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This article presents a methodology for compartmental model (CM) creation for long-term simulation of water resource recovery facilities (WRRFs). CMs are often focused on reproducing with a lower computational cost, previously simulated scenarios. In contrast, the methodology presented here can represent variable hydraulic conditions, based on the interpolation of data gathered from a set of computational fluid dynamics (CFD) simulations that reproduce representative hydraulic scenarios. This is achieved by modelling with bidirectional flows the exchange flows between fixed compartments, which are defined based on the geometry of the reactors. The resultant hydraulic surrogate model can be implemented in commercial water treatment software to solve biochemical kinetics. The methodology was applied to simulate in WEST®-DHI a WRRF in Vila-Real, Spain. In this contribution, the CM was validated with real plant data. The developed CM provided a quick response simulation with a high level of hydraulic and biochemical detail. This allowed observation of a spatial distribution of component concentration, which could help with sensor location or plant optimisation. The methodology presented here could also be a useful enabler of digital twins to be implemented in WRRF.

Bioreactors are usually modelled as continuous stirred tank reactors (CSTRs) or CSTRs connected in series (Tanks-In-Series configuration). In large systems with non-ideal mixing, such approaches do not sufficiently capture the complex hydrodynamics, leading to model inaccuracies due to the lumping of spatial gradients. Highly detailed computational fluid dynamics (CFD) models provide insight into complex hydrodynamics but are computationally too expensive for flow-sheet models and digital twin applications. A compartmental model (CM) can be a middle-ground by providing a more realistic representation of the hydrodynamics and still being computationally affordable. However, the hydrodynamics of a plant can be very different under varying flow conditions. Dynamic CMs can capture these changes in an elegant way. So far, the application of CMs has been limited mostly to continuous flow systems. In this study, a dynamic CM of a sequencing batch reactor (SBR) is developed for a bio-P removal process. The SBR comes with challenges for CM development due to its distinct operational stages. The dynamic CM shows significant improvements over the CSTR model (using the same biokinetic parameters) for dissolved oxygen and phosphate predictions reducing the need for model recalibration that can lead to over-fitting and limited extrapolation capability of the model.

We propose a mathematical model to investigate the current outbreak of the coronavirus disease 2019 (COVID-19) in Wuhan, China. Our model describes the multiple transmission pathways in the infection dynamics, and emphasizes the role of the environmental reservoir in the transmission and spread of this disease. Our model also employs non-constant transmission rates which change with the epidemiological status and environmental conditions and which reflect the impact of the on-going disease control measures. We conduct a detailed analysis of this model, and demonstrate its application using publicly reported data. Among other findings, our analytical and numerical results indicate that the coronavirus infection would remain endemic, which necessitates long-term disease prevention and intervention programs.

PurposeInhaled delivery of pirfenidone to the lungs of patients with idiopathic pulmonary fibrosis holds promise to eliminate oral-observed side effects while enhancing efficacy. This study aimed to comprehensively describe the pulmonary pharmacokinetics of inhaled aerosol pirfenidone in healthy adult sheep. Methods: Pirfenidone concentrations were evaluated in plasma, lung-derived lymph and epithelial lining fluid (ELF) with data subjected to non-compartmental pharmacokinetic analysis. Results: Compartmental pharmacokinetic evaluation indicated that a 49 mg lung-deposited dose delivered an ELF Cmax of 62 ± 23 mg/L, and plasma Cmax of 3.1 ± 1.7 mg/L. Further analysis revealed that plasma pirfenidone reached Tmax faster and at higher concentrations than in lymph. These results suggested inhaled pirfenidone was cleared from the alveolar interstitium via blood faster than the drug could equilibrate between the lung interstitial fluid and lung lymphatics. However, the data also suggested that a ‘reservoir’ of pirfenidone feeds into lung lymph at later time points (after it has largely been cleared from plasma), prolonging lung lymphatic exposure.ConclusionsThis study indicates inhaled pirfenidone efficiently deposits in ELF and is cleared from the lungs by initial absorption into plasma, followed by later equilibrium with lung interstitial and lymph fluid.

