase the oral bioavailability of gentiopicroside (GTP). The factors affecting the formation of GTP-PC were studied with the complexation efficiency and dissociation rate. The properties of the complex were investigated by means of differential scanning calorimetry (DSC), X-ray diffraction (XRD), Fourier transform infrared spectra (FT-IR), dissolution, etc. Then, GTP-PC was loaded into SNEDDS by investigating the effects of weight ratios of GTP-PC to blank SNEDDS, preparation technology, dilution media, and dilution multi, based on the screening results of oils, surfactants, and cosurfactants. In rats, GTP, GTP-PC, and GTP-PC-SNEDDS were orally administered at different times, and GTP concentrations were determined using RP-HPLC. The optimal GTP-PC was prepared with tetrahydrofuran as the reaction solvent, GTP:phospholipid = 1:2, and stirring for 4 h. The optimal prescription for GTP-PC-SNEDDS was as follows: Maisin 35-1:Miglycol = 30%, Labrasol:Cremophor EL = 1:4 = 40%, Transcutol P = 30%; Maisin 35-1:Miglycol = 12, and the ratio of GTP-PC to blank was 1:10-then the mixture was stirred at 37 °C for 1 d and then placed for 2 d to form stable GTP-PC-SNEDDS. After oral administration of GTP, GTP-PC and GTP-PC-SNEDDS, and mean plasma GTP concentration-time curves were all in accordance with the single-compartment model. The Cmax, AUC0-∞, and Fr of the three formulations were significantly higher than that of GTP, demonstrating that GTP was metabolized rapidly, and its higher bioavailability could be achieved by the formation of GTP-PC and GTP-PC-SNEDDS. Among the three formations, the bioavailability of GTP-PC-SNEDDS was highest, with approximately 2.6-fold and 1.3-fold of Fr value, compared with GTP-PC (suspension) and GTP-PC (oil solution), respectively. Compared with GTP, GTP-PC and GTP-PC-SNEDDS enhanced the bioavailability of GTP significantly. In the future, this study could serve as a reference for clinical trials using GTP-PC and GTP-PC-SNEDDS.

How hard is it to breathe? Quantification of lung elastance and inspiratory work of breathing in healthy and COPD patients.

Chronic Obstructive Pulmonary Disease (COPD) covers a range of underlying lung conditions. Lung mechanics, particularly airway resistance, are altered, increasing the work of breathing (WOB). Model-based methods to estimate lung parameters may help reduce the clinical burden of diagnosis and monitoring. This analysis presents a modified single compartment model describing lung mechanics and WOB. Plethysmographic data, including derived alveolar pressure, is used to identify inspiratory airway resistance (Rinsp), lung elastance (E), and inspiratory effort (Peff, cmH2O). Four (n=10 each) clinical cohorts comprise subjects who are healthy (young and old) and with COPD (with (FL) and without (NFL) expiratory flow limitation). E and R are correlated (R2 = 0.73) and within the normal range in healthy cohorts (Rinsp <5 cmH2O/L/s, E = 0-6 cmH2O/L), but elevated to R = 5-15 cmH2O/L/s and E = 5 - 12 cmH2O/L in patients with COPD. The peak negative Peff was highest in FL COPD patients, reflecting higher WOB required to overcome E and Rinsp dynamics. Increased Rinsp was more dominant than changes in E in COPD patients. Overall, the modelled Peff match pleural and esophageal pressure measurements in literature. The model presented appears to capture key inspiratory effort dynamics, and is a first step towards a more generalised model for non-invasive clinical diagnosis and monitoring of COPD lung conditions.