Sample records for transit compartment model

  1. Ages and transit times as important diagnostics of model performance for predicting C allocation in ecosystem models

    NASA Astrophysics Data System (ADS)

    Ceballos-Núñez, Verónika; Richardson, Andrew; Sierra, Carlos

    2017-04-01

    The global carbon cycle is strongly controlled by the source/sink strength of vegetation as well as the capacity of terrestrial ecosystems to retain this carbon. However, it is uncertain how some vegetation dynamics such as the allocation of carbon to different ecosystem compartments should be represented in models. The assumptions behind model structures may result in highly divergent model predictions. Here, we asses model performance by calculating the age of the carbon in the system and in each compartment, and the overall transit time of C in the system. We used these diagnostics to assess the influence of three different carbon allocation schemes on the rates of C cycling in vegetation. First, we used published measurements of ecosystem C compartments from the Harvard Forest Environmental Measurement Site to find the best set of parameters for the different model structures. Second, we calculated C stocks, respiration fluxes, radiocarbon values, ages, and transit times. We found a good fit of the three model structures to the available data, but the time series of C in foliage and wood need to be complemented with other ecosystem compartments in order to reduce the high parameter collinearity that we observed and reduce model equifinality. Differences in model structures had a small impact on predicting ecosystem C compartments, but overall they resulted in very different predictions of age and transit time distributions. In particular, the inclusion of a storage compartment had an important impact on predicting system ages and transit times. In the case of the models with 1 or 2 storage compartments, the age of carbon in the system and in each of the compartments was distributed more towards younger ages than in the model that had no storage; the mean system age of these two models with storage was 80 years younger than in the model without storage. As expected from these age distributions, the mean transit time for the two models with storage compartments was 50 years faster than for the model without storage. These results suggest that ages and transit times, which can be indirectly measured using isotope tracers, serve as important diagnostics of model structure and could largely help to reduce uncertainties in model predictions. Furthermore, by considering age and transit times of C in vegetation compartments as distributions, not only their mean values, we obtain additional insights on the temporal dynamics of carbon use, storage, and allocation to plant parts, which not only depends on the rate at which this C is transferred in and out of the compartments, but also on the stochastic nature of the process itself.

  2. Transit and lifespan in neutrophil production: implications for drug intervention.

    PubMed

    Câmara De Souza, Daniel; Craig, Morgan; Cassidy, Tyler; Li, Jun; Nekka, Fahima; Bélair, Jacques; Humphries, Antony R

    2018-02-01

    A comparison of the transit compartment ordinary differential equation modelling approach to distributed and discrete delay differential equation models is studied by focusing on Quartino's extension to the Friberg transit compartment model of myelosuppression, widely relied upon in the pharmaceutical sciences to predict the neutrophil response after chemotherapy, and on a QSP delay differential equation model of granulopoiesis. An extension to the Quartino model is provided by considering a general number of transit compartments and introducing an extra parameter that allows for the decoupling of the maturation time from the production rate of cells. An overview of the well established linear chain technique, used to reformulate transit compartment models with constant transit rates as distributed delay differential equations (DDEs), is then given. A state-dependent time rescaling of the Quartino model is performed to apply the linear chain technique and rewrite the Quartino model as a distributed DDE, yielding a discrete DDE model in a certain parameter limit. Next, stability and bifurcation analyses are undertaken in an effort to situate such studies in a mathematical pharmacology context. We show that both the original Friberg and the Quartino extension models incorrectly define the mean maturation time, essentially treating the proliferative pool as an additional maturation compartment. This misspecification can have far reaching consequences on the development of future models of myelosuppression in PK/PD.

  3. Ages and transit times as important diagnostics of model performance for predicting carbon dynamics in terrestrial vegetation models

    NASA Astrophysics Data System (ADS)

    Ceballos-Núñez, Verónika; Richardson, Andrew D.; Sierra, Carlos A.

    2018-03-01

    The global carbon cycle is strongly controlled by the source/sink strength of vegetation as well as the capacity of terrestrial ecosystems to retain this carbon. These dynamics, as well as processes such as the mixing of old and newly fixed carbon, have been studied using ecosystem models, but different assumptions regarding the carbon allocation strategies and other model structures may result in highly divergent model predictions. We assessed the influence of three different carbon allocation schemes on the C cycling in vegetation. First, we described each model with a set of ordinary differential equations. Second, we used published measurements of ecosystem C compartments from the Harvard Forest Environmental Measurement Site to find suitable parameters for the different model structures. And third, we calculated C stocks, release fluxes, radiocarbon values (based on the bomb spike), ages, and transit times. We obtained model simulations in accordance with the available data, but the time series of C in foliage and wood need to be complemented with other ecosystem compartments in order to reduce the high parameter collinearity that we observed, and reduce model equifinality. Although the simulated C stocks in ecosystem compartments were similar, the different model structures resulted in very different predictions of age and transit time distributions. In particular, the inclusion of two storage compartments resulted in the prediction of a system mean age that was 12-20 years older than in the models with one or no storage compartments. The age of carbon in the wood compartment of this model was also distributed towards older ages, whereas fast cycling compartments had an age distribution that did not exceed 5 years. As expected, models with C distributed towards older ages also had longer transit times. These results suggest that ages and transit times, which can be indirectly measured using isotope tracers, serve as important diagnostics of model structure and could largely help to reduce uncertainties in model predictions. Furthermore, by considering age and transit times of C in vegetation compartments as distributions, not only their mean values, we obtain additional insights into the temporal dynamics of carbon use, storage, and allocation to plant parts, which not only depends on the rate at which this C is transferred in and out of the compartments but also on the stochastic nature of the process itself.

  4. Stimulus-induced transitions between spike-wave discharges and spindles with the modulation of thalamic reticular nucleus.

    PubMed

    Fan, Denggui; Wang, Qingyun; Su, Jianzhong; Xi, Hongguang

    2017-12-01

    It is believed that thalamic reticular nucleus (TRN) controls spindles and spike-wave discharges (SWD) in seizure or sleeping processes. The dynamical mechanisms of spatiotemporal evolutions between these two types of activity, however, are not well understood. In light of this, we first use a single-compartment thalamocortical neural field model to investigate the effects of TRN on occurrence of SWD and its transition. Results show that the increasing inhibition from TRN to specific relay nuclei (SRN) can lead to the transition of system from SWD to slow-wave oscillation. Specially, it is shown that stimulations applied in the cortical neuronal populations can also initiate the SWD and slow-wave oscillation from the resting states under the typical inhibitory intensity from TRN to SRN. Then, we expand into a 3-compartment coupled thalamocortical model network in linear and circular structures, respectively, to explore the spatiotemporal evolutions of wave states in different compartments. The main results are: (i) for the open-ended model network, SWD induced by stimulus in the first compartment can be transformed into sleep-like slow UP-DOWN and spindle states as it propagates into the downstream compartments; (ii) for the close-ended model network, weak stimulations performed in the first compartment can result in the consistent experimentally observed spindle oscillations in all three compartments; in contrast, stronger periodic single-pulse stimulations applied in the first compartment can induce periodic transitions between SWD and spindle oscillations. Detailed investigations reveal that multi-attractor coexistence mechanism composed of SWD, spindles and background state underlies these state evolutions. What's more, in order to demonstrate the state evolution stability with respect to the topological structures of neural network, we further expand the 3-compartment coupled network into 10-compartment coupled one, with linear and circular structures, and nearest-neighbor (NN) coupled network as well as its realization of small-world (SW) topology via random rewiring, respectively. Interestingly, for the cases of linear and circular connetivities, qualitatively similar results were obtained in addition to the more irregularity of firings. However, SWD can be eventually transformed into the consistent low-amplitude oscillations for both NN and SW networks. In particular, SWD evolves into the slow spindling oscillations and background tonic oscillations within the NN and SW network, respectively. Our modeling and simulation studies highlight the effect of network topology in the evolutions of SWD and spindling oscillations, which provides new insights into the mechanisms of cortical seizures development.

  5. Transit-time and age distributions for nonlinear time-dependent compartmental systems.

    PubMed

    Metzler, Holger; Müller, Markus; Sierra, Carlos A

    2018-02-06

    Many processes in nature are modeled using compartmental systems (reservoir/pool/box systems). Usually, they are expressed as a set of first-order differential equations describing the transfer of matter across a network of compartments. The concepts of age of matter in compartments and the time required for particles to transit the system are important diagnostics of these models with applications to a wide range of scientific questions. Until now, explicit formulas for transit-time and age distributions of nonlinear time-dependent compartmental systems were not available. We compute densities for these types of systems under the assumption of well-mixed compartments. Assuming that a solution of the nonlinear system is available at least numerically, we show how to construct a linear time-dependent system with the same solution trajectory. We demonstrate how to exploit this solution to compute transit-time and age distributions in dependence on given start values and initial age distributions. Furthermore, we derive equations for the time evolution of quantiles and moments of the age distributions. Our results generalize available density formulas for the linear time-independent case and mean-age formulas for the linear time-dependent case. As an example, we apply our formulas to a nonlinear and a linear version of a simple global carbon cycle model driven by a time-dependent input signal which represents fossil fuel additions. We derive time-dependent age distributions for all compartments and calculate the time it takes to remove fossil carbon in a business-as-usual scenario.

  6. Dynamics of tax evasion through an epidemic-like model

    NASA Astrophysics Data System (ADS)

    Brum, Rafael M.; Crokidakis, Nuno

    In this work, we study a model of tax evasion. We considered a fixed population divided in three compartments, namely honest tax payers, tax evaders and a third class between the mentioned two, which we call susceptibles to become evaders. The transitions among those compartments are ruled by probabilities, similarly to a model of epidemic spreading. These probabilities model social interactions among the individuals, as well as the government’s fiscalization. We simulate the model on fully-connected graphs, as well as on scale-free and random complex networks. For the fully-connected and random graph cases, we observe that the emergence of tax evaders in the population is associated with an active-absorbing nonequilibrium phase transition, that is absent in scale-free networks.

  7. Simultaneous Characterization of Intravenous and Oral Pharmacokinetics of Lychnopholide in Rats by Transit Compartment Model.

    PubMed

    Lachi-Silva, Larissa; Sy, Sherwin K B; Voelkner, Alexander; de Sousa, João Paulo Barreto; Lopes, João Luis C; Silva, Denise B; Lopes, Norberto P; Kimura, Elza; Derendorf, Hartmut; Diniz, Andrea

    2015-08-01

    The pharmacokinetic properties of a new molecular entity are important aspects in evaluating the viability of the compound as a pharmacological agent. The sesquiterpene lactone lychnopholide exhibits important biological activities. The objective of this study was to characterize the pharmacokinetics of lychnopholide after intravenous administration of 1.65 mg/kg (n = 5) and oral administration of 3.3 mg/kg (n = 3) lychnopholide in rats (0.2 ± 0.02 kg in weight) through nonlinear mixed effects modeling and non-compartmental pharmacokinetic analysis. A highly sensitive analytical method was used to quantify the plasma lychnopholide concentrations in rats. Plasma protein binding of this compound was over 99 % as determined by a filtration method. A two-compartment body model plus three transit compartments to characterize the absorption process best described the disposition of lychnopholide after both routes of administration. The oral bioavailability was approximately 68 %. The clearance was 0.131 l/min and intercompartmental clearance was 0.171 l/min; steady-state volume of distribution was 4.83 l. The mean transit time for the absorption process was 9.15 minutes. No flip-flop phenomenon was observed after oral administration. The pharmacokinetic properties are favorable for further development of lychnopholide as a potential oral pharmacological agent. Georg Thieme Verlag KG Stuttgart · New York.

  8. The pacemaker role of thalamic reticular nucleus in controlling spike-wave discharges and spindles.

    PubMed

    Fan, Denggui; Liao, Fucheng; Wang, Qingyun

    2017-07-01

    Absence epilepsy, characterized by 2-4 Hz spike-wave discharges (SWDs), can be caused by pathological interactions within the thalamocortical system. Cortical spindling oscillations are also demonstrated to involve the oscillatory thalamocortical rhythms generated by the synaptic circuitry of the thalamus and cortex. This implies that SWDs and spindling oscillations can share the common thalamocortical mechanism. Additionally, the thalamic reticular nucleus (RE) is hypothesized to regulate the onsets and propagations of both the epileptic SWDs and sleep spindles. Based on the proposed single-compartment thalamocortical neural field model, we firstly investigate the stimulation effect of RE on the initiations, terminations, and transitions of SWDs. It is shown that the activations and deactivations of RE triggered by single-pulse stimuli can drive the cortical subsystem to behave as the experimentally observed onsets and self-abatements of SWDs, as well as the transitions from 2-spike and wave discharges (2-SWDs) to SWDs. In particular, with increasing inhibition from RE to the specific relay nucleus (TC), rich transition behaviors in cortex can be obtained through the upstream projection path, RE→TC→Cortex. Although some of the complex dynamical patterns can be expected from the earlier single compartment thalamocortical model, the effect of brain network topology on the emergence of SWDs and spindles, as well as the transitions between them, has not been fully investigated. We thereby develop a spatially extended 3-compartment coupled network model with open-/closed-end connective configurations, to investigate the spatiotemporal effect of RE on the SWDs and spindles. Results show that the degrees of activations of RE 1 can induce the rich spatiotemporal evolution properties including the propagations from SWDs to spindles within different compartments and the transitions between them, through the RE 1 →TC 1 →Cortex 1 and Cortex 1 →Cortex 2 →Cortex 3 projecting paths, respectively. Overall, those results imply that RE possesses the pacemaker function in controlling SWDs and spindling oscillations, which computationally provide causal support for the involvement of RE in absence seizures and sleep spindles.

  9. The pacemaker role of thalamic reticular nucleus in controlling spike-wave discharges and spindles

    NASA Astrophysics Data System (ADS)

    Fan, Denggui; Liao, Fucheng; Wang, Qingyun

    2017-07-01

    Absence epilepsy, characterized by 2-4 Hz spike-wave discharges (SWDs), can be caused by pathological interactions within the thalamocortical system. Cortical spindling oscillations are also demonstrated to involve the oscillatory thalamocortical rhythms generated by the synaptic circuitry of the thalamus and cortex. This implies that SWDs and spindling oscillations can share the common thalamocortical mechanism. Additionally, the thalamic reticular nucleus (RE) is hypothesized to regulate the onsets and propagations of both the epileptic SWDs and sleep spindles. Based on the proposed single-compartment thalamocortical neural field model, we firstly investigate the stimulation effect of RE on the initiations, terminations, and transitions of SWDs. It is shown that the activations and deactivations of RE triggered by single-pulse stimuli can drive the cortical subsystem to behave as the experimentally observed onsets and self-abatements of SWDs, as well as the transitions from 2-spike and wave discharges (2-SWDs) to SWDs. In particular, with increasing inhibition from RE to the specific relay nucleus (TC), rich transition behaviors in cortex can be obtained through the upstream projection path, RE → TC → Cortex . Although some of the complex dynamical patterns can be expected from the earlier single compartment thalamocortical model, the effect of brain network topology on the emergence of SWDs and spindles, as well as the transitions between them, has not been fully investigated. We thereby develop a spatially extended 3-compartment coupled network model with open-/closed-end connective configurations, to investigate the spatiotemporal effect of RE on the SWDs and spindles. Results show that the degrees of activations of RE 1 can induce the rich spatiotemporal evolution properties including the propagations from SWDs to spindles within different compartments and the transitions between them, through the RE 1 → TC 1 → Cortex 1 and Cortex 1 → Cortex 2 → Cortex 3 projecting paths, respectively. Overall, those results imply that RE possesses the pacemaker function in controlling SWDs and spindling oscillations, which computationally provide causal support for the involvement of RE in absence seizures and sleep spindles.

  10. A three-compartment model of osmotic water exchange in the lung microvasculature.

    PubMed

    Seale, K T; Harris, T R

    2000-08-01

    A bolus injection of hypertonic NaCl into the pulmonary arterial circulation of an isolated perfused dog lung causes the osmotic movement of water first into, and then out of the capillary. The associated changes in blood constituent concentrations and density are referred to as the osmotic transient (OT). Measurement of the sound conduction velocity of effluent blood during an OT is a highly sensitive way to monitor water movement between the vascular and extravascular spaces. It was our objective to develop a mathematical model that adequately describes this transient change in the sound conduction velocity and evaluate its application under conditions of homogeneous and heterogeneous capillary flow distributions. The model accounts for osmotic water exchange between the capillary and two parallel extravascular compartments, and includes as parameters the osmotic conductances (sigmaK1 ,sigmaK2) of the two compartments. The osmotic conductance parameters incorporate the filtration coefficient for water and reflection coefficient for salt for the two pathways of water exchange. The partition of total extravascular lung water (EVLW) between the two extravascular compartments is a third parameter of the model. The homogeneous model parameter estimates (per gram wet lung weight +/-95% confidence limits) from the best-fit analysis of a typical curve were sigmaK1=2.15 +/-0.07, sigmaK2 = 0.03 + 0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)] and V1 = 23.83+/-0.12 ml, with a coefficient of variation (CV) of 0.08. The heterogeneous parameter estimates for a capillary transit time distribution with mean transit time (MTTc) = 1.72 s, and relative dispersion (RDc) = 0.35 were KI = 2.38+/-0.05, or K2 = 0.03+/-0.00 [ml h(-1) (mosmol/liter)(-1) g(-1)], V1 = 23.91+/-0.08 ml, and CV=0.05. EVLW was 42.1 ml for both models. We conclude that the three-compartment mathematical model adequately describes a typical OT under both homogeneous and heterogeneous blood flow assumptions.

  11. Mathematical properties and parameter estimation for transit compartment pharmacodynamic models.

    PubMed

    Yates, James W T

    2008-07-03

    One feature of recent research in pharmacodynamic modelling has been the move towards more mechanistically based model structures. However, in all of these models there are common sub-systems, such as feedback loops and time-delays, whose properties and contribution to the model behaviour merit some mathematical analysis. In this paper a common pharmacodynamic model sub-structure is considered: the linear transit compartment. These models have a number of interesting properties as the length of the cascade chain is increased. In the limiting case a pure time-delay is achieved [Milsum, J.H., 1966. Biological Control Systems Analysis. McGraw-Hill Book Company, New York] and the initial behaviour becoming increasingly sensitive to parameter value perturbation. It is also shown that the modelled drug effect is attenuated, though the duration of action is longer. Through this analysis the range of behaviours that such models are capable of reproducing are characterised. The properties of these models and the experimental requirements are discussed in order to highlight how mathematical analysis prior to experimentation can enhance the utility of mathematical modelling.

  12. Practical Modeling Concepts for Connective Tissue Stem Cell and Progenitor Compartment Kinetics

    PubMed Central

    2003-01-01

    Stem cell activation and development is central to skeletal development, maintenance, and repair, as it is for all tissues. However, an integrated model of stem cell proliferation, differentiation, and transit between functional compartments has yet to evolve. In this paper, the authors review current concepts in stem cell biology and progenitor cell growth and differentiation kinetics in the context of bone formation. A cell-based modeling strategy is developed and offered as a tool for conceptual and quantitative exploration of the key kinetic variables and possible organizational hierarchies in bone tissue development and remodeling, as well as in tissue engineering strategies for bone repair. PMID:12975533

  13. Mechanistic Fluid Transport Model to Estimate Gastrointestinal Fluid Volume and Its Dynamic Change Over Time.

    PubMed

    Yu, Alex; Jackson, Trachette; Tsume, Yasuhiro; Koenigsknecht, Mark; Wysocki, Jeffrey; Marciani, Luca; Amidon, Gordon L; Frances, Ann; Baker, Jason R; Hasler, William; Wen, Bo; Pai, Amit; Sun, Duxin

    2017-11-01

    Gastrointestinal (GI) fluid volume and its dynamic change are integral to study drug disintegration, dissolution, transit, and absorption. However, key questions regarding the local volume and its absorption, secretion, and transit remain unanswered. The dynamic fluid compartment absorption and transit (DFCAT) model is proposed to estimate in vivo GI volume and GI fluid transport based on magnetic resonance imaging (MRI) quantified fluid volume. The model was validated using GI local concentration of phenol red in human GI tract, which was directly measured by human GI intubation study after oral dosing of non-absorbable phenol red. The measured local GI concentration of phenol red ranged from 0.05 to 168 μg/mL (stomach), to 563 μg/mL (duodenum), to 202 μg/mL (proximal jejunum), and to 478 μg/mL (distal jejunum). The DFCAT model characterized observed MRI fluid volume and its dynamic changes from 275 to 46.5 mL in stomach (from 0 to 30 min) with mucus layer volume of 40 mL. The volumes of the 30 small intestine compartments were characterized by a max of 14.98 mL to a min of 0.26 mL (0-120 min) and a mucus layer volume of 5 mL per compartment. Regional fluid volumes over 0 to 120 min ranged from 5.6 to 20.38 mL in the proximal small intestine, 36.4 to 44.08 mL in distal small intestine, and from 42 to 64.46 mL in total small intestine. The DFCAT model can be applied to predict drug dissolution and absorption in the human GI tract with future improvements.

  14. Fractal analysis of lateral movement in biomembranes.

    PubMed

    Gmachowski, Lech

    2018-04-01

    Lateral movement of a molecule in a biomembrane containing small compartments (0.23-μm diameter) and large ones (0.75 μm) is analyzed using a fractal description of its walk. The early time dependence of the mean square displacement varies from linear due to the contribution of ballistic motion. In small compartments, walking molecules do not have sufficient time or space to develop an asymptotic relation and the diffusion coefficient deduced from the experimental records is lower than that measured without restrictions. The model makes it possible to deduce the molecule step parameters, namely the step length and time, from data concerning confined and unrestricted diffusion coefficients. This is also possible using experimental results for sub-diffusive transport. The transition from normal to anomalous diffusion does not affect the molecule step parameters. The experimental literature data on molecular trajectories recorded at a high time resolution appear to confirm the modeled value of the mean free path length of DOPE for Brownian and anomalous diffusion. Although the step length and time give the proper values of diffusion coefficient, the DOPE speed calculated as their quotient is several orders of magnitude lower than the thermal speed. This is interpreted as a result of intermolecular interactions, as confirmed by lateral diffusion of other molecules in different membranes. The molecule step parameters are then utilized to analyze the problem of multiple visits in small compartments. The modeling of the diffusion exponent results in a smooth transition to normal diffusion on entering a large compartment, as observed in experiments.

  15. 19 CFR 123.24 - Sealing of conveyances or compartments.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... in the same manner as less than load or compartment lots; (3) Live animals identifiable by specific... of the parties in interest, in unsealed conveyances or compartments. (b) Seals to be affixed. The carrier shall affix blue in-transit seals to all openings of conveyances and compartments containing in...

  16. 19 CFR 123.24 - Sealing of conveyances or compartments.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... loads or lots in the same manner as less than load or compartment lots; (3) Live animals identifiable by... the expense of the parties in interest, in unsealed conveyances or compartments. (b) Seals to be affixed. The carrier shall affix blue in-transit seals to all openings of conveyances and compartments...

  17. Population Pharmacokinetics to Model the Time-Varying Clearance of the PEGylated Asparaginase Oncaspar® in Children with Acute Lymphoblastic Leukemia.

    PubMed

    Würthwein, Gudrun; Lanvers-Kaminsky, Claudia; Hempel, Georg; Gastine, Silke; Möricke, Anja; Schrappe, Martin; Karlsson, Mats O; Boos, Joachim

    2017-12-01

    The pharmacokinetics of the polyethylene glycol (PEG)-conjugated asparaginase Oncaspar ® are characterized by an increase in elimination over time. The focus of our analysis is the better understanding of this time-dependency. In paediatric acute lymphoblastic leukemia therapy (AIEOP-BFM ALL 2009), two administrations of Oncaspar ® (2500 U/m 2 intravenously) in induction phase (14-day interval) and one single administration in reinduction were followed by weekly monitoring of asparaginase activity. Non-linear mixed-effects modeling techniques (NONMEM) were used. Samples indicating immunological inactivation were excluded to describe the pharmacokinetics under standard conditions. Models with time-constant or time-varying clearance (CL) as well as transit compartment models with an increase in CL over a chain of compartments were investigated. Models with time-constant elimination could not adequately describe 6107 asparaginase activities from 1342 patients. Implementing a time-varying CL improved the fit. Modeling an increase of CL over time after dose (E max - and Weibull-functions) were superior to models with an increase of CL over time after the first administration. However, a transit compartment model came out to be the best structural model. The increase in elimination of PEGylated asparaginase appears to be driven by physicochemical processes that are drug-related. The observed hydrolytically in vitro instability of the drug leads to the hypothesis that this increase in CL might be due to an in vivo hydrolysis of the instable ester bond between PEG and the enzyme combined with an increased elimination of the partly de-PEGylated enzyme (Trial registered at www.clinicaltrials.gov , NCT0111744).

  18. Modeling and optimization of Look-Locker spin labeling for measuring perfusion and transit time changes in activation studies taking into account arterial blood volume.

    PubMed

    Francis, S T; Bowtell, R; Gowland, P A

    2008-02-01

    This work describes a new compartmental model with step-wise temporal analysis for a Look-Locker (LL)-flow-sensitive alternating inversion-recovery (FAIR) sequence, which combines the FAIR arterial spin labeling (ASL) scheme with a LL echo planar imaging (EPI) measurement, using a multireadout EPI sequence for simultaneous perfusion and T*(2) measurements. The new model highlights the importance of accounting for the transit time of blood through the arteriolar compartment, delta, in the quantification of perfusion. The signal expected is calculated in a step-wise manner to avoid discontinuities between different compartments. The optimal LL-FAIR pulse sequence timings for the measurement of perfusion with high signal-to-noise ratio (SNR), and high temporal resolution at 1.5, 3, and 7T are presented. LL-FAIR is shown to provide better SNR per unit time compared to standard FAIR. The sequence has been used experimentally for simultaneous monitoring of perfusion, transit time, and T*(2) changes in response to a visual stimulus in four subjects. It was found that perfusion increased by 83 +/- 4% on brain activation from a resting state value of 94 +/- 13 ml/100 g/min, while T*(2) increased by 3.5 +/- 0.5%. (c) 2008 Wiley-Liss, Inc.

  19. Metal Transport across Biomembranes: Emerging Models for a Distinct Chemistry*

    PubMed Central

    Argüello, José M.; Raimunda, Daniel; González-Guerrero, Manuel

    2012-01-01

    Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models. PMID:22389499

  20. Metal transport across biomembranes: emerging models for a distinct chemistry.

    PubMed

    Argüello, José M; Raimunda, Daniel; González-Guerrero, Manuel

    2012-04-20

    Transition metals are essential components of important biomolecules, and their homeostasis is central to many life processes. Transmembrane transporters are key elements controlling the distribution of metals in various compartments. However, due to their chemical properties, transition elements require transporters with different structural-functional characteristics from those of alkali and alkali earth ions. Emerging structural information and functional studies have revealed distinctive features of metal transport. Among these are the relevance of multifaceted events involving metal transfer among participating proteins, the importance of coordination geometry at transmembrane transport sites, and the presence of the largely irreversible steps associated with vectorial transport. Here, we discuss how these characteristics shape novel transition metal ion transport models.

  1. Population Pharmacokinetics of Methylphenidate in Healthy Adults Emphasizing Novel and Known Effects of Several Carboxylesterase 1 (CES1) Variants

    PubMed Central

    Stage, C; Bergmann, TK; Ferrero‐Milliani, L; Bjerre, D; Thomsen, R; Dalhoff, KP; Rasmussen, HB; Jürgens, G

    2016-01-01

    The aim of this study was to identify demographic and genetic factors that significantly affect methylphenidate (MPH) pharmacokinetics (PK), and may help explain interindividual variability and further increase the safety of MPH. d‐MPH plasma concentrations, demographic covariates, and carboxylesterase 1 (CES1) genotypes were gathered from 122 healthy adults and analyzed using nonlinear mixed effects modeling. The structural model that best described the data was a two‐compartment disposition model with absorption transit compartments. Novel effects of rs115629050 and CES1 diplotypes, as well as previously reported effects of rs71647871 and body weight, were included in the final model. Assessment of the independent and combined effect of CES1 covariates identified several specific risk factors that may result in severely increased d‐MPH plasma exposure. PMID:27754602

  2. 19 CFR 24.13 - Car, compartment, and package seals; kind, procurement.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Car, compartment, and package seals; kind... SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS FINANCIAL AND ACCOUNTING PROCEDURE § 24.13 Car, compartment.... Customs] [Can. Transit] for use on railroad cars, and “United States-Canada Customs” for use on samples...

  3. 19 CFR 24.13 - Car, compartment, and package seals; kind, procurement.

    Code of Federal Regulations, 2014 CFR

    2014-04-01

    ... 19 Customs Duties 1 2014-04-01 2014-04-01 false Car, compartment, and package seals; kind... SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS FINANCIAL AND ACCOUNTING PROCEDURE § 24.13 Car, compartment.... Customs] [Can. Transit] for use on railroad cars, and “United States-Canada Customs” for use on samples...

  4. 19 CFR 24.13 - Car, compartment, and package seals; kind, procurement.

    Code of Federal Regulations, 2011 CFR

    2011-04-01

    ... 19 Customs Duties 1 2011-04-01 2011-04-01 false Car, compartment, and package seals; kind... SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS FINANCIAL AND ACCOUNTING PROCEDURE § 24.13 Car, compartment.... Customs] [Can. Transit] for use on railroad cars, and “United States-Canada Customs” for use on samples...

  5. 19 CFR 24.13 - Car, compartment, and package seals; kind, procurement.

    Code of Federal Regulations, 2010 CFR

    2010-04-01

    ... 19 Customs Duties 1 2010-04-01 2010-04-01 false Car, compartment, and package seals; kind... SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS FINANCIAL AND ACCOUNTING PROCEDURE § 24.13 Car, compartment.... Customs] [Can. Transit] for use on railroad cars, and “United States-Canada Customs” for use on samples...

  6. 19 CFR 24.13 - Car, compartment, and package seals; kind, procurement.

    Code of Federal Regulations, 2013 CFR

    2013-04-01

    ... 19 Customs Duties 1 2013-04-01 2013-04-01 false Car, compartment, and package seals; kind... SECURITY; DEPARTMENT OF THE TREASURY CUSTOMS FINANCIAL AND ACCOUNTING PROCEDURE § 24.13 Car, compartment.... Customs] [Can. Transit] for use on railroad cars, and “United States-Canada Customs” for use on samples...

  7. Illness-death model: statistical perspective and differential equations.

    PubMed

    Brinks, Ralph; Hoyer, Annika

    2018-01-27

    The aim of this work is to relate the theory of stochastic processes with the differential equations associated with multistate (compartment) models. We show that the Kolmogorov Forward Differential Equations can be used to derive a relation between the prevalence and the transition rates in the illness-death model. Then, we prove mathematical well-definedness and epidemiological meaningfulness of the prevalence of the disease. As an application, we derive the incidence of diabetes from a series of cross-sections.

  8. Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data

    PubMed Central

    Wojciechowski, Jessica; Mudge, Stuart; Upton, Richard N.; Foster, David J. R.

    2017-01-01

    ABSTRACT The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion (P < 0.01) and then backward deletion (P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability (F), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. PMID:28052851

  9. Population Pharmacokinetic Model of Doxycycline Plasma Concentrations Using Pooled Study Data.

    PubMed

    Hopkins, Ashley M; Wojciechowski, Jessica; Abuhelwa, Ahmad Y; Mudge, Stuart; Upton, Richard N; Foster, David J R

    2017-03-01

    The literature presently lacks a population pharmacokinetic analysis of doxycycline. This study aimed to develop a population pharmacokinetic model of doxycycline plasma concentrations that could be used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC. Doxycycline pharmacokinetic data were available from eight phase 1 clinical trials following single/multiple doses of conventional-release doxycycline capsules, Doryx delayed-release tablets, and Doryx MPC under fed and fasted conditions. A population pharmacokinetic model was developed in a stepwise manner using NONMEM, version 7.3. The final covariate model was developed according to a forward inclusion ( P < 0.01) and then backward deletion ( P < 0.001) procedure. The final model was a two-compartment model with two-transit absorption compartments. Structural covariates in the base model included formulation effects on relative bioavailability ( F ), absorption lag (ALAG), and the transit absorption rate (KTR) under the fed status. An absorption delay (lag) for the fed status (FTLAG2 = 0.203 h) was also included in the model as a structural covariate. The fed status was observed to decrease F by 10.5%, and the effect of female sex was a 14.4% increase in clearance. The manuscript presents the first population pharmacokinetic model of doxycycline plasma concentrations following oral doxycycline administration. The model was used to assess the power of bioequivalence between Doryx delayed-release tablets and Doryx MPC, and it could potentially be used to critically examine and optimize doxycycline dose regimens. Copyright © 2017 American Society for Microbiology.

  10. Change rates and prevalence of a dichotomous variable: simulations and applications.

    PubMed

    Brinks, Ralph; Landwehr, Sandra

    2015-01-01

    A common modelling approach in public health and epidemiology divides the population under study into compartments containing persons that share the same status. Here we consider a three-state model with the compartments: A, B and Dead. States A and B may be the states of any dichotomous variable, for example, Healthy and Ill, respectively. The transitions between the states are described by change rates, which depend on calendar time and on age. So far, a rigorous mathematical calculation of the prevalence of property B has been difficult, which has limited the use of the model in epidemiology and public health. We develop a partial differential equation (PDE) that simplifies the use of the three-state model. To demonstrate the validity of the PDE, it is applied to two simulation studies, one about a hypothetical chronic disease and one about dementia in Germany. In two further applications, the PDE may provide insights into smoking behaviour of males in Germany and the knowledge about the ovulatory cycle in Egyptian women.

  11. 19 CFR 123.24 - Sealing of conveyances or compartments.

    Code of Federal Regulations, 2012 CFR

    2012-04-01

    ... 19 Customs Duties 1 2012-04-01 2012-04-01 false Sealing of conveyances or compartments. 123.24 Section 123.24 Customs Duties U.S. CUSTOMS AND BORDER PROTECTION, DEPARTMENT OF HOMELAND SECURITY; DEPARTMENT OF THE TREASURY CBP RELATIONS WITH CANADA AND MEXICO Shipments in Transit Through Canada or Mexico...

  12. Population pharmacokinetics of a three-day chloroquine treatment in patients with Plasmodium vivax infection on the Thai-Myanmar border.

    PubMed

    Höglund, Richard; Moussavi, Younis; Ruengweerayut, Ronnatrai; Cheomung, Anurak; Äbelö, Angela; Na-Bangchang, Kesara

    2016-02-29

    A three-day course of chloroquine remains a standard treatment of Plasmodium vivax infection in Thailand with satisfactory clinical efficacy and tolerability although a continuous decline in in vitro parasite sensitivity has been reported. Information on the pharmacokinetics of chloroquine and its active metabolite desethylchloroquine are required for optimization of treatment to attain therapeutic exposure and thus prevent drug resistance development. The study was conducted at Mae Tao Clinic for migrant worker, Tak province, Thailand. Blood samples were collected from a total of 75 (8 Thais and 67 Burmeses; 36 males and 39 females; aged 17-52 years) patients with mono-infection with P. vivax malaria [median (95 % CI) admission parasitaemia 4898 (1206-29,480)/µL] following treatment with a three-day course of chloroquine (25 mg/kg body weight chloroquine phosphate over 3 days). Whole blood concentrations of chloroquine and desethylchloroquine were measured using high performance liquid chromatography with UV detection. Concentration-time profiles of both compounds were analysed using a population-based pharmacokinetic approach. All patients showed satisfactory response to standard treatment with a three-day course of chloroquine with 100 % cure rate within the follow-up period of 42 days. Neither recurrence of P. vivax parasitaemia nor appearance of P. falciparum occurred. A total of 1045 observations from 75 participants were included in the pharmacokinetic analysis. Chloroquine disposition was most adequately described by the two-compartment model with one transit compartment absorption model into the central compartment and a first-order transformation of chloroquine into desethylchloroquine with an additional peripheral compartment added to desethylchloroquine. First-order elimination from the central compartment of chloroquine and desethylchloroquine was assumed. The model exhibited a strong predictive ability and the pharmacokinetic parameters were estimated with adequate precision. The developed population-based pharmacokinetic model could be applied for future prediction of optimal dosage regimen of chloroquine in patients with P. vivax infection.

  13. Formation of the transition zone by Mks5/Rpgrip1L establishes a ciliary zone of exclusion (CIZE) that compartmentalises ciliary signalling proteins and controls PIP2 ciliary abundance

    PubMed Central

    Jensen, Victor L; Li, Chunmei; Bowie, Rachel V; Clarke, Lara; Mohan, Swetha; Blacque, Oliver E; Leroux, Michel R

    2015-01-01

    Cilia are thought to harbour a membrane diffusion barrier within their transition zone (TZ) that compartmentalises signalling proteins. How this “ciliary gate” assembles and functions remains largely unknown. Contrary to current models, we present evidence that Caenorhabditis elegans MKS-5 (orthologue of mammalian Mks5/Rpgrip1L/Nphp8 and Rpgrip1) may not be a simple structural scaffold for anchoring > 10 different proteins at the TZ, but instead, functions as an assembly factor. This activity is needed to form TZ ultrastructure, which comprises Y-shaped axoneme-to-membrane connectors. Coiled-coil and C2 domains within MKS-5 enable TZ localisation and functional interactions with two TZ modules, consisting of Meckel syndrome (MKS) and nephronophthisis (NPHP) proteins. Discrete roles for these modules at basal body-associated transition fibres and TZ explain their redundant functions in making essential membrane connections and thus sealing the ciliary compartment. Furthermore, MKS-5 establishes a ciliary zone of exclusion (CIZE) at the TZ that confines signalling proteins, including GPCRs and NPHP-2/inversin, to distal ciliary subdomains. The TZ/CIZE, potentially acting as a lipid gate, limits the abundance of the phosphoinositide PIP2 within cilia and is required for cell signalling. Together, our findings suggest a new model for Mks5/Rpgrip1L in TZ assembly and function that is essential for establishing the ciliary signalling compartment. PMID:26392567

  14. MR-perfusion (MRP) and diffusion-weighted imaging (DWI) in prostate cancer: quantitative and model-based gadobenate dimeglumine MRP parameters in detection of prostate cancer.