The study of brain clearance mechanisms is an active area of research. While we know that the cerebrospinal fluid (CSF) plays a central role in one of the main existing clearance pathways, the exact processes for the secretion of CSF and the removal of waste products from tissue are under debate. CSF is thought to be created by the exchange of water and ions from the blood, which is believed to mainly occur in the choroid plexus. This exchange has not been thoroughly studied in vivo. We propose a modified arterial spin labeling (ASL) MRI sequence and image analysis to track blood water as it is transported to the CSF, and to characterize its exchange from blood to CSF. We acquired six pseudo-continuous ASL sequences with varying labeling duration (LD) and post-labeling delay (PLD) and a segmented 3D-GRASE readout with a long echo train (8 echo times (TE)) which allowed separation of the very long-T2 CSF signal. ASL signal was observed at long TEs (793 ms and higher), indicating presence of labeled water transported from blood to CSF. This signal appeared both in the CSF proximal to the choroid plexus and in the subarachnoid space surrounding the cortex. ASL signal was separated into its blood, gray matter and CSF components by fitting a triexponential function with T2s taken from literature. A two-compartment dynamic model was introduced to describe the exchange of water through time and TE. From this, a water exchange time from the blood to the CSF (Tbl->CSF) was mapped, with an order of magnitude of approximately 60 s.

The Incompatible Insect Technique (IIT) strategy involves the release of male mosquitoes infected with the bacterium Wolbachia. Regular releases of male Wolbachia-infected mosquitoes can lead to the suppression of mosquito populations, thereby reducing the risk of transmission of vector-borne diseases such as dengue. However, due to imperfect sex-sorting under IIT, fertile Wolbachia-infected female mosquitoes may potentially be unintentionally released into the environment, which may result in replacement and failure to suppress the mosquito populations. As such, mitigating Wolbachia establishment requires a combination of IIT with other strategies. We introduced a simple compartmental model to simulate ex-ante mosquito population dynamics subjected to a Wolbachia-IIT programme. In silico, we explored the risk of replacement, and strategies that could mitigate the establishment of the released Wolbachia strain in the mosquito population. Our results suggest that mitigation may be achieved through the application of a sterile insect technique. Our simulations indicate that these interventions do not override the intended wild type suppression of the IIT approach. These findings will inform policy makers of possible ways to mitigate the potential establishment of Wolbachia using the IIT population control strategy.

Aims/hypothesis We determined whether hepatic fat content and plasma adiponectin concentration regulate VLDL₁ production. Methods A multicompartment model was used to simultaneously determine the kinetic parameters of triglycerides (TGs) and apolipoprotein B (ApoB) in VLDL₁ and VLDL₂ after a bolus of [²H₃]leucine and [²H₅]glycerol in ten men with type 2 diabetes and in 18 non-diabetic men. Liver fat content was determined by proton spectroscopy and intra-abdominal fat content by MRI. Results Univariate regression analysis showed that liver fat content, intra-abdominal fat volume, plasma glucose, insulin and HOMA-IR (homeostasis model assessment of insulin resistance) correlated with VLDL₁ TG and ApoB production. However, only liver fat and plasma glucose were significant in multiple regression models, emphasising the critical role of substrate fluxes and lipid availability in the liver as the driving force for overproduction of VLDL₁ in subjects with type 2 diabetes. Despite negative correlations with fasting TG levels, liver fat content, and VLDL₁ TG and ApoB pool sizes, adiponectin was not linked to VLDL₁ TG or ApoB production and thus was not a predictor of VLDL₁ production. However, adiponectin correlated negatively with the removal rates of VLDL₁ TG and ApoB. Conclusions/interpretation We propose that the metabolic effect of insulin resistance, partly mediated by depressed plasma adiponectin levels, increases fatty acid flux from adipose tissue to the liver and induces the accumulation of fat in the liver. Elevated plasma glucose can further increase hepatic fat content through multiple pathways, resulting in overproduction of VLDL₁ particles and leading to the characteristic dyslipidaemia associated with type 2 diabetes.

Increasing use of the botanical kratom to self-manage opioid withdrawal and pain has led to increased kratom-linked overdose deaths. Despite these serious safety concerns, rigorous fundamental pharmacokinetic knowledge of kratom in humans remains lacking. We assessed the pharmacokinetics of a single low dose (2 g) of a well-characterized kratom product administered orally to six healthy participants. Median concentration-time profiles for the kratom alkaloids examined were best described by a two-compartment model with central elimination. Pronounced pharmacokinetic differences between alkaloids with the 3S configuration (mitragynine, speciogynine, paynantheine) and alkaloids with the 3R configuration (mitraciliatine, speciociliatine, isopaynantheine) were attributed to differences in apparent intercompartmental distribution clearance, volumes of distribution, and clearance. Based on noncompartmental analysis of individual concentration-time profiles, the 3S alkaloids exhibited a shorter median time to maximum concentration (1–2 vs. 2.5–4.5 h), lower area under the plasma concentration-time curve (430–490 vs. 794–5120 nM × h), longer terminal half-life (24–45 vs. ~12–18 h), and higher apparent volume of distribution during the terminal phase (960–12,700 vs. ~46–130 L) compared to the 3R alkaloids. Follow-up mechanistic in vitro studies suggested differential hepatic/intestinal metabolism, plasma protein binding, blood-to-plasma partitioning, and/or distribution coefficients may explain the pharmacokinetic differences between the two alkaloid types. This first comprehensive pharmacokinetic characterization of kratom alkaloids in humans provides the foundation for further research to establish safety and effectiveness of this emerging botanical product.

We present detailed models of pyramidal cells from human neocortex, including models on their excitatory synapses, dendritic spines, dendritic NMDA- and somatic/axonal spikes that provided new insights into signal processing and computational capabilities of these principal cells. Six human layer 2 and layer 3 pyramidal cells (HL2/L3 PCs) were modeled, integrating detailed anatomical and physiological data from both fresh and postmortem tissues from human temporal cortex. The models predicted particularly large AMPA- and NMDA-conductances per synaptic contact (0.88 and 1.31 nS, respectively) and a steep dependence of the NMDA-conductance on voltage. These estimates were based on intracellular recordings from synaptically-connected HL2/L3 pairs, combined with extra-cellular current injections and use of synaptic blockers, and the assumption of five contacts per synaptic connection. A large dataset of high-resolution reconstructed HL2/L3 dendritic spines provided estimates for the EPSPs at the spine head (12.7 ± 4.6 mV), spine base (9.7 ± 5.0 mV), and soma (0.3 ± 0.1 mV), and for the spine neck resistance (50-80 MΩ). Matching the shape and firing pattern of experimental somatic -spikes provided estimates for the density of the somatic/axonal excitable membrane ion channels, predicting that 134 ± 28 simultaneously activated HL2/L3-HL2/L3 synapses are required for generating (with 50% probability) a somatic spike. Dendritic NMDA spikes were triggered in the model when 20 ± 10 excitatory spinous synapses were simultaneously activated on individual dendritic branches. The particularly large number of basal dendrites in HL2/L3 PCs and the distinctive cable elongation of their terminals imply that ~25 NMDA-spikes could be generated independently and simultaneously in these cells, as compared to ~14 in L2/3 PCs from the rat somatosensory cortex. These multi-sites non-linear signals, together with the large (~30,000) excitatory synapses/cell, equip human L2/L3 PCs with enhanced computational capabilities. Our study provides the most comprehensive model of any human neuron to-date demonstrating the biophysical and computational distinctiveness of human cortical neurons.

A recent discovery highlighted that mosquitoes infected with Microsporidia MB are unable to transmit the Plasmodium to humans. Microsporidia MB is a symbiont transmitted vertically and horizontally in the mosquito population, and these transmission routes are known to favor the persistence of the parasite in the mosquito population. Despite the dual transmission, data from field experiments reveal a low prevalence of MB -infected mosquitoes in nature. This study proposes a compartmental model to understand the prevalence of MB -infected mosquitoes. The dynamic of the model is obtained through the computation of the basic reproduction number and the analysis of the stability of the MB-free and coexistence equilibria. The model shows that, in spite of the high vertical transmission efficiency of Microsporidia MB , there can still be a low prevalence of MB -infected mosquitoes. Numerical analysis of the model shows that male-to-female horizontal transmission contributes more than female-to-male horizontal transmission to the spread of MB-infected mosquitoes. Moreover, the female-to-male horizontal transmission contributes to the spread of the symbiont only if there are multiple mating occurrences for male mosquitoes. Furthermore, when fixing the efficiencies of vertical transmission, the parameters having the greater influence on the ratio of MB-positive to wild mosquitoes are identified. In addition, by assuming a similar impact of the temperature on wild and MB -infected mosquitoes, our model shows the seasonal fluctuation of MB -infected mosquitoes. This study serves as a reference for further studies, on the release strategies of MB-infected mosquitoes, to avoid overestimating the MB-infection spread.