    PubMed

    Scherr, M K; Seitz, M; Müller-Lisse, U G; Ingrisch, M; Reiser, M F; Müller-Lisse, U L

    2010-12-01

    Various MR methods, including MR-spectroscopy (MRS), dynamic, contrast-enhanced MRI (DCE-MRI), and diffusion-weighted imaging (DWI) have been applied to improve test quality of standard MRI of the prostate. To determine if quantitative, model-based MR-perfusion (MRP) with gadobenate dimeglumine (Gd-BOPTA) discriminates between prostate cancer, benign tissue, and transitional zone (TZ) tissue. 27 patients (age, 65±4 years; PSA 11.0±6.1 ng/ml) with clinical suspicion of prostate cancer underwent standard MRI, 3D MR-spectroscopy (MRS), and MRP with Gd-BOPTA. Based on results of combined MRI/MRS and subsequent guided prostate biopsy alone (17/27), biopsy and radical prostatectomy (9/27), or sufficient negative follow-up (7/27), maps of model-free, deconvolution-based mean transit time (dMTT) were generated for 29 benign regions (bROIs), 14 cancer regions (cROIs), and 18 regions of transitional zone (tzROIs). Applying a 2-compartment exchange model, quantitative perfusion analysis was performed including as parameters: plasma flow (PF), plasma volume (PV), plasma mean transit time (PMTT), extraction flow (EFL), extraction fraction (EFR), interstitial volume (IV) and interstitial mean transit time (IMTT). Two-sided T-tests (significance level p<0.05) discriminated bROIs vs. cROIs and cROIs vs. tzROIs, respectively. PMTT discriminated best between bROIs (11.8±3.0 s) and cROIs (24.3±9.6 s) (p<0.0001), while PF, PV, PS, EFR, IV, IMTT also differed significantly (p 0.00002-0.0136). Discrimination between cROIs and tzROIs was insignificant for all parameters except PV (14.3±2.5 ml vs. 17.6±2.6 ml, p<0.05). Besides MRI, MRS and DWI quantitative, 2-compartment MRP with Gd-BOPTA discriminates between prostate cancer and benign tissue with several parameters. However, distinction of prostate cancer and TZ does not appear to be reliable. Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

  15. The vesosome-- a multicompartment drug delivery vehicle.

    PubMed

    Kisak, E T; Coldren, B; Evans, C A; Boyer, C; Zasadzinski, J A

    2004-01-01

    Assembling structures to divide space controllably and spontaneously into subunits at the nanometer scale is a significant challenge, although one that biology has solved in two distinct ways: prokaryotes and eukaryotes. Prokaryotes have a single compartment delimited by one or more lipid-protein membranes. Eukaryotes have nested-membrane structures that provide internal compartments--such as the cell nucleus and cell organelles in which specialized functions are carried out. We have developed a simple method of creating nested bilayer compartments in vitro via the "interdigitated" bilayer phase formed by adding ethanol to a variety of saturated phospholipids. At temperatures below the gel-liquid crystalline transition, T(m), the interdigitated lipid-ethanol sheets are rigid and flat; when the temperature is raised above T(m), the sheets become flexible and close on themselves and the surrounding solution to form closed compartments. During this closure, the sheets can entrap other vesicles, biological macromolecules, or colloidal particles. The result is efficient and spontaneous encapsulation without disruption of even fragile materials to form biomimetic nano-environments for possible use in drug delivery, colloidal stabilization, or as microreactors. The vesosome structure can take full advantage of the 40 years of progress in liposome development including steric stabilization, pH loading of drugs, and intrinsic biocompatibility. However, the multiple compartments of the vesosome give better protection to the interior contents in serum, leading to extended release of model compounds in comparison to unilamellar liposomes.

  16. Patient-related factors influence stiffness of the soft tissue complex during intraoperative gap balancing in cruciate-retaining total knee arthroplasty.

    PubMed

    Heesterbeek, P J C; Haffner, N; Wymenga, A B; Stifter, J; Ritschl, P

    2017-09-01

    How much force is needed to pre-tension the ligaments during total knee arthroplasty? The goal of this study was to determine this force for extension and flexion, and for both compartments, and to identify predicting patient-related factors. Eighty patients [55 females, mean age 71 (SD 9.7)] were recruited and had a navigated cruciate-retaining total knee arthroplasty. Distraction of the medial and lateral compartments of the extension and flexion gap (90°) with an instrumented bi-compartmental double-spring tensioner took place after finishing the bone cuts. Applied forces and resulting gap distances were recorded by the navigation system, resulting in a force-elongation curve. Lines were fitted with the intersection defined as the stiffness transition point. The slopes (N/mm) represented the stiffness of the ligamentous complex. Linear multiple regression analysis was performed to identify predicting factors. The amount of force at the stiffness transition point was on average 52.3 (CI 95 50.7-53.9), 54.5 (CI 95 52.7-56.3), 48.3 (CI 95 46.2-50.2), and 59.3 (CI 95 57.0-61.6) N for the medial and lateral extension and flexion gap, respectively, and varied considerably between patients. The force at the stiffness transition point was significantly different between extension and flexion and both compartments (P < 0.05). Stiffness of the ligaments statistically significantly helped to predict the amount of force at the stiffness transition point, as well as body mass index, gender, and varus-valgus alignment. The amount of force at the stiffness transition point varies between 48 and 59 N, depending on flexion/extension and compartment. Patient-related factors influence the stiffness transition point and can help predict the stiffness transition point. When forces higher than 60 N are used for gap distraction, the ligamentous sleeve of the knee might be over-tensioned. Prognostic study, Level I-high-quality prospective cohort study with >80 % follow-up, and all patients enrolled at same time point in disease.

  17. The role of the bi-compartmental stem cell niche in delaying cancer

    NASA Astrophysics Data System (ADS)

    Shahriyari, Leili; Komarova, Natalia L.

    2015-10-01

    In recent years, by using modern imaging techniques, scientists have found evidence of collaboration between different types of stem cells (SCs), and proposed a bi-compartmental organization of the SC niche. Here we create a class of stochastic models to simulate the dynamics of such a heterogeneous SC niche. We consider two SC groups: the border compartment, S1, is in direct contact with transit-amplifying (TA) cells, and the central compartment, S2, is hierarchically upstream from S1. The S1 SCs differentiate or divide asymmetrically when the tissue needs TA cells. Both groups proliferate when the tissue requires SCs (thus maintaining homeostasis). There is an influx of S2 cells into the border compartment, either by migration, or by proliferation. We examine this model in the context of double-hit mutant generation, which is a rate-limiting step in the development of many cancers. We discover that this type of a cooperative pattern in the stem niche with two compartments leads to a significantly smaller rate of double-hit mutant production compared with a homogeneous, one-compartmental SC niche. Furthermore, the minimum probability of double-hit mutant generation corresponds to purely symmetric division of SCs, consistent with the literature. Finally, the optimal architecture (which minimizes the rate of double-hit mutant production) requires a large proliferation rate of S1 cells along with a small, but non-zero, proliferation rate of S2 cells. This result is remarkably similar to the niche structure described recently by several authors, where one of the two SC compartments was found more actively engaged in tissue homeostasis and turnover, while the other was characterized by higher levels of quiescence (but contributed strongly to injury recovery). Both numerical and analytical results are presented.

  18. Non-linear absorption pharmacokinetics of amoxicillin: consequences for dosing regimens and clinical breakpoints.

    PubMed

    de Velde, Femke; de Winter, Brenda C M; Koch, Birgit C P; van Gelder, Teun; Mouton, Johan W

    2016-10-01

    To describe the population pharmacokinetics of oral amoxicillin and to compare the PTA of current dosing regimens. Two groups, each with 14 healthy male volunteers, received oral amoxicillin/clavulanic acid tablets on two separate days 1 week apart. One group received 875/125 mg twice daily and 500/125 mg three times daily and the other group 500/125 mg twice daily and 250/125 mg three times daily. A total of 1428 amoxicillin blood samples were collected before and after administration. We analysed the concentration-time profiles using a non-compartmental pharmacokinetic method (PKSolver) and a population pharmacokinetic method (NONMEM). The PTA was computed using Monte Carlo simulations for several dosing regimens. AUC0-24 and Cmax increased non-linearly with dose. The final model included the following components: Savic's transit compartment model, Michaelis-Menten absorption, two distribution compartments and first-order elimination. The mean central volume of distribution was 27.7 L and mean clearance was 21.3 L/h. We included variability for the central volume of distribution (34.4%), clearance (25.8%), transit compartment model parameters and Michaelis-Menten absorption parameters. For 40% fT>MIC and >97.5% PTA, the breakpoints were 0.125 mg/L (500 mg twice daily), 0.25 mg/L (250 mg three times daily and 875 mg twice daily), 0.5 mg/L (500 mg three times daily) and 1 mg/L (750, 875 or 1000 mg three times daily and 500 mg four times daily). The amoxicillin absorption rate appears to be saturable. The PTAs of high-dose as well as twice-daily regimens are less favourable than regimens with lower doses and higher frequency. © The Author 2016. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  19. Cesium-137 Decorporation Model

    DTIC Science & Technology

    2014-10-01

    Compartment Transit Times Male Female Mouth 15 sec 15 sec Esophagus 45 sec 45 sec Stomach 75 min 105 min Small Intestines 4 hr 4 hr Right colon 12...that is commonly used for radiation protection associated with internal hazards and it is also the unit upon which most long-term or cancer incident...Equivalent While it is imperative to understand doses to specific organs for acute effects, most predictors of long-term effects, such as cancer induction

  20. Dynamics of the Establishment of Multinucleate Compartments in Fusarium oxysporum

    PubMed Central

    Shahi, Shermineh; Beerens, Bas; Manders, Erik M. M.

    2014-01-01

    Nuclear dynamics can vary widely between fungal species and between stages of development of fungal colonies. Here we compared nuclear dynamics and mitotic patterns between germlings and mature hyphae in Fusarium oxysporum. Using fluorescently labeled nuclei and live-cell imaging, we show that F. oxysporum is subject to a developmental transition from a uninucleate to a multinucleate state after completion of colony initiation. We observed a special type of hypha that exhibits a higher growth rate, possibly acting as a nutrient scout. The higher growth rate is associated with a higher nuclear count and mitotic waves involving 2 to 6 nuclei in the apical compartment. Further, we found that dormant nuclei of intercalary compartments can reenter the mitotic cycle, resulting in multinucleate compartments with up to 18 nuclei in a single compartment. PMID:25398376

  1. In situ macrophage phenotypic transition is affected by altered cellular composition prior to acute sterile muscle injury.

    PubMed

    Patsalos, Andreas; Pap, Attila; Varga, Tamas; Trencsenyi, Gyorgy; Contreras, Gerardo Alvarado; Garai, Ildiko; Papp, Zoltan; Dezso, Balazs; Pintye, Eva; Nagy, Laszlo

    2017-09-01

    The in situ phenotypic switch of macrophages is delayed in acute injury following irradiation. The combination of bone marrow transplantation and local muscle radiation protection allows for the identification of a myeloid cell contribution to tissue repair. PET-MRI allows monitoring of myeloid cell invasion and metabolism. Altered cellular composition prior to acute sterile injury affects the in situ phenotypic transition of invading myeloid cells to repair macrophages. There is reciprocal intercellular communication between local muscle cell compartments, such as PAX7 positive cells, and recruited macrophages during skeletal muscle regeneration. Skeletal muscle regeneration is a complex interplay between various cell types including invading macrophages. Their recruitment to damaged tissues upon acute sterile injuries is necessary for clearance of necrotic debris and for coordination of tissue regeneration. This highly dynamic process is characterized by an in situ transition of infiltrating monocytes from an inflammatory (Ly6C high ) to a repair (Ly6C low ) macrophage phenotype. The importance of the macrophage phenotypic shift and the cross-talk of the local muscle tissue with the infiltrating macrophages during tissue regeneration upon injury are not fully understood and their study lacks adequate methodology. Here, using an acute sterile skeletal muscle injury model combined with irradiation, bone marrow transplantation and in vivo imaging, we show that preserved muscle integrity and cell composition prior to the injury is necessary for the repair macrophage phenotypic transition and subsequently for proper and complete tissue regeneration. Importantly, by using a model of in vivo ablation of PAX7 positive cells, we show that this radiosensitive skeletal muscle progenitor pool contributes to macrophage phenotypic transition following acute sterile muscle injury. In addition, local muscle tissue radioprotection by lead shielding during irradiation preserves normal macrophage transition dynamics and subsequently muscle tissue regeneration. Taken together, our data suggest the existence of a more extensive and reciprocal cross-talk between muscle tissue compartments, including satellite cells, and infiltrating myeloid cells upon tissue damage. These interactions shape the macrophage in situ phenotypic shift, which is indispensable for normal muscle tissue repair dynamics. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  2. Pharmacokinetics and Pharmacodynamics of Curcumin in regulating anti-inflammatory and epigenetic gene expression.

    PubMed

    Boyanapalli, Sarandeep S S; Huang, Ying; Su, Zhengyuan; Cheng, David; Zhang, Chengyue; Guo, Yue; Rao, Rohit; Androulakis, Ioannis P; Kong, Ah-Ng

    2018-06-05

    Chronic inflammation is a key driver of cancer development. Nitrite levels, which are regulated by inducible nitric oxide synthase (iNOS), play a critical role in inflammation. While the anti-oxidant and anti-inflammatory effects of curcumin, a natural product present in the roots of Curcuma longa have been widely studied, the acute pharmacokinetics (PK) and pharmacodynamics (PD) of curcumin in suppressing pro-inflammatory markers and epigenetic modulators remain unclear. In this study, we evaluated the PK and PD of curcumin-induced suppression of lipopolysaccharide (LPS)-mediated inflammation in rat lymphocytes. LPS was administered intravenously either alone or with curcumin to female Sprague-Dawley rats. Plasma samples were analyzed for curcumin concentration and mRNA expression was quantified in lymphocytes. Relative gene expression of several inflammatory and epigenetic modulators was analyzed. To investigate the relationship between curcumin concentration and iNOS, TNF-α, and IL-6 gene expression, PK/PD modeling using Jusko's indirect response model (IDR) integrating transit compartments (TC) describing the delayed response was conducted. The concentration-time profile of curcumin exhibited a bi-exponential decline, which was well described by a two-compartmental pharmacokinetic model. Importantly our results demonstrate that LPS induced gene expression of pro-inflammatory markers in lymphocytes, with peak expression at approximately 3 h and curcumin suppressed the gene expression in animals administered with LPS. These effects were well captured using the IDR model and an IDR model with the transit compartments. In summary, the PK/PD modeling approach could potentially provide a robust quantitative framework for evaluating the acute anti-inflammatory and epigenetic effects of curcumin in future clinical trials. This article is protected by copyright. All rights reserved.

  3. Synthetic Biology in Aqueous Compartments at the Micro- and Nanoscale

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Boreyko, Jonathan; Caveney, Patrick M.; Norred, Sarah L.

    ABSTRACT Aqueous two-phase systems and related emulsion-based structures defined within micro- and nanoscale environments enable a bottom-up synthetic biological approach to mimicking the dynamic compartmentation of biomaterial that naturally occurs within cells. Model systems we have developed to aid in understanding these phenomena include on-demand generation and triggering of reversible phase transitions in ATPS confined in microscale droplets, morpho-logical changes in networks of femtoliter-volume aqueous droplet interface bilayers (DIBs) formulated in microfluidic channels, and temperature-driven phase transitions in interfacial lipid bilayer systems supported on micro and nanostructured substrates. For each of these cases, the dynamics were intimately linked to changesmore » in the chemical potential of water, which becomes increasingly susceptible to confinement and crowding. At these length scales, where interfacial and surface areas predominate over compartment volumes, both evaporation and osmotic forces become enhanced relative to ideal dilute solutions. Finally, consequences of confinement and crowding in cell-sized microcompartments for increasingly complex scenarios will be discussed, from single-molecule mobility measurements with fluorescence correlation spectroscopy to spatio-temporal modulation of resource sharing in cell-free gene expression bursting.« less

  4. Synthetic Biology in Aqueous Compartments at the Micro- and Nanoscale

    DOE PAGES

    Boreyko, Jonathan; Caveney, Patrick M.; Norred, Sarah L.; ...

    2017-07-10

    ABSTRACT Aqueous two-phase systems and related emulsion-based structures defined within micro- and nanoscale environments enable a bottom-up synthetic biological approach to mimicking the dynamic compartmentation of biomaterial that naturally occurs within cells. Model systems we have developed to aid in understanding these phenomena include on-demand generation and triggering of reversible phase transitions in ATPS confined in microscale droplets, morpho-logical changes in networks of femtoliter-volume aqueous droplet interface bilayers (DIBs) formulated in microfluidic channels, and temperature-driven phase transitions in interfacial lipid bilayer systems supported on micro and nanostructured substrates. For each of these cases, the dynamics were intimately linked to changesmore » in the chemical potential of water, which becomes increasingly susceptible to confinement and crowding. At these length scales, where interfacial and surface areas predominate over compartment volumes, both evaporation and osmotic forces become enhanced relative to ideal dilute solutions. Finally, consequences of confinement and crowding in cell-sized microcompartments for increasingly complex scenarios will be discussed, from single-molecule mobility measurements with fluorescence correlation spectroscopy to spatio-temporal modulation of resource sharing in cell-free gene expression bursting.« less

  5. Evaluation of performance of distributed delay model for chemotherapy-induced myelosuppression.

    PubMed

    Krzyzanski, Wojciech; Hu, Shuhua; Dunlavey, Michael

    2018-04-01

    The distributed delay model has been introduced that replaces the transit compartments in the classic model of chemotherapy-induced myelosuppression with a convolution integral. The maturation of granulocyte precursors in the bone marrow is described by the gamma probability density function with the shape parameter (ν). If ν is a positive integer, the distributed delay model coincides with the classic model with ν transit compartments. The purpose of this work was to evaluate performance of the distributed delay model with particular focus on model deterministic identifiability in the presence of the shape parameter. The classic model served as a reference for comparison. Previously published white blood cell (WBC) count data in rats receiving bolus doses of 5-fluorouracil were fitted by both models. The negative two log-likelihood objective function (-2LL) and running times were used as major markers of performance. Local sensitivity analysis was done to evaluate the impact of ν on the pharmacodynamics response WBC. The ν estimate was 1.46 with 16.1% CV% compared to ν = 3 for the classic model. The difference of 6.78 in - 2LL between classic model and the distributed delay model implied that the latter performed significantly better than former according to the log-likelihood ratio test (P = 0.009), although the overall performance was modestly better. The running times were 1 s and 66.2 min, respectively. The long running time of the distributed delay model was attributed to computationally intensive evaluation of the convolution integral. The sensitivity analysis revealed that ν strongly influences the WBC response by controlling cell proliferation and elimination of WBCs from the circulation. In conclusion, the distributed delay model was deterministically identifiable from typical cytotoxic data. Its performance was modestly better than the classic model with significantly longer running time.

  6. Discrete stochastic analogs of Erlang epidemic models.

    PubMed

    Getz, Wayne M; Dougherty, Eric R

    2018-12-01

    Erlang differential equation models of epidemic processes provide more realistic disease-class transition dynamics from susceptible (S) to exposed (E) to infectious (I) and removed (R) categories than the ubiquitous SEIR model. The latter is itself is at one end of the spectrum of Erlang SE[Formula: see text]I[Formula: see text]R models with [Formula: see text] concatenated E compartments and [Formula: see text] concatenated I compartments. Discrete-time models, however, are computationally much simpler to simulate and fit to epidemic outbreak data than continuous-time differential equations, and are also much more readily extended to include demographic and other types of stochasticity. Here we formulate discrete-time deterministic analogs of the Erlang models, and their stochastic extension, based on a time-to-go distributional principle. Depending on which distributions are used (e.g. discretized Erlang, Gamma, Beta, or Uniform distributions), we demonstrate that our formulation represents both a discretization of Erlang epidemic models and generalizations thereof. We consider the challenges of fitting SE[Formula: see text]I[Formula: see text]R models and our discrete-time analog to data (the recent outbreak of Ebola in Liberia). We demonstrate that the latter performs much better than the former; although confining fits to strict SEIR formulations reduces the numerical challenges, but sacrifices best-fit likelihood scores by at least 7%.

  7. Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum.

    PubMed

    Smith, Jennifer L; Reloj, Allison R; Nataraj, Parvathi S; Bartos, Daniel C; Schroder, Elizabeth A; Moss, Arthur J; Ohno, Seiko; Horie, Minoru; Anderson, Corey L; January, Craig T; Delisle, Brian P

    2013-11-01

    KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K(+) current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4-5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential.

  8. Pharmacological correction of long QT-linked mutations in KCNH2 (hERG) increases the trafficking of Kv11.1 channels stored in the transitional endoplasmic reticulum

    PubMed Central

    Smith, Jennifer L.; Reloj, Allison R.; Nataraj, Parvathi S.; Bartos, Daniel C.; Schroder, Elizabeth A.; Moss, Arthur J.; Ohno, Seiko; Horie, Minoru; Anderson, Corey L.; January, Craig T.

    2013-01-01

    KCNH2 encodes Kv11.1 and underlies the rapidly activating delayed rectifier K+ current (IKr) in the heart. Loss-of-function KCNH2 mutations cause the type 2 long QT syndrome (LQT2), and most LQT2-linked missense mutations inhibit the trafficking of Kv11.1 channels. Drugs that bind to Kv11.1 and block IKr (e.g., E-4031) can act as pharmacological chaperones to increase the trafficking and functional expression for most LQT2 channels (pharmacological correction). We previously showed that LQT2 channels are selectively stored in a microtubule-dependent compartment within the endoplasmic reticulum (ER). We tested the hypothesis that pharmacological correction promotes the trafficking of LQT2 channels stored in this compartment. Confocal analyses of cells expressing the trafficking-deficient LQT2 channel G601S showed that the microtubule-dependent ER compartment is the transitional ER. Experiments with E-4031 and the protein synthesis inhibitor cycloheximide suggested that pharmacological correction promotes the trafficking of G601S stored in this compartment. Treating cells in E-4031 or ranolazine (a drug that blocks IKr and has a short half-life) for 30 min was sufficient to cause pharmacological correction. Moreover, the increased functional expression of G601S persisted 4–5 h after drug washout. Coexpression studies with a dominant-negative form of Rab11B, a small GTPase that regulates Kv11.1 trafficking, prevented the pharmacological correction of G601S trafficking from the transitional ER. These data suggest that pharmacological correction quickly increases the trafficking of LQT2 channels stored in the transitional ER via a Rab11B-dependent pathway, and we conclude that the pharmacological chaperone activity of drugs like ranolazine might have therapeutic potential. PMID:23864605

  9. Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of Notch.

    PubMed

    López-Arribillaga, Erika; Rodilla, Verónica; Pellegrinet, Luca; Guiu, Jordi; Iglesias, Mar; Roman, Angel Carlos; Gutarra, Susana; González, Susana; Muñoz-Cánoves, Pura; Fernández-Salguero, Pedro; Radtke, Freddy; Bigas, Anna; Espinosa, Lluís

    2015-01-01

    Genetic data indicate that abrogation of Notch-Rbpj or Wnt-β-catenin pathways results in the loss of the intestinal stem cells (ISCs). However, whether the effect of Notch is direct or due to the aberrant differentiation of the transit-amplifying cells into post-mitotic goblet cells is unknown. To address this issue, we have generated composite tamoxifen-inducible intestine-specific genetic mouse models and analyzed the expression of intestinal differentiation markers. Importantly, we found that activation of β-catenin partially rescues the differentiation phenotype of Rbpj deletion mutants, but not the loss of the ISC compartment. Moreover, we identified Bmi1, which is expressed in the ISC and progenitor compartments, as a gene that is co-regulated by Notch and β-catenin. Loss of Bmi1 resulted in reduced proliferation in the ISC compartment accompanied by p16(INK4a) and p19(ARF) (splice variants of Cdkn2a) accumulation, and increased differentiation to the post-mitotic goblet cell lineage that partially mimics Notch loss-of-function defects. Finally, we provide evidence that Bmi1 contributes to ISC self-renewal. © 2015. Published by The Company of Biologists Ltd.

  10. Analysis of tracer transit in rat brain after carotid artery and femoral vein administrations using linear system theory.

    PubMed

    Rudin, M; Beckmann, N; Sauter, A

    1997-01-01

    Determination of tissue perfusion rates by MRI bolus tracking methods relies on the central volume principle which states that tissue blood flow is given by the tissue blood volume divided by the mean tracer transit time (MTT). Accurate determination of the MTT requires knowledge of the arterial input function which in MRI experiments is usually not known, especially when using small animals. The problem of unknown arterial input can be circumvented in animal experiments by directly injecting the contrast agent into a feeding artery of the tissue of interest. In the present article the passage of magnetite nanoparticles through the rat cerebral cortex is analyzed after injection into the internal carotid artery. The results are discussed in the framework of linear system theory using a one-compartment model for brain tissue and by using the well characterized gamma-variate function to describe the tissue concentration profile of the contrast agent. The results obtained from the intra-arterial tracer administration experiments are then compared with the commonly used intra-venous injection of the contrast agent in order to estimate the contribution of the peripheral circulation to the MTT values in the latter case. The experiments were analyzed using a two-compartment model and the gamma-variate function. As an application perfusion rates in normal and ischemic cerebral cortex of hypertensive rats were estimated in a model of focal cerebral ischemia. The results indicate that peripheral circulation has a significant influence on the MTT values and thus on the perfusion rates, which cannot be neglected.

  11. Noninvasive Intracranial Pressure and Tissue Oxygen Measurements for Space and Earth

    NASA Technical Reports Server (NTRS)

    Hargens, A. R.; Ballard, R. E.; Murthy, G.; Watenpaugh, D. E.

    1994-01-01

    The paper discusses the following: Increasing intracranial pressure in humans during simulated microgravity. and near-infrared monitoring of model chronic compartment syndrome in exercising skeletal muscle. Compared to upright-seated posture, 0 deg. supine, 6 deg. HDT, and 15 deg. HDT produced TMD changes of 317 +/- 112, 403 +/- 114, and 474 +/- 112 n1 (means +/- S.E.), respectively. Furthermore, postural transitions from 0 deg. supine to 6 deg. HDT and from 6 deg. to 15 deg. HDT generated significant TMD changes (p less than 0.05). There was no hysteresis when postural transitions to HDT were compared to reciprocal transitions toward upright seated posture. Currently, diagnosis of chronic compartment syndrome (CCS) depends on measurement of intramuscular pressure by invasive catheterization. We hypothesized that this syndrome can be detected noninvasively by near-infrared (NIR) spectroscopy, which tracks variations in muscle hemoglobin/myoglobin oxygen saturation. CCS was simulated in the tibialis anterior muscle of 7 male and 3 female subjects by gradual inflation of a cuff placed around the leg to 40 mmHg during 14 minutes of cyclic isokinetic dorsiflexion exercise. On a separate day, subjects underwent the identical exercise protocol with no external compression. In both cases, tissue oxygenation (T(sub O2) was measured in the tibialis anterior by NIR spectroscopy and normalized to a percentage scale between baseline and a T(sub O2) nadir reached during exercise to ischemic exhaustion. Over the course of exercise, T(sub O2) declined at a rate of 1.4 +/- 0.3% per minute with model CCS, yet did not decrease during control exercise. Post-exercise recovery of T(sub O2) was slower with model CCS (2.5 +/- 0.6 min) than in control (1.3 +/- 0.2 min). These results demonstrate that NIR spectroscopy can detect muscle deoxygenation caused by pathologically elevated intramuscular pressure in exercising skeletal muscle. Consequently, this technique shows promise as a noninvasive diagnostic tool for CCS.

  12. Ciliopathy proteins establish a bipartite signaling compartment in a C. elegans thermosensory neuron

    PubMed Central

    Nguyen, Phuong Anh T.; Liou, Willisa; Hall, David H.; Leroux, Michel R.

    2014-01-01

    ABSTRACT How signaling domains form is an important, yet largely unexplored question. Here, we show that ciliary proteins help establish two contiguous, yet distinct cyclic GMP (cGMP) signaling compartments in Caenorhabditis elegans thermosensory AFD neurons. One compartment, a bona fide cilium, is delineated by proteins associated with Bardet–Biedl syndrome (BBS), Meckel syndrome and nephronophthisis at its base, and requires NPHP-2 (known as inversin in mammals) to anchor a cGMP-gated ion channel within the proximal ciliary region. The other, a subcompartment with profuse microvilli and a different lipid environment, is separated from the dendrite by a cellular junction and requires BBS-8 and DAF-25 (known as Ankmy2 in mammals) for correct localization of guanylyl cyclases needed for thermosensation. Consistent with a requirement for a membrane diffusion barrier at the subcompartment base, we reveal the unexpected presence of ciliary transition zone proteins where no canonical transition zone ultrastructure exists. We propose that differential compartmentalization of signal transduction components by ciliary proteins is important for the functions of ciliated sensory neurons. PMID:25335890

  13. Parabolic quantitative structure-activity relationships and photodynamic therapy: application of a three-compartment model with clearance to the in vivo quantitative structure-activity relationships of a congeneric series of pyropheophorbide derivatives used as photosensitizers for photodynamic therapy.

    PubMed

    Potter, W R; Henderson, B W; Bellnier, D A; Pandey, R K; Vaughan, L A; Weishaupt, K R; Dougherty, T J

    1999-11-01

    An open three-compartment pharmacokinetic model was applied to the in vivo quantitative structure-activity relationship (QSAR) data of a homologous series of pyropheophorbide photosensitizers for photodynamic therapy (PDT). The physical model was a lipid compartment sandwiched between two identical aqueous compartments. The first compartment was assumed to clear irreversibly at a rate K0. The measured octanol-water partition coefficients, P(i) (where i is the number of carbons in the alkyl chain) and the clearance rate K0 determined the clearance kinetics of the drugs. Solving the coupled differential equations of the three-compartment model produced clearance kinetics for each of the sensitizers in each of the compartments. The third compartment was found to contain the target of PDT. This series of compounds is quite lipophilic. Therefore these drugs are found mainly in the second compartment. The drug level in the third compartment represents a small fraction of the tissue level and is thus not accessible to direct measurement by extraction. The second compartment of the model accurately predicted the clearance from the serum of mice of the hexyl ether of pyropheophorbide a, one member of this series of compounds. The diffusion and clearance rate constants were those found by fitting the pharmacokinetics of the third compartment to the QSAR data. This result validated the magnitude and mechanistic significance of the rate constants used to model the QSAR data. The PDT response to dose theory was applied to the kinetic behavior of the target compartment drug concentration. This produced a pharmacokinetic-based function connecting PDT response to dose as a function of time postinjection. This mechanistic dose-response function was fitted to published, single time point QSAR data for the pheophorbides. As a result, the PDT target threshold dose together with the predicted QSAR as a function of time postinjection was found.

  14. Differential expression of the polysialyl capsule during blood-to-brain transit of neuropathogenic Escherichia coli K1.

    PubMed

    Zelmer, Andrea; Bowen, Mark; Jokilammi, Anne; Finne, Jukka; Luzio, J Paul; Taylor, Peter W

    2008-08-01

    Escherichia coli K1 isolates synthesize a polysialic acid (polySia) capsule, are components of the adult gastrointestinal microbiota and may cause lethal bacteraemia and meningitis if acquired maternally by newborn infants. We used a neonatal rat pup K1 infection model to establish that prompt administration of a selective capsule depolymerase reverses the bacteraemic state and prevents death of almost all pups. In untreated animals, bacteria colonize the gastrointestinal tract and gain entry to the blood compartment, where they express the non-O-acetylated form of polySia. The bacteria invade the major organs of the host; histological and histochemical analysis of brain sections revealed that at least some bacteria enter the central nervous system through the blood-cerebrospinal fluid barrier at the choroid plexus prior to colonization of the meninges. Once in this location, they cease expression of polySia. The unexpected abrogation of polySia, a factor associated with the pathogenesis of meningitis and essential for transit through the blood, suggests that the neuropathogen dispenses with its protective capsule once it has colonized protected niches. Thus, systemic infections due to encapsulated pathogens may be resolved by capsule depolymerization only if the enzyme modifies the bacteria whilst they are in the blood compartment.

  15. A human cadaver fascial compartment pressure measurement model.

    PubMed

    Messina, Frank C; Cooper, Dylan; Huffman, Gretchen; Bartkus, Edward; Wilbur, Lee

    2013-10-01

    Fresh human cadavers provide an effective model for procedural training. Currently, there are no realistic models to teach fascial compartment pressure measurement. We created a human cadaver fascial compartment pressure measurement model and studied its feasibility with a pre-post design. Three faculty members, following instructions from a common procedure textbook, used a standard handheld intra-compartment pressure monitor (Stryker(®), Kalamazoo, MI) to measure baseline pressures ("unembalmed") in the anterior, lateral, deep posterior, and superficial posterior compartments of the lower legs of a fresh human cadaver. The right femoral artery was then identified by superficial dissection, cannulated distally towards the lower leg, and connected to a standard embalming machine. After a 5-min infusion, the same three faculty members re-measured pressures ("embalmed") of the same compartments on the cannulated right leg. Unembalmed and embalmed readings for each compartment, and baseline readings for each leg, were compared using a two-sided paired t-test. The mean baseline compartment pressures did not differ between the right and left legs. Using the embalming machine, compartment pressure readings increased significantly over baseline for three of four fascial compartments; all in mm Hg (±SD): anterior from 40 (±9) to 143 (±44) (p = 0.08); lateral from 22 (±2.5) to 160 (±4.3) (p < 0.01); deep posterior from 34 (±7.9) to 161 (±15) (p < 0.01); superficial posterior from 33 (±0) to 140 (±13) (p < 0.01). We created a novel and measurable fascial compartment pressure measurement model in a fresh human cadaver using a standard embalming machine. Set-up is minimal and the model can be incorporated into teaching curricula. Copyright © 2013 Elsevier Inc. All rights reserved.

  16. Population pharmacokinetics of oxcarbazepine and its metabolite 10-hydroxycarbazepine in healthy subjects.

    PubMed

    Antunes, Natalicia de Jesus; van Dijkman, Sven C; Lanchote, Vera Lucia; Wichert-Ana, Lauro; Coelho, Eduardo Barbosa; Alexandre Junior, Veriano; Takayanagui, Osvaldo Massaiti; Tozatto, Eduardo; van Hasselt, J G Coen; Della Pasqua, Oscar

    2017-11-15

    Oxcarbazepine is indicated for the treatment of partial or generalised tonic-clonic seizures. Most of the absorbed oxcarbazepine is converted into its active metabolite, 10-hydroxycarbazepine (MHD), which can exist as R-(-)- and S-(+)-MHD enantiomers. Here we describe the influence of the P-glycoprotein (P-gp) inhibitor verapamil, on the disposition of oxcarbazepine and MHD enantiomers, both of which are P-gp substrates. Healthy subjects (n=12) were randomised to oxcarbazepine or oxcarbazepine combined with verapamil at doses of 300mg b.i.d. and 80mg t.i.d., respectively. Blood samples (n=185) were collected over a period of 12h post oxcarbazepine dose. An integrated PK model was developed using nonlinear mixed effects modelling using a meta-analytical approach. The pharmacokinetics of oxcarbazepine was described by a two-compartment model with absorption transit compartments and first-order elimination. The concentration-time profiles of both MHD enantiomers were characterised by a one-compartment distribution model. Clearance estimates (95% CI) were 84.9L/h (69.5-100.3) for oxcarbazepine and 2.0L/h (1.9-2.1) for both MHD enantiomers. The volume of distribution was much larger for oxcarbazepine (131L (97-165)) as compared to R-(-)- and S-(+)-MHD (23.6L (14.4-32.8) vs. 31.7L (22.5-40.9), respectively). Co-administration of verapamil resulted in a modest increase of the apparent bioavailability of oxcarbazepine by 12% (10-28), but did not affect parent or metabolite clearances. Despite the evidence of comparable systemic levels of OXC and MHD following administration of verapamil, differences in brain exposure to both moieties cannot be excluded after P-glycoprotein inhibition. Copyright © 2017. Published by Elsevier B.V.

  17. A three-compartment thermometry model for the improved estimation of changes in body heat content.

    PubMed

    Jay, Ollie; Gariépy, Louise M; Reardon, Francis D; Webb, Paul; Ducharme, Michel B; Ramsay, Tim; Kenny, Glen P

    2007-01-01

    The aim of this study was to use whole body calorimetry to directly measure the change in body heat content (DeltaH(b)) during steady-state exercise and compare these values with those estimated using thermometry. The thermometry models tested were the traditional two-compartment model of "core" and "shell" temperatures, and a three-compartment model of "core," "muscle," and "shell" temperatures; with individual compartments within each model weighted for their relative influence upon DeltaH(b) by coefficients subject to a nonnegative and a sum-to-one constraint. Fifty-two participants performed 90 min of moderate-intensity exercise (40% of Vo(2 peak)) on a cycle ergometer in the Snellen air calorimeter, at regulated air temperatures of 24 degrees C or 30 degrees C and a relative humidity of either 30% or 60%. The "core" compartment was represented by temperatures measured in the esophagus (T(es)), rectum (T(re)), and aural canal (T(au)), while the "muscle" compartment was represented by regional muscle temperature measured in the vastus lateralis (T(vl)), triceps brachii (T(tb)), and upper trapezius (T(ut)). The "shell" compartment was represented by the weighted mean of 12 skin temperatures (T(sk)). The whole body calorimetry data were used to derive optimally fitting two- and three-compartment thermometry models. The traditional two-compartment model was found to be statistically biased, systematically underestimating DeltaH(b) by 15.5% (SD 31.3) at 24 degrees C and by 35.5% (SD 21.9) at 30 degrees C. The three-compartment model showed no such bias, yielding a more precise estimate of DeltaH(b) as evidenced by a mean estimation error of 1.1% (SD 29.5) at 24 degrees C and 5.4% (SD 30.0) at 30 degrees C with an adjusted R(2) of 0.48 and 0.51, respectively. It is concluded that a major source of error in the estimation of DeltaH(b) using the traditional two-compartment thermometry model is the lack of an expression independently representing the heat storage in muscle during exercise.

  18. Wide-range high-resolution transmission electron microscopy reveals morphological and distributional changes of endomembrane compartments during log to stationary transition of growth phase in tobacco BY-2 cells.

    PubMed

    Toyooka, Kiminori; Sato, Mayuko; Kutsuna, Natsumaro; Higaki, Takumi; Sawaki, Fumie; Wakazaki, Mayumi; Goto, Yumi; Hasezawa, Seiichiro; Nagata, Noriko; Matsuoka, Ken

    2014-09-01

    Rapid growth of plant cells by cell division and expansion requires an endomembrane trafficking system. The endomembrane compartments, such as the Golgi stacks, endosome and vesicles, are important in the synthesis and trafficking of cell wall materials during cell elongation. However, changes in the morphology, distribution and number of these compartments during the different stages of cell proliferation and differentiation have not yet been clarified. In this study, we examined these changes at the ultrastructural level in tobacco Bright yellow 2 (BY-2) cells during the log and stationary phases of growth. We analyzed images of the BY-2 cells prepared by the high-pressure freezing/freeze substitution technique with the aid of an auto-acquisition transmission electron microscope system. We quantified the distribution of secretory and endosomal compartments in longitudinal sections of whole cells by using wide-range gigapixel-class images obtained by merging thousands of transmission electron micrographs. During the log phase, all Golgi stacks were composed of several thick cisternae. Approximately 20 vesicle clusters (VCs), including the trans-Golgi network and secretory vesicle cluster, were observed throughout the cell. In the stationary-phase cells, Golgi stacks were thin with small cisternae, and only a few VCs were observed. Nearly the same number of multivesicular body and small high-density vesicles were observed in both the stationary and log phases. Results from electron microscopy and live fluorescence imaging indicate that the morphology and distribution of secretory-related compartments dramatically change when cells transition from log to stationary phases of growth. © The Author 2014. Published by Oxford University Press on behalf of Japanese Society of Plant Physiologists. All rights reserved. For permissions, please email: journals.permissions@oup.com.

  19. Semi-physiological model of postprandial triglyceride response in lean, obese and very obese individuals after a high-fat meal.

    PubMed

    Leohr, Jennifer; Heathman, Michael; Kjellsson, Maria C

    2018-03-01

    To quantify the postprandial triglyceride (TG) response of chylomicrons and very-low-density lipoprotein-V6 (VLDL-V6) after a high-fat meal in lean, obese and very obese healthy individuals, using a mechanistic population lipokinetic modelling approach. Healthy individuals from three body mass index population categories: lean (18.5-24.9 kg/m 2 ), obese (30-33 kg/m 2 ), and very obese (34-40 kg/m 2 ) were enrolled in a clinical study to assess the TG response after a high-fat meal, containing 60% fat. Non-linear mixed-effect modelling was used to analyse the TG concentrations of chylomicrons and large VLDL-V6 particles. The TGs in chylomicrons and VLDL-V6 particles had a prominent postprandial peak and represented the majority of the postprandial response; only the VLDL-V6 showed a difference across the populations. A turn-over model successfully described the TG concentration-time profiles of both chylomicrons and large VLDL-V6 particles after the high-fat meal. This model consisted of four compartments: two transit compartments for the lag between meal consumption and appearance of TGs in the blood, and one compartment each for the chylomicrons and large VLDL-V6 particles. The rate constants for the production of chylomicrons and elimination of large VLDL-V6 particles, along with the conversion rate of chylomicrons to large VLDL-V6 particles were well defined. This is the first lipokinetic model to describe the absorption of TGs from dietary fats into the blood stream and compares the dynamics of TGs in chylomicrons and large VLDL-V6 particles among lean, obese and very obese people. Such a model can be used to identify where pharmacological therapies act, thereby improving the determination of efficacy, and identifying complementary mechanisms for combinational drug therapies. © 2017 John Wiley & Sons Ltd.

  20. Whole-body mathematical model for simulating intracranial pressure dynamics

    NASA Technical Reports Server (NTRS)

    Lakin, William D. (Inventor); Penar, Paul L. (Inventor); Stevens, Scott A. (Inventor); Tranmer, Bruce I. (Inventor)

    2007-01-01

    A whole-body mathematical model (10) for simulating intracranial pressure dynamics. In one embodiment, model (10) includes 17 interacting compartments, of which nine lie entirely outside of intracranial vault (14). Compartments (F) and (T) are defined to distinguish ventricular from extraventricular CSF. The vasculature of the intracranial system within cranial vault (14) is also subdivided into five compartments (A, C, P, V, and S, respectively) representing the intracranial arteries, capillaries, choroid plexus, veins, and venous sinus. The body's extracranial systemic vasculature is divided into six compartments (I, J, O, Z, D, and X, respectively) representing the arteries, capillaries, and veins of the central body and the lower body. Compartments (G) and (B) include tissue and the associated interstitial fluid in the intracranial and lower regions. Compartment (Y) is a composite involving the tissues, organs, and pulmonary circulation of the central body and compartment (M) represents the external environment.

  1. Population Pharmacokinetics of Oral Baclofen in Pediatric Patients with Cerebral Palsy

    PubMed Central

    He, Yang; Brunstrom-Hernandez, Janice E.; Thio, Liu Lin; Lackey, Shellie; Gaebler-Spira, Deborah; Kuroda, Maxine M.; Stashinko, Elaine; Hoon, Alexander H.; Vargus-Adams, Jilda; Stevenson, Richard D.; Lowenhaupt, Stephanie; McLaughlin, John F.; Christensen, Ana; Dosa, Nienke P.; Butler, Maureen; Schwabe, Aloysia; Lopez, Christina; Roge, Desiree; Kennedy, Diane; Tilton, Ann; Krach, Linda E.; Lewandowski, Andrew; Dai, Hongying; Gaedigk, Andrea; Leeder, J. Steven; Jusko, William J.

    2014-01-01

    Objective To characterize the population pharmacokinetics (PK) of oral baclofen and assess impact of patient-specific covariates in children with cerebral palsy (CP) in order to support its clinical use. Subjects design Children (2-17 years of age) with CP received a dose of titrated oral baclofen from 2.5 mg 3 times a day to a maximum tolerated dose of up to 20 mg 4 times a day. PK sampling followed titration of 10-12 weeks. Serial R- and S-baclofen plasma concentrations were measured for up to 16 hours in 49 subjects. Population PK modeling was performed using NONMEM 7.1 (ICON PLC; Ellicott City, Maryland). Results R- and S-baclofen showed identical concentration-time profiles. Both baclofen enantiomers exhibited linear and dose/kg-proportional PK, and no sex differences were observed. Average baclofen terminal half-life was 4.5 hours. A 2-compartment PK model with linear elimination and transit absorption steps adequately described concentration-time profiles of both baclofen enantiomers. The mean population estimate of apparent clearance/F was 0.273 L/h/kg with 33.4% inter-individual variability (IIV), and the apparent volume of distribution (Vss/F) was 1.16 L/kg with 43.9% IIV. Delayed absorption was expressed by a mean transit time of 0.389 hours with 83.7% IIV. Body weight, a possible genetic factor, and age were determinants of apparent clearance in these children. Conclusion The PK of oral baclofen exhibited dose-proportionality and were adequately described by a 2-compartment model. Our population PK findings suggest that baclofen dosage can be based on body weight (2 mg/kg per day) and the current baclofen dose escalation strategy is appropriate in the treatment of children with CP older than 2 years of age. PMID:24607242

  2. Application of separable parameter space techniques to multi-tracer PET compartment modeling.

    PubMed

    Zhang, Jeff L; Michael Morey, A; Kadrmas, Dan J

    2016-02-07

    Multi-tracer positron emission tomography (PET) can image two or more tracers in a single scan, characterizing multiple aspects of biological functions to provide new insights into many diseases. The technique uses dynamic imaging, resulting in time-activity curves that contain contributions from each tracer present. The process of separating and recovering separate images and/or imaging measures for each tracer requires the application of kinetic constraints, which are most commonly applied by fitting parallel compartment models for all tracers. Such multi-tracer compartment modeling presents challenging nonlinear fits in multiple dimensions. This work extends separable parameter space kinetic modeling techniques, previously developed for fitting single-tracer compartment models, to fitting multi-tracer compartment models. The multi-tracer compartment model solution equations were reformulated to maximally separate the linear and nonlinear aspects of the fitting problem, and separable least-squares techniques were applied to effectively reduce the dimensionality of the nonlinear fit. The benefits of the approach are then explored through a number of illustrative examples, including characterization of separable parameter space multi-tracer objective functions and demonstration of exhaustive search fits which guarantee the true global minimum to within arbitrary search precision. Iterative gradient-descent algorithms using Levenberg-Marquardt were also tested, demonstrating improved fitting speed and robustness as compared to corresponding fits using conventional model formulations. The proposed technique overcomes many of the challenges in fitting simultaneous multi-tracer PET compartment models.

  3. Application of separable parameter space techniques to multi-tracer PET compartment modeling

    NASA Astrophysics Data System (ADS)

    Zhang, Jeff L.; Morey, A. Michael; Kadrmas, Dan J.

    2016-02-01

    Multi-tracer positron emission tomography (PET) can image two or more tracers in a single scan, characterizing multiple aspects of biological functions to provide new insights into many diseases. The technique uses dynamic imaging, resulting in time-activity curves that contain contributions from each tracer present. The process of separating and recovering separate images and/or imaging measures for each tracer requires the application of kinetic constraints, which are most commonly applied by fitting parallel compartment models for all tracers. Such multi-tracer compartment modeling presents challenging nonlinear fits in multiple dimensions. This work extends separable parameter space kinetic modeling techniques, previously developed for fitting single-tracer compartment models, to fitting multi-tracer compartment models. The multi-tracer compartment model solution equations were reformulated to maximally separate the linear and nonlinear aspects of the fitting problem, and separable least-squares techniques were applied to effectively reduce the dimensionality of the nonlinear fit. The benefits of the approach are then explored through a number of illustrative examples, including characterization of separable parameter space multi-tracer objective functions and demonstration of exhaustive search fits which guarantee the true global minimum to within arbitrary search precision. Iterative gradient-descent algorithms using Levenberg-Marquardt were also tested, demonstrating improved fitting speed and robustness as compared to corresponding fits using conventional model formulations. The proposed technique overcomes many of the challenges in fitting simultaneous multi-tracer PET compartment models.

  4. Transport of fluid and solutes in the body I. Formulation of a mathematical model.

    PubMed

    Gyenge, C C; Bowen, B D; Reed, R K; Bert, J L

    1999-09-01

    A compartmental model of short-term whole body fluid, protein, and ion distribution and transport is formulated. The model comprises four compartments: a vascular and an interstitial compartment, each with an embedded cellular compartment. The present paper discusses the assumptions on which the model is based and describes the equations that make up the model. Fluid and protein transport parameters from a previously validated model as well as ionic exchange parameters from the literature or from statistical estimation [see companion paper: C. C. Gyenge, B. D. Bowen, R. K. Reed, and J. L. Bert. Am. J. Physiol. 277 (Heart Circ. Physiol. 46): H1228-H1240, 1999] are used in formulating the model. The dynamic model has the ability to simulate 1) transport across the capillary membrane of fluid, proteins, and small ions and their distribution between the vascular and interstitial compartments; 2) the changes in extracellular osmolarity; 3) the distribution and transport of water and ions associated with each of the cellular compartments; 4) the cellular transmembrane potential; and 5) the changes of volume in the four fluid compartments. The validation and testing of the proposed model against available experimental data are presented in the companion paper.

  5. A nonlinear model for myogenic regulation of blood flow to bone: equilibrium states and stability characteristics.

    PubMed

    Harrigan, T P

    1996-01-01

    A simple compartmental model for myogenic regulation of interstitial pressure in bone is developed, and the interaction between changes in interstitial pressure and changes in arterial and venous resistance is studied. The arterial resistance is modeled by a myogenic model that depends on transmural pressure, and the venous resistance is modeled by using a vascular waterfall. Two series capacitances model blood storage in the vascular system and interstitial fluid storage in the extravascular space. The static results mimic the observed effect that vasodilators work less well in bone than do vasoconstrictors. The static results also show that the model gives constant flow rates over a limited range of arterial pressure. The dynamic model shows unstable behavior at small values of bony capacitance and at high enough myogenic gain. At low myogenic gain, only a single equilibrium state is present, but a high enough myogenic gain, two new equilibrium states appear. At additional increases in gain, one of the two new states merges with and then separates from the original state, and the original state becomes a saddle point. The appearance of the new states and the transition of the original state to a saddle point do not depend on the bony capacitance, and these results are relevant to general fluid compartments. Numerical integration of the rate equations confirms the stability calculations and shows limit cycling behavior in several situations. The relevance of this model to circulation in bone and to other compartments is discussed.

  6. Rethinking pattern formation in reaction-diffusion systems

    NASA Astrophysics Data System (ADS)

    Halatek, J.; Frey, E.

    2018-05-01

    The present theoretical framework for the analysis of pattern formation in complex systems is mostly limited to the vicinity of fixed (global) equilibria. Here we present a new theoretical approach to characterize dynamical states arbitrarily far from (global) equilibrium. We show that reaction-diffusion systems that are driven by locally mass-conserving interactions can be understood in terms of local equilibria of diffusively coupled compartments. Diffusive coupling generically induces lateral redistribution of the globally conserved quantities, and the variable local amounts of these quantities determine the local equilibria in each compartment. We find that, even far from global equilibrium, the system is well characterized by its moving local equilibria. We apply this framework to in vitro Min protein pattern formation, a paradigmatic model for biological pattern formation. Within our framework we can predict and explain transitions between chemical turbulence and order arbitrarily far from global equilibrium. Our results reveal conceptually new principles of self-organized pattern formation that may well govern diverse dynamical systems.

  7. Morphological characterization of ckd in cats: Insights of fibrogenesis to be recognized.

    PubMed

    Morais, G B; Viana, D A; Verdugo, J M; Roselló, M G; Porcel, J O; Rocha, D D; Xavier Júnior, F A F; Barbosa, K D S M; Silva, F M O; Brito, G A C; Sampaio, C M S; Evangelista, J S A M

    2018-01-01

    Renal fibrosis is characterized by glomerulosclerosis and tubulointerstitial fibrosis and its pathogenesis is associated with the activity of mesenchymal cells (fibroblasts), being essentially characterized by a process of excessive accumulation resulting from the deposition of extracellular matrix components. The aim of this study was to characterize the morphological presentation of chronic and fibrotic lesions in the glomerular, tubular, interstitial, and vascular compartments in feline CKD, as well as the possible participation of myofibroblasts in renal fibrotic processes in this species. Cat kidneys were collected and processed according to the conventional techniques for light microscopy, circular polarization, immunohistochemistry, and electron microscopy. Fibrotic alterations were present in all compartments analyzed. The main findings in the glomerular compartment were different degrees of glomerular sclerosis, synechia formation, Bowman's capsule calcification, in addition to glomerular basement membrane thickening and pericapsular fibrosis. The tubulointerstitial compartment had intense tubular degeneration and the immunostaining in tubular cells for mesenchymal cell markers demonstrated the possibility of mesenchymal epithelial transition and consequent involvement of myofibroblasts in the development of interstitial tubule damage. Infiltration of inflammatory cells, added to vessel thickening and fibrosis, demonstrated the severity and role of inflammation in the development and perpetuation of damage. Thus, we may conclude that fibrotic lesions play a relevant role in feline CKD and the mechanism of perpetuation of these lesions need further elucidation regarding the origin and participation of myofibroblasts and consequent mesenchymal epithelial transition in this species. © 2017 Wiley Periodicals, Inc.

  8. Population pharmacokinetics of hydroxyurea for children and adolescents with sickle cell disease.

    PubMed

    Wiczling, Paweł; Liem, Robert I; Panepinto, Julie A; Garg, Uttam; Abdel-Rahman, Susan M; Kearns, Gregory L; Neville, Kathleen A

    2014-09-01

    The objective of this study was to develop a population pharmacokinetic (PK) model sufficient to describe hydroxyurea (HU) concentrations in serum and urine following oral drug administration in pediatric patients with sickle cell disease. Additionally, the measured hydroxyurea concentrations for particular sampling time were correlated with exposure measures (AUC) to find the most predictive relationship. Hydroxyurea concentrations were determined in 21 subjects. Using a population nonlinear mixed-effect modeling, the HU PK was best described by a one-compartment model with two elimination pathways (metabolic and renal) and a transit compartment absorption. The typical mean absorption time was 0.222 hour. The typical apparent volume of distribution was 21.8 L and the apparent systemic clearance was 6.88 L/h for an average weight patient of 30.7 kg. The 50% of the HU dose was renally excreted. Linear correlations were apparent between the plasma HU concentration at 1, 1.5, 2, 4, and 6 hours post-dose and AUC with the most significant (R(2)  = 0.71) observed at 1.5 hours. A population PK model was successful in describing HU disposition in plasma and urine. Data from the model also demonstrated that HU plasma concentrations at 1.5 hours after an oral dose of the drug were highly predictive of systemic drug exposure. © 2014, The American College of Clinical Pharmacology.

  9. A general multiple-compartment model for the transport of trace elements through animals

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Assimakopoulos, P.A.; Ioannides, K.G.; Pakou, A.A.

    1991-08-01

    Multiple-compartment models employed in the analysis of trace element transport in animals are often based on linear differential equations which relate the rate of change of contaminant (or contaminant concentration) in each compartment to the amount of contaminant (or contaminant concentration) in every other compartment in the system. This has the serious disadvantage of mixing intrinsic physiological properties with the geometry of the animal. The basic equations on which the model presented here is developed are derived from the actual physical process under way and are capable of separating intrinsic physiological properties from geometry. It is thus expected that ratemore » coefficients determined through this model will be applicable to a wider category of physiologically similar animals. A specific application of the model for the study of contamination of sheep--or indeed for any ruminant--is presented, and the temporal evolution of contaminant concentration in the various compartments of the animal is calculated. The application of this model to a system of compartments with changing geometry is also presented.« less

  10. Two-compartmental population balance modeling of a pulsed spray fluidized bed granulation based on computational fluid dynamics (CFD) analysis.

    PubMed

    Liu, Huolong; Li, Mingzhong

    2014-11-20

    In this work a two-compartmental population balance model (TCPBM) was proposed to model a pulsed top-spray fluidized bed granulation. The proposed TCPBM considered the spatially heterogeneous granulation mechanisms of the granule growth by dividing the granulator into two perfectly mixed zones of the wetting compartment and drying compartment, in which the aggregation mechanism was assumed in the wetting compartment and the breakage mechanism was considered in the drying compartment. The sizes of the wetting and drying compartments were constant in the TCPBM, in which 30% of the bed was the wetting compartment and 70% of the bed was the drying compartment. The exchange rate of particles between the wetting and drying compartments was determined by the details of the flow properties and distribution of particles predicted by the computational fluid dynamics (CFD) simulation. The experimental validation has shown that the proposed TCPBM can predict evolution of the granule size and distribution within the granulator under different binder spray operating conditions accurately. Copyright © 2014 Elsevier B.V. All rights reserved.

  11. Pharmacokinetic/Pharmacodynamic Relationship of Gabapentin in a CFA-induced Inflammatory Hyperalgesia Rat Model.

    PubMed

    Larsen, Malte Selch; Keizer, Ron; Munro, Gordon; Mørk, Arne; Holm, René; Savic, Rada; Kreilgaard, Mads

    2016-05-01

    Gabapentin displays non-linear drug disposition, which complicates dosing for optimal therapeutic effect. Thus, the current study was performed to elucidate the pharmacokinetic/pharmacodynamic (PKPD) relationship of gabapentin's effect on mechanical hypersensitivity in a rat model of CFA-induced inflammatory hyperalgesia. A semi-mechanistic population-based PKPD model was developed using nonlinear mixed-effects modelling, based on gabapentin plasma and brain extracellular fluid (ECF) time-concentration data and measurements of CFA-evoked mechanical hyperalgesia following administration of a range of gabapentin doses (oral and intravenous). The plasma/brain ECF concentration-time profiles of gabapentin were adequately described with a two-compartment plasma model with saturable intestinal absorption rate (K m  = 44.1 mg/kg, V max  = 41.9 mg/h∙kg) and dose-dependent oral bioavailability linked to brain ECF concentration through a transit compartment. Brain ECF concentration was directly linked to a sigmoid E max function describing reversal of hyperalgesia (EC 50, plasma  = 16.7 μg/mL, EC 50, brain  = 3.3 μg/mL). The proposed semi-mechanistic population-based PKPD model provides further knowledge into the understanding of gabapentin's non-linear pharmacokinetics and the link between plasma/brain disposition and anti-hyperalgesic effects. The model suggests that intestinal absorption is the primary source of non-linearity and that the investigated rat model provides reasonable predictions of clinically effective plasma concentrations for gabapentin.

  12. Evidence from a mouse model that epithelial cell migration and mesenchymal-epithelial transition contribute to rapid restoration of uterine tissue integrity during menstruation.

    PubMed

    Cousins, Fiona L; Murray, Alison; Esnal, Arantza; Gibson, Douglas A; Critchley, Hilary O D; Saunders, Philippa T K

    2014-01-01

    In women dynamic changes in uterine tissue architecture occur during each menstrual cycle. Menses, characterised by the shedding of the upper functional layer of the endometrium, is the culmination of a cascade of irreversible changes in tissue function including stromal decidualisation, inflammation and production of degradative enzymes. The molecular mechanisms that contribute to the rapid restoration of tissue homeostasis at time of menses are poorly understood. A modified mouse model of menses was developed to focus on the events occurring within the uterine lining during endometrial shedding/repair. Decidualisation, vaginal bleeding, tissue architecture and cell proliferation were evaluated at 4, 8, 12, and 24 hours after progesterone (P4) withdrawal; mice received a single injection of bromodeoxyuridine (BrdU) 90 mins before culling. Expression of genes implicated in the regulation of mesenchymal to epithelial transition (MET) was determined using a RT2 PCR profiler array, qRTPCR and bioinformatic analysis. Mice exhibited vaginal bleeding between 4 and 12 hours after P4 withdrawal, concomitant with detachment of the decidualised cell mass from the basal portion of the endometrial lining. Immunostaining for BrdU and pan cytokeratin revealed evidence of epithelial cell proliferation and migration. Cells that appeared to be in transition from a mesenchymal to an epithelial cell identity were identified within the stromal compartment. Analysis of mRNAs encoding genes expressed exclusively in the epithelial or stromal compartments, or implicated in MET, revealed dynamic changes in expression, consistent with a role for reprogramming of mesenchymal cells so that they could contribute to re-epithelialisation. These studies have provided novel insights into the cellular processes that contribute to re-epithelialisation post-menses implicating both epithelial cell migration and mesenchymal cell differentiation in restoration of an intact epithelial cell layer. These insights may inform development of new therapies to induce rapid healing in the endometrium and other tissues and offer hope to women who suffer from heavy menstrual bleeding.

  13. Application of separable parameter space techniques to multi-tracer PET compartment modeling

    PubMed Central

    Zhang, Jeff L; Morey, A Michael; Kadrmas, Dan J

    2016-01-01

    Multi-tracer positron emission tomography (PET) can image two or more tracers in a single scan, characterizing multiple aspects of biological functions to provide new insights into many diseases. The technique uses dynamic imaging, resulting in time-activity curves that contain contributions from each tracer present. The process of separating and recovering separate images and/or imaging measures for each tracer requires the application of kinetic constraints, which are most commonly applied by fitting parallel compartment models for all tracers. Such multi-tracer compartment modeling presents challenging nonlinear fits in multiple dimensions. This work extends separable parameter space kinetic modeling techniques, previously developed for fitting single-tracer compartment models, to fitting multi-tracer compartment models. The multi-tracer compartment model solution equations were reformulated to maximally separate the linear and nonlinear aspects of the fitting problem, and separable least-squares techniques were applied to effectively reduce the dimensionality of the nonlinear fit. The benefits of the approach are then explored through a number of illustrative examples, including characterization of separable parameter space multi-tracer objective functions and demonstration of exhaustive search fits which guarantee the true global minimum to within arbitrary search precision. Iterative gradient-descent algorithms using Levenberg–Marquardt were also tested, demonstrating improved fitting speed and robustness as compared to corresponding fits using conventional model formulations. The proposed technique overcomes many of the challenges in fitting simultaneous multi-tracer PET compartment models. PMID:26788888

  14. Population Pharmacokinetic and Pharmacodynamic Modeling of Lusutrombopag, a Newly Developed Oral Thrombopoietin Receptor Agonist, in Healthy Subjects.

    PubMed

    Katsube, Takayuki; Ishibashi, Toru; Kano, Takeshi; Wajima, Toshihiro

    2016-11-01

    The aim of this study was to develop a population pharmacokinetic (PK)/pharmacodynamic (PD) model for describing plasma lusutrombopag concentrations and platelet response following oral lusutrombopag dosing and for evaluating covariates in the PK/PD profiles. A population PK/PD model was developed using a total of 2539 plasma lusutrombopag concentration data and 1408 platelet count data from 78 healthy adult subjects following oral single and multiple (14-day once-daily) dosing. Covariates in PK and PK/PD models were explored for subject age, body weight, sex, and ethnicity. A three-compartment model with first-order rate and lag time for absorption was selected as a PK model. A three-transit and one-platelet compartment model with a sigmoid E max model for drug effect and feedback of platelet production was selected as the PD model. The PK and PK/PD models well described the plasma lusutrombopag concentrations and the platelet response, respectively. Body weight was a significant covariate in PK. The bioavailability of non-Japanese subjects (White and Black/African American subjects) was 13 % lower than that of Japanese subjects, while the simulated platelet response profiles using the PK/PD model were similar between Japanese and non-Japanese subjects. There were no significant covariates of the tested background data including age, sex, and ethnicity (Japanese or non-Japanese) for the PD sensitivity. A population PK/PD model was developed for lusutrombopag and shown to provide good prediction for the PK/PD profiles. The model could be used as a basic PK/PD model in the drug development of lusutrombopag.

  15. Transportation of market-weight pigs: II. effect of season and location within truck on behavior with an eight-hour transport.

    PubMed

    Torrey, S; Bergeron, R; Faucitano, L; Widowski, T; Lewis, N; Crowe, T; Correa, J A; Brown, J; Hayne, S; Gonyou, H W

    2013-06-01

    Transportation of pigs to slaughter has the potential to negatively impact animal welfare, particularly in hot temperatures and over long transport durations. The objective of this experiment was to determine if season and location within vehicle influenced the behavior of market-weight pigs during loading, transit, unloading, and lairage after a long-distance trip to slaughter. On a pot-belly truck, 1,170 pigs were transported (n = 195 pigs/wk in 7 experimental compartments) for 8 h to a commercial abattoir in summer (6 wk) and winter (5 wk). Pig behavior was observed at loading, in transit, at unloading, and in lairage. Handler intervention at loading was observed, and the time to load and unload was recorded. Although season did not (P = 0.91) affect loading time, more prods (P = 0.014) were necessary to load pigs in summer than winter. Loading in winter also tended to be longer (P = 0.071) into compartments involving internal ramps. In transit, more pigs (P = 0.025) were standing in winter compared with summer. Unloading took longer (P < 0.006) in winter than in summer and from compartments where pigs had to negotiate ramps and 180° turns. Furthermore, pigs in summer experienced more slipping (P = 0.032), falling (P = 0.004), overlapping (P < 0.001), and walking backward (P < 0.001) than pigs in winter. Pigs unloading from compartments with internal ramps slipped more (P < 0.0001) than other pigs. Season influenced latency to rest in lairage, with those transported in summer resting sooner (P < 0.0001) than those in winter. In conclusion, season and location within trucks differentially affect pig behavior before, during, and after long-distance transportation. Differences in lighting and temperature between seasons and the inclusion of internal ramps within vehicles may play important roles in the welfare of pigs transported to slaughter.

  16. Rust fungal effectors mimic host transit peptides to translocate into chloroplasts.

    PubMed

    Petre, Benjamin; Lorrain, Cécile; Saunders, Diane G O; Win, Joe; Sklenar, Jan; Duplessis, Sébastien; Kamoun, Sophien

    2016-04-01

    Parasite effector proteins target various host cell compartments to alter host processes and promote infection. How effectors cross membrane-rich interfaces to reach these compartments is a major question in effector biology. Growing evidence suggests that effectors use molecular mimicry to subvert host cell machinery for protein sorting. We recently identified chloroplast-targeted protein 1 (CTP1), a candidate effector from the poplar leaf rust fungus Melampsora larici-populina that carries a predicted transit peptide and accumulates in chloroplasts and mitochondria. Here, we show that the CTP1 transit peptide is necessary and sufficient for accumulation in the stroma of chloroplasts. CTP1 is part of a Melampsora-specific family of polymorphic secreted proteins. Two members of that family, CTP2 and CTP3, also translocate in chloroplasts in an N-terminal signal-dependent manner. CTP1, CTP2 and CTP3 are cleaved when they accumulate in chloroplasts, while they remain intact when they do not translocate into chloroplasts. Our findings reveal that fungi have evolved effector proteins that mimic plant-specific sorting signals to traffic within plant cells. © 2015 John Wiley & Sons Ltd.

  17. Gamma time-dependency in Blaxter's compartmental model.

    NASA Technical Reports Server (NTRS)

    Matis, J. H.

    1972-01-01

    A new two-compartment model for the passage of particles through the gastro-intestinal tract of ruminants is proposed. In this model, a gamma distribution of lifetimes is introduced in the first compartment; thereby, passage from that compartment becomes time-dependent. This modification is strongly suggested by the physical alteration which certain substances, e.g. hay particles, undergo in the digestive process. The proposed model is applied to experimental data.

  18. Modeling of delays in PKPD: classical approaches and a tutorial for delay differential equations.

    PubMed

    Koch, Gilbert; Krzyzanski, Wojciech; Pérez-Ruixo, Juan Jose; Schropp, Johannes

    2014-08-01

    In pharmacokinetics/pharmacodynamics (PKPD) the measured response is often delayed relative to drug administration, individuals in a population have a certain lifespan until they maturate or the change of biomarkers does not immediately affects the primary endpoint. The classical approach in PKPD is to apply transit compartment models (TCM) based on ordinary differential equations to handle such delays. However, an alternative approach to deal with delays are delay differential equations (DDE). DDEs feature additional flexibility and properties, realize more complex dynamics and can complementary be used together with TCMs. We introduce several delay based PKPD models and investigate mathematical properties of general DDE based models, which serve as subunits in order to build larger PKPD models. Finally, we review current PKPD software with respect to the implementation of DDEs for PKPD analysis.

  19. Shortened acquisition protocols for the quantitative assessment of the 2-tissue-compartment model using dynamic PET/CT 18F-FDG studies.

    PubMed

    Strauss, Ludwig G; Pan, Leyun; Cheng, Caixia; Haberkorn, Uwe; Dimitrakopoulou-Strauss, Antonia

    2011-03-01

    (18)F-FDG kinetics are quantified by a 2-tissue-compartment model. The routine use of dynamic PET is limited because of this modality's 1-h acquisition time. We evaluated shortened acquisition protocols up to 0-30 min regarding the accuracy for data analysis with the 2-tissue-compartment model. Full dynamic series for 0-60 min were analyzed using a 2-tissue-compartment model. The time-activity curves and the resulting parameters for the model were stored in a database. Shortened acquisition data were generated from the database using the following time intervals: 0-10, 0-16, 0-20, 0-25, and 0-30 min. Furthermore, the impact of adding a 60-min uptake value to the dynamic series was evaluated. The datasets were analyzed using dedicated software to predict the results of the full dynamic series. The software is based on a modified support vector machines (SVM) algorithm and predicts the compartment parameters of the full dynamic series. The SVM-based software provides user-independent results and was accurate at predicting the compartment parameters of the full dynamic series. If a squared correlation coefficient of 0.8 (corresponding to 80% explained variance of the data) was used as a limit, a shortened acquisition of 0-16 min was accurate at predicting the 60-min 2-tissue-compartment parameters. If a limit of 0.9 (90% explained variance) was used, a dynamic series of at least 0-20 min together with the 60-min uptake values is required. Shortened acquisition protocols can be used to predict the parameters of the 2-tissue-compartment model. Either a dynamic PET series of 0-16 min or a combination of a dynamic PET/CT series of 0-20 min and a 60-min uptake value is accurate for analysis with a 2-tissue-compartment model.

  20. Predicting Drug Concentration‐Time Profiles in Multiple CNS Compartments Using a Comprehensive Physiologically‐Based Pharmacokinetic Model

    PubMed Central

    Yamamoto, Yumi; Välitalo, Pyry A.; Huntjens, Dymphy R.; Proost, Johannes H.; Vermeulen, An; Krauwinkel, Walter; Beukers, Margot W.; van den Berg, Dirk‐Jan; Hartman, Robin; Wong, Yin Cheong; Danhof, Meindert; van Hasselt, John G. C.

    2017-01-01

    Drug development targeting the central nervous system (CNS) is challenging due to poor predictability of drug concentrations in various CNS compartments. We developed a generic physiologically based pharmacokinetic (PBPK) model for prediction of drug concentrations in physiologically relevant CNS compartments. System‐specific and drug‐specific model parameters were derived from literature and in silico predictions. The model was validated using detailed concentration‐time profiles from 10 drugs in rat plasma, brain extracellular fluid, 2 cerebrospinal fluid sites, and total brain tissue. These drugs, all small molecules, were selected to cover a wide range of physicochemical properties. The concentration‐time profiles for these drugs were adequately predicted across the CNS compartments (symmetric mean absolute percentage error for the model prediction was <91%). In conclusion, the developed PBPK model can be used to predict temporal concentration profiles of drugs in multiple relevant CNS compartments, which we consider valuable information for efficient CNS drug development. PMID:28891201

  1. Microgravity-Induced Physiological Fluid Redistribution: Computational Analysis to Assess Influence of Physiological Parameters

    NASA Technical Reports Server (NTRS)

    Myers, J. G.; Eke, Chika; Werner, C.; Nelson, E. S.; Mulugeta, L.; Feola, A.; Raykin, J.; Samuels, B.; Ethier, C. R.

    2016-01-01

    Space flight impacts human physiology in many ways, the most immediate being the marked cephalad (headward) shift of fluid upon introduction into the microgravity environment. This physiological response to microgravity points to the redistribution of blood and interstitial fluid as a major factor in the loss of venous tone and reduction in heart muscle efficiency which impact astronaut performance. In addition, researchers have hypothesized that a reduction in astronaut visual acuity, part of the Visual Impairment and Intracranial Pressure (VIIP) syndrome, is associated with this redistribution of fluid. VIIP arises within several months of beginning space flight and includes a variety of ophthalmic changes including posterior globe flattening, distension of the optic nerve sheath, and kinking of the optic nerve. We utilize a suite of lumped parameter models to simulate microgravity-induced fluid redistribution in the cardiovascular, central nervous and ocular systems to provide initial and boundary data to a 3D finite element simulation of ocular biomechanics in VIIP. Specifically, the lumped parameter cardiovascular model acts as the primary means of establishing how microgravity, and the associated lack of hydrostatic gradient, impacts fluid redistribution. The cardiovascular model consists of 16 compartments, including three cerebrospinal fluid (CSF) compartments, three cranial blood compartments, and 10 thoracic and lower limb blood compartments. To assess the models capability to address variations in physiological parameters, we completed a formal uncertainty and sensitivity analysis that evaluated the relative importance of 42 input parameters required in the model on relative compartment flows and compartment pressures. Utilizing the model in a pulsatile flow configuration, the sensitivity analysis identified the ten parameters that most influenced each compartment pressure. Generally, each compartment responded appropriately to parameter variations associated with itself and adjacent compartments. However, several unexpected interactions between components, such as between the choroid plexus and the lower capillaries, were found, and are due to simplifications in the formulation of the model. The analysis illustrates that highly influential parameters and those that have unique influences within the model formulation must be tightly controlled for successful model application.

  2. Bayesian parameter estimation for the Wnt pathway: an infinite mixture models approach.

    PubMed

    Koutroumpas, Konstantinos; Ballarini, Paolo; Votsi, Irene; Cournède, Paul-Henry

    2016-09-01

    Likelihood-free methods, like Approximate Bayesian Computation (ABC), have been extensively used in model-based statistical inference with intractable likelihood functions. When combined with Sequential Monte Carlo (SMC) algorithms they constitute a powerful approach for parameter estimation and model selection of mathematical models of complex biological systems. A crucial step in the ABC-SMC algorithms, significantly affecting their performance, is the propagation of a set of parameter vectors through a sequence of intermediate distributions using Markov kernels. In this article, we employ Dirichlet process mixtures (DPMs) to design optimal transition kernels and we present an ABC-SMC algorithm with DPM kernels. We illustrate the use of the proposed methodology using real data for the canonical Wnt signaling pathway. A multi-compartment model of the pathway is developed and it is compared to an existing model. The results indicate that DPMs are more efficient in the exploration of the parameter space and can significantly improve ABC-SMC performance. In comparison to alternative sampling schemes that are commonly used, the proposed approach can bring potential benefits in the estimation of complex multimodal distributions. The method is used to estimate the parameters and the initial state of two models of the Wnt pathway and it is shown that the multi-compartment model fits better the experimental data. Python scripts for the Dirichlet Process Gaussian Mixture model and the Gibbs sampler are available at https://sites.google.com/site/kkoutroumpas/software konstantinos.koutroumpas@ecp.fr. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  3. Topologically associating domains are stable units of replication-timing regulation.

    PubMed

    Pope, Benjamin D; Ryba, Tyrone; Dileep, Vishnu; Yue, Feng; Wu, Weisheng; Denas, Olgert; Vera, Daniel L; Wang, Yanli; Hansen, R Scott; Canfield, Theresa K; Thurman, Robert E; Cheng, Yong; Gülsoy, Günhan; Dennis, Jonathan H; Snyder, Michael P; Stamatoyannopoulos, John A; Taylor, James; Hardison, Ross C; Kahveci, Tamer; Ren, Bing; Gilbert, David M

    2014-11-20

    Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program. In mammals, replication timing is cell-type-specific with at least half the genome switching replication timing during development, primarily in units of 400-800 kilobases ('replication domains'), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements. Early and late replication correlate, respectively, with open and closed three-dimensional chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, late replication correlates with lamina-associated domains (LADs). Recent Hi-C mapping has unveiled substructure within chromatin compartments called topologically associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to replication domains. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure. Here we localize boundaries of replication domains to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, replication domain boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure replication domain boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type-specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell-type-specific sub-nuclear compartmentalization and replication timing with developmentally stable structural domains and offer a unified model for large-scale chromosome structure and function.

  4. Limitations of the permeability-limited compartment model in estimating vascular permeability and interstitial volume fraction in DCE-MRI.

    PubMed

    Carreira, Guido Correia; Gemeinhardt, Ole; Gorenflo, Rudolf; Beyersdorff, Dirk; Franiel, Tobias; Plendl, Johanna; Lüdemann, Lutz

    2011-06-01

    Dynamic contrast-enhanced magnetic resonance imaging commonly uses compartment models to estimate tissue parameters in general and perfusion parameters in particular. Compartment models assume a homogeneous distribution of the injected tracer throughout the compartment volume. Since tracer distribution within a compartment cannot be assessed, the parameters obtained by means of a compartment model might differ from the actual physical values. This work systematically examines the widely used permeability-surface-limited one-compartment model to determine the reliability of the parameters obtained by comparing them with their actual values. A computer simulation was used to model spatial tracer distribution within the interstitial volume using diffusion of contrast agent in tissue. Vascular parameters were varied as well as tissue parameters. The vascular parameters used were capillary radius (4 and 12 μm), capillary permeability (from 0.03 to 3.3 μm/s) and intercapillary distances from 30 to 300 μm. The tissue parameters used were tortuosity (λ), porosity (α) and interstitial volume fraction (v(e)). Our results suggest that the permeability-surface-limited compartment model generally underestimates capillary permeability for capillaries with a radius of 4 μm by factors from ≈0.03 for α=0.04, to ≈ 0.1 for α=0.2, to ≈ 0.5 for α=1.0. An overestimation of actual capillary permeability for capillaries with a radius of 12 μm by a factor of ≥1.3 was found for α=1.0, while α=0.2 yielded an underestimation by a factor of ≈0.3 and α=0.04 by a factor of ≈ 0.03. The interstitial volume fraction, v(e), obtained by the compartment model differed with increasing intercapillary distances and for low vessel permeability, whereas v(e) was found to be estimated approximately accurately for P=0.3 μm/s and P=3.3 μm/s for vessel distances <100 μm. Copyright © 2011 Elsevier Inc. All rights reserved.

  5. DISTING: A web application for fast algorithmic computation of alternative indistinguishable linear compartmental models.

    PubMed

    Davidson, Natalie R; Godfrey, Keith R; Alquaddoomi, Faisal; Nola, David; DiStefano, Joseph J

    2017-05-01

    We describe and illustrate use of DISTING, a novel web application for computing alternative structurally identifiable linear compartmental models that are input-output indistinguishable from a postulated linear compartmental model. Several computer packages are available for analysing the structural identifiability of such models, but DISTING is the first to be made available for assessing indistinguishability. The computational algorithms embedded in DISTING are based on advanced versions of established geometric and algebraic properties of linear compartmental models, embedded in a user-friendly graphic model user interface. Novel computational tools greatly speed up the overall procedure. These include algorithms for Jacobian matrix reduction, submatrix rank reduction, and parallelization of candidate rank computations in symbolic matrix analysis. The application of DISTING to three postulated models with respectively two, three and four compartments is given. The 2-compartment example is used to illustrate the indistinguishability problem; the original (unidentifiable) model is found to have two structurally identifiable models that are indistinguishable from it. The 3-compartment example has three structurally identifiable indistinguishable models. It is found from DISTING that the four-compartment example has five structurally identifiable models indistinguishable from the original postulated model. This example shows that care is needed when dealing with models that have two or more compartments which are neither perturbed nor observed, because the numbering of these compartments may be arbitrary. DISTING is universally and freely available via the Internet. It is easy to use and circumvents tedious and complicated algebraic analysis previously done by hand. Copyright © 2017 Elsevier B.V. All rights reserved.

  6. The pseudo-compartment method for coupling partial differential equation and compartment-based models of diffusion.

    PubMed

    Yates, Christian A; Flegg, Mark B

    2015-05-06

    Spatial reaction-diffusion models have been employed to describe many emergent phenomena in biological systems. The modelling technique most commonly adopted in the literature implements systems of partial differential equations (PDEs), which assumes there are sufficient densities of particles that a continuum approximation is valid. However, owing to recent advances in computational power, the simulation and therefore postulation, of computationally intensive individual-based models has become a popular way to investigate the effects of noise in reaction-diffusion systems in which regions of low copy numbers exist. The specific stochastic models with which we shall be concerned in this manuscript are referred to as 'compartment-based' or 'on-lattice'. These models are characterized by a discretization of the computational domain into a grid/lattice of 'compartments'. Within each compartment, particles are assumed to be well mixed and are permitted to react with other particles within their compartment or to transfer between neighbouring compartments. Stochastic models provide accuracy, but at the cost of significant computational resources. For models that have regions of both low and high concentrations, it is often desirable, for reasons of efficiency, to employ coupled multi-scale modelling paradigms. In this work, we develop two hybrid algorithms in which a PDE in one region of the domain is coupled to a compartment-based model in the other. Rather than attempting to balance average fluxes, our algorithms answer a more fundamental question: 'how are individual particles transported between the vastly different model descriptions?' First, we present an algorithm derived by carefully redefining the continuous PDE concentration as a probability distribution. While this first algorithm shows very strong convergence to analytical solutions of test problems, it can be cumbersome to simulate. Our second algorithm is a simplified and more efficient implementation of the first, it is derived in the continuum limit over the PDE region alone. We test our hybrid methods for functionality and accuracy in a variety of different scenarios by comparing the averaged simulations with analytical solutions of PDEs for mean concentrations. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  7. Coupling volume-excluding compartment-based models of diffusion at different scales: Voronoi and pseudo-compartment approaches

    PubMed Central

    Taylor, P. R.; Baker, R. E.; Simpson, M. J.; Yates, C. A.

    2016-01-01

    Numerous processes across both the physical and biological sciences are driven by diffusion. Partial differential equations are a popular tool for modelling such phenomena deterministically, but it is often necessary to use stochastic models to accurately capture the behaviour of a system, especially when the number of diffusing particles is low. The stochastic models we consider in this paper are ‘compartment-based’: the domain is discretized into compartments, and particles can jump between these compartments. Volume-excluding effects (crowding) can be incorporated by blocking movement with some probability. Recent work has established the connection between fine- and coarse-grained models incorporating volume exclusion, but only for uniform lattices. In this paper, we consider non-uniform, hybrid lattices that incorporate both fine- and coarse-grained regions, and present two different approaches to describe the interface of the regions. We test both techniques in a range of scenarios to establish their accuracy, benchmarking against fine-grained models, and show that the hybrid models developed in this paper can be significantly faster to simulate than the fine-grained models in certain situations and are at least as fast otherwise. PMID:27383421

  8. Endoplasmic reticulum-Golgi intermediate compartment protein 3 knockdown suppresses lung cancer through endoplasmic reticulum stress-induced autophagy.

    PubMed

    Hong, Seong-Ho; Chang, Seung-Hee; Cho, Kyung-Cho; Kim, Sanghwa; Park, Sungjin; Lee, Ah Young; Jiang, Hu-Lin; Kim, Hyeon-Jeong; Lee, Somin; Yu, Kyeong-Nam; Seo, Hwi Won; Chae, Chanhee; Kim, Kwang Pyo; Park, Jongsun; Cho, Myung-Haing

    2016-10-04

    Trafficking from the endoplasmic reticulum (ER) to the Golgi apparatus is elevated in cancer cells. Therefore, proteins of the ER-Golgi intermediate compartment (ERGIC) attract significant attention as targets for cancer treatment. Enhanced cancer cell growth and epithelial-mesenchymal transition by ERGICs correlates with poor-prognosis of lung cancer. This prompted us to assess whether knockdown of ERGIC3 may decrease lung cancer growth. To test the hypothesis, the effects of ERGIC3 short hairpin RNA (shERGIC3) on ER stress-induced cell death and lung tumorigenesis were investigated both in vitro and in vivo. Knockdown of ERGIC3 led to ER stress-induced autophagic cell death and suppression of proliferation in the A549 human lung cancer cell-line. Moreover, non-invasive aerosol-delivery of shERGIC3 using the biocompatible carrier glycerol propoxylate triacrylate and spermine (GPT-SPE) inhibited lung tumorigenesis in the K-rasLA1 murine model of lung cancer. Our data suggest that suppression of ERGIC3 could provide a framework for the development of effective lung cancer therapies.

  9. Chylomicron metabolism in rats: kinetic modeling indicates that the particles remain at endothelial sites for minutes[S

    PubMed Central

    Hultin, Magnus; Savonen, Roger; Chevreuil, Olivier; Olivecrona, Thomas

    2013-01-01

    Chylomicrons labeled in vivo with 14C-oleic acid (primarily in triglycerides, providing a tracer for lipolysis) and 3H-retinol (primarily in ester form, providing a tracer for the core lipids) were injected into rats. Radioactivity in tissues was followed at a series of times up to 40 min and the data were analyzed by compartmental modeling. For heart-like tissues it was necessary to allow the chylomicrons to enter into a compartment where lipolysis is rapid and then transfer to a second compartment where lipolysis is slower. The particles remained in these compartments for minutes and when they returned to blood they had reduced affinity for binding in the tissue. In contrast, the data for liver could readily be fitted with a single compartment for native and lipolyzed chylomicrons in blood, and there was no need for a pathway back to blood. A composite model was built from the individual tissue models. This whole-body model could simultaneously fit all data for both fed and fasted rats and allowed estimation of fluxes and residence times in the four compartments; native and lipolyzed chylomicrons (“remnants”) in blood, and particles in the tissue compartments where lipolysis is rapid and slow, respectively. PMID:23922383

  10. Network signatures of nuclear and cytoplasmic density alterations in a model of pre and postmetastatic colorectal cancer

    NASA Astrophysics Data System (ADS)

    Damania, Dhwanil; Subramanian, Hariharan; Backman, Vadim; Anderson, Eric C.; Wong, Melissa H.; McCarty, Owen J. T.; Phillips, Kevin G.

    2014-01-01

    Cells contributing to the pathogenesis of cancer possess cytoplasmic and nuclear structural alterations that accompany their aberrant genetic, epigenetic, and molecular perturbations. Although it is known that architectural changes in primary and metastatic tumor cells can be quantified through variations in cellular density at the nanometer and micrometer spatial scales, the interdependent relationships among nuclear and cytoplasmic density as a function of tumorigenic potential has not been thoroughly investigated. We present a combined optical approach utilizing quantitative phase microscopy and partial wave spectroscopic microscopy to perform parallel structural characterizations of cellular architecture. Using the isogenic SW480 and SW620 cell lines as a model of pre and postmetastatic transition in colorectal cancer, we demonstrate that nuclear and cytoplasmic nanoscale disorder, micron-scale dry mass content, mean dry mass density, and shape metrics of the dry mass density histogram are uniquely correlated within and across different cellular compartments for a given cell type. The correlations of these physical parameters can be interpreted as networks whose nodal importance and level of connection independence differ according to disease stage. This work demonstrates how optically derived biophysical parameters are linked within and across different cellular compartments during the architectural orchestration of the metastatic phenotype.

  11. Sorafenib Dose Recommendation in Acute Myeloid Leukemia Based on Exposure-FLT3 Relationship.

    PubMed

    Liu, Tao; Ivaturi, Vijay; Sabato, Philip; Gobburu, Jogarao V S; Greer, Jacqueline M; Wright, John J; Smith, B Douglas; Pratz, Keith W; Rudek, Michelle A

    2018-04-27

    Sorafenib administered at the approved dose continuously is not tolerated long-term in patients with acute myeloid leukemia (AML). The purpose of this study was to optimize the dosing regimen by characterizing the sorafenib exposure-response relationship in patients with AML. A one-compartment model with a transit absorption compartment and enterohepatic recirculation described the exposure. The relationship between sorafenib exposure and target modulation of kinase targets (FMS-like tyrosine kinase 3 (FLT3)-ITD and extracellular signal-regulated kinase (ERK)) were described by an inhibitory maximum effect (E max ) model. Sorafenib could inhibit FLT3-ITD activity by 100% with an IC 50 of 69.3 ng/mL and ERK activity by 84% with an IC 50 of 85.7 ng/mL (both adjusted for metabolite potency). Different dosing regimens utilizing 200 or 400 mg at varying frequencies were simulated based on the exposure-response relationship. Simulations demonstrate that a 200 mg twice daily (b.i.d.) dosing regimen showed similar FLT3-ITD and ERK inhibitory activity compared with 400 mg b.i.d. and is recommended in further clinical trials in patients with AML. © 2018 The Authors. Clinical and Translational Science published by Wiley Periodicals, Inc. on behalf of American Society for Clinical Pharmacology and Therapeutics.

  12. SimpleBox 4.0: Improving the model while keeping it simple….

    PubMed

    Hollander, Anne; Schoorl, Marian; van de Meent, Dik

    2016-04-01

    Chemical behavior in the environment is often modeled with multimedia fate models. SimpleBox is one often-used multimedia fate model, firstly developed in 1986. Since then, two updated versions were published. Based on recent scientific developments and experience with SimpleBox 3.0, a new version of SimpleBox was developed and is made public here: SimpleBox 4.0. In this new model, eight major changes were implemented: removal of the local scale and vegetation compartments, addition of lake compartments and deep ocean compartments (including the thermohaline circulation), implementation of intermittent rain instead of drizzle and of depth dependent soil concentrations, adjustment of the partitioning behavior for organic acids and bases as well as of the value for enthalpy of vaporization. In this paper, the effects of the model changes in SimpleBox 4.0 on the predicted steady-state concentrations of chemical substances were explored for different substance groups (neutral organic substances, acids, bases, metals) in a standard emission scenario. In general, the largest differences between the predicted concentrations in the new and the old model are caused by the implementation of layered ocean compartments. Undesirable high model complexity caused by vegetation compartments and a local scale were removed to enlarge the simplicity and user friendliness of the model. Copyright © 2016 Elsevier Ltd. All rights reserved.

  13. The FieldTrip-SimBio pipeline for EEG forward solutions.

    PubMed

    Vorwerk, Johannes; Oostenveld, Robert; Piastra, Maria Carla; Magyari, Lilla; Wolters, Carsten H

    2018-03-27

    Accurately solving the electroencephalography (EEG) forward problem is crucial for precise EEG source analysis. Previous studies have shown that the use of multicompartment head models in combination with the finite element method (FEM) can yield high accuracies both numerically and with regard to the geometrical approximation of the human head. However, the workload for the generation of multicompartment head models has often been too high and the use of publicly available FEM implementations too complicated for a wider application of FEM in research studies. In this paper, we present a MATLAB-based pipeline that aims to resolve this lack of easy-to-use integrated software solutions. The presented pipeline allows for the easy application of five-compartment head models with the FEM within the FieldTrip toolbox for EEG source analysis. The FEM from the SimBio toolbox, more specifically the St. Venant approach, was integrated into the FieldTrip toolbox. We give a short sketch of the implementation and its application, and we perform a source localization of somatosensory evoked potentials (SEPs) using this pipeline. We then evaluate the accuracy that can be achieved using the automatically generated five-compartment hexahedral head model [skin, skull, cerebrospinal fluid (CSF), gray matter, white matter] in comparison to a highly accurate tetrahedral head model that was generated on the basis of a semiautomatic segmentation with very careful and time-consuming manual corrections. The source analysis of the SEP data correctly localizes the P20 component and achieves a high goodness of fit. The subsequent comparison to the highly detailed tetrahedral head model shows that the automatically generated five-compartment head model performs about as well as a highly detailed four-compartment head model (skin, skull, CSF, brain). This is a significant improvement in comparison to a three-compartment head model, which is frequently used in praxis, since the importance of modeling the CSF compartment has been shown in a variety of studies. The presented pipeline facilitates the use of five-compartment head models with the FEM for EEG source analysis. The accuracy with which the EEG forward problem can thereby be solved is increased compared to the commonly used three-compartment head models, and more reliable EEG source reconstruction results can be obtained.

  14. A Short-Term Population Model of the Suicide Risk: The Case of Spain.

    PubMed

    De la Poza, Elena; Jódar, Lucas

    2018-06-14

    A relevant proportion of deaths by suicide have been attributed to other causes that produce the number of suicides remains hidden. The existence of a hidden number of cases is explained by the nature of the problem. Problems like this involve violence, and produce fear and social shame in victims' families. The existence of violence, fear and social shame experienced by victims favours a considerable number of suicides, identified as accidents or natural deaths. This paper proposes a short time discrete compartmental mathematical model to measure the suicidal risk for the case of Spain. The compartment model classifies and quantifies the amount of the Spanish population within the age intervals (16, 78) by their degree of suicide risk and their changes over time. Intercompartmental transits are due to the combination of quantitative and qualitative factors. Results are computed and simulations are performed to analyze the sensitivity of the model under uncertain coefficients.

  15. Cross-disciplinary links in environmental systems science: Current state and claimed needs identified in a meta-review of process models.

    PubMed

    Ayllón, Daniel; Grimm, Volker; Attinger, Sabine; Hauhs, Michael; Simmer, Clemens; Vereecken, Harry; Lischeid, Gunnar

    2018-05-01

    Terrestrial environmental systems are characterised by numerous feedback links between their different compartments. However, scientific research is organized into disciplines that focus on processes within the respective compartments rather than on interdisciplinary links. Major feedback mechanisms between compartments might therefore have been systematically overlooked so far. Without identifying these gaps, initiatives on future comprehensive environmental monitoring schemes and experimental platforms might fail. We performed a comprehensive overview of feedbacks between compartments currently represented in environmental sciences and explores to what degree missing links have already been acknowledged in the literature. We focused on process models as they can be regarded as repositories of scientific knowledge that compile findings of numerous single studies. In total, 118 simulation models from 23 model types were analysed. Missing processes linking different environmental compartments were identified based on a meta-review of 346 published reviews, model intercomparison studies, and model descriptions. Eight disciplines of environmental sciences were considered and 396 linking processes were identified and ascribed to the physical, chemical or biological domain. There were significant differences between model types and scientific disciplines regarding implemented interdisciplinary links. The most wide-spread interdisciplinary links were between physical processes in meteorology, hydrology and soil science that drive or set the boundary conditions for other processes (e.g., ecological processes). In contrast, most chemical and biological processes were restricted to links within the same compartment. Integration of multiple environmental compartments and interdisciplinary knowledge was scarce in most model types. There was a strong bias of suggested future research foci and model extensions towards reinforcing existing interdisciplinary knowledge rather than to open up new interdisciplinary pathways. No clear pattern across disciplines exists with respect to suggested future research efforts. There is no evidence that environmental research would clearly converge towards more integrated approaches or towards an overarching environmental systems theory. Copyright © 2017 Elsevier B.V. All rights reserved.

  16. Evidence from a Mouse Model That Epithelial Cell Migration and Mesenchymal-Epithelial Transition Contribute to Rapid Restoration of Uterine Tissue Integrity during Menstruation

    PubMed Central

    Cousins, Fiona L.; Murray, Alison; Esnal, Arantza; Gibson, Douglas A.; Critchley, Hilary O. D.; Saunders, Philippa T. K.

    2014-01-01

    Background In women dynamic changes in uterine tissue architecture occur during each menstrual cycle. Menses, characterised by the shedding of the upper functional layer of the endometrium, is the culmination of a cascade of irreversible changes in tissue function including stromal decidualisation, inflammation and production of degradative enzymes. The molecular mechanisms that contribute to the rapid restoration of tissue homeostasis at time of menses are poorly understood. Methodology A modified mouse model of menses was developed to focus on the events occurring within the uterine lining during endometrial shedding/repair. Decidualisation, vaginal bleeding, tissue architecture and cell proliferation were evaluated at 4, 8, 12, and 24 hours after progesterone (P4) withdrawal; mice received a single injection of bromodeoxyuridine (BrdU) 90 mins before culling. Expression of genes implicated in the regulation of mesenchymal to epithelial transition (MET) was determined using a RT2 PCR profiler array, qRTPCR and bioinformatic analysis. Principal Findings Mice exhibited vaginal bleeding between 4 and 12 hours after P4 withdrawal, concomitant with detachment of the decidualised cell mass from the basal portion of the endometrial lining. Immunostaining for BrdU and pan cytokeratin revealed evidence of epithelial cell proliferation and migration. Cells that appeared to be in transition from a mesenchymal to an epithelial cell identity were identified within the stromal compartment. Analysis of mRNAs encoding genes expressed exclusively in the epithelial or stromal compartments, or implicated in MET, revealed dynamic changes in expression, consistent with a role for reprogramming of mesenchymal cells so that they could contribute to re-epithelialisation. Conclusions/Significance These studies have provided novel insights into the cellular processes that contribute to re-epithelialisation post-menses implicating both epithelial cell migration and mesenchymal cell differentiation in restoration of an intact epithelial cell layer. These insights may inform development of new therapies to induce rapid healing in the endometrium and other tissues and offer hope to women who suffer from heavy menstrual bleeding. PMID:24466063

  17. Probabilistic pharmacokinetic models of decompression sickness in humans, part 1: Coupled perfusion-limited compartments.

    PubMed

    Murphy, F Gregory; Hada, Ethan A; Doolette, David J; Howle, Laurens E

    2017-07-01

    Decompression sickness (DCS) is a disease caused by gas bubbles forming in body tissues following a reduction in ambient pressure, such as occurs in scuba diving. Probabilistic models for quantifying the risk of DCS are typically composed of a collection of independent, perfusion-limited theoretical tissue compartments which describe gas content or bubble volume within these compartments. It has been previously shown that 'pharmacokinetic' gas content models, with compartments coupled in series, show promise as predictors of the incidence of DCS. The mechanism of coupling can be through perfusion or diffusion. This work examines the application of five novel pharmacokinetic structures with compartments coupled by perfusion to the prediction of the probability and time of onset of DCS in humans. We optimize these models against a training set of human dive trial data consisting of 4335 exposures with 223 DCS cases. Further, we examine the extrapolation quality of the models on an additional set of human dive trial data consisting of 3140 exposures with 147 DCS cases. We find that pharmacokinetic models describe the incidence of DCS for single air bounce dives better than a single-compartment, perfusion-limited model. We further find the U.S. Navy LEM-NMRI98 is a better predictor of DCS risk for the entire training set than any of our pharmacokinetic models. However, one of the pharmacokinetic models we consider, the CS2T3 model, is a better predictor of DCS risk for single air bounce dives and oxygen decompression dives. Additionally, we find that LEM-NMRI98 outperforms CS2T3 on the extrapolation data. Copyright © 2017 Elsevier Ltd. All rights reserved.

  18. Pharmacokinetics of Isoniazid, Pyrazinamide, and Ethambutol in Newly Diagnosed Pulmonary TB Patients in Tanzania

    PubMed Central

    Chigutsa, Emmanuel; Faurholt-Jepsen, Daniel; PrayGod, George; Range, Nyagosya; Castel, Sandra; Wiesner, Lubbe; Hagen, Christian Munch; Christiansen, Michael; Changalucha, John; McIlleron, Helen; Friis, Henrik; Andersen, Aase Bengaard

    2015-01-01

    Exposure to lower-than-therapeutic levels of anti-tuberculosis drugs is likely to cause selection of resistant strains of Mycobacterium tuberculosis and treatment failure. The first-line anti-tuberculosis (TB) regimen consists of rifampicin, isoniazid, pyrazinamide, and ethambutol, and correct management reduces risk of TB relapse and development of drug resistance. In this study we aimed to investigate the effect of standard of care plus nutritional supplementation versus standard care on the pharmacokinetics of isoniazid, pyrazinamide and ethambutol among sputum smear positive TB patients with and without HIV. In a clinical trial in 100 Tanzanian TB patients, with or without HIV infection, drug concentrations were determined at 1 week and 2 months post initiation of anti-TB medication. Data was analysed using population pharmacokinetic modelling. The effect of body size was described using allometric scaling, and the effects of nutritional supplementation, HIV, age, sex, CD4+ count, weight-adjusted dose, NAT2 genotype, and time on TB treatment were investigated. The kinetics of all drugs was well characterised using first-order elimination and transit compartment absorption, with isoniazid and ethambutol described by two-compartment disposition models, and pyrazinamide by a one-compartment model. Patients with a slow NAT2 genotype had higher isoniazid exposure and a lower estimate of oral clearance (15.5 L/h) than rapid/intermediate NAT2 genotype (26.1 L/h). Pyrazinamide clearance had an estimated typical value of 3.32 L/h, and it was found to increase with time on treatment, with a 16.3% increase after the first 2 months of anti-TB treatment. The typical clearance of ethambutol was estimated to be 40.7 L/h, and was found to decrease with age, at a rate of 1.41% per year. Neither HIV status nor nutritional supplementations were found to affect the pharmacokinetics of these drugs in our cohort of patients. PMID:26501782

  19. [Application of three compartment model and response surface model to clinical anesthesia using Microsoft Excel].

    PubMed

    Abe, Eiji; Abe, Mari

    2011-08-01

    With the spread of total intravenous anesthesia, clinical pharmacology has become more important. We report Microsoft Excel file applying three compartment model and response surface model to clinical anesthesia. On the Microsoft Excel sheet, propofol, remifentanil and fentanyl effect-site concentrations are predicted (three compartment model), and probabilities of no response to prodding, shaking, surrogates of painful stimuli and laryngoscopy are calculated using predicted effect-site drug concentration. Time-dependent changes in these calculated values are shown graphically. Recent development in anesthetic drug interaction studies are remarkable, and its application to clinical anesthesia with this Excel file is simple and helpful for clinical anesthesia.

  20. Two-Compartment Pharmacokinetic Models for Chemical Engineers

    ERIC Educational Resources Information Center

    Kanneganti, Kumud; Simon, Laurent

    2011-01-01

    The transport of potassium permanganate between two continuous-stirred vessels was investigated to help chemical and biomedical engineering students understand two-compartment pharmacokinetic models. Concepts of modeling, mass balance, parameter estimation and Laplace transform were applied to the two-unit process. A good agreement was achieved…

  1. Multicompartmental model for iodide, thyroxine, and triiodothyronine metabolism in normal and spontaneously hyperthyroid cats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Hays, M.T.; Broome, M.R.; Turrel, J.M.

    A comprehensive multicompartmental kinetic model was developed to account for the distribution and metabolism of simultaneously injected radioactive iodide (iodide*), T3 (T3*), and T4 (T4*) in six normal and seven spontaneously hyperthyroid cats. Data from plasma samples (analyzed by HPLC), urine, feces, and thyroid accumulation were incorporated into the model. The submodels for iodide*, T3*, and T4* all included both a fast and a slow exchange compartment connecting with the plasma compartment. The best-fit iodide* model also included a delay compartment, presumed to be pooling of gastrosalivary secretions. This delay was 62% longer in the hyperthyroid cats than in themore » euthyroid cats. Unexpectedly, all of the exchange parameters for both T4 and T3 were significantly slowed in hyperthyroidism, possibly because the hyperthyroid cats were older. None of the plasma equivalent volumes of the exchange compartments of iodide*, T3*, or T4* was significantly different in the hyperthyroid cats, although the plasma equivalent volume of the fast T4 exchange compartments were reduced. Secretion of recycled T4* from the thyroid into the plasma T4* compartment was essential to model fit, but its quantity could not be uniquely identified in the absence of multiple thyroid data points. Thyroid secretion of T3* was not detectable. Comparing the fast and slow compartments, there was a shift of T4* deiodination into the fast exchange compartment in hyperthyroidism. Total body mean residence times (MRTs) of iodide* and T3* were not affected by hyperthyroidism, but mean T4* MRT was decreased 23%. Total fractional T4 to T3 conversion was unchanged in hyperthyroidism, although the amount of T3 produced by this route was increased nearly 5-fold because of higher concentrations of donor stable T4.« less

  2. Rescue of the mature B cell compartment in BAFF-deficient mice by treatment with recombinant Fc-BAFF.

    PubMed

    Swee, Lee Kim; Tardivel, Aubry; Schneider, Pascal; Rolink, Antonius

    2010-06-15

    BAFF deficiency in mice impairs B cell development beyond the transitional stage 1 in the spleen and thus severely reduces the size of follicular and marginal zone B cell compartments. Moreover, humoral immune responses in these mice are dramatically impaired. We now addressed the question whether the decrease in mature B cell numbers and the reduced humoral immune responses in BAFF-deficient mice could be overcome by the injection of recombinant BAFF. We therefore engineered a recombinant protein containing the human IgG1 Fc moiety fused to receptor-binding domain of human BAFF (Fc-BAFF). At 1 week after the second injection of this fusion protein a complete rescue of the marginal zone B cell compartment and a 50% rescue of the follicular B cell compartment was observed. Moreover these mice mounted a T cell-dependent humoral immune response indistinguishable from wild-type mice. By day 14 upon arrest of Fc-BAFF treatment mature B cell numbers in the blood dropped by 50%, indicating that the life span of mature B cells in the absence of BAFF is 14 days or less. Collectively these findings demonstrate that injection of Fc-BAFF in BAFF-deficient mice results in a temporary rescue of a functional mature B cell compartment. Copyright (c) 2010 Elsevier B.V. All rights reserved.

  3. Computation Molecular Kinetics Model of HZE Induced Cell Cycle Arrest

    NASA Technical Reports Server (NTRS)

    Cucinotta, Francis A.; Ren, Lei

    2004-01-01

    Cell culture models play an important role in understanding the biological effectiveness of space radiation. High energy and charge (HZE) ions produce prolonged cell cycle arrests at the G1/S and G2/M transition points in the cell cycle. A detailed description of these phenomena is needed to integrate knowledge of the expression of DNA damage in surviving cells, including the determination of relative effectiveness factors between different types of radiation that produce differential types of DNA damage and arrest durations. We have developed a hierarchical kinetics model that tracks the distribution of cells in various cell phase compartments (early G1, late G1, S, G2, and M), however with transition rates that are controlled by rate-limiting steps in the kinetics of cyclin-cdk's interactions with their families of transcription factors and inhibitor molecules. The coupling of damaged DNA molecules to the downstream cyclin-cdk inhibitors is achieved through a description of the DNA-PK and ATM signaling pathways. For HZE irradiations we describe preliminary results, which introduce simulation of the stochastic nature of the number of direct particle traversals per cell in the modulation of cyclin-cdk and cell cycle population kinetics. Comparison of the model to data for fibroblast cells irradiated photons or HZE ions are described.

  4. Population Pharmacokinetics of Rifapentine and Desacetyl Rifapentine in Healthy Volunteers: Nonlinearities in Clearance and Bioavailability

    PubMed Central

    Lu, Yanhui; Bliven-Sizemore, Erin; Weiner, Marc; Nuermberger, Eric; Burman, William; Dorman, Susan E.; Dooley, Kelly E.

    2014-01-01

    Rifapentine is under active investigation as a potent drug that may help shorten the tuberculosis (TB) treatment duration. A previous rifapentine dose escalation study with daily dosing indicated a possible decrease in bioavailability as the dose increased and an increase in clearance over time for rifapentine and its active metabolite, desacetyl rifapentine. This study aimed to assess the effects of increasing doses on rifapentine absorption and bioavailability and to evaluate the clearance changes over 14 days. A population analysis was performed with nonlinear mixed-effects modeling. Absorption, time-varying clearance, bioavailability, and empirical and semimechanistic autoinduction models were investigated. A one-compartment model linked to a transit compartment absorption model best described the data. The bioavailability of rifapentine decreased linearly by 2.5% for each 100-mg increase in dose. The autoinduction model suggested a dose-independent linear increase in clearance of the parent drug and metabolite over time from 1.2 and 3.1 liters · h−1, respectively, after a single dose to 2.2 and 5.0 liters · h−1, respectively, after 14 once-daily doses, with no plateau being reached by day 14. In clinical trial simulations using the final model, rifapentine demonstrated less-than-dose-proportional pharmacokinetics, but there was no plateau in exposures over the dose range tested (450 to 1,800 mg), and divided dosing increased exposures significantly. Thus, the proposed compartmental model incorporating daily dosing of rifapentine over a wide range of doses and time-related changes in bioavailability and clearance provides a useful tool for estimation of drug exposure that can be used to optimize rifapentine dosing for TB treatment. (This study has been registered at ClinicalTrials.gov under registration no. NCT01162486.) PMID:24614383

  5. Understanding the drug release mechanism from a montmorillonite matrix and its binary mixture with a hydrophilic polymer using a compartmental modelling approach

    NASA Astrophysics Data System (ADS)

    Choiri, S.; Ainurofiq, A.

    2018-03-01

    Drug release from a montmorillonite (MMT) matrix is a complex mechanism controlled by swelling mechanism of MMT and an interaction of drug and MMT. The aim of this research was to explain a suitable model of the drug release mechanism from MMT and its binary mixture with a hydrophilic polymer in the controlled release formulation based on a compartmental modelling approach. Theophylline was used as a drug model and incorporated into MMT and a binary mixture with hydroxyl propyl methyl cellulose (HPMC) as a hydrophilic polymer, by a kneading method. The dissolution test was performed and the modelling of drug release was assisted by a WinSAAM software. A 2 model was purposed based on the swelling capability and basal spacing of MMT compartments. The model evaluation was carried out to goodness of fit and statistical parameters and models were validated by a cross-validation technique. The drug release from MMT matrix regulated by a burst release mechanism of unloaded drug, swelling ability, basal spacing of MMT compartment, and equilibrium between basal spacing and swelling compartments. Furthermore, the addition of HPMC in MMT system altered the presence of swelling compartment and equilibrium between swelling and basal spacing compartment systems. In addition, a hydrophilic polymer reduced the burst release mechanism of unloaded drug.

  6. Experimental and statistical analyses to characterize in-vehicle fine particulate matter behavior inside public transit buses operating on B20-grade biodiesel fuel

    NASA Astrophysics Data System (ADS)

    Vijayan, Abhilash; Kumar, Ashok

    2010-11-01

    This paper presents results from an in-vehicle air quality study of public transit buses in Toledo, Ohio, involving continuous monitoring, and experimental and statistical analyses to understand in-vehicle particulate matter (PM) behavior inside buses operating on B20-grade biodiesel fuel. The study also focused on evaluating the effects of vehicle's fuel type, operating periods, operation status, passenger counts, traffic conditions, and the seasonal and meteorological variation on particulates with aerodynamic diameter less than 1 micron (PM 1.0). The study found that the average PM 1.0 mass concentrations in B20-grade biodiesel-fueled bus compartments were approximately 15 μg m -3, while PM 2.5 and PM 10 concentration averages were approximately 19 μg m -3 and 37 μg m -3, respectively. It was also observed that average hourly concentration trends of PM 1.0 and PM 2.5 followed a "μ-shaped" pattern during transit hours. Experimental analyses revealed that the in-vehicle PM 1.0 mass concentrations were higher inside diesel-fueled buses (10.0-71.0 μg m -3 with a mean of 31.8 μg m -3) as compared to biodiesel buses (3.3-33.5 μg m -3 with a mean of 15.3 μg m -3) when the windows were kept open. Vehicle idling conditions and open door status were found to facilitate smaller particle concentrations inside the cabin, while closed door facilitated larger particle concentrations suggesting that smaller particles were originating outside the vehicle and larger particles were formed within the cabin, potentially from passenger activity. The study also found that PM 1.0 mass concentrations at the back of bus compartment (5.7-39.1 μg m -3 with a mean of 28.3 μg m -3) were higher than the concentrations in the front (5.7-25.9 μg m -3 with a mean of 21.9 μg m -3), and the mass concentrations inside the bus compartment were generally 30-70% lower than the just-outside concentrations. Further, bus route, window position, and time of day were found to affect the in-vehicle PM concentrations significantly. Overall, the in-vehicle PM 1.0 concentrations inside the buses operating on B20-grade biodiesel ranged from 0.7 μg m -3 to 243 μg m -3, with a median of 11.6 μg m -3. Statistical models developed to study the effects of vehicle operation and ambient conditions on in-vehicle PM concentrations suggested that while open door status was the most important influencing variable for finer particles and higher passenger activity resulted in higher coarse particles concentrations inside the vehicle compartments, ambient PM concentrations contributed to all PM fractions inside the bus irrespective of particle size.

  7. An earthquake instability model based on faults containing high fluid-pressure compartments

    USGS Publications Warehouse

    Lockner, D.A.; Byerlee, J.D.

    1995-01-01

    It has been proposed that large strike-slip faults such as the San Andreas contain water in seal-bounded compartments. Arguments based on heat flow and stress orientation suggest that in most of the compartments, the water pressure is so high that the average shear strength of the fault is less than 20 MPa. We propose a variation of this basic model in which most of the shear stress on the fault is supported by a small number of compartments where the pore pressure is relatively low. As a result, the fault gouge in these compartments is compacted and lithified and has a high undisturbed strength. When one of these locked regions fails, the system made up of the neighboring high and low pressure compartments can become unstable. Material in the high fluid pressure compartments is initially underconsolidated since the low effective confining pressure has retarded compaction. As these compartments are deformed, fluid pressure remains nearly unchanged so that they offer little resistance to shear. The low pore pressure compartments, however, are overconsolidated and dilate as they are sheared. Decompression of the pore fluid in these compartments lowers fluid pressure, increasing effective normal stress and shear strength. While this effect tends to stabilize the fault, it can be shown that this dilatancy hardening can be more than offset by displacement weakening of the fault (i.e., the drop from peak to residual strength). If the surrounding rock mass is sufficiently compliant to produce an instability, slip will propagate along the fault until the shear fracture runs into a low-stress region. Frictional heating and the accompanying increase in fluid pressure that are suggested to occur during shearing of the fault zone will act as additional destabilizers. However, significant heating occurs only after a finite amount of slip and therefore is more likely to contribute to the energetics of rupture propagation than to the initiation of the instability. We present results of a one-dimensional dynamic Burridge-Knopoff-type model to demonstrate various aspects of the fluid-assisted fault instability described above. In the numerical model, the fault is represented by a series of blocks and springs, with fault rheology expressed by static and dynamic friction. In addition, the fault surface of each block has associated with it pore pressure, porosity and permeability. All of these variables are allowed to evolve with time, resulting in a wide range of phenomena related to fluid diffusion, dilatancy, compaction and heating. These phenomena include creep events, diffusion-controlled precursors, triggered earthquakes, foreshocks, aftershocks, and multiple earthquakes. While the simulations have limitations inherent to 1-D fault models, they demonstrate that the fluid compartment model can, in principle, provide the rich assortment of phenomena that have been associated with earthquakes. ?? 1995 Birkha??user Verlag.

  8. [Porous matrix and primary-cell culture: a shared concept for skin and cornea tissue engineering].

    PubMed

    Auxenfans, C; Builles, N; Andre, V; Lequeux, C; Fievet, A; Rose, S; Braye, F-M; Fradette, J; Janin-Manificat, H; Nataf, S; Burillon, C; Damour, O

    2009-06-01

    Skin and cornea both feature an epithelium firmly anchored to its underlying connective compartment: dermis for skin and stroma for cornea. A breakthrough in tissue engineering occurred in 1975 when skin stem cells were successfully amplified in culture by Rheinwald and Green. Since 1981, they are used in the clinical arena as cultured epidermal autografts for the treatment of patients with extensive burns. A similar technique has been later adapted to the amplification of limbal-epithelial cells. The basal layer of the limbal epithelium is located in a transitional zone between the cornea and the conjunctiva and contains the stem cell population of the corneal epithelium called limbal-stem cells (LSC). These cells maintain the proper renewal of the corneal epithelium by generating transit-amplifying cells that migrate from the basal layer of the limbus towards the basal layer of the cornea. Tissue-engineering protocols enable the reconstruction of three-dimensional (3D) complex tissues comprising both an epithelium and its underlying connective tissue. Our in vitro reconstruction model is based on the combined use of cells and of a natural collagen-based biodegradable polymer to produce the connective-tissue compartment. This porous substrate acts as a scaffold for fibroblasts, thereby, producing a living dermal/stromal equivalent, which once epithelialized results into a reconstructed skin/hemicornea. This paper presents the reconstruction of surface epithelia for the treatment of pathological conditions of skin and cornea and the development of 3D tissue-engineered substitutes based on a collagen-GAG-chitosan matrix for the regeneration of skin and cornea.

  9. Rugged Energy Landscapes in Multiphase Porous Media Flow: A Discrete-Domain Description

    NASA Astrophysics Data System (ADS)

    Cueto-Felgueroso, L.; Juanes, R.

    2015-12-01

    Immiscible displacements in porous media involve a complex sequence of pore-scale events, from the smooth, reversible displacement of interfaces to abrupt interfacial reconfigurations and rapid pore invasion cascades. Discontinuous changes in pressure or saturation have been referred to as Haines jumps, and they emerge as a key mechanism to understand the origin of hysteresis in porous media flow. Hysteresis persists at the many-pore scale: when multiple cycles of drainage and imbibition of a porous sample are conducted, a dense hysteresis diagram emerges. The interpretation of hysteresis as a consequence of irreversible transitions and multistability is at the heart of early hysteresis models, and in recent experiments, and points to an inherently non-equilibrium behavior. For a given volume fraction of fluids occupying the pore space, many stable configurations are possible, due to the tortuous network of nonuniform pores and throats that compose the porous medium, and to complex wetting and capillary transitions. Multistability indicates that porous media systems exhibit rugged energy landscapes, where the system may remain pinned at local energy minima for long times. We address the question of developing a zero-dimensional model that inherits the path-dependence and `'bursty'' behavior of immiscible displacements, and propose a discrete-domain model that captures the role of metastability and local equilibria in the origin of hysteresis. We describe the porous medium and fluid system as a discrete set of weakly connected, multistable compartments, charaterized by a unique free energy function. This description does not depend explicitly on past saturations, turning points, or drainage/imbibition labels. The system behaves hysteretically, and we rationalize its behavior as sweeping a complex metastability diagram, with dissipation arising from discrete switches among metastable branches. The hysteretic behavior of the pressure-saturation curve is controlled by the topography of the energy landscape, through the number of metastable regions of the compartments and characteristic height of the energy barriers separating the different basins. Our model opens the door to fully explore the interplay between hysteresis and fluctuations in multiphase displacements in porous media.

  10. Modelling cell population growth with applications to cancer therapy in human tumour cell lines.

    PubMed

    Basse, Britta; Baguley, Bruce C; Marshall, Elaine S; Wake, Graeme C; Wall, David J N

    2004-01-01

    In this paper we present an overview of the work undertaken to model a population of cells and the effects of cancer therapy. We began with a theoretical one compartment size structured cell population model and investigated its asymptotic steady size distributions (SSDs) (On a cell growth model for plankton, MMB JIMA 21 (2004) 49). However these size distributions are not similar to the DNA (size) distributions obtained experimentally via the flow cytometric analysis of human tumour cell lines (data obtained from the Auckland Cancer Society Research Centre, New Zealand). In our one compartment model, size was a generic term, but in order to obtain realistic steady size distributions we chose size to be DNA content and devised a multi-compartment mathematical model for the cell division cycle where each compartment corresponds to a distinct phase of the cell cycle (J. Math. Biol. 47 (2003) 295). We then incorporated another compartment describing the possible induction of apoptosis (cell death) from mitosis phase (Modelling cell death in human tumour cell lines exposed to anticancer drug paclitaxel, J. Math. Biol. 2004, in press). This enabled us to compare our model to flow cytometric data of a melanoma cell line where the anticancer drug, paclitaxel, had been added. The model gives a dynamic picture of the effects of paclitaxel on the cell cycle. We hope to use the model to describe the effects of other cancer therapies on a number of different cell lines. Copyright 2004 Elsevier Ltd.

  11. Phosphorylation-mediated RNA/peptide complex coacervation as a model for intracellular liquid organelles

    NASA Astrophysics Data System (ADS)

    Aumiller, William M.; Keating, Christine D.

    2016-02-01

    Biological cells are highly organized, with numerous subcellular compartments. Phosphorylation has been hypothesized as a means to control the assembly/disassembly of liquid-like RNA- and protein-rich intracellular bodies, or liquid organelles, that lack delimiting membranes. Here, we demonstrate that charge-mediated phase separation, or complex coacervation, of RNAs with cationic peptides can generate simple model liquid organelles capable of reversibly compartmentalizing biomolecules. Formation and dissolution of these liquid bodies was controlled by changes in peptide phosphorylation state using a kinase/phosphatase enzyme pair. The droplet-generating phase transition responded to modification of even a single serine residue. Electrostatic interactions between the short cationic peptides and the much longer polyanionic RNAs drove phase separation. Coacervates were also formed on silica beads, a primitive model for localization at specific intracellular sites. This work supports phosphoregulation of complex coacervation as a viable mechanism for dynamic intracellular compartmentalization in membraneless organelles.

  12. 3-compartment talaporfin sodium pharmacokinetic model by optimization using fluorescence measurement data from canine skin to estimate the concentration in interstitial space

    NASA Astrophysics Data System (ADS)

    Uno, Yuko; Ogawa, Emiyu; Aiyoshi, Eitaro; Arai, Tsunenori

    2018-02-01

    We constructed the 3-compartment talaporfin sodium pharmacokinetic model for canine by an optimization using the fluorescence measurement data from canine skin to estimate the concentration in the interstitial space. It is difficult to construct the 3-compartment model consisted of plasma, interstitial space, and cell because there is a lack of the dynamic information. Therefore, we proposed the methodology to construct the 3-compartment model using the measured talaporfin sodium skin fluorescence change considering originated tissue part by a histological observation. In a canine animal experiment, the talaporfin sodium concentration time history in plasma was measured by a spectrophotometer with a prepared calibration curve. The time history of talaporfin sodium Q-band fluorescence on left femoral skin of a beagle dog excited by talaporfin sodium Soret-band of 409 nm was measured in vivo by our previously constructed measurement system. The measured skin fluorescence was classified to its source, that is, specific ratio of plasma, interstitial space, and cell. We represented differential rate equations of the talaporfin sodium concentration in plasma, interstitial space, cell. The specific ratios and a converting constant to obtain absolute value of skin concentration were arranged. Minimizing the squared error of the difference between the measured fluorescence data and calculated concentration by the conjugate gradient method in MATLAB, the rate constants in the 3-compartment model were determined. The accuracy of the fitting operation was confirmed with determination coefficient of 0.98. We could construct the 3-compartment pharmacokinetic model for canine using the measured talaporfin sodium fluorescence change from canine skin.

  13. Environmental behaviors and potential ecological risks of heavy metals (Cd, Cr, Cu, Pb, and Zn) in multimedia in an oilfield in China.

    PubMed

    Hu, Yan; Wang, Dazhou; Li, Yu

    2016-07-01

    The environmental behaviors of five heavy metals (Cd, Cr, Cu, Pb, and Zn) in a Chinese oilfield were investigated using a steady-state multimedia aquivalence (SMA) model. The modeling results showed good agreement with the actual measured values, with average residual errors of 0.69, 0.83, 0.35, 0.16, and 0.54 logarithmic units for air, water, soil, sediment, and vegetation compartments, respectively. Model results indicated that most heavy metals were buried in sediment, and that transfers between adjacent compartments were mainly deposition from the water to the sediment compartment (48.59 %) and from the air to the soil compartment (47.74 %) via atmospheric dry/wet deposition. Sediment and soil were the dominant sinks, accounting for 68.80 and 25.26 % of all the heavy metals in the multimedia system, respectively. The potential ecological risks from the five heavy metals in the sediment and soil compartments were assessed by the potential ecological risk index (PERI). The assessment results demonstrate that the heavy metals presented low levels of ecological risk in the sediment compartment, and that Cd was the most significant contributor to the integrated potential ecological risk in the oilfield. The SMA model provided useful simulations of the transport and fate of heavy metals and is a useful tool for ecological risk assessment and contaminated site management.

  14. Body composition in elderly people: effect of criterion estimates on predictive equations

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Baumgartner, R.N.; Heymsfield, S.B.; Lichtman, S.

    1991-06-01

    The purposes of this study were to determine whether there are significant differences between two- and four-compartment model estimates of body composition, whether these differences are associated with aqueous and mineral fractions of the fat-free mass (FFM); and whether the differences are retained in equations for predicting body composition from anthropometry and bioelectric resistance. Body composition was estimated in 98 men and women aged 65-94 y by using a four-compartment model based on hydrodensitometry, {sup 3}H{sub 2}O dilution, and dual-photon absorptiometry. These estimates were significantly different from those obtained by using Siri's two-compartment model. The differences were associated significantly (Pmore » less than 0.0001) with variation in the aqueous fraction of FFM. Equations for predicting body composition from anthropometry and resistance, when calibrated against two-compartment model estimates, retained these systematic errors. Equations predicting body composition in elderly people should be calibrated against estimates from multicompartment models that consider variability in FFM composition.« less

  15. A mathematical model of a recombinant humanized anti-cocaine monoclonal antibody's effects on cocaine pharmacokinetics in mice.

    PubMed

    Wetzel, Hanna N; Zhang, Tongli; Norman, Andrew B

    2017-09-01

    A recombinant humanized anti-cocaine monoclonal antibody (mAb), h2E2, is at an advanced stage of pre-clinical development as an immunotherapy for cocaine abuse. It is hypothesized that h2E2 binds to and sequesters cocaine in the blood. A three-compartment model of the effects of h2E2 on cocaine's distribution was constructed. The model assumes that h2E2 binds to cocaine and that the h2E2-cocaine complex does not enter the brain but distributes between the central and peripheral compartments. Free cocaine is eliminated from both the central and peripheral compartments, and h2E2 and the h2E2-cocaine complex are eliminated from the central compartment only. This model was tested against a new dataset measuring cocaine concentrations in the brain and plasma over 1h in the presence and absence of h2E2. The mAb significantly increased plasma cocaine concentrations with a concomitant significant decrease in brain concentration. Plasma concentrations declined over the 1-hour sampling period in both groups. With a set of parameters within reasonable physiological ranges, the three-compartment model was able to qualitatively and quantitatively simulate the increased plasma concentration in the presence of the antibody and the decreased peak brain concentration in the presence of antibody. Importantly, the model explained the decline in plasma concentrations over time as distribution of the cocaine-h2E2 complex into a peripheral compartment. This model will facilitate the targeting of ideal mAb PK/PD properties thus accelerating the identification of lead candidate anti-drug mAbs. Copyright © 2017 Elsevier Inc. All rights reserved.

  16. Modelling the balance between quiescence and cell death in normal and tumour cell populations.

    PubMed

    Spinelli, Lorenzo; Torricelli, Alessandro; Ubezio, Paolo; Basse, Britta

    2006-08-01

    When considering either human adult tissues (in vivo) or cell cultures (in vitro), cell number is regulated by the relationship between quiescent cells, proliferating cells, cell death and other controls of cell cycle duration. By formulating a mathematical description we see that even small alterations of this relationship may cause a non-growing population to start growing with doubling times characteristic of human tumours. Our model consists of two age structured partial differential equations for the proliferating and quiescent cell compartments. Model parameters are death rates from and transition rates between these compartments. The partial differential equations can be solved for the steady-age distributions, giving the distribution of the cells through the cell cycle, dependent on specific model parameter values. Appropriate formulas can then be derived for various population characteristic quantities such as labelling index, proliferation fraction, doubling time and potential doubling time of the cell population. Such characteristic quantities can be estimated experimentally, although with decreasing precision from in vitro, to in vivo experimental systems and to the clinic. The model can be used to investigate the effects of a single alteration of either quiescence or cell death control on the growth of the whole population and the non-trivial dependence of the doubling time and other observable quantities on particular underlying cell cycle scenarios of death and quiescence. The model indicates that tumour evolution in vivo is a sequence of steady-states, each characterised by particular death and quiescence rate functions. We suggest that a key passage of carcinogenesis is a loss of the communication between quiescence, death and cell cycle machineries, causing a defect in their precise, cell cycle dependent relationship.

  17. Two-compartment modeling of tissue microcirculation revisited.

    PubMed

    Brix, Gunnar; Salehi Ravesh, Mona; Griebel, Jürgen

    2017-05-01

    Conventional two-compartment modeling of tissue microcirculation is used for tracer kinetic analysis of dynamic contrast-enhanced (DCE) computed tomography or magnetic resonance imaging studies although it is well-known that the underlying assumption of an instantaneous mixing of the administered contrast agent (CA) in capillaries is far from being realistic. It was thus the aim of the present study to provide theoretical and computational evidence in favor of a conceptually alternative modeling approach that makes it possible to characterize the bias inherent to compartment modeling and, moreover, to approximately correct for it. Starting from a two-region distributed-parameter model that accounts for spatial gradients in CA concentrations within blood-tissue exchange units, a modified lumped two-compartment exchange model was derived. It has the same analytical structure as the conventional two-compartment model, but indicates that the apparent blood flow identifiable from measured DCE data is substantially overestimated, whereas the three other model parameters (i.e., the permeability-surface area product as well as the volume fractions of the plasma and interstitial distribution space) are unbiased. Furthermore, a simple formula was derived to approximately compute a bias-corrected flow from the estimates of the apparent flow and permeability-surface area product obtained by model fitting. To evaluate the accuracy of the proposed modeling and bias correction method, representative noise-free DCE curves were analyzed. They were simulated for 36 microcirculation and four input scenarios by an axially distributed reference model. As analytically proven, the considered two-compartment exchange model is structurally identifiable from tissue residue data. The apparent flow values estimated for the 144 simulated tissue/input scenarios were considerably biased. After bias-correction, the deviations between estimated and actual parameter values were (11.2 ± 6.4) % (vs. (105 ± 21) % without correction) for the flow, (3.6 ± 6.1) % for the permeability-surface area product, (5.8 ± 4.9) % for the vascular volume and (2.5 ± 4.1) % for the interstitial volume; with individual deviations of more than 20% being the exception and just marginal. Increasing the duration of CA administration only had a statistically significant but opposite effect on the accuracy of the estimated flow (declined) and intravascular volume (improved). Physiologically well-defined tissue parameters are structurally identifiable and accurately estimable from DCE data by the conceptually modified two-compartment model in combination with the bias correction. The accuracy of the bias-corrected flow is nearly comparable to that of the three other (theoretically unbiased) model parameters. As compared to conventional two-compartment modeling, this feature constitutes a major advantage for tracer kinetic analysis of both preclinical and clinical DCE imaging studies. © 2017 American Association of Physicists in Medicine.

  18. Microenvironment Induced Spheroid to Sheeting Transition of Immortalized Human Keratinocytes (HaCaT) Cultured in Microbubbles Formed in Polydimethylsiloxane

    PubMed Central

    Chandrasekaran, Siddarth; Giang, Ut-Binh; King, Michael R.; DeLouise, Lisa A

    2011-01-01

    The in vivo cellular microenvironment is regulated by a complex interplay of soluble factors and signaling molecules secreted by cells and it plays a critical role in the growth and development of normal and diseased tissues. In vitro systems that can recapitulate the microenvironment at the cellular level are needed to investigate the influence of autocrine signaling and extracellular matrix effects on tissue homeostasis, regeneration, and disease development and progression. In this study we report the use of microbubble technology as a means to culture cells in a controlled microenvironment in which cells can influence their function through autocrine signaling. Microbubbles (MB) are small spherical cavities about 100–300 µm in diameter formed in hydrophobic polymer polydimethylsiloxane (PDMS) with ~60–100 µm circular openings and aspect ratio ~3.5. We demonstrate that the unique architecture of the microbubble compartment is advantaged for cell culture using HaCaT cells, an immortalized keratinocyte cell line. We observe that HaCaT cells, seeded in microbubbles (15–20 cells / MB) and cultured under standard conditions, adopt a compact 3-D spheroidal morphology. Within 2–3 days, the cells transition to a sheeting morphology. Through experimentation and simulation we show that this transition in morphology is due to the unique architecture of the microbubble compartment which enables cells to condition their local microenvironment. The small media volume per cell and the development of shallow concentration gradients allow factors secreted by the cells to rise to bioactive levels. The kinetics of the morphology transition depends on the number of cells seeded per microbubble; higher cell seeding induces a more rapid transition. HaCaT cells seeded onto PDMS cured in 96-well plates also form compact spheroids but they do not transition to a sheeting morphology even after several weeks of culture. The importance of soluble factor accumulation in driving this morphology transition in microbubbles is supported by the observation that spheroids do not form when cells - seeded into microbubbles or onto PDMS cured in 96 well plates - are cultured in media conditioned by HaCaT cells grown in standard tissue culture plate. We observed that the addition of TGF-β1 to the growth media induced cells to proliferate in a sheeting morphology from the onset both on PDMS cured in 96-well plates and in microbubbles. TGF-β1 is a morphogen known to regulate epithelial-to-mesenchymal transition (EMT). Studies of the role of Ca2+ concentration and changes in Ecadherin expression additionally support an EMT-like HaCaT morphology transition. These findings taken together validate the microbubble compartment as a unique cell culture platform that can potentially transform investigative studies in cell biology and in particular the tumor microenvironment. Targeting the tumor microenvironment is an emerging area of anti-cancer therapy. PMID:21724250

  19. Treatment model of dengue hemorrhagic fever infection in human body

    NASA Astrophysics Data System (ADS)

    Handayani, D.; Nuraini, N.; Primasari, N.; Wijaya, K. P.

    2014-03-01

    The treatment model of DHF presented in this paper involves the dynamic of five time-dependent compartments, i.e. susceptible, infected, free virus particle, immune cell, and haematocrit level. The treatment model is investigated based on normalization of haematocrit level, which is expressed as intravenous fluid infusion control. We analyze the stability of the disease free equilibrium and the endemic equilibrium. The numerical simulations will explain the dynamic of each compartment in human body. These results show particularly that infected compartment and free virus particle compartment are tend to be vanished in two weeks after the onset of dengue virus. However, these simulation results also show that without the treatment, the haematocrit level will decrease even though not up to the normal level. Therefore the effective haematocrit normalization should be done with the treatment control.

  20. Integrated self-organization of transitional ER and early Golgi compartments.

    PubMed

    Glick, Benjamin S

    2014-02-01

    COPII coated vesicles bud from an ER domain termed the transitional ER (tER), but the mechanism that clusters COPII vesicles at tER sites is unknown. tER sites are closely associated with early Golgi or pre-Golgi structures, suggesting that the clustering of nascent COPII vesicles could be achieved by tethering to adjacent membranes. This model challenges the prevailing view that COPII vesicles are clustered by a scaffolding protein at the ER surface. Although Sec16 was proposed to serve as such a scaffolding protein, recent data suggest that rather than organizing COPII into higher-order structures, Sec16 acts at the level of individual COPII vesicles to regulate COPII turnover. A plausible synthesis is that tER sites are created by tethering to Golgi membranes and are regulated by Sec16. Meanwhile, the COPII vesicles that bud from tER sites are thought to nucleate new Golgi cisternae. Thus, an integrated self-organization process may generate tER-Golgi units. © 2014 WILEY Periodicals, Inc.

  1. Epidemic Spreading in a Multi-compartment System

    NASA Astrophysics Data System (ADS)

    Gao, Zong-Mao; Gu, Jiao; Li, Wei

    2012-02-01

    We introduce the variant rate and white noise into the susceptible-infected-removed (SIR) model for epidemics, discuss the epidemic dynamics of a multiple-compartment system, and describe this system by using master equations. For both the local epidemic spreading system and the whole multiple-compartment system, we find that a threshold could be useful in forecasting when the epidemic vanishes. Furthermore, numerical simulations show that a model with the variant infection rate and white noise can improve fitting with real SARS data.

  2. Associations of beef calf wellness and body weight gain with internal location in a truck during transportation.

    PubMed

    White, B J; Blasi, D; Vogel, L C; Epp, M

    2009-12-01

    Cattle transportation by commercial truck carrier is common in the United States, and often cattle are placed within 1 of 8 potential compartments within the truck for the journey. The objective of this research was to determine potential associations between animal wellness (as measured by ADG and health outcomes) during a relatively short backgrounding phase (46.6 +/- 8.5 d) and location within the truck during transit. Data from 21 loads (average calves per load = 101.5; average BW = 210.1 +/- 19.4 kg) were included in the analysis. For each shipment, calves were divided among 8 compartments within the trailer: nose on top deck (NOT), nose on bottom deck (NOB), bottom deck middle forward (BDF), bottom deck middle rear (BDR), rear on the bottom (ROB), top deck middle forward (TDF), top deck middle rear (TDR), and rear on the top deck (ROT). General logistic (health outcomes) and mixed (ADG) models were employed to analyze the data accounting for effects due to truck section as well as the hierarchical data structure of multiple arrival times, loads, and pens. Cattle in the ROT section had less short-term BW gains compared with NOT and tended (P < 0.10) to be less than NOB. Cattle in the forward sections (NOT, NOB) were less (P = 0.02) likely [odds ratio (OR): 0.67, 95% confidence limits (CL): 0.50, 0.94] to be treated at least once compared with cattle in the middle sections (TDF, TDR, TOP, BDF, BDR, BOT). Calves in compartments with 15 head or less tended (P < 0.10) to have reduced odds of being treated compared with cattle in compartments with 16 to 30 head (OR: 0.79, 95% CL: 0.60, 1.0) or greater than 31 head (OR: 0.73, 95% CL: 0.53, 1.0). Our current project reveals that the location within the truck may affect calf health and performance.

  3. Bistability: Requirements on Cell-Volume, Protein Diffusion, and Thermodynamics

    PubMed Central

    Endres, Robert G.

    2015-01-01

    Bistability is considered wide-spread among bacteria and eukaryotic cells, useful e.g. for enzyme induction, bet hedging, and epigenetic switching. However, this phenomenon has mostly been described with deterministic dynamic or well-mixed stochastic models. Here, we map known biological bistable systems onto the well-characterized biochemical Schlögl model, using analytical calculations and stochastic spatiotemporal simulations. In addition to network architecture and strong thermodynamic driving away from equilibrium, we show that bistability requires fine-tuning towards small cell volumes (or compartments) and fast protein diffusion (well mixing). Bistability is thus fragile and hence may be restricted to small bacteria and eukaryotic nuclei, with switching triggered by volume changes during the cell cycle. For large volumes, single cells generally loose their ability for bistable switching and instead undergo a first-order phase transition. PMID:25874711

  4. Chemical-Specific Representation of Air-Soil Exchange and Soil Penetration in Regional Multimedia Models

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    McKone, T.E.; Bennett, D.H.

    2002-08-01

    In multimedia mass-balance models, the soil compartment is an important sink as well as a conduit for transfers to vegetation and shallow groundwater. Here a novel approach for constructing soil transport algorithms for multimedia fate models is developed and evaluated. The resulting algorithms account for diffusion in gas and liquid components; advection in gas, liquid, or solid phases; and multiple transformation processes. They also provide an explicit quantification of the characteristic soil penetration depth. We construct a compartment model using three and four soil layers to replicate with high reliability the flux and mass distribution obtained from the exact analyticalmore » solution describing the transient dispersion, advection, and transformation of chemicals in soil with fixed properties and boundary conditions. Unlike the analytical solution, which requires fixed boundary conditions, the soil compartment algorithms can be dynamically linked to other compartments (air, vegetation, ground water, surface water) in multimedia fate models. We demonstrate and evaluate the performance of the algorithms in a model with applications to benzene, benzo(a)pyrene, MTBE, TCDD, and tritium.« less

  5. Physiological water model development

    NASA Technical Reports Server (NTRS)

    Doty, Susan

    1993-01-01

    The water of the human body can be categorized as existing in two main compartments: intracellular water and extracellular water. The intracellular water consists of all the water within the cells and constitutes over half of the total body water. Since red blood cells are surrounded by plasma, and all other cells are surrounded by interstitial fluid, the intracellular compartment has been subdivided to represent these two cell types. The extracellular water, which includes all of the fluid outside of the cells, can be further subdivided into compartments which represent the interstitial fluid, circulating blood plasma, lymph, and transcellular water. The interstitial fluid surrounds cells outside of the vascular system whereas plasma is contained within the blood vessels. Avascular tissues such as dense connective tissue and cartilage contain interstitial water which slowly equilibrates with tracers used to determine extracellular fluid volume. For this reason, additional compartments are sometimes used to represent these avascular tissues. The average size of each compartment, in terms of percent body weight, has been determined for adult males and females. These compartments and the forces which cause flow between them are presented. The kidneys, a main compartment, receive about 25 percent of the cardiac output and filters out a fluid similar to plasma. The composition of this filtered fluid changes as it flows through the kidney tubules since compounds are continually being secreted and reabsorbed. Through this mechanism, the kidneys eliminate wastes while conserving body water, electrolytes, and metabolites. Since sodium accounts for over 90 percent of the cations in the extracellular fluid, and the number of cations is balanced by the number of anions, considering the renal handling sodium and water only should sufficiently describe the relationship between the plasma compartment and kidneys. A kidney function model is presented which has been adapted from a previous model of normal renal function in man. To test the validity of the proposed kidney model, results predicted by the model will be compared to actual data involving injected or ingested fluids and subsequent urine flow rates. Comparison of the model simulation to actual data following the ingestion of 1 liter of water is shown. The model simulation is also shown with actual data following the intravenous infusion of hypertonic saline.

  6. Modeling of Tracer Transport Delays for Improved Quantification of Regional Pulmonary 18F-FDG Kinetics, Vascular Transit Times, and Perfusion

    PubMed Central

    Wellman, Tyler J.; Winkler, Tilo; Vidal Melo, Marcos F.

    2015-01-01

    18F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary 18F-FDG kinetics do not account for delays in 18F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of 18F-FDG kinetics that includes a delay between the right heart and the local capillary blood pool, and used this model to estimate regional pulmonary perfusion. We acquired dynamic 18F-FDG scans in 12 mechanically ventilated sheep divided into control and lung injury groups (n=6 each). The model was fit to tracer kinetics in three isogravitational regions-of-interest to estimate regional lung transport delays and regional perfusion. 13NN bolus infusion scans were acquired during a period of apnea to measure regional perfusion using an established reference method. The delayed input function model improved description of 18F-FDG kinetics (lower Akaike Information Criterion) in 98% of studied regions. Local transport delays ranged from 2.0–13.6s, averaging 6.4±2.9s, and were highest in non-dependent regions. Estimates of regional perfusion derived from model parameters were highly correlated with perfusion measurements based on 13NN-PET (R2=0.92, p<0.001). By incorporating local vascular transports delays, this model of pulmonary 18F-FDG kinetics allows for simultaneous assessment of regional lung perfusion, transit times, and inflammation. PMID:25940652

  7. Genetic defects in PI3Kδ affect B-cell differentiation and maturation leading to hypogammaglobulineamia and recurrent infections.

    PubMed

    Wentink, Marjolein; Dalm, Virgil; Lankester, Arjan C; van Schouwenburg, Pauline A; Schölvinck, Liesbeth; Kalina, Tomas; Zachova, Radana; Sediva, Anna; Lambeck, Annechien; Pico-Knijnenburg, Ingrid; van Dongen, Jacques J M; Pac, Malgorzata; Bernatowska, Ewa; van Hagen, Martin; Driessen, Gertjan; van der Burg, Mirjam

    2017-03-01

    Mutations in PIK3CD and PIK3R1 cause activated PI3K-δ syndrome (APDS) by dysregulation of the PI3K-AKT pathway. We studied precursor and peripheral B-cell differentiation and apoptosis via flowcytometry. Furthermore, we performed AKT-phosphorylation assays and somatic hypermutations (SHM) and class switch recombination (CSR) analysis. We identified 13 patients of whom 3 had new mutations in PIK3CD or PIK3R1. Patients had low total B-cell numbers with increased frequencies of transitional B cells and plasmablasts, while the precursor B-cell compartment in bone marrow was relatively normal. Basal AKT phosphorylation was increased in lymphocytes from APDS patients and natural effector B cells where most affected. PI3K mutations resulted in altered SHM and CSR and increased apoptosis. The B-cell compartment in APDS patients is affected by the mutations in PI3K. There is reduced differentiation beyond the transitional stage, increased AKT phosphorylation and increased apoptosis. This B-cell phenotype contributes to the clinical phenotype. Copyright © 2017. Published by Elsevier Inc.

  8. Deciphering the shape and deformation of secondary structures through local conformation analysis

    PubMed Central

    2011-01-01

    Background Protein deformation has been extensively analysed through global methods based on RMSD, torsion angles and Principal Components Analysis calculations. Here we use a local approach, able to distinguish among the different backbone conformations within loops, α-helices and β-strands, to address the question of secondary structures' shape variation within proteins and deformation at interface upon complexation. Results Using a structural alphabet, we translated the 3 D structures of large sets of protein-protein complexes into sequences of structural letters. The shape of the secondary structures can be assessed by the structural letters that modeled them in the structural sequences. The distribution analysis of the structural letters in the three protein compartments (surface, core and interface) reveals that secondary structures tend to adopt preferential conformations that differ among the compartments. The local description of secondary structures highlights that curved conformations are preferred on the surface while straight ones are preferred in the core. Interfaces display a mixture of local conformations either preferred in core or surface. The analysis of the structural letters transition occurring between protein-bound and unbound conformations shows that the deformation of secondary structure is tightly linked to the compartment preference of the local conformations. Conclusion The conformation of secondary structures can be further analysed and detailed thanks to a structural alphabet which allows a better description of protein surface, core and interface in terms of secondary structures' shape and deformation. Induced-fit modification tendencies described here should be valuable information to identify and characterize regions under strong structural constraints for functional reasons. PMID:21284872

  9. Deciphering the shape and deformation of secondary structures through local conformation analysis.

    PubMed

    Baussand, Julie; Camproux, Anne-Claude

    2011-02-01

    Protein deformation has been extensively analysed through global methods based on RMSD, torsion angles and Principal Components Analysis calculations. Here we use a local approach, able to distinguish among the different backbone conformations within loops, α-helices and β-strands, to address the question of secondary structures' shape variation within proteins and deformation at interface upon complexation. Using a structural alphabet, we translated the 3 D structures of large sets of protein-protein complexes into sequences of structural letters. The shape of the secondary structures can be assessed by the structural letters that modeled them in the structural sequences. The distribution analysis of the structural letters in the three protein compartments (surface, core and interface) reveals that secondary structures tend to adopt preferential conformations that differ among the compartments. The local description of secondary structures highlights that curved conformations are preferred on the surface while straight ones are preferred in the core. Interfaces display a mixture of local conformations either preferred in core or surface. The analysis of the structural letters transition occurring between protein-bound and unbound conformations shows that the deformation of secondary structure is tightly linked to the compartment preference of the local conformations. The conformation of secondary structures can be further analysed and detailed thanks to a structural alphabet which allows a better description of protein surface, core and interface in terms of secondary structures' shape and deformation. Induced-fit modification tendencies described here should be valuable information to identify and characterize regions under strong structural constraints for functional reasons.

  10. An open source software for analysis of dynamic contrast enhanced magnetic resonance images: UMMPerfusion revisited.

    PubMed

    Zöllner, Frank G; Daab, Markus; Sourbron, Steven P; Schad, Lothar R; Schoenberg, Stefan O; Weisser, Gerald

    2016-01-14

    Perfusion imaging has become an important image based tool to derive the physiological information in various applications, like tumor diagnostics and therapy, stroke, (cardio-) vascular diseases, or functional assessment of organs. However, even after 20 years of intense research in this field, perfusion imaging still remains a research tool without a broad clinical usage. One problem is the lack of standardization in technical aspects which have to be considered for successful quantitative evaluation; the second problem is a lack of tools that allow a direct integration into the diagnostic workflow in radiology. Five compartment models, namely, a one compartment model (1CP), a two compartment exchange (2CXM), a two compartment uptake model (2CUM), a two compartment filtration model (2FM) and eventually the extended Toft's model (ETM) were implemented as plugin for the DICOM workstation OsiriX. Moreover, the plugin has a clean graphical user interface and provides means for quality management during the perfusion data analysis. Based on reference test data, the implementation was validated against a reference implementation. No differences were found in the calculated parameters. We developed open source software to analyse DCE-MRI perfusion data. The software is designed as plugin for the DICOM Workstation OsiriX. It features a clean GUI and provides a simple workflow for data analysis while it could also be seen as a toolbox providing an implementation of several recent compartment models to be applied in research tasks. Integration into the infrastructure of a radiology department is given via OsiriX. Results can be saved automatically and reports generated automatically during data analysis ensure certain quality control.

  11. Muscle contributions to medial tibiofemoral compartment contact loading following ACL reconstruction using semitendinosus and gracilis tendon grafts.

    PubMed

    Konrath, Jason M; Saxby, David J; Killen, Bryce A; Pizzolato, Claudio; Vertullo, Christopher J; Barrett, Rod S; Lloyd, David G

    2017-01-01

    The muscle-tendon properties of the semitendinosus (ST) and gracilis (GR) are substantially altered following tendon harvest for the purpose of anterior cruciate ligament reconstruction (ACLR). This study adopted a musculoskeletal modelling approach to determine how the changes to the ST and GR muscle-tendon properties alter their contribution to medial compartment contact loading within the tibiofemoral joint in post ACLR patients, and the extent to which other muscles compensate under the same external loading conditions during walking, running and sidestep cutting. Motion capture and electromyography (EMG) data from 16 lower extremity muscles were acquired during walking, running and cutting in 25 participants that had undergone an ACLR using a quadruple (ST+GR) hamstring auto-graft. An EMG-driven musculoskeletal model was used to estimate the medial compartment contact loads during the stance phase of each gait task. An adjusted model was then created by altering muscle-tendon properties for the ST and GR to reflect their reported changes following ACLR. Parameters for the other muscles in the model were calibrated to match the experimental joint moments. The medial compartment contact loads for the standard and adjusted models were similar. The combined contributions of ST and GR to medial compartment contact load in the adjusted model were reduced by 26%, 17% and 17% during walking, running and cutting, respectively. These deficits were balanced by increases in the contribution made by the semimembranosus muscle of 33% and 22% during running and cutting, respectively. Alterations to the ST and GR muscle-tendon properties in ACLR patients resulted in reduced contribution to medial compartment contact loads during gait tasks, for which the semimembranosus muscle can compensate.

  12. Simulating wall and corner fire tests on wood products with the OSU room fire model

    Treesearch

    H. C. Tran

    1994-01-01

    This work demonstrates the complexity of modeling wall and corner fires in a compartment. The model chosen for this purpose is the Ohio State University (OSU) room fire model. This model was designed to simulate fire growth on walls in a compartment and therefore lends itself to direct comparison with standard room test results. The model input were bench-scale data...

  13. Measurement of compartment elasticity using pressure related ultrasound: a method to identify patients with potential compartment syndrome.

    PubMed

    Sellei, R M; Hingmann, S J; Kobbe, P; Weber, C; Grice, J E; Zimmerman, F; Jeromin, S; Gansslen, A; Hildebrand, F; Pape, H C

    2015-01-01

    PURPOSE OF THE STUDY Decision-making in treatment of an acute compartment syndrome is based on clinical assessment, supported by invasive monitoring. Thus, evolving compartment syndrome may require repeated pressure measurements. In suspected cases of potential compartment syndromes clinical assessment alone seems to be unreliable. The objective of this study was to investigate the feasibility of a non-invasive application estimating whole compartmental elasticity by ultrasound, which may improve accuracy of diagnostics. MATERIAL AND METHODS In an in-vitro model, using an artificial container simulating dimensions of the human anterior tibial compartment, intracompartmental pressures (p) were raised subsequently up to 80 mm Hg by infusion of saline solution. The compartmental depth (mm) in the cross-section view was measured before and after manual probe compression (100 mm Hg) upon the surface resulting in a linear compartmental displacement (Δd). This was repeated at rising compartmental pressures. The resulting displacements were related to the corresponding intra-compartmental pressures simulated in our model. A hypothesized relationship between pressures related compartmental displacement and the elasticity at elevated compartment pressures was investigated. RESULTS With rising compartmental pressures, a non-linear, reciprocal proportional relation between the displacement (mm) and the intra-compartmental pressure (mm Hg) occurred. The Pearson's coefficient showed a high correlation (r2 = -0.960). The intraobserver reliability value kappa resulted in a statistically high reliability (κ = 0.840). The inter-observer value indicated a fair reliability (κ = 0.640). CONCLUSIONS Our model reveals that a strong correlation between compartmental strain displacements assessed by ultrasound and the intra-compartmental pressure changes occurs. Further studies are required to prove whether this assessment is transferable to human muscle tissue. Determining the complete compartmental elasticity by ultrasound enhancement, this application may improve detection of early signs of potential compartment syndrome. Key words: compartment syndrome, intra-compartmental pressure, non-invasive diagnostic, elasticity measurement, elastography.

  14. Modeling the impact of biota on polychlorinated biphenyls (PCBs) fate and transport in Lake Ontario using a population-based multi-compartment fugacity approach.

    PubMed

    Sun, Xiangfei; Ng, Carla A; Small, Mitchell J

    2018-06-12

    Organisms have long been treated as receptors in exposure studies of polychlorinated biphenyls (PCBs) and other persistent organic pollutants (POPs). The influences of environmental pollution on organisms are well recognized. However, the impact of biota on PCB transport in an environmental system has not been considered in sufficient detail. In this study, a population-based multi-compartment fugacity model is developed by reconfiguring the organisms as populated compartments and reconstructing all the exchange processes between the organism compartments and environmental compartments, especially the previously ignored feedback routes from biota to the environment. We evaluate the model performance by simulating the PCB concentration distribution in Lake Ontario using published loading records. The lake system is divided into three environment compartments (air, water, and sediment) and several organism groups according to the dominant local biotic species. The comparison indicates that the simulated results are well-matched by a list of published field measurements from different years. We identify a new process, called Facilitated Biotic Intermedia Transport (FBIT), to describe the enhanced pollution transport that occurs between environmental media and organisms. As the hydrophobicity of PCB congener increases, the organism population exerts greater influence on PCB mass flows. In a high biomass scenario, the model simulation indicates significant FBIT effects and biotic storage effects with hydrophobic PCB congeners, which also lead to significant shifts in systemic contaminant exchange rates between organisms and the environment. Copyright © 2018 Elsevier Ltd. All rights reserved.

  15. Numerical calculation on a two-step subdiffusion behavior of lateral protein movement in plasma membranes

    NASA Astrophysics Data System (ADS)

    Sumi, Tomonari; Okumoto, Atsushi; Goto, Hitoshi; Sekino, Hideo

    2017-10-01

    A two-step subdiffusion behavior of lateral movement of transmembrane proteins in plasma membranes has been observed by using single-molecule experiments. A nested double-compartment model where large compartments are divided into several smaller ones has been proposed in order to explain this observation. These compartments are considered to be delimited by membrane-skeleton "fences" and membrane-protein "pickets" bound to the fences. We perform numerical simulations of a master equation using a simple two-dimensional lattice model to investigate the heterogeneous diffusion dynamics behavior of transmembrane proteins within plasma membranes. We show that the experimentally observed two-step subdiffusion process can be described using fence and picket models combined with decreased local diffusivity of transmembrane proteins in the vicinity of the pickets. This allows us to explain the two-step subdiffusion behavior without explicitly introducing nested double compartments.

  16. A recycling model of the biokinetics of systemic tellurium.

    PubMed

    Giussani, Augusto

    2014-11-01

    To develop a compartmental model of the systemic biokinetics of tellurium required for calculating the internal dose and interpreting bioassay measurements after incorporation of radioactive tellurium. The compartmental model for tellurium was developed with the software SAAM II v. 2.0 (©The Epsilon Group, Charlottesville, Virginia, USA). Model parameters were determined on the basis of published retention and excretion data in humans and animals. The model consists of two blood compartments, one compartment each for liver, kidneys, thyroid, four compartments for bone tissues and a generic compartment for the soft tissues. The model predicts a rapid urinary excretion of systemic tellurium: 45% in the first 24 h and 84% after 50 d. Faecal excretion amounts to 0.4% after 3 d and 9% after 50 d. Whole body retention is 55% after one day, and 2.8% after 100 d. These values as well as the retained fractions in the single organs are reasonably consistent with the available human and animal data (studies with swine and guinea pigs). The proposed model gives a realistic description of the available biokinetic data for tellurium and will be adopted by the International Commission on Radiological Protection for applications in internal dosimetry.

  17. Validation of Perfusion Quantification with 3D Gradient Echo Dynamic Contrast-Enhanced Magnetic Resonance Imaging Using a Blood Pool Contrast Agent in Skeletal Swine Muscle

    PubMed Central

    Hindel, Stefan; Sauerbrey, Anika; Maaß, Marc; Maderwald, Stefan; Schlamann, Marc; Lüdemann, Lutz

    2015-01-01

    The purpose of our study was to validate perfusion quantification in a low-perfused tissue by dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) with shared k-space sampling using a blood pool contrast agent. Perfusion measurements were performed in a total of seven female pigs. An ultrasonic Doppler probe was attached to the right femoral artery to determine total flow in the hind leg musculature. The femoral artery was catheterized for continuous local administration of adenosine to increase blood flow up to four times the baseline level. Three different stable perfusion levels were induced. The MR protocol included a 3D gradient-echo sequence with a temporal resolution of approximately 1.5 seconds. Before each dynamic sequence, static MR images were acquired with flip angles of 5°, 10°, 20°, and 30°. Both static and dynamic images were used to generate relaxation rate and baseline magnetization maps with a flip angle method. 0.1 mL/kg body weight of blood pool contrast medium was injected via a central venous catheter at a flow rate of 5 mL/s. The right hind leg was segmented in 3D into medial, cranial, lateral, and pelvic thigh muscles, lower leg, bones, skin, and fat. The arterial input function (AIF) was measured in the aorta. Perfusion of the different anatomic regions was calculated using a one- and a two-compartment model with delay- and dispersion-corrected AIFs. The F-test for model comparison was used to decide whether to use the results of the one- or two-compartment model fit. Total flow was calculated by integrating volume-weighted perfusion values over the whole measured region. The resulting values of delay, dispersion, blood volume, mean transit time, and flow were all in physiologically and physically reasonable ranges. In 107 of 160 ROIs, the blood signal was separated, using a two-compartment model, into a capillary and an arteriolar signal contribution, decided by the F-test. Overall flow in hind leg muscles, as measured by the ultrasound probe, highly correlated with total flow determined by MRI, R = 0.89 and P = 10−7. Linear regression yielded a slope of 1.2 and a y-axis intercept of 259 mL/min. The mean total volume of the investigated muscle tissue corresponds to an offset perfusion of 4.7mL/(min ⋅ 100cm3). The DCE-MRI technique presented here uses a blood pool contrast medium in combination with a two-compartment tracer kinetic model and allows absolute quantification of low-perfused non-cerebral organs such as muscles. PMID:26061498

  18. Numerical analysis of air-flow and temperature field in a passenger car compartment

    NASA Astrophysics Data System (ADS)

    Kamar, Haslinda Mohamed; Kamsah, Nazri; Mohammad Nor, Ahmad Miski

    2012-06-01

    This paper presents a numerical study on the temperature field inside a passenger's compartment of a Proton Wira saloon car using computational fluid dynamics (CFD) method. The main goal is to investigate the effects of different glazing types applied onto the front and rear windscreens of the car on the distribution of air-temperature inside the passenger compartment in the steady-state conditions. The air-flow condition in the passenger's compartment is also investigated. Fluent CFD software was used to develop a three-dimensional symmetrical model of the passenger's compartment. Simplified representations of the driver and one rear passenger were incorporated into the CFD model of the passenger's compartment. Two types of glazing were considered namely clear insulated laminated tint (CIL) with a shading coefficient of 0.78 and green insulated laminate tint (GIL) with a shading coefficient of 0.5. Results of the CFD analysis were compared with those obtained when the windscreens are made up of clear glass having a shading coefficient of 0.86. Results of the CFD analysis show that for a given glazing material, the temperature of the air around the driver is slightly lower than the air around the rear passenger. Also, the use of GIL glazing material on both the front and rear windscreens significantly reduces the air temperature inside the passenger's compartment of the car. This contributes to a better thermal comfort condition to the occupants. Swirling air flow condition occurs in the passenger compartment. The air-flow intensity and velocity are higher along the side wall of the passenger's compartment compared to that along the middle section of the compartment. It was also found that the use of glazing materials on both the front and rear windscreen has no significant effects on the air-flow condition inside the passenger's compartment of the car.

  19. Modeling the Pharmacokinetics of Perfluorooctanoic Acid (PFOA) During Gestation and Lactation in Mice

    EPA Science Inventory

    To address the pharmacokinetics of PFOA during gestation and lactation, a biologically supported dynamic model was developed. A two compartment system linked via placental blood flow described gestation, while milk production linked the dam to a pup litter compartment during lact...

  20. Non-invasive model of neuropathogenic Escherichia coli infection in the neonatal rat.

    PubMed

    Dalgakiran, Fatma; Witcomb, Luci A; McCarthy, Alex J; Birchenough, George M H; Taylor, Peter W

    2014-10-29

    Investigation of the interactions between animal host and bacterial pathogen is only meaningful if the infection model employed replicates the principal features of the natural infection. This protocol describes procedures for the establishment and evaluation of systemic infection due to neuropathogenic Escherichia coli K1 in the neonatal rat. Colonization of the gastrointestinal tract leads to dissemination of the pathogen along the gut-lymph-blood-brain course of infection and the model displays strong age dependency. A strain of E. coli O18:K1 with enhanced virulence for the neonatal rat produces exceptionally high rates of colonization, translocation to the blood compartment and invasion of the meninges following transit through the choroid plexus. As in the human host, penetration of the central nervous system is accompanied by local inflammation and an invariably lethal outcome. The model is of proven utility for studies of the mechanism of pathogenesis, for evaluation of therapeutic interventions and for assessment of bacterial virulence.

  1. Fluid and Electrolyte Balance model (FEB)

    NASA Technical Reports Server (NTRS)

    Fitzjerrell, D. G.

    1973-01-01

    The effects of various oral input water loads on solute and water distribution throughout the body are presented in the form of a model. The model was a three compartment model; the three compartments being plasma, interstitial fluid and cellular fluid. Sodium, potassium, chloride and urea were the only major solutes considered explicitly. The control of body water and electrolyte distribution was affected via drinking and hormone levels.

  2. Pregnancy alters the circulating B cell compartment in atopic asthmatic women, and transitional B cells are positively associated with the development of allergy manifestations in their progeny.

    PubMed

    Martins, Catarina; Lima, Jorge; Nunes, Glória; Borrego, Luís Miguel

    2016-12-01

    Maternal atopy is a risk factor for allergy. B cells are poorly studied in reproduction and atopy. We aimed to assess how pregnancy affects B cells in atopic women and whether B cells relate to allergic manifestations in offspring. Women with and without atopic asthma, pregnant and non-pregnant were enrolled for the study, and circulating B cells were evaluated by flow cytometry, using CD19, CD27, CD38, IgD, and IgM. Compared to healthy non-pregnant, atopic asthmatic non-pregnant (ANP) women presented increased B cell counts, enlarged memory subsets, less transitional cells, and plasmablasts. Atopic asthmatic pregnant (AP) and healthy pregnant (HP) women showed similarities: reduced B cell counts and percentages, fewer memory cells, especially switched, and higher plasmablast percentages. Transitional B cell percentages were increased in AP women with allergic manifestations in their progeny. Atopic asthmatic non-pregnant women have a distinctive B cell compartment. B cells change in pregnancy, similarly in AP and HP women. The recognition that AP women with allergy in their progeny have a typical immune profile may help, in the future, the adoption of preventive measures to avoid the manifestation of allergic diseases in their newborns. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  3. C/EBPα and C/EBPβ Are Required for Sebocyte Differentiation and Stratified Squamous Differentiation in Adult Mouse Skin

    PubMed Central

    House, John S.; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C.

    2010-01-01

    C/EBPα and C/EBPβ are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPα and C/EBPβ in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPα or C/EBPβ alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPα and C/EBPβ in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPα and C/EBPβ in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPα and C/EBPβ are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal. PMID:20352127

  4. C/EBPalpha and C/EBPbeta are required for Sebocyte differentiation and stratified squamous differentiation in adult mouse skin.

    PubMed

    House, John S; Zhu, Songyun; Ranjan, Rakesh; Linder, Keith; Smart, Robert C

    2010-03-23

    C/EBPalpha and C/EBPbeta are bZIP transcription factors that are highly expressed in the interfollicular epidermis and sebaceous glands of skin and yet germ line deletion of either family member alone has only mild or no effect on keratinocyte biology and their role in sebocyte biology has never been examined. To address possible functional redundancies and reveal functional roles of C/EBPalpha and C/EBPbeta in postnatal skin, mouse models were developed in which either family member could be acutely ablated alone or together in the epidermis and sebaceous glands of adult mice. Acute removal of either C/EBPalpha or C/EBPbeta alone in adult mouse skin revealed modest to no discernable changes in epidermis or sebaceous glands. In contrast, co-ablation of C/EBPalpha and C/EBPbeta in postnatal epidermis resulted in disruption of stratified squamous differentiation characterized by hyperproliferation of basal and suprabasal keratinocytes and a defective basal to spinous keratinocyte transition involving an expanded basal compartment and a diminished and delayed spinous compartment. Acute co-ablation of C/EBPalpha and C/EBPbeta in sebaceous glands resulted in severe morphological defects, and sebocyte differentiation was blocked as determined by lack of sebum production and reduced expression of stearoyl-CoA desaturase (SCD3) and melanocortin 5 receptor (MC5R), two markers of terminal sebocyte differentiation. Specialized sebocytes of Meibomian glands and preputial glands were also affected. Our results indicate that in adult mouse skin, C/EBPalpha and C/EBPbeta are critically involved in regulating sebocyte differentiation and epidermal homeostasis involving the basal to spinous keratinocyte transition and basal cell cycle withdrawal.

  5. Estimation of pharmacokinetic parameters from non-compartmental variables using Microsoft Excel.

    PubMed

    Dansirikul, Chantaratsamon; Choi, Malcolm; Duffull, Stephen B

    2005-06-01

    This study was conducted to develop a method, termed 'back analysis (BA)', for converting non-compartmental variables to compartment model dependent pharmacokinetic parameters for both one- and two-compartment models. A Microsoft Excel spreadsheet was implemented with the use of Solver and visual basic functions. The performance of the BA method in estimating pharmacokinetic parameter values was evaluated by comparing the parameter values obtained to a standard modelling software program, NONMEM, using simulated data. The results show that the BA method was reasonably precise and provided low bias in estimating fixed and random effect parameters for both one- and two-compartment models. The pharmacokinetic parameters estimated from the BA method were similar to those of NONMEM estimation.

  6. Cytoplasmic rearrangements associated with amphibian egg symmetrization

    NASA Technical Reports Server (NTRS)

    Malacinski, G. M.

    1984-01-01

    Cytoplasmic rearrangements which follow fertilization were mentioned in normal and inverted eggs. A set of yolk compartments was resolved by cytological analyses of both normally oriented and inverted eggs. Those compartments were characterized by their yolk platelet compositions and movement during egg inversion. It is found that during egg inversion the yolk compartments shift minor cytoplasmic compartments which line the egg cortex. Those yolk mass shifts occurred only after the inverted egg was activated. The direction of shift of the major yolk components, rather than the sperm entrance site, determines the dorsal/ventral polarity of the inverted egg. Among different spawnings the rate of shift varied. Eggs that displayed the fastest rate of shift exhibited the highest frequency of developmental abnormalities during organogenesis. Interpretation of novel observations on cytoplasmic organization provide criticism of some earlier models. A new density compartment model is presented as a coherent way to view the organization of the egg cytoplasm and the development of bilateral symmetry.

  7. Dicamptodon tenebrosus larvae within hyporheic zones of intermittent streams in California

    Treesearch

    David Feral; Michael A. Camann; Hartwell H. Welsh Jr.

    2005-01-01

    Lotic ecosystems are increasingly viewed as having three interactive spatial compartments, i.e., channel sediments, the hyporheic zone, and flood plains or riparian areas (Cummins et al. 1983; Ward 1989). The hyporheic zone is the sub-benthic habitat of interstitial spaces between substrate particles in the stream bed, and is the transition zone between surface flow...

  8. The renal compartment: a hydraulic view.

    PubMed

    Cruces, Pablo; Salas, Camila; Lillo, Pablo; Salomon, Tatiana; Lillo, Felipe; Hurtado, Daniel E

    2014-12-01

    The hydraulic behavior of the renal compartment is poorly understood. In particular, the role of the renal capsule on the intrarenal pressure has not been thoroughly addressed to date. We hypothesized that pressure and volume in the renal compartment are not linearly related, similar to other body compartments. The pressure-volume curve of the renal compartment was obtained by injecting fluid into the renal pelvis and recording the rise in intrarenal pressure in six anesthetized and mechanically ventilated piglets, using a catheter Camino 4B® inserted into the renal parenchyma. In healthy kidneys, pressure has a highly nonlinear dependence on the injected volume, as revealed by an exponential fit to the data (R (2) = 0.92). On the contrary, a linear relation between pressure and volume is observed in decapsulated kidneys. We propose a biomechanical model for the renal capsule that is able to explain the nonlinear pressure-volume dependence for moderate volume increases. We have presented experimental evidence and a theoretical model that supports the existence of a renal compartment. The mechanical role of the renal capsule investigated in this work may have important implications in elucidating the role of decompressive capsulotomy in reducing the intrarenal pressure in acutely injured kidneys.

  9. Pharmacokinetics of plasma enfuvirtide after subcutaneous administration to patients with human immunodeficiency virus: Inverse Gaussian density absorption and 2-compartment disposition.

    PubMed

    Zhang, Xiaoping; Nieforth, Keith; Lang, Jean-Marie; Rouzier-Panis, Regine; Reynes, Jacques; Dorr, Albert; Kolis, Stanley; Stiles, Mark R; Kinchelow, Tosca; Patel, Indravadan H

    2002-07-01

    Enfuvirtide (T-20) is the first of a novel class of human immunodeficiency virus (HIV) drugs that block gp41-mediated viral fusion to host cells. The objectives of this study were to develop a structural pharmacokinetic model that would adequately characterize the absorption and disposition of enfuvirtide pharmacokinetics after both intravenous and subcutaneous administration and to evaluate the dose proportionality of enfuvirtide pharmacokinetic parameters at a subcutaneous dose higher than that currently used in phase III studies. Twelve patients with HIV infection received 4 single doses of enfuvirtide separated by a 1-week washout period in an open-label, randomized, 4-way crossover fashion. The doses studied were 90 mg (intravenous) and 45 mg, 90 mg, and 180 mg (subcutaneous). Serial blood samples were collected up to 48 hours after each dose. Plasma enfuvirtide concentrations were measured with use of a validated liquid chromatography-tandem mass spectrometry method. Enfuvirtide plasma concentration-time data after subcutaneous administration were well described by an inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment. The model-derived mean pharmacokinetic parameters (+/-SD) were volume of distribution of the central compartment (3.8 +/- 0.8 L), volume of distribution of the peripheral compartment (1.7 +/- 0.6 L), total clearance (1.44 +/- 0.30 L/h), intercompartmental distribution (2.3 +/- 1.1 L/h), bioavailability (89% +/- 11%), and mean absorption time (7.26 hours, 8.65 hours, and 9.79 hours for the 45-mg, 90-mg, and 180-mg dose groups, respectively). The terminal half-life increased from 3.46 to 4.35 hours for the subcutaneous dose range from 45 to 180 mg. An inverse Gaussian density function-input model linked to a 2-compartment open distribution model with first-order elimination from the central compartment was appropriate to describe complex absorption and disposition kinetics of enfuvirtide plasma concentration-time data after subcutaneous administration to patients with HIV infection. Enfuvirtide was nearly completely absorbed from subcutaneous depot, and pharmacokinetic parameters were linear up to a dose of 180 mg in this study.

  10. Identifiability Results for Several Classes of Linear Compartment Models.

    PubMed

    Meshkat, Nicolette; Sullivant, Seth; Eisenberg, Marisa

    2015-08-01

    Identifiability concerns finding which unknown parameters of a model can be estimated, uniquely or otherwise, from given input-output data. If some subset of the parameters of a model cannot be determined given input-output data, then we say the model is unidentifiable. In this work, we study linear compartment models, which are a class of biological models commonly used in pharmacokinetics, physiology, and ecology. In past work, we used commutative algebra and graph theory to identify a class of linear compartment models that we call identifiable cycle models, which are unidentifiable but have the simplest possible identifiable functions (so-called monomial cycles). Here we show how to modify identifiable cycle models by adding inputs, adding outputs, or removing leaks, in such a way that we obtain an identifiable model. We also prove a constructive result on how to combine identifiable models, each corresponding to strongly connected graphs, into a larger identifiable model. We apply these theoretical results to several real-world biological models from physiology, cell biology, and ecology.

  11. A simple model of fluid flow and electrolyte balance in the body

    NASA Technical Reports Server (NTRS)

    White, R. J.; Neal, L.

    1973-01-01

    The model is basically a three-compartment model, the three compartments being the plasma, interstitial fluid and cellular fluid. Sodium, potassium, chloride and urea are the only major solutes considered explicitly. The control of body water and electrolyte distribution is affected via drinking and hormone levels. Basically, the model follows the effect of various oral input water loads on solute and water distribution throughout the body.

  12. Boundaries of the thoracic paravertebral space: potential risks and benefits of the thoracic paravertebral block from an anatomical perspective.

    PubMed

    Bouman, Esther A C; Sieben, Judith M; Balthasar, Andrea J R; Joosten, Elbert A; Gramke, Hans-Fritz; van Kleef, Maarten; Lataster, Arno

    2017-10-01

    Thoracic paravertebral block (TPVB) may be an alternative to thoracic epidural analgesia. A detailed knowledge of the anatomy of the TPV-space (TPVS), content and adnexa is essential in understanding the clinical consequences of TPVB. The exploration of the posterior TPVS accessibility in this study allows (1) determination of the anatomical boundaries, content and adnexa, (2) description of an ultrasound-guided spread of low and high viscous liquid. In two formalin-fixed specimens, stratification of the several layers and the 3D-architecture of the TPVS were dissected, observed and photographed. In a third unembalmed specimen, ultrasound-guided posterolateral injections at several levels of the TPVS were performed with different fluids. TPVS communicated with all surrounding spaces including the segmental dorsal intercostal compartments (SDICs) and the prevertebral space. TPVS transitions to the SDICs were wide, whereas the SDICs showed narrowed transitions to the lateral intercostal spaces at the costal angle. Internal subdivision of the TPVS in a subendothoracic and an extra-pleural compartment by the endothoracic fascia was not observed. Caudally injected fluids spread posteriorly to the costodiaphragmatic recess, showing segmental intercostal and slight prevertebral spread. Our detailed anatomical study shows that TPVS is a potential space continuous with the SDICs. The separation of the TPVS in a subendothoracic and an extra-pleural compartment by the endothoracic fascia was not observed. Based on the ultrasound-guided liquid spread we conclude that the use of a more lateral approach might increase the probability of intravascular puncture or catheter position.

  13. Population pharmacokinetic analysis of clopidogrel in healthy Jordanian subjects with emphasis optimal sampling strategy.

    PubMed

    Yousef, A M; Melhem, M; Xue, B; Arafat, T; Reynolds, D K; Van Wart, S A

    2013-05-01

    Clopidogrel is metabolized primarily into an inactive carboxyl metabolite (clopidogrel-IM) or to a lesser extent an active thiol metabolite. A population pharmacokinetic (PK) model was developed using NONMEM(®) to describe the time course of clopidogrel-IM in plasma and to design a sparse-sampling strategy to predict clopidogrel-IM exposures for use in characterizing anti-platelet activity. Serial blood samples from 76 healthy Jordanian subjects administered a single 75 mg oral dose of clopidogrel were collected and assayed for clopidogrel-IM using reverse phase high performance liquid chromatography. A two-compartment (2-CMT) PK model with first-order absorption and elimination plus an absorption lag-time was evaluated, as well as a variation of this model designed to mimic enterohepatic recycling (EHC). Optimal PK sampling strategies (OSS) were determined using WinPOPT based upon collection of 3-12 post-dose samples. A two-compartment model with EHC provided the best fit and reduced bias in C(max) (median prediction error (PE%) of 9.58% versus 12.2%) relative to the basic two-compartment model, AUC(0-24) was similar for both models (median PE% = 1.39%). The OSS for fitting the two-compartment model with EHC required the collection of seven samples (0.25, 1, 2, 4, 5, 6 and 12 h). Reasonably unbiased and precise exposures were obtained when re-fitting this model to a reduced dataset considering only these sampling times. A two-compartment model considering EHC best characterized the time course of clopidogrel-IM in plasma. Use of the suggested OSS will allow for the collection of fewer PK samples when assessing clopidogrel-IM exposures. Copyright © 2013 John Wiley & Sons, Ltd.

  14. Kinetic modeling of benzodiazepine receptor binding with PET and high specific activity [(11)C]Iomazenil in healthy human subjects.

    PubMed

    Bremner, J D; Horti, A; Staib, L H; Zea-Ponce, Y; Soufer, R; Charney, D S; Baldwin, R

    2000-01-01

    Quantitation of the PET benzodiazepine receptor antagonist, [(11)C]Iomazenil, using low specific activity radioligand was recently described. The purpose of this study was to quantitate benzodiazepine receptor binding in human subjects using PET and high specific activity [(11)C]Iomazenil. Six healthy human subjects underwent PET imaging following a bolus injection of high specific activity (>100 Ci/mmol) [(11)C]iomazenil. Arterial samples were collected at multiple time points after injection for measurement of unmetabolized total and nonprotein-bound parent compound in plasma. Time activity curves of radioligand concentration in brain and plasma were analyzed using two and three compartment model. Kinetic rate constants of transfer of radioligand between plasma, nonspecifically bound brain tissue, and specifically bound brain tissue compartments were fitted to the model. Values for fitted kinetic rate constants were used in the calculation of measures of benzodiazepine receptor binding, including binding potential (the ratio of receptor density to affinity), and product of BP and the fraction of free nonprotein-bound parent compound (V(3)'). Use of the three compartment model improved the goodness of fit in comparison to the two compartment model. Values for kinetic rate constants and measures of benzodiazepine receptor binding, including BP and V(3)', were similar to results obtained with the SPECT radioligand [(123)I]iomazenil, and a prior report with low specific activity [(11)C]Iomazenil. Kinetic modeling using the three compartment model with PET and high specific activity [(11)C]Iomazenil provides a reliable measure of benzodiazepine receptor binding. Synapse 35:68-77, 2000. Published 2000 Wiley-Liss, Inc.

  15. Towards an improved understanding of processes controlling absorption efficiency and biomagnification of organic chemicals by fish.

    PubMed

    Xiao, Ruiyang; Arnot, Jon A; MacLeod, Matthew

    2015-11-01

    Dietary exposure is considered the dominant pathway for fish exposed to persistent, hydrophobic chemicals in the environment. Here we present a dynamic, fugacity-based three-compartment bioaccumulation model that describes the fish body as one compartment and the gastrointestinal tract (GIT) as two compartments. The model simulates uptake from the GIT by passive diffusion and micelle-mediated diffusion, and chemical degradation in the fish and the GIT compartments. We applied the model to a consistent measured dietary uptake and depuration dataset for rainbow trout (n=215) that is comprised of chlorinated benzenes, biphenyls, dioxins, diphenyl ethers, and polycyclic aromatic hydrocarbons (PAHs). Model performance relative to the measured data is statistically similar regardless of whether micelle-mediated diffusion is included; however, there are considerable uncertainties in modeling this process. When degradation in the GIT is assumed to be negligible, modeled chemical elimination rates are similar to measured rates; however, predicted concentrations of the PAHs are consistently higher than measurements by up to a factor of 20. Introducing a kinetic limit on chemical transport from the fish compartment to the GIT and increasing the rate constant for degradation of PAHs in tissues of the liver and/or GIT are required to achieve good agreement between the modelled and measured concentrations for PAHs. Our results indicate that the apparent low absorption efficiency of PAHs relative to the chemicals with similar hydrophobicity is attributable to biotransformation in the liver and/or the GIT. Our results provide process-level insights about controls on the extent of bioaccumulation of chemicals. Copyright © 2015 Elsevier Ltd. All rights reserved.

  16. Apoplastic and intracellular plant sugars regulate developmental transitions in witches’ broom disease of cacao

    PubMed Central

    Barau, Joan; Grandis, Adriana; Carvalho, Vinicius Miessler de Andrade; Teixeira, Gleidson Silva; Zaparoli, Gustavo Henrique Alcalá; do Rio, Maria Carolina Scatolin; Rincones, Johana; Buckeridge, Marcos Silveira; Pereira, Gonçalo Amarante Guimarães

    2015-01-01

    Witches’ broom disease (WBD) of cacao differs from other typical hemibiotrophic plant diseases by its unusually long biotrophic phase. Plant carbon sources have been proposed to regulate WBD developmental transitions; however, nothing is known about their availability at the plant–fungus interface, the apoplastic fluid of cacao. Data are provided supporting a role for the dynamics of soluble carbon in the apoplastic fluid in prompting the end of the biotrophic phase of infection. Carbon depletion and the consequent fungal sensing of starvation were identified as key signalling factors at the apoplast. MpNEP2, a fungal effector of host necrosis, was found to be up-regulated in an autophagic-like response to carbon starvation in vitro. In addition, the in vivo artificial manipulation of carbon availability in the apoplastic fluid considerably modulated both its expression and plant necrosis rate. Strikingly, infected cacao tissues accumulated intracellular hexoses, and showed stunted photosynthesis and the up-regulation of senescence markers immediately prior to the transition to the necrotrophic phase. These opposite findings of carbon depletion and accumulation in different host cell compartments are discussed within the frame of WBD development. A model is suggested to explain phase transition as a synergic outcome of fungal-related factors released upon sensing of extracellular carbon starvation, and an early senescence of infected tissues probably triggered by intracellular sugar accumulation. PMID:25540440

  17. On dependency properties of the ISIs generated by a two-compartmental neuronal model.

    PubMed

    Benedetto, Elisa; Sacerdote, Laura

    2013-02-01

    One-dimensional leaky integrate and fire neuronal models describe interspike intervals (ISIs) of a neuron as a renewal process and disregarding the neuron geometry. Many multi-compartment models account for the geometrical features of the neuron but are too complex for their mathematical tractability. Leaky integrate and fire two-compartment models seem a good compromise between mathematical tractability and an improved realism. They indeed allow to relax the renewal hypothesis, typical of one-dimensional models, without introducing too strong mathematical difficulties. Here, we pursue the analysis of the two-compartment model studied by Lansky and Rodriguez (Phys D 132:267-286, 1999), aiming of introducing some specific mathematical results used together with simulation techniques. With the aid of these methods, we investigate dependency properties of ISIs for different values of the model parameters. We show that an increase of the input increases the strength of the dependence between successive ISIs.

  18. Absorption of Bupivacaine after Administration of a Lozenge as Topical Treatment for Pain from Oral Mucositis.

    PubMed

    Mogensen, Stine; Sverrisdóttir, Eva; Sveinsdóttir, Kolbrún; Treldal, Charlotte; Jensen, Kenneth; Jensen, Anders Bonde; Kristensen, Claus Andrup; Jacobsen, Jette; Kreilgaard, Mads; Petersen, Janne; Andersen, Ove

    2017-01-01

    The aim was to investigate systemic exposure after administration of a novel bupivacaine lozenge in healthy individuals with normal mucosa and in head and neck cancer (HNC) patients with oral mucositis. A lozenge containing 5, 10, 25 and 50 mg bupivacaine, respectively, was administered as single dose to 10 healthy individuals, and a lozenge containing 25 mg bupivacaine was administered as single dose to 10 HNC patients with oral mucositis and as multiple doses to five patients with HNC. Blood samples were collected for 6 hr from the healthy individuals and 3 hr from the patients with HNC, respectively, after administration. The plasma concentration-time profiles of bupivacaine were fitted to pharmacokinetic models using nonlinear mixed-effects modelling, evaluating demographics and health status as covariates. The population pharmacokinetics (PK) of bupivacaine lozenge was best described by a two-compartment distribution model with absorption transit compartments. All the observed plasma concentrations were well below the bupivacaine concentrations (2000-2250 ng/ml) which have caused toxic symptoms. The PK model suggested that relative bioavailability was two times higher in HNC patients with oral mucositis grade 1-2 and three times higher in HNC patients with oral mucositis grade 3-4 than in the healthy individuals. Simulations showed that the plasma concentrations would be below the toxic limit after repeated dosing every second hour with 25 mg bupivacaine for five days. The 25-mg bupivacaine lozenges were safe without systemic toxic levels of bupivacaine or risk of side effects. Based on PK simulations of repeated doses of 25 mg every two hours for 16 hr a day, the lozenges can be administered with minimum risk of exceeding the toxic limit. © 2016 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society).

  19. A NOVEL PNYSIOLOGICALLY BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT

    EPA Science Inventory

    A NOVEL PHYSIOLOGICALLY-BASED PHARMACOKINETIC (PBPK) MODEL FOR DIMETHYLARSINIC ACID (DMA): THE LUNG AS A STORAGE COMPARTMENT. Evans, M.V., Hughes, M.F., and Kenyon, E.M. USEPA, ORD, NHEERL, RTP, NC 27711

    DMA is the major methylated metabolite of inorganic arsenic, a kno...

  20. Compartment elasticity measured by pressure-related ultrasound to determine patients "at risk" for compartment syndrome: an experimental in vitro study.

    PubMed

    Sellei, Richard Martin; Hingmann, Simon Johannes; Kobbe, Philipp; Weber, Christian; Grice, John Edward; Zimmerman, Frauke; Jeromin, Sabine; Hildebrand, Frank; Pape, Hans-Christoph

    2015-01-01

    Decision-making in treatment of an acute compartment syndrome is based on clinical assessment, supported by invasive monitoring. Thus, evolving compartment syndrome may require repeated pressure measurements. In suspected cases of potential compartment syndromes clinical assessment alone seems to be unreliable. The objective of this study was to investigate the feasibility of a non-invasive application estimating whole compartmental elasticity by ultrasound, which may improve accuracy of diagnostics. In an in vitro model, using an artificial container simulating dimensions of the human anterior tibial compartment, intra-compartmental pressures (p) were raised subsequently up to 80 mmHg by infusion of saline solution. The compartmental depth (mm) in the cross-section view was measured before and after manual probe compression (100 mmHg) upon the surface resulting in a linear compartmental displacement (∆d). This was repeated at rising compartmental pressures. The resulting displacements were related to the corresponding intra-compartmental pressures simulated in our model. A hypothesized relationship between pressures related compartmental displacement and the elasticity at elevated compartment pressures was investigated. With rising compartmental pressures, a non-linear, reciprocal proportional relation between the displacement (mm) and the intra-compartmental pressure (mmHg) occurred. The Pearson coefficient showed a high correlation (r(2) = -0.960). The intra-observer reliability value kappa resulted in a statistically high reliability (κ = 0.840). The inter-observer value indicated a fair reliability (κ = 0.640). Our model reveals that a strong correlation between compartmental strain displacements assessed by ultrasound and the intra-compartmental pressure changes occurs. Further studies are required to prove whether this assessment is transferable to human muscle tissue. Determining the complete compartmental elasticity by ultrasound enhancement, this application may improve detection of early signs of potential compartment syndrome.

  1. A model describing diffusion in prostate cancer.

    PubMed

    Gilani, Nima; Malcolm, Paul; Johnson, Glyn

    2017-07-01

    Quantitative diffusion MRI has frequently been studied as a means of grading prostate cancer. Interpretation of results is complicated by the nature of prostate tissue, which consists of four distinct compartments: vascular, ductal lumen, epithelium, and stroma. Current diffusion measurements are an ill-defined weighted average of these compartments. In this study, prostate diffusion is analyzed in terms of a model that takes explicit account of tissue compartmentalization, exchange effects, and the non-Gaussian behavior of tissue diffusion. The model assumes that exchange between the cellular (ie, stromal plus epithelial) and the vascular and ductal compartments is slow. Ductal and cellular diffusion characteristics are estimated by Monte Carlo simulation and a two-compartment exchange model, respectively. Vascular pseudodiffusion is represented by an additional signal at b = 0. Most model parameters are obtained either from published data or by comparing model predictions with the published results from 41 studies. Model prediction error is estimated using 10-fold cross-validation. Agreement between model predictions and published results is good. The model satisfactorily explains the variability of ADC estimates found in the literature. A reliable model that predicts the diffusion behavior of benign and cancerous prostate tissue of different Gleason scores has been developed. Magn Reson Med 78:316-326, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

  2. Why does walking economy improve after weight loss in obese adolescents?

    PubMed

    Peyrot, Nicolas; Thivel, David; Isacco, Laurie; Morin, Jean-Benoît; Belli, Alain; Duche, Pascale

    2012-04-01

    This study tested the hypothesis that the increase in walking economy (i.e., decrease in net metabolic rate per kilogram) after weight loss in obese adolescents is induced by a lower metabolic rate required to support the lower body weight and maintain balance during walking. Sixteen obese adolescent boys and girls were tested before and after a weight reduction program. Body composition and oxygen uptake while standing and walking at four preset speeds (0.75, 1, 1.25, and 1.5 m·s⁻¹) and at the preferred speed were quantified. Net metabolic rate and gross metabolic cost of walking-versus-speed relationships were determined. A three-compartment model was used to distinguish the respective parts of the metabolic rate associated with standing (compartment 1), maintaining balance and supporting body weight during walking (compartment 2), and muscle contractions required to move the center of mass and limbs (compartment 3). Standing metabolic rate per kilogram (compartment 1) significantly increased after weight loss, whereas net metabolic rate per kilogram during walking decreased by 9% on average across speeds. Consequently, the gross metabolic cost of walking per unit of distance-versus-speed relationship and hence preferred walking speeds did not change with weight loss. Compartment 2 of the model was significantly lower after weight loss, whereas compartment 3 did not change. The model showed that the improvement in walking economy after weight loss in obese adolescents was likely related to the lower metabolic rate of the isometric muscular contractions required to support the lower body weight and maintain balance during walking. Contrastingly, the part of the total metabolic rate associated with muscle contractions required to move the center of mass and limbs did not seem to be related to the improvement in walking economy in weight-reduced individuals.

  3. Multiproxy analyses of Lake Allos reveal synchronicity and divergence in geosystem dynamics during the Lateglacial/Holocene in the Alps

    NASA Astrophysics Data System (ADS)

    Cartier, Rosine; Brisset, Elodie; Guiter, Frédéric; Sylvestre, Florence; Tachikawa, Kazuyo; Anthony, Edward J.; Paillès, Christine; Bruneton, Hélène; Bard, Edouard; Miramont, Cécile

    2018-04-01

    Palaeoenvironmental reconstructions of ecosystem responses to external forcing are generally limited by the difficulty of understanding the geosystem as a whole, because of the complex interactions between ecological compartments. Therefore, identifying which geosystem compartments or proxies co-vary is a prerequisite in unravelling the propagation of disturbances (e.g. climatic or anthropogenic) from one compartment to another. A multiproxy study of a continuous 13,500-year sedimentary profile cored in Lake Allos (European Alps, 2200 m a.s.l) was carried out on the basis of high-resolution sedimentological, geochemical, and botanical analyses, as well as determination of aquatic biotic proxies (diatoms, ostracods). These multiproxy datasets are rare at these high altitudes. Major changes occurred in the course of the palaeoenvironmental history of this alpine watershed at 12,000, 8600, 7200 and 3000 cal. BP. During the Holocene, two main transitions were recorded in all the ecological compartments (8600 and 3000 cal. BP), but the period 4500-3000 cal. BP stands out because of major changes that concerned only the lacustrine ecosystem. The frequent switches in lake level might correspond to the 4.2 ka climatic event. Proximity of this alpine lake to climatically-sensitive thresholds (ice-cover, thermal stratification, hydrological balance) may have amplified climatic signals in the lake ecosystem. This study illustrates the difficulties inherent to the use of common intra-Holocene stratigraphical limits, given that ecological compartments are likely to have different responses to forcing factors depending on the characteristics of the watershed and its capacity to accommodate disturbances.

  4. Measuring Compartment Size and Gas Solubility in Marine Mammals

    DTIC Science & Technology

    2015-09-30

    bends? Effect of diving behaviour and physiology on modelled gas exchange for three species: Ziphius cavirostris, Mesoplodon densirostris and Hyperoodon...1 DISTRIBUTION STATEMENT A. Approved for public release; distribution is unlimited. Measuring Compartment Size and Gas Solubility in Marine...is to develop methods to estimate marine mamal tissue compartment sizes, and tissue gas solubility. We aim to improve the data available for the

  5. Reaction time for trimolecular reactions in compartment-based reaction-diffusion models

    NASA Astrophysics Data System (ADS)

    Li, Fei; Chen, Minghan; Erban, Radek; Cao, Yang

    2018-05-01

    Trimolecular reaction models are investigated in the compartment-based (lattice-based) framework for stochastic reaction-diffusion modeling. The formulae for the first collision time and the mean reaction time are derived for the case where three molecules are present in the solution under periodic boundary conditions. For the case of reflecting boundary conditions, similar formulae are obtained using a computer-assisted approach. The accuracy of these formulae is further verified through comparison with numerical results. The presented derivation is based on the first passage time analysis of Montroll [J. Math. Phys. 10, 753 (1969)]. Montroll's results for two-dimensional lattice-based random walks are adapted and applied to compartment-based models of trimolecular reactions, which are studied in one-dimensional or pseudo one-dimensional domains.

  6. A fugacity-based indoor residential pesticide fate model

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Bennett, Deborah H.; Furtaw, Edward J.; McKone, Thomas E.

    Dermal and non-dietary pathways are potentially significant exposure pathways to pesticides used in residences. Exposure pathways include dermal contact with residues on surfaces, ingestion from hand- and object-to-mouth activities, and absorption of pesticides into food. A limited amount of data has been collected on pesticide concentrations in various residential compartments following an application. But models are needed to interpret this data and make predictions about other pesticides based on chemical properties. In this paper, we propose a mass-balance compartment model based on fugacity principles. We include air (both gas phase and aerosols), carpet, smooth flooring, and walls as model compartments.more » Pesticide concentrations on furniture and toys, and in food, are being added to the model as data becomes available. We determine the compartmental fugacity capacity and mass transfer-rate coefficient for wallboard as an example. We also present the framework and equations needed for a dynamic mass-balance model.« less

  7. An experimental approach towards the development of an in vitro cortical-thalamic co-culture model.

    PubMed

    Kanagasabapathi, Thirukumaran T; Massobrio, Paolo; Tedesco, Mariateresa; Martinoia, Sergio; Wadman, Wytse J; Decré, Michel M J

    2011-01-01

    In this paper, we propose an experimental approach to develop an in vitro dissociated cortical-thalamic co-culture model using a dual compartment neurofluidic device. The device has two compartments separated by 10 μm wide and 3 μm high microchannels. The microchannels provide a physical isolation of neurons allowing only neurites to grow between the compartments. Long-term viable co-culture was maintained in the compartmented device, neurite growth through the microchannels was verified using immunofluorescence staining, and electrophysiological recordings from the co-culture system was investigated. Preliminary analysis of spontaneous activities from the co-culture shows a distinctively different firing pattern associated with cultures of individual cell types and further analysis is proposed for a deeper understanding of the dynamics involved in the network connectivity in such a co-culture system.

  8. A physiology-based parametric imaging method for FDG-PET data

    NASA Astrophysics Data System (ADS)

    Scussolini, Mara; Garbarino, Sara; Sambuceti, Gianmario; Caviglia, Giacomo; Piana, Michele

    2017-12-01

    Parametric imaging is a compartmental approach that processes nuclear imaging data to estimate the spatial distribution of the kinetic parameters governing tracer flow. The present paper proposes a novel and efficient computational method for parametric imaging which is potentially applicable to several compartmental models of diverse complexity and which is effective in the determination of the parametric maps of all kinetic coefficients. We consider applications to [18 F]-fluorodeoxyglucose positron emission tomography (FDG-PET) data and analyze the two-compartment catenary model describing the standard FDG metabolization by an homogeneous tissue and the three-compartment non-catenary model representing the renal physiology. We show uniqueness theorems for both models. The proposed imaging method starts from the reconstructed FDG-PET images of tracer concentration and preliminarily applies image processing algorithms for noise reduction and image segmentation. The optimization procedure solves pixel-wise the non-linear inverse problem of determining the kinetic parameters from dynamic concentration data through a regularized Gauss-Newton iterative algorithm. The reliability of the method is validated against synthetic data, for the two-compartment system, and experimental real data of murine models, for the renal three-compartment system.

  9. Modeling of Tracer Transport Delays for Improved Quantification of Regional Pulmonary ¹⁸F-FDG Kinetics, Vascular Transit Times, and Perfusion.

    PubMed

    Wellman, Tyler J; Winkler, Tilo; Vidal Melo, Marcos F

    2015-11-01

    ¹⁸F-FDG-PET is increasingly used to assess pulmonary inflammatory cell activity. However, current models of pulmonary ¹⁸F-FDG kinetics do not account for delays in ¹⁸F-FDG transport between the plasma sampling site and the lungs. We developed a three-compartment model of ¹⁸F-FDG kinetics that includes a delay between the right heart and the local capillary blood pool, and used this model to estimate regional pulmonary perfusion. We acquired dynamic ¹⁸F-FDG scans in 12 mechanically ventilated sheep divided into control and lung injury groups (n = 6 each). The model was fit to tracer kinetics in three isogravitational regions-of-interest to estimate regional lung transport delays and regional perfusion. ¹³NN bolus infusion scans were acquired during a period of apnea to measure regional perfusion using an established reference method. The delayed input function model improved description of ¹⁸F-FDG kinetics (lower Akaike Information Criterion) in 98% of studied regions. Local transport delays ranged from 2.0 to 13.6 s, averaging 6.4 ± 2.9 s, and were highest in non-dependent regions. Estimates of regional perfusion derived from model parameters were highly correlated with perfusion measurements based on ¹³NN-PET (R² = 0.92, p < 0.001). By incorporating local vascular transports delays, this model of pulmonary ¹⁸F-FDG kinetics allows for simultaneous assessment of regional lung perfusion, transit times, and inflammation.

  10. How tibiofemoral alignment and contact locations affect predictions of medial and lateral tibiofemoral contact forces.

    PubMed

    Lerner, Zachary F; DeMers, Matthew S; Delp, Scott L; Browning, Raymond C

    2015-02-26

    Understanding degeneration of biological and prosthetic knee joints requires knowledge of the in-vivo loading environment during activities of daily living. Musculoskeletal models can estimate medial/lateral tibiofemoral compartment contact forces, yet anthropometric differences between individuals make accurate predictions challenging. We developed a full-body OpenSim musculoskeletal model with a knee joint that incorporates subject-specific tibiofemoral alignment (i.e. knee varus-valgus) and geometry (i.e. contact locations). We tested the accuracy of our model and determined the importance of these subject-specific parameters by comparing estimated to measured medial and lateral contact forces during walking in an individual with an instrumented knee replacement and post-operative genu valgum (6°). The errors in the predictions of the first peak medial and lateral contact force were 12.4% and 11.9%, respectively, for a model with subject-specific tibiofemoral alignment and contact locations determined through radiographic analysis, vs. 63.1% and 42.0%, respectively, for a model with generic parameters. We found that each degree of tibiofemoral alignment deviation altered the first peak medial compartment contact force by 51N (r(2)=0.99), while each millimeter of medial-lateral translation of the compartment contact point locations altered the first peak medial compartment contact force by 41N (r(2)=0.99). The model, available at www.simtk.org/home/med-lat-knee/, enables the specification of subject-specific joint alignment and compartment contact locations to more accurately estimate medial and lateral tibiofemoral contact forces in individuals with non-neutral alignment. Copyright © 2015 Elsevier Ltd. All rights reserved.

  11. How Tibiofemoral Alignment and Contact Locations Affect Predictions of Medial and Lateral Tibiofemoral Contact Forces

    PubMed Central

    Lerner, Zachary F.; DeMers, Matthew S.; Delp, Scott L.; Browning, Raymond C.

    2015-01-01

    Understanding degeneration of biological and prosthetic knee joints requires knowledge of the in-vivo loading environment during activities of daily living. Musculoskeletal models can estimate medial/lateral tibiofemoral compartment contact forces, yet anthropometric differences between individuals make accurate predictions challenging. We developed a full-body OpenSim musculoskeletal model with a knee joint that incorporates subject-specific tibiofemoral alignment (i.e. knee varus-valgus) and geometry (i.e. contact locations). We tested the accuracy of our model and determined the importance of these subject-specific parameters by comparing estimated to measured medial and lateral contact forces during walking in an individual with an instrumented knee replacement and post-operative genu valgum (6°). The errors in the predictions of the first peak medial and lateral contact force were 12.4% and 11.9%, respectively, for a model with subject-specific tibiofemoral alignment and contact locations determined via radiographic analysis, vs. 63.1% and 42.0%, respectively, for a model with generic parameters. We found that each degree of tibiofemoral alignment deviation altered the first peak medial compartment contact force by 51N (r2=0.99), while each millimeter of medial-lateral translation of the compartment contact point locations altered the first peak medial compartment contact force by 41N (r2=0.99). The model, available at www.simtk.org/home/med-lat-knee/, enables the specification of subject-specific joint alignment and compartment contact locations to more accurately estimate medial and lateral tibiofemoral contact forces in individuals with non-neutral alignment. PMID:25595425

  12. Cell proliferation in normal epidermis

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weinstein, G.D.; McCullough, J.L.; Ross, P.

    1984-06-01

    A detailed examination of cell proliferation kinetics in normal human epidermis is presented. Using tritiated thymidine with autoradiographic techniques, proliferative and differentiated cell kinetics are defined and interrelated. The proliferative compartment of normal epidermis has a cell cycle duration (Tc) of 311 h derived from 3 components: the germinative labeling index (LI), the duration of DNA synthesis (ts), and the growth fraction (GF). The germinative LI is 2.7% +/- 1.2 and ts is 14 h, the latter obtained from a composite fraction of labeled mitoses curve obtained from 11 normal subjects. The GF obtained from the literature and from humanmore » skin xenografts to nude mice is estimated to be 60%. Normal-appearing epidermis from patients with psoriasis appears to have a higher proliferation rate. The mean LI is 4.2% +/- 0.9, approximately 50% greater than in normal epidermis. Absolute cell kinetic values for this tissue, however, cannot yet be calculated for lack of other information on ts and GF. A kinetic model for epidermal cell renewal in normal epidermis is described that interrelates the rate of birth/entry, transit, and/or loss of keratinocytes in the 3 epidermal compartments: proliferative, viable differentiated (stratum malpighii), and stratum corneum. Expected kinetic homeostasis in the epidermis is confirmed by the very similar ''turnover'' rates in each of the compartments that are, respectively, 1246, 1417, and 1490 cells/day/mm2 surface area. The mean epidermal turnover time of the entire tissue is 39 days. The Tc of 311 h in normal cells in 8-fold longer than the psoriatic Tc of 36 h and is necessary for understanding the hyperproliferative pathophysiologic process in psoriasis.« less

  13. Current concepts in the pathophysiology, evaluation, and diagnosis of compartment syndrome

    NASA Technical Reports Server (NTRS)

    Hargens, A. R.; Mubarak, S. J.

    1998-01-01

    This article reviews present knowledge of the pathophysiology and diagnosis of acute compartment syndromes. Recent results using compression of legs in normal volunteers provide objective data concerning local pressure thresholds for neuromuscular dysfunction in the anterior compartment. Results with this model indicate that a progression of neuromuscular deficits occurs when IMP increases to within 35 to 40 mm Hg of diastolic blood pressure. These findings provide useful information on the diagnosis and compression thresholds for acute compartment syndromes. Time factors are also important, however, and usually are incompletely known in most cases of acute compartment syndrome. Although the slit catheter is a very good technique for monitoring IMP during rest, these catheters and their associated extracorporeal transducer systems are not ideal. Recently developed miniature transducer-tipped catheters and, perhaps, future development of noninvasive techniques may provide accurate recordings of IMP in patients with acute compartment syndromes.

  14. Granular fountains: convection cascade in a compartmentalized granular gas.

    PubMed

    van der Meer, Devaraj; van der Weele, Ko; Reimann, Peter

    2006-06-01

    This paper extends the two-compartment granular fountain [D. van der Meer, P. Reimann, K. van der Weele, and D. Lohse, Phys. Rev. Lett. 92, 184301 (2004)] to an arbitrary number of compartments: the tendency of a granular gas to form clusters is exploited to generate spontaneous convective currents, with particles going down in the well-filled compartments and going up in the diluted ones. We focus upon the bifurcation diagram of the general -compartment system, which is constructed using a dynamical flux model and which proves to agree quantitatively with results from molecular dynamics simulations.

  15. GLI1 inhibition promotes epithelial-to-mesenchymal transition in pancreatic cancer cells

    PubMed Central

    Joost, Simon; Almada, Luciana L.; Rohnalter, Verena; Holz, Philipp S.; Vrabel, Anne M.; Fernandez-Barrena, Maite G.; McWilliams, Robert R.; Krause, Michael; Fernandez-Zapico, Martin E.; Lauth, Matthias

    2011-01-01

    The Hedgehog (HH) pathway has been identified as an important deregulated signal transduction pathway in pancreatic ductal adenocarcinoma (PDAC), a cancer type characterized by a highly metastatic phenotype. In PDAC, the canonical HH pathway activity is restricted to the stromal compartment while HH signaling in the tumor cells is reduced as a consequence of constitutive KRAS activation. Here we report that in the tumor compartment of PDAC the HH pathway effector transcription factor GLI1 regulates epithelial differentiation. RNAi-mediated knockdown of GLI1 abolished characteristics of epithelial differentiation, increased cell motility and synergized with TGFβ to induce an epithelial-to-mesenchymal transition (EMT). Notably, EMT conversion in PDAC cells occurred in the absence of induction of SNAIL or SLUG, two canonical inducers of EMT in many other settings. Further mechanistic analysis revealed that GLI1 directly regulated the transcription of E-cadherin, a key determinant of epithelial tissue organization. Collectively, our findings identify GLI1 as an important positive regulator of epithelial differentiation, and they offer an explanation for how decreased levels of GLI1 are likely to contribute to the highly metastatic phenotype of PDAC. PMID:22086851

  16. The Blood-Testis Barrier and Its Implications for Male Contraception

    PubMed Central

    Mruk, Dolores D.

    2012-01-01

    The blood-testis barrier (BTB) is one of the tightest blood-tissue barriers in the mammalian body. It divides the seminiferous epithelium into the basal and the apical (adluminal) compartments. Meiosis I and II, spermiogenesis, and spermiation all take place in a specialized microenvironment behind the BTB in the apical compartment, but spermatogonial renewal and differentiation and cell cycle progression up to the preleptotene spermatocyte stage take place outside of the BTB in the basal compartment of the epithelium. However, the BTB is not a static ultrastructure. Instead, it undergoes extensive restructuring during the seminiferous epithelial cycle of spermatogenesis at stage VIII to allow the transit of preleptotene spermatocytes at the BTB. Yet the immunological barrier conferred by the BTB cannot be compromised, even transiently, during the epithelial cycle to avoid the production of antibodies against meiotic and postmeiotic germ cells. Studies have demonstrated that some unlikely partners, namely adhesion protein complexes (e.g., occludin-ZO-1, N-cadherin-β-catenin, claudin-5-ZO-1), steroids (e.g., testosterone, estradiol-17β), nonreceptor protein kinases (e.g., focal adhesion kinase, c-Src, c-Yes), polarity proteins (e.g., PAR6, Cdc42, 14-3-3), endocytic vesicle proteins (e.g., clathrin, caveolin, dynamin 2), and actin regulatory proteins (e.g., Eps8, Arp2/3 complex), are working together, apparently under the overall influence of cytokines (e.g., transforming growth factor-β3, tumor necrosis factor-α, interleukin-1α). In short, a “new” BTB is created behind spermatocytes in transit while the “old” BTB above transiting cells undergoes timely degeneration, so that the immunological barrier can be maintained while spermatocytes are traversing the BTB. We also discuss recent findings regarding the molecular mechanisms by which environmental toxicants (e.g., cadmium, bisphenol A) induce testicular injury via their initial actions at the BTB to elicit subsequent damage to germ-cell adhesion, thereby leading to germ-cell loss, reduced sperm count, and male infertility or subfertility. Moreover, we also critically evaluate findings in the field regarding studies on drug transporters in the testis and discuss how these influx and efflux pumps regulate the entry of potential nonhormonal male contraceptives to the apical compartment to exert their effects. Collectively, these findings illustrate multiple potential targets are present at the BTB for innovative contraceptive development and for better delivery of drugs to alleviate toxicant-induced reproductive dysfunction in men. PMID:22039149

  17. Estimating fat-free mass in elite-level male rowers: a four-compartment model validation of laboratory and field methods.

    PubMed

    Kendall, Kristina L; Fukuda, David H; Hyde, Parker N; Smith-Ryan, Abbie E; Moon, Jordon R; Stout, Jeffrey R

    2017-04-01

    The purpose of this study was to investigate the accuracy of fat-free mass (FFM) estimates from two-compartment (2C) models including air displacement plethysmography (ADP), ultrasound (US), near-infrared interactance (NIR), and the Jackson and Pollock skinfold equation (SKF) against a criterion four-compartment (4C) model in elite male rowers. Twenty-three elite-level male rowers (mean± SD; age 24.6 ± 2.2 years; stature: 191.4 ± 7.2 cm; mass: 87.2 ± 11.2 kg) participated in this investigation. All body composition assessments were performed on the same day in random order, except for hydrostatic weighing (HW), which was measured last. FFM was evaluated using a 4C model, which included total body water from bioimpedance spectroscopy, body volume from HW, and total body bone mineral via dual-energy X-ray absorptiometry. The major findings of the study were that the 2C models evaluated overestimated FFM and should be considered with caution for the assessment of FFM in elite male rowers. Future studies should use multiple-compartment models, with measurement of TBW and bone mineral content, for the estimation of FFM.

  18. A Hybrid Windkessel Model of Blood Flow in Arterial Tree Using Velocity Profile Method

    NASA Astrophysics Data System (ADS)

    Aboelkassem, Yasser; Virag, Zdravko

    2016-11-01

    For the study of pulsatile blood flow in the arterial system, we derived a coupled Windkessel-Womersley mathematical model. Initially, a 6-elements Windkessel model is proposed to describe the hemodynamics transport in terms of constant resistance, inductance and capacitance. This model can be seen as a two compartment model, in which the compartments are connected by a rigid pipe, modeled by one inductor and resistor. The first viscoelastic compartment models proximal part of the aorta, the second elastic compartment represents the rest of the arterial tree and aorta can be seen as the connection pipe. Although the proposed 6-elements lumped model was able to accurately reconstruct the aortic pressure, it can't be used to predict the axial velocity distribution in the aorta and the wall shear stress and consequently, proper time varying pressure drop. We then modified this lumped model by replacing the connection pipe circuit elements with a vessel having a radius R and a length L. The pulsatile flow motions in the vessel are resolved instantaneously along with the Windkessel like model enable not only accurate prediction of the aortic pressure but also wall shear stress and frictional pressure drop. The proposed hybrid model has been validated using several in-vivo aortic pressure and flow rate data acquired from different species such as, humans, dogs and pigs. The method accurately predicts the time variation of wall shear stress and frictional pressure drop. Institute for Computational Medicine, Dept. Biomedical Engineering.

  19. Temporal and spatial changes of cells positive for stem-like markers in different compartments and stages of human colorectal adenoma-carcinoma sequence

    PubMed Central

    Cui, Guanglin; Xu, Gang; Zhu, Li; Pang, Zhigang; Zheng, Wei; Li, Zhenfeng; Yuan, Aping

    2017-01-01

    Considerable evidence supports the idea that stem-like cells may play an essential role during the development of colorectal cancer (CRC). To accomplish this aim, we use immunohistochemistry (IHC) and double IHC with different potential stem-like markers, anti-musashi (Msi), anti-CD133, anti- LGR5 and anti-ALDH1 to examine the presentation of stem-like cells in different compartments including adenoma/CRC epithelium, transitional crypts and tumor stroma in colorectal adenoma and CRC. The results showed that cells positive for stem-like markers were remarkably increased in number and frequently observed in the adenoma/CRC epithelium, transitional crypts and tumor stroma. Notably, the population of cells positive for stem-liker markers was expanded from the base to the middle part of the transitional crypt in both adenoma and CRC tissues, reflecting that stem-like cells are likely involved in the process of colorectal tumorigenesis. Counting results showed that the grading scores of cells positive for LGR5 and ALDH1 in the adenoma/CRC epithelium were significantly increased relative with the control epithelium, and associated with the degree of dysplasia in the adenoma and node involvement in the CRC (all P < 0.05). In addition, the density of cells positive for stem–like markers in the adenomatous/cancerous stroma was also increased and paralleled an increase in the density of proliferative stromal cells labeled by PCNA, which were primarily identified as vimentin positive fibroblasts. Our results have revealed a changed temporal and spatial presentation of stem-like markers in different stages of human colorectal adenoma-carcinoma sequence, which might be a hallmark of the adenoma-carcinoma transition. PMID:28484082

  20. A new statistical method for transfer coefficient calculations in the framework of the general multiple-compartment model of transport for radionuclides in biological systems.

    PubMed

    Garcia, F; Arruda-Neto, J D; Manso, M V; Helene, O M; Vanin, V R; Rodriguez, O; Mesa, J; Likhachev, V P; Filho, J W; Deppman, A; Perez, G; Guzman, F; de Camargo, S P

    1999-10-01

    A new and simple statistical procedure (STATFLUX) for the calculation of transfer coefficients of radionuclide transport to animals and plants is proposed. The method is based on the general multiple-compartment model, which uses a system of linear equations involving geometrical volume considerations. By using experimentally available curves of radionuclide concentrations versus time, for each animal compartment (organs), flow parameters were estimated by employing a least-squares procedure, whose consistency is tested. Some numerical results are presented in order to compare the STATFLUX transfer coefficients with those from other works and experimental data.

  1. Modelling the delay between pharmacokinetics and EEG effects of morphine in rats: binding kinetic versus effect compartment models.

    PubMed

    de Witte, Wilhelmus E A; Rottschäfer, Vivi; Danhof, Meindert; van der Graaf, Piet H; Peletier, Lambertus A; de Lange, Elizabeth C M

    2018-05-18

    Drug-target binding kinetics (as determined by association and dissociation rate constants, k on and k off ) can be an important determinant of the kinetics of drug action. However, the effect compartment model is used most frequently instead of a target binding model to describe hysteresis. Here we investigate when the drug-target binding model should be used in lieu of the effect compartment model. The utility of the effect compartment (EC), the target binding kinetics (TB) and the combined effect compartment-target binding kinetics (EC-TB) model were tested on either plasma (EC PL , TB PL and EC-TB PL ) or brain extracellular fluid (ECF) (EC ECF , TB ECF and EC-TB ECF ) morphine concentrations and EEG amplitude in rats. It was also analyzed when a significant shift in the time to maximal target occupancy (Tmax TO ) with increasing dose, the discriminating feature between the TB and EC model, occurs in the TB model. All TB models assumed a linear relationship between target occupancy and drug effect on the EEG amplitude. All three model types performed similarly in describing the morphine pharmacodynamics data, although the EC model provided the best statistical result. The analysis of the shift in Tmax TO (∆Tmax TO ) as a result of increasing dose revealed that ∆Tmax TO is decreasing towards zero if the k off is much smaller than the elimination rate constant or if the target concentration is larger than the initial morphine concentration. The results for the morphine PKPD modelling and the analysis of ∆Tmax TO indicate that the EC and TB models do not necessarily lead to different drug effect versus time curves for different doses if a delay between drug concentrations and drug effect (hysteresis) is described. Drawing mechanistic conclusions from successfully fitting one of these two models should therefore be avoided. Since the TB model can be informed by in vitro measurements of k on and k off , a target binding model should be considered more often for mechanistic modelling purposes.

  2. A review of models for near-field exposure pathways of chemicals in consumer products.

    PubMed

    Huang, Lei; Ernstoff, Alexi; Fantke, Peter; Csiszar, Susan A; Jolliet, Olivier

    2017-01-01

    Exposure to chemicals in consumer products has been gaining increasing attention, with multiple studies showing that near-field exposures from products is high compared to far-field exposures. Regarding the numerous chemical-product combinations, there is a need for an overarching review of models able to quantify the multiple transfers of chemicals from products used near-field to humans. The present review therefore aims at an in-depth overview of modeling approaches for near-field chemical release and human exposure pathways associated with consumer products. It focuses on lower-tier, mechanistic models suitable for life cycle assessments (LCA), chemical alternative assessment (CAA) and high-throughput screening risk assessment (HTS). Chemicals in a product enter the near-field via a defined "compartment of entry", are transformed or transferred to adjacent compartments, and eventually end in a "human receptor compartment". We first focus on models of physical mass transfers from the product to 'near-field' compartments. For transfers of chemicals from article interior, adequate modeling of in-article diffusion and of partitioning between article surface and air/skin/food is key. Modeling volatilization and subsequent transfer to the outdoor is crucial for transfers of chemicals used in the inner space of appliances, on object surfaces or directly emitted to indoor air. For transfers from skin surface, models need to reflect the competition between dermal permeation, volatilization and fraction washed-off. We then focus on transfers from the 'near-field' to 'human' compartments, defined as respiratory tract, gastrointestinal tract and epidermis, for which good estimates of air concentrations, non-dietary ingestion parameters and skin permeation are essential, respectively. We critically characterize for each exposure pathway the ability of models to estimate near-field transfers and to best inform LCA, CAA and HTS, summarizing the main characteristics of the potentially best-suited models. This review identifies large knowledge gaps for several near-field pathways and suggests research needs and future directions. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. Compartment models of the diffusion MR signal in brain white matter: a taxonomy and comparison.

    PubMed

    Panagiotaki, Eleftheria; Schneider, Torben; Siow, Bernard; Hall, Matt G; Lythgoe, Mark F; Alexander, Daniel C

    2012-02-01

    This paper aims to identify the minimum requirements for an accurate model of the diffusion MR signal in white matter of the brain. We construct a taxonomy of multi-compartment models of white matter from combinations of simple models for the intra- and the extra-axonal spaces. We devise a new diffusion MRI protocol that provides measurements with a wide range of imaging parameters for diffusion sensitization both parallel and perpendicular to white matter fibres. We use the protocol to acquire data from two fixed rat brains, which allows us to fit, study and compare the different models. The study examines a total of 47 analytic models, including several well-used models from the literature, which we place within the taxonomy. The results show that models that incorporate intra-axonal restriction, such as ball and stick or CHARMED, generally explain the data better than those that do not, such as the DT or the biexponential models. However, three-compartment models which account for restriction parallel to the axons and incorporate pore size explain the measurements most accurately. The best fit comes from combining a full diffusion tensor (DT) model of the extra-axonal space with a cylindrical intra-axonal component of single radius and a third spherical compartment of non-zero radius. We also measure the stability of the non-zero radius intra-axonal models and find that single radius intra-axonal models are more stable than gamma distributed radii models with similar fitting performance. Copyright © 2011 Elsevier Inc. All rights reserved.

  4. Fates of Acid-Resistant and Non-Acid-Resistant Shiga Toxin-Producing Escherichia coli Strains in Ruminant Digestive Contents in the Absence and Presence of Probiotics ▿

    PubMed Central

    Chaucheyras-Durand, Frédérique; Faqir, Fahima; Ameilbonne, Aurélie; Rozand, Christine; Martin, Christine

    2010-01-01

    Healthy ruminants are the main reservoir of Shiga toxin-producing Escherichia coli (STEC). During their transit through the ruminant gastrointestinal tract, STEC encounters a number of acidic environments. As all STEC strains are not equally resistant to acidic conditions, the purpose of this study was to investigate whether acid resistance confers an ecological advantage to STEC strains in ruminant digestive contents and whether acid resistance mechanisms are induced in the rumen compartment. We found that acid-resistant STEC survived at higher rates during prolonged incubation in rumen fluid than acid-sensitive STEC and that they resisted the highly acidic conditions of the abomasum fluid, whereas acid-sensitive strains were killed. However, transit through the rumen contents allowed acid-sensitive strains to survive in the abomasum fluid at levels similar to those of acid-resistant STEC. The acid resistance status of the strains had little influence on STEC growth in jejunal and cecal contents. Supplementation with the probiotic Saccharomyces cerevisiae CNCM I-1077 or Lactobacillus acidophilus BT-1386 led to killing of all of the strains tested during prolonged incubation in the rumen contents, but it did not have any influence in the other digestive compartments. In addition, S. cerevisiae did not limit the induction of acid resistance in the rumen fluid. Our results indicate that the rumen compartment could be a relevant target for intervention strategies that could both limit STEC survival and eliminate induction of acid resistance mechanisms in order to decrease the number of viable STEC cells reaching the hindgut and thus STEC shedding and food contamination. PMID:19948865

  5. Multi-compartmental modeling of SORLA’s influence on amyloidogenic processing in Alzheimer’s disease

    PubMed Central

    2012-01-01

    Background Proteolytic breakdown of the amyloid precursor protein (APP) by secretases is a complex cellular process that results in formation of neurotoxic Aβ peptides, causative of neurodegeneration in Alzheimer’s disease (AD). Processing involves monomeric and dimeric forms of APP that traffic through distinct cellular compartments where the various secretases reside. Amyloidogenic processing is also influenced by modifiers such as sorting receptor-related protein (SORLA), an inhibitor of APP breakdown and major AD risk factor. Results In this study, we developed a multi-compartment model to simulate the complexity of APP processing in neurons and to accurately describe the effects of SORLA on these processes. Based on dose–response data, our study concludes that SORLA specifically impairs processing of APP dimers, the preferred secretase substrate. In addition, SORLA alters the dynamic behavior of β-secretase, the enzyme responsible for the initial step in the amyloidogenic processing cascade. Conclusions Our multi-compartment model represents a major conceptual advance over single-compartment models previously used to simulate APP processing; and it identified APP dimers and β-secretase as the two distinct targets of the inhibitory action of SORLA in Alzheimer’s disease. PMID:22727043

  6. Organic Pollutant Penetration through Fruit Polyester Skin: A Modified Three-compartment Diffusion Model

    NASA Astrophysics Data System (ADS)

    Li, Yungui; Li, Qingqing; Chen, Baoliang

    2016-03-01

    The surface of plants is covered by a continuous but heterogeneous cuticular membrane (CM). Serving as the first protective barrier, the uptake and transport behavior of organic pollutants at this interface continue to engage the research efforts of environmental chemist. To date, the contributions of cuticular components as a defense against the organic pollutants penetration remain unresolved. In this study, the unsteady-state penetration characteristics of phenanthrene (PHE) through isolated fruit CM was investigated. PHE penetration was differentiated by three cuticular compartments: epicuticular waxes (EW), cuticle proper (CP) and cuticular layer (CL). The driving force for PHE penetration was ascribed to the sharp concentration gradient built up endogenously by cuticular compartments with different lipophilic affinities. A modified penetration model was established and verified in terms of its general suitability for the hydrophobic chemicals and CMs of various plant species (apple, tomato and potato). The new three-compartment model demonstrates much higher accuracy in characterizing the uptake and transport behavior of semivolatile chemicals with fewer limitations in terms of environmental conditions and complexity (e.g., coexisting contaminants and temperature). This model could contribute to a more comprehensive understanding on the role of polymeric lipids in the organic pollutant sorption and transport into plants.

  7. Organic Pollutant Penetration through Fruit Polyester Skin: A Modified Three-compartment Diffusion Model.

    PubMed

    Li, Yungui; Li, Qingqing; Chen, Baoliang

    2016-03-24

    The surface of plants is covered by a continuous but heterogeneous cuticular membrane (CM). Serving as the first protective barrier, the uptake and transport behavior of organic pollutants at this interface continue to engage the research efforts of environmental chemist. To date, the contributions of cuticular components as a defense against the organic pollutants penetration remain unresolved. In this study, the unsteady-state penetration characteristics of phenanthrene (PHE) through isolated fruit CM was investigated. PHE penetration was differentiated by three cuticular compartments: epicuticular waxes (EW), cuticle proper (CP) and cuticular layer (CL). The driving force for PHE penetration was ascribed to the sharp concentration gradient built up endogenously by cuticular compartments with different lipophilic affinities. A modified penetration model was established and verified in terms of its general suitability for the hydrophobic chemicals and CMs of various plant species (apple, tomato and potato). The new three-compartment model demonstrates much higher accuracy in characterizing the uptake and transport behavior of semivolatile chemicals with fewer limitations in terms of environmental conditions and complexity (e.g., coexisting contaminants and temperature). This model could contribute to a more comprehensive understanding on the role of polymeric lipids in the organic pollutant sorption and transport into plants.

  8. Compartmental modeling with nitrogen-15 to determine effects of degree of fat saturation on intraruminal N recycling.

    PubMed

    Oldick, B S; Firkins, J L; Kohn, R A

    2000-09-01

    Two- and three-compartment models were developed to describe N kinetics within the rumen using three Holstein heifers and one nonlactating Holstein cow fitted with ruminal and duodenal cannulas. A 4 x 4 Latin square design included a control diet containing no supplemental fat and diets containing 4.85% of diet dry matter as partially hydrogenated tallow (iodine value = 13), tallow (iodine value = 51), or animal-vegetable fat (iodine value = 110). Effects of fat on intraruminal N recycling and relationships between intraruminal N recycling and ruminal protozoa concentration or the efficiency of microbial protein synthesis were determined. A pulse dose of 15(NH4)2SO4 was introduced into the ruminal NH3 N pool, and samples were taken over time from the ruminal NH3 N and nonammonia N pools. For the three-compartment model, precipitates of nonammonia N after trichloroacetic acid and ethanol extraction were defined as slowly turning over nonammonia N; rapidly turning over nonammonia N was determined by difference. Curves of 15N enrichment were fit to models with two (NH3 N and nonammonia N) or three (NH3 N, rapidly turning over nonammonia N, and slowly turning over nonammonia N) compartments using the software SAAM II. Because the three-compartment model did not remove a small systematic bias or improve the fit of the data, the two-compartment model was used to provide measurements of intraruminal N recycling. Intraruminal NH3 N recycling (45% for control) decreased linearly as fat unsaturation increased (50.2, 43.0, and 41.7% for partially hydrogenated tallow, tallow, and animal-vegetable fat, respectively). Intraruminal nitrogen recycling was not correlated with efficiency of microbial protein synthesis or ruminal protozoa counts.

  9. Differences in Mouse and Human Non-Memory B Cell Pools1

    PubMed Central

    Benitez, Abigail; Weldon, Abby J.; Tatosyan, Lynnette; Velkuru, Vani; Lee, Steve; Milford, Terry-Ann; Francis, Olivia L.; Hsu, Sheri; Nazeri, Kavoos; Casiano, Carlos M.; Schneider, Rebekah; Gonzalez, Jennifer; Su, Rui-Jun; Baez, Ineavely; Colburn, Keith; Moldovan, Ioana; Payne, Kimberly J.

    2014-01-01

    Identifying cross-species similarities and differences in immune development and function is critical for maximizing the translational potential of animal models. Co-expression of CD21 and CD24 distinguishes transitional and mature B cell subsets in mice. Here, we validate these markers for identifying analogous subsets in humans and use them to compare the non-memory B cell pools in mice and humans, across tissues, during fetal/neonatal and adult life. Among human CD19+IgM+ B cells, the CD21/CD24 schema identifies distinct populations that correspond to T1 (transitional 1), T2 (transitional 2), FM (follicular mature), and MZ (marginal zone) subsets identified in mice. Markers specific to human B cell development validate the identity of MZ cells and the maturation status of human CD21/CD24 non-memory B cell subsets. A comparison of the non-memory B cell pools in bone marrow (BM), blood, and spleen in mice and humans shows that transitional B cells comprise a much smaller fraction in adult humans than mice. T1 cells are a major contributor to the non-memory B cell pool in mouse BM where their frequency is more than twice that in humans. Conversely, in spleen the T1:T2 ratio shows that T2 cells are proportionally ∼8 fold higher in humans than mouse. Despite the relatively small contribution of transitional B cells to the human non-memory pool, the number of naïve FM cells produced per transitional B cell is 3-6 fold higher across tissues than in mouse. These data suggest differing dynamics or mechanisms produce the non-memory B cell compartments in mice and humans. PMID:24719464

  10. Water diffusion-exchange effect on the paramagnetic relaxation enhancement in off-resonance rotating frame

    NASA Astrophysics Data System (ADS)

    Zhang, Huiming; Xie, Yang; Ji, Tongyu

    2007-06-01

    The off-resonance rotating frame technique based on the spin relaxation properties of off-resonance T1 ρ can significantly increase the sensitivity of detecting paramagnetic labeling at high magnetic fields by MRI. However, the in vivo detectable dimension for labeled cell clusters/tissues in T1 ρ-weighted images is limited by the water diffusion-exchange between mesoscopic scale compartments. An experimental investigation of the effect of water diffusion-exchange between compartments on the paramagnetic relaxation enhancement of paramagnetic agent compartment is presented for in vitro/ in vivo models. In these models, the size of paramagnetic agent compartment is comparable to the mean diffusion displacement of water molecules during the long RF pulses that are used to generate the off-resonance rotating frame. The three main objectives of this study were: (1) to qualitatively correlate the effect of water diffusion-exchange with the RF parameters of the long pulse and the rates of water diffusion, (2) to explore the effect of water diffusion-exchange on the paramagnetic relaxation enhancement in vitro, and (3) to demonstrate the paramagnetic relaxation enhancement in vivo. The in vitro models include the water permeable dialysis tubes or water permeable hollow fibers embedded in cross-linked proteins gels. The MWCO of the dialysis tubes was chosen from 0.1 to 15 kDa to control the water diffusion rate. Thin hollow fibers were chosen to provide sub-millimeter scale compartments for the paramagnetic agents. The in vivo model utilized the rat cerebral vasculatures as a paramagnetic agent compartment, and intravascular agents (Gd-DTPA) 30-BSA were administrated into the compartment via bolus injections. Both in vitro and in vivo results demonstrate that the paramagnetic relaxation enhancement is predominant in the T1 ρ-weighted image in the presence of water diffusion-exchange. The T1 ρ contrast has substantially higher sensitivity than the conventional T1 contrast in detecting paramagnetic agents, especially at low paramagnetic agent volumetric fractions, low paramagnetic agent concentrations, and low RF amplitudes. Short pulse duration, short pulse recycle delay and efficient paramagnetic relaxation can reduce the influence of water diffusion-exchange on the paramagnetic enhancement. This study paves the way for the design of off-resonance rotating experiments to detect labeled cell clusters/tissue compartments in vivo at a sub-millimeter scale.

  11. Modelling food and population dynamics in honey bee colonies.

    PubMed

    Khoury, David S; Barron, Andrew B; Myerscough, Mary R

    2013-01-01

    Honey bees (Apis mellifera) are increasingly in demand as pollinators for various key agricultural food crops, but globally honey bee populations are in decline, and honey bee colony failure rates have increased. This scenario highlights a need to understand the conditions in which colonies flourish and in which colonies fail. To aid this investigation we present a compartment model of bee population dynamics to explore how food availability and bee death rates interact to determine colony growth and development. Our model uses simple differential equations to represent the transitions of eggs laid by the queen to brood, then hive bees and finally forager bees, and the process of social inhibition that regulates the rate at which hive bees begin to forage. We assume that food availability can influence both the number of brood successfully reared to adulthood and the rate at which bees transition from hive duties to foraging. The model predicts complex interactions between food availability and forager death rates in shaping colony fate. Low death rates and high food availability results in stable bee populations at equilibrium (with population size strongly determined by forager death rate) but consistently increasing food reserves. At higher death rates food stores in a colony settle at a finite equilibrium reflecting the balance of food collection and food use. When forager death rates exceed a critical threshold the colony fails but residual food remains. Our model presents a simple mathematical framework for exploring the interactions of food and forager mortality on colony fate, and provides the mathematical basis for more involved simulation models of hive performance.

  12. Estimation of the Number of Compartments Associated With the Apparent Diffusion Coefficient in MRI: The Theoretical and Experimental Investigations.

    PubMed

    Ashoor, Mansour; Khorshidi, Abdollah

    2016-03-01

    The goal of the present study was to estimate the number of compartments and the mean apparent diffusion coefficient (ADC) value with the use of the DWI signal curve. A useful new mathematic model that includes internal correlation among subcompartments with a distinct number of compartments was proposed. The DWI signal was simulated to estimate the approximate association between the number of subcompartments and the molecular density, with density corresponding to the ratio of the ADC values of the compartments, as determined using the Monte Carlo method. Various factors, such as energy depletion, temperature, intracellular water accumulation, changes in the tortuosity of the extracellular diffusion paths, and changes in cell membrane permeability, have all been implicated as factors contributing to changes in the ADC of water (ADCw); therefore, one may consider them as pseudocompartments in the new model proposed in this study. The lower the coefficient is, the lower the contribution of the compartment to the net signal will be. The results of the simulation indicate that when the number of compartments increases, the signal will become significantly lower, because the gradient factor (i.e., the b value) will increase. In other words, the signal curve is approximately linear at all b values when the number of compartments in which the tissues have been severely damaged is low; however, when the number of compartments is high, the curve will become constant at high b values, and the perfusion parameters will prevail on the diffusion parameters at low b values. Therefore, normal tissues will be investigated when the number of compartments and the ADC values are high and the b values are low, whereas damaged tissues will be evaluated when the number of compartments and the ADC values are low and the b values are high. The present study investigates damaged tissues at high b values for which the effect of eddy currents will also be compensated. These b values will probably be used in functional MRI.

  13. Passengers in containers

    NASA Technical Reports Server (NTRS)

    Tarkhanovskiy, V.

    1977-01-01

    A futuristic vision of future passenger and cargo transport is presented. To speed up lengthy transit operations, passengers would be accomodated in comfortable, compartment-like containers. Several diagrams show how such containers can be accomodated aboard an aircraft or a helicopter, on a truck, or in a railroad car. A system would result in great economy in both cost and time. Of particular importance is such a system for cargo traffic.

  14. Quantitative Analysis of First-Pass Contrast-Enhanced Myocardial Perfusion Multidetector CT Using a Patlak Plot Method and Extraction Fraction Correction During Adenosine Stress

    NASA Astrophysics Data System (ADS)

    Ichihara, Takashi; George, Richard T.; Silva, Caterina; Lima, Joao A. C.; Lardo, Albert C.

    2011-02-01

    The purpose of this study was to develop a quantitative method for myocardial blood flow (MBF) measurement that can be used to derive accurate myocardial perfusion measurements from dynamic multidetector computed tomography (MDCT) images by using a compartment model for calculating the first-order transfer constant (K1) with correction for the capillary transit extraction fraction (E). Six canine models of left anterior descending (LAD) artery stenosis were prepared and underwent first-pass contrast-enhanced MDCT perfusion imaging during adenosine infusion (0.14-0.21 mg/kg/min). K1 , which is the first-order transfer constant from left ventricular (LV) blood to myocardium, was measured using the Patlak plot method applied to time-attenuation curve data of the LV blood pool and myocardium. The results were compared against microsphere MBF measurements, and the extraction fraction of contrast agent was calculated. K1 is related to the regional MBF as K1=EF, E=(1-exp(-PS/F)), where PS is the permeability-surface area product and F is myocardial flow. Based on the above relationship, a look-up table from K1 to MBF can be generated and Patlak plot-derived K1 values can be converted to the calculated MBF. The calculated MBF and microsphere MBF showed a strong linear association. The extraction fraction in dogs as a function of flow (F) was E=(1-exp(-(0.2532F+0.7871)/F)) . Regional MBF can be measured accurately using the Patlak plot method based on a compartment model and look-up table with extraction fraction correction from K1 to MBF.

  15. Phenotypic plasticity and targeting of Siglec-F(high) CD11c(low) eosinophils to the airway in a murine model of asthma.

    PubMed

    Abdala Valencia, H; Loffredo, L F; Misharin, A V; Berdnikovs, S

    2016-02-01

    Eosinophil recruitment in asthma is a multistep process, involving both trans-endothelial migration to the lung interstitium and trans-epithelial migration into the airways. While the trans-endothelial step is well studied, trans-epithelial recruitment is less understood. To contrast eosinophil recruitment between these two compartments, we employed a murine kinetics model of asthma. Eosinophils were phenotyped by multicolor flow cytometry in digested lung tissue and bronchoalveolar lavage (BAL) simultaneously, 6 h after each ovalbumin (OVA) challenge. There was an early expansion of tissue eosinophils after OVA challenge followed by eosinophil buildup in both compartments and a shift in phenotype over the course of the asthma model. Gradual transition from a Siglec-F(med) CD11c(-) to a Siglec-F(high) CD11c(low) phenotype in lung tissue was associated with eosinophil recruitment to the airways, as all BAL eosinophils were of the latter phenotype. Secondary microarray analysis of tissue-activated eosinophils demonstrated upregulation of specific integrin and chemokine receptor signature suggesting interaction with the mucosa. Using adhesion assays, we demonstrated that integrin CD11c mediated adhesion of eosinophils to fibrinogen, a significant component of epithelial barrier repair and remodeling. To the best of our knowledge, this is the only report to date dissecting compartmentalization of eosinophil recruitment as it unfolds during allergic inflammation. By capturing the kinetics of eosinophil phenotypic change in both tissue and BAL using flow cytometry and sorting, we were able to demonstrate a previously undocumented association between phenotypic shift of tissue-recruited eosinophils and their trans-epithelial movement, which implicates the existence of a specific mechanism targeting these cells to mucosal airways. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  16. A Modified Tri-Exponential Model for Multi-b-value Diffusion-Weighted Imaging: A Method to Detect the Strictly Diffusion-Limited Compartment in Brain

    PubMed Central

    Zeng, Qiang; Shi, Feina; Zhang, Jianmin; Ling, Chenhan; Dong, Fei; Jiang, Biao

    2018-01-01

    Purpose: To present a new modified tri-exponential model for diffusion-weighted imaging (DWI) to detect the strictly diffusion-limited compartment, and to compare it with the conventional bi- and tri-exponential models. Methods: Multi-b-value diffusion-weighted imaging (DWI) with 17 b-values up to 8,000 s/mm2 were performed on six volunteers. The corrected Akaike information criterions (AICc) and squared predicted errors (SPE) were calculated to compare these three models. Results: The mean f0 values were ranging 11.9–18.7% in white matter ROIs and 1.2–2.7% in gray matter ROIs. In all white matter ROIs: the AICcs of the modified tri-exponential model were the lowest (p < 0.05 for five ROIs), indicating the new model has the best fit among these models; the SPEs of the bi-exponential model were the highest (p < 0.05), suggesting the bi-exponential model is unable to predict the signal intensity at ultra-high b-value. The mean ADCvery−slow values were extremely low in white matter (1–7 × 10−6 mm2/s), but not in gray matter (251–445 × 10−6 mm2/s), indicating that the conventional tri-exponential model fails to represent a special compartment. Conclusions: The strictly diffusion-limited compartment may be an important component in white matter. The new model fits better than the other two models, and may provide additional information. PMID:29535599

  17. Switching from a unicellular to multicellular organization in an Aspergillus niger hypha.

    PubMed

    Bleichrodt, Robert-Jan; Hulsman, Marc; Wösten, Han A B; Reinders, Marcel J T

    2015-03-03

    Pores in fungal septa enable cytoplasmic streaming between hyphae and their compartments. Consequently, the mycelium can be considered unicellular. However, we show here that Woronin bodies close ~50% of the three most apical septa of growing hyphae of Aspergillus niger. The incidence of closure of the 9th and 10th septa was even ≥94%. Intercompartmental streaming of photoactivatable green fluorescent protein (PA-GFP) was not observed when the septa were closed, but open septa acted as a barrier, reducing the mobility rate of PA-GFP ~500 times. This mobility rate decreased with increasing septal age and under stress conditions, likely reflecting a regulatory mechanism affecting septal pore diameter. Modeling revealed that such regulation offers effective control of compound concentration between compartments. Modeling also showed that the incidence of septal closure in A. niger had an even stronger impact on cytoplasmic continuity. Cytoplasm of hyphal compartments was shown not to be in physical contact when separated by more than 4 septa. Together, data show that apical compartments of growing hyphae behave unicellularly, while older compartments have a multicellular organization. The hyphae of higher fungi are compartmentalized by porous septa that enable cytosolic streaming. Therefore, it is believed that the mycelium shares cytoplasm. However, it is shown here that the septa of Aspergillus niger are always closed in the oldest part of the hyphae, and therefore, these compartments are physically isolated from each other. In contrast, only part of the septa is closed in the youngest part of the hyphae. Still, compartments in this hyphal part are physically isolated when separated by more than 4 septa. Even open septa act as a barrier for cytoplasmic mixing. The mobility rate through such septa reduces with increasing septal age and under stress conditions. Modeling shows that the septal pore width is set such that its regulation offers maximal control of compound concentration levels within the compartments. Together, we show for the first time that Aspergillus hyphae switch from a unicellular to multicellular organization. Copyright © 2015 Bleichrodt et al.

  18. Apoplastic and intracellular plant sugars regulate developmental transitions in witches' broom disease of cacao.

    PubMed

    Barau, Joan; Grandis, Adriana; Carvalho, Vinicius Miessler de Andrade; Teixeira, Gleidson Silva; Zaparoli, Gustavo Henrique Alcalá; do Rio, Maria Carolina Scatolin; Rincones, Johana; Buckeridge, Marcos Silveira; Pereira, Gonçalo Amarante Guimarães

    2015-03-01

    Witches' broom disease (WBD) of cacao differs from other typical hemibiotrophic plant diseases by its unusually long biotrophic phase. Plant carbon sources have been proposed to regulate WBD developmental transitions; however, nothing is known about their availability at the plant-fungus interface, the apoplastic fluid of cacao. Data are provided supporting a role for the dynamics of soluble carbon in the apoplastic fluid in prompting the end of the biotrophic phase of infection. Carbon depletion and the consequent fungal sensing of starvation were identified as key signalling factors at the apoplast. MpNEP2, a fungal effector of host necrosis, was found to be up-regulated in an autophagic-like response to carbon starvation in vitro. In addition, the in vivo artificial manipulation of carbon availability in the apoplastic fluid considerably modulated both its expression and plant necrosis rate. Strikingly, infected cacao tissues accumulated intracellular hexoses, and showed stunted photosynthesis and the up-regulation of senescence markers immediately prior to the transition to the necrotrophic phase. These opposite findings of carbon depletion and accumulation in different host cell compartments are discussed within the frame of WBD development. A model is suggested to explain phase transition as a synergic outcome of fungal-related factors released upon sensing of extracellular carbon starvation, and an early senescence of infected tissues probably triggered by intracellular sugar accumulation. © The Author 2014. Published by Oxford University Press on behalf of the Society for Experimental Biology.

  19. Imaging regional renal function parameters using radionuclide tracers

    NASA Astrophysics Data System (ADS)

    Qiao, Yi

    A compartmental model is given for evaluating kidney function accurately and noninvasively. This model is cast into a parallel multi-compartment structure and each pixel region (picture element) of kidneys is considered as a single kidney compartment. The loss of radionuclide tracers from the blood to the kidney and from the kidney to the bladder are modelled in great detail. Both the uptake function and the excretion function of the kidneys can be evaluated pixel by pixel, and regional diagnostic information on renal function is obtained. Gamma Camera image data are required by this model and a screening test based renal function measurement is provided. The regional blood background is subtracted from the kidney region of interest (ROI) and the kidney regional rate constants are estimated analytically using the Kuhn-Pucker multiplier method in convex programming by considering the input/output behavior of the kidney compartments. The detailed physiological model of the peripheral compartments of the system, which is not available for most radionuclide tracers, is not required in the determination of the kidney regional rate constants and the regional blood background factors within the kidney ROI. Moreover, the statistical significance of measurements is considered to assure the improved statistical properties of the estimated kidney rate constants. The relations between various renal function parameters and the kidney rate constants are established. Multiple renal function measurements can be found from the renal compartmental model. The blood radioactivity curve and the regional (or total) radiorenogram determining the regional (or total) summed behavior of the kidneys are obtained analytically with the consideration of the statistical significance of measurements using convex programming methods for a single peripheral compartment system. In addition, a new technique for the determination of 'initial conditions' in both the blood compartment and the kidney compartment is presented. The blood curve and the radiorenogram are analyzed in great detail and a physiological analysis from the radiorenogram is given. Applications of Kuhn-Tucker multiplier methods are illustrated for the renal compartmental model in the field of nuclear medicine. Conventional kinetic data analysis methods, the maximum likehood method, and the weighted integration method are investigated and used for comparisons. Moreover, the effect of the blood background subtraction is shown by using the gamma camera images in man. Several functional images are calculated and the functional imaging technique is applied for evaluating renal function in man quantitatively and visually and compared with comments from a physician.

  20. The dynamical analysis of modified two-compartment neuron model and FPGA implementation

    NASA Astrophysics Data System (ADS)

    Lin, Qianjin; Wang, Jiang; Yang, Shuangming; Yi, Guosheng; Deng, Bin; Wei, Xile; Yu, Haitao

    2017-10-01

    The complexity of neural models is increasing with the investigation of larger biological neural network, more various ionic channels and more detailed morphologies, and the implementation of biological neural network is a task with huge computational complexity and power consumption. This paper presents an efficient digital design using piecewise linearization on field programmable gate array (FPGA), to succinctly implement the reduced two-compartment model which retains essential features of more complicated models. The design proposes an approximate neuron model which is composed of a set of piecewise linear equations, and it can reproduce different dynamical behaviors to depict the mechanisms of a single neuron model. The consistency of hardware implementation is verified in terms of dynamical behaviors and bifurcation analysis, and the simulation results including varied ion channel characteristics coincide with the biological neuron model with a high accuracy. Hardware synthesis on FPGA demonstrates that the proposed model has reliable performance and lower hardware resource compared with the original two-compartment model. These investigations are conducive to scalability of biological neural network in reconfigurable large-scale neuromorphic system.

  1. Pharmacokinetic Studies of Oxathio-Heterocycle Fused Chalcones.

    PubMed

    Okoniewska, Krystyna; Konieczny, Marek T; Lemke, Krzysztof; Grabowski, Tomasz

    2017-02-01

    Chalcone constitutes one of the most used molecular frameworks in medicinal chemistry and its derivatives exhibit a broad spectrum of biological activities. Low absolute bioavailability, poor distribution, intensive metabolism and elimination of chalcones are the main problems in designing new drugs based on their structure. One of the fundamental steps in evaluation of drug candidates is a comparative analysis of pharmacokinetic parameters. The aim of the studies was the pharmacokinetic characterization of the selected oxathio-heterocycle fused chalcones. The pharmacokinetic parameters of 19 compounds were reported. The analyzed chalcones were examined after a single intravenous administration to forty 7-week-old mature male rats of Wistar stock. Pharmacokinetic analysis was performed independently using SHAM (slopes, highest, amounts, and moments) and the two-compartment model. Basic physiochemical parameters were calculated. The bioanalytical methods were validated in terms of repeatability, linearity, accuracy, precision, and selectivity. The pharmacokinetics of the examined group of chalcones are compatible with the two-compartment model. The physicochemical characteristics of this group are quite homogeneous. The kinetics of the examined chalcones are indicative of a distribution to the tissue compartment with the predominance of a rate constant from central to peripheral compartments (k 12 ) over the rate constant from peripheral to central compartments (k 21 ). The elimination from the central compartment (k 10 ) is higher than the transfer from the central compartment to the tissues (k 10  > k 12 ) in almost all examined cases. The presented group of compounds may form a starting point for studies into drugs treating autoimmune diseases of the gastro-intestinal tract.

  2. A Three Component Model to Estimate Sensible Heat Flux Over Sparse Shrubs in Nevada

    USGS Publications Warehouse

    Chehbouni, A.; Nichols, W.D.; Njoku, E.G.; Qi, J.; Kerr, Y.H.; Cabot, F.

    1997-01-01

    It is now recognized that accurate partitioning of available energy into sensible and latent heat flux is crucial to understanding surface-atmosphere interactions. This issue is more complicated in arid and semi-arid regions where the relative contribution to surface fluxes from the soil and vegetation may vary significantly throughout the day and throughout the season. The objective of this paper is to present a three-component model to estimate sensible heat flux over heterogeneous surfaces. The surface was represented with two adjacent compartments. The first compartment is made up of two components, shrubs and shaded soil; the second compartment consists of bare, unshaded soil. Data collected at two different sites in Nevada during the summers of 1991 and 1992 were used to evaluate model performance. The results show that the present model is sufficiently general to yield satisfactory results for both sites.

  3. Comparing models for perfluorooctanoic acid pharmacokinetics using Bayesian analysis.

    PubMed

    Wambaugh, John F; Barton, Hugh A; Setzer, R Woodrow

    2008-12-01

    Selecting the appropriate pharmacokinetic (PK) model given the available data is investigated for perfluorooctanoic acid (PFOA), which has been widely analyzed with an empirical, one-compartment model. This research examined the results of experiments [Kemper R. A., DuPont Haskell Laboratories, USEPA Administrative Record AR-226.1499 (2003)] that administered single oral or iv doses of PFOA to adult male and female rats. PFOA concentration was observed over time; in plasma for some animals and in fecal and urinary excretion for others. There were four rats per dose group, for a total of 36 males and 36 females. Assuming that the PK parameters for each individual within a gender were drawn from the same, biologically varying population, plasma and excretion data were jointly analyzed using a hierarchical framework to separate uncertainty due to measurement error from actual biological variability. Bayesian analysis using Markov Chain Monte Carlo (MCMC) provides tools to perform such an analysis as well as quantitative diagnostics to evaluate and discriminate between models. Starting from a one-compartment PK model with separate clearances to urine and feces, the model was incrementally expanded using Bayesian measures to assess if the expansion was supported by the data. PFOA excretion is sexually dimorphic in rats; male rats have bi-phasic elimination that is roughly 40 times slower than that of the females, which appear to have a single elimination phase. The male and female data were analyzed separately, keeping only the parameters describing the measurement process in common. For male rats, including excretion data initially decreased certainty in the one-compartment parameter estimates compared to an analysis using plasma data only. Allowing a third, unspecified clearance improved agreement and increased certainty when all the data was used, however a significant amount of eliminated PFOA was estimated to be missing from the excretion data. Adding an additional PK compartment reduced the unaccounted-for elimination to amounts comparable to the cage wash. For both sexes, an MCMC estimate of the appropriateness of a model for a given data type, the Deviance Information Criterion, indicated that this two-compartment model was better suited to describing PFOA PK. The median estimate was 142.1 +/- 37.6 ml/kg for the volume of the primary compartment and 1.24 +/- 1.1 ml/kg/h for the clearances of male rats and 166.4 +/- 46.8 ml/kg and 30.3 +/- 13.2 ml/kg/h, respectively for female rats. The estimates for the second compartment differed greatly with gender-volume 311.8 +/- 453.9 ml/kg with clearance 3.2 +/- 6.2 for males and 1400 +/- 2507.5 ml/kg and 4.3 +/- 2.2 ml/kg/h for females. The median estimated clearance was 12 +/- 6% to feces and 85 +/- 7% to urine for male rats and 8 +/- 6% and 77 +/- 9% for female rats. We conclude that the available data may support more models for PFOA PK beyond two-compartments and that the methods employed here will be generally useful for more complicated, including PBPK, models.

  4. Lisdexamfetamine reduces the compulsive and perseverative behaviour of binge-eating rats in a novel food reward/punished responding conflict model.

    PubMed

    Heal, David J; Goddard, Simon; Brammer, Richard J; Hutson, Peter H; Vickers, Steven P

    2016-07-01

    Compulsive and perseverative behaviour in binge-eating, female, Wistar rats was investigated in a novel food reward/punished responding conflict model. Rats were trained to perform the conditioned avoidance response task. When proficient, the paradigm was altered to a food-associated conflict test by placing a chocolate-filled jar (empty jar for controls) in one compartment of the shuttle box. Entry into the compartment with the jar triggered the conditioning stimulus after a variable interval, and foot-shock 10 seconds later if the rat did not leave. Residence in the 'safe' compartment with no jar did not initiate trials or foot-shocks. By frequently entering the chocolate-paired compartment, binge-eating rats completed their 10 trials more quickly than non-binge controls. Binge-eating rats spent a greater percentage of the session in the chocolate-paired compartment, received foot-shocks more frequently, and tolerated foot-shocks for longer periods; all consistent with compulsive and perseverative behaviour. The d-amphetamine prodrug, lisdexamfetamine, has recently received US approval for the treatment of moderate to severe binge-eating disorder in adults. Lisdexamfetamine (0.8 mg/kg po [d-amphetamine base]) decreased chocolate consumption by binge-eating rats by 55% and markedly reduced compulsive and perseverative responding in the model. These findings complement clinical results showing lisdexamfetamine reduced compulsiveness scores in subjects with binge-eating disorder. © The Author(s) 2016.

  5. Compartmental analysis of [11C]flumazenil kinetics for the estimation of ligand transport rate and receptor distribution using positron emission tomography.

    PubMed

    Koeppe, R A; Holthoff, V A; Frey, K A; Kilbourn, M R; Kuhl, D E

    1991-09-01

    The in vivo kinetic behavior of [11C]flumazenil ([11C]FMZ), a non-subtype-specific central benzodiazepine antagonist, is characterized using compartmental analysis with the aim of producing an optimized data acquisition protocol and tracer kinetic model configuration for the assessment of [11C]FMZ binding to benzodiazepine receptors (BZRs) in human brain. The approach presented is simple, requiring only a single radioligand injection. Dynamic positron emission tomography data were acquired on 18 normal volunteers using a 60- to 90-min sequence of scans and were analyzed with model configurations that included a three-compartment, four-parameter model, a three-compartment, three-parameter model, with a fixed value for free plus nonspecific binding; and a two-compartment, two-parameter model. Statistical analysis indicated that a four-parameter model did not yield significantly better fits than a three-parameter model. Goodness of fit was improved for three- versus two-parameter configurations in regions with low receptor density, but not in regions with moderate to high receptor density. Thus, a two-compartment, two-parameter configuration was found to adequately describe the kinetic behavior of [11C]FMZ in human brain, with stable estimates of the model parameters obtainable from as little as 20-30 min of data. Pixel-by-pixel analysis yields functional images of transport rate (K1) and ligand distribution volume (DV"), and thus provides independent estimates of ligand delivery and BZR binding.

  6. Simulation of the inhibition of microbial sulfate reduction in a two-compartment upflow bioreactor subjected to molybdate injection.

    PubMed

    de Jesus, E B; de Andrade Lima, L R P

    2016-08-01

    Souring of oil fields during secondary oil recovery by water injection occurs mainly due to the action of sulfate-reducing bacteria (SRB) adhered to the rock surface in the vicinity of injection wells. Upflow packed-bed bioreactors have been used in petroleum microbiology because of its similarity to the oil field near the injection wells or production. However, these reactors do not realistically describe the regions near the injection wells, which are characterized by the presence of a saturated zone and a void region close to the well. In this study, the hydrodynamics of the two-compartment packing-free/packed-bed pilot bioreactor that mimics an oil reservoir was studied. The packed-free compartment was modeled using a continuous stirred tank model with mass exchange between active and stagnant zones, whereas the packed-bed compartment was modeled using a piston-dispersion-exchange model. The proposed model adequately represents the hydrodynamic of the packed-free/packed-bed bioreactor while the simulations provide important information about the characteristics of the residence time distribution (RTD) curves for different sets of model parameters. Simulations were performed to represent the control of the sulfate-reducing bacteria activity in the bioreactor with the use of molybdate in different scenarios. The simulations show that increased amounts of molybdate cause an effective inhibition of the souring sulfate-reducing bacteria activity.

  7. Ex-ORISKANY Artificial Reef Project: Ecological Risk Assessment

    DTIC Science & Technology

    2006-01-25

    preferences used by PRAM and the Trophic Level determined by diet for each compartment modeled in the food chain...grouping organisms according to their habitat and diet preferences , PRAM also provided output to evaluate exposure point concentrations for the pelagic...dietary preferences used by PRAM (version 1.4C) and the Trophic Level determined by diet for each compartment modeled in the food chain. PRAM Default

  8. Isolation of the Lateral Border Recycling Compartment using a diaminobenzidine-induced density shift

    PubMed Central

    Sullivan, David P.; Rüffer, Claas; Muller, William A.

    2014-01-01

    The migration of leukocytes across the endothelium and into tissue is critical to mounting an inflammatory response. The Lateral Border Recycling Compartment (LBRC), a complex vesicular-tubule invagination of the plasma membrane found at endothelial cell borders, plays an important role in the this process. Although a few proteins have been shown to be present in the LBRC, no unique marker is known. Here we detail methods that can be used to characterize a subcellular compartment that lacks an identifying marker. Initial characterization of the LBRC was performed using standard subcellular fractionation with sucrose gradients and took advantage of the observation that the compartment migrated at a lower density than other membrane compartments. To isolate larger quantities of the compartment, we modified a classic technique known as a diaminobenzidine (DAB)-induced density shift. The DAB-induced density shift allowed for specific isolation of membranes labeled with HRP conjugated antibody. Because the LBRC could be differentially labeled at 4°C and 37°C, we were able to identify proteins that are enriched in the compartment, despite lacking a unique marker. These methods serve as a model to others studying poorly characterized compartments and organelles and are applicable to a wide variety of biological systems. PMID:24915828

  9. The Chicken Creek catchment as observatory for early-stage landscape development

    NASA Astrophysics Data System (ADS)

    Schaaf, W.; Gerwin, W.; Pohle, I.; Maurer, T. J.

    2017-12-01

    Constructed in 2005, the Chicken Creek catchment offers unique opportunities to observe ecosystem and landscape development. The site was constructed within the post-mining landscape of a lignite mine in Germany (State of Brandenburg, 100 km southeast from Berlin). Using large mining machinery a clay layer was dumped as an aquiclude covered by a sandy layer as the aquifer of this 6 ha artificial watershed. After leveling the surface no further reclamation measures were applied and the site was left to a non-managed primary succession. A comprehensive monitoring program was established directly after the end of construction works including meteorological, hydrological, biogeochemical and biological parameters. Time series for these measured parameters are available for the last 12 years. Based on these data, the growing interactions between different compartments of the developing landscape give valuable insights into the functioning of ecosystems under transition. We will introduce the site as well as recent analyzes of hydrological data against the background of the ongoing development of the soil and the vegetation cover. The annual water balance was calculated based on known and modeled substrate volumes and water contents. The dynamics of the balance are clearly influenced by the development of the ecosystem, e.g. by the occurrence and rapid propagation of woody species. It was possible to define transitional states, which can be characterized by specific feedback processes between abiotic and biotic compartments. Our results indicate that for small catchments with a highly dynamic ecological development like the Chicken Creek, the knowledge about saturated and unsaturated storage volumes enables a good estimate and closure of the water balance using a rather simple approach. Uncertainties in storage changes partly compensate each other and the high variability of soil moisture in the unsaturated zone is of minor impact compared to the storage volume changes. The monitoring at Chicken Creek in high spatial and temporal resolution provides a valuable database underlining the high importance of abiotic/biotic feedback effects that changed the hydrologic functioning and response of the catchment more than the water balance itself revealed and thus have to be included in catchment models.

  10. Analysis of steady-state flow and advective transport in the eastern Snake River Plain aquifer system, Idaho

    USGS Publications Warehouse

    Ackerman, D.J.

    1995-01-01

    Quantitative estimates of ground-water flow directions and traveltimes for advective flow were developed for the regional aquifer system of the eastern Snake River Plain, Idaho. The work included: (1) descriptions of compartments in the aquifer that function as intermediate and regional flow systems, (2) descriptions of pathlines for flow originating at or near the water table, and (3) quantitative estimates of traveltimes for advective transport originating at or near the water table. A particle-tracking postprocessing program was used to compute pathlines on the basis of output from an existing three-dimensional steady-state flow model. The flow model uses 1980 conditions to approximate average annual conditions for 1950-80. The advective transport model required additional information about the nature of flow across model boundaries, aquifer thickness, and porosity. Porosity of two types of basalt strata has been reported for more than 1,500 individual cores from test holes, wells, and outcrops near the south side of the Idaho National Engineering Laboratory. The central 80 percent of samples had porosities of 0.08 to 0.25, the central 50 percent of samples, O. 11 to 0.21. Calibration of the model involved choosing a value for porosity that yielded the best solution. Two radiologic contaminants, iodine-129 and tritium, both introduced to the flow system about 40 years ago, are relatively conservative tracers. Iodine- 129 was considered to be more useful because of a lower analytical detection limit, longer half-life, and longer flow path. The calibration value for porosity was 0.21. Most flow in the aquifer is contained within a regional-scale compartment and follows paths that discharge to the Snake River downstream from Milner Dam. Two intermediate-scale compartments exist along the southeast side of the aquifer and near Mud Lake.One intermediate-scale compartment along the southeast side of the aquifer discharges to the Snake River near American Fails Reservoir and covers an area of nearly 1,000 square miles. This compartment, which receives recharge from an area of intensive surface-water irrigation, is apparently fairly stable. The other intermediate-scale compartment near Mud Lake covers an area of 300 square miles. The stability and size of this compartment are uncertain, but are assumed to be in a state of change. Traveltimes for advective flow from the water table to discharge points in the regional compartment ranged from 12 to 350 years for 80 percent of the particles; in the intermediate-scale flow compartment near American Falls Reservoir, from 7 to 60 years for 80 percent of the particles; and in the intermediate-scale compartment near Mud Lake, from 25 to 100 years for 80 percent of the particles. Traveltimes are sensitive to porosity and assumptions regarding the importance of the strength of internal sinks, which represent ground-water pumpage. A decrease in porosity results in shorter traveltimes but not a uniform decrease in traveltime, because the porosity and thickness is different in each model layer. Most flow was horizontal and occurred in the top 500 feet of the aquifer. An important limitation of the model is the assumption of steady-state flow. The most recent trend in the flow system has been a decrease in recharge since 1987 because of an extended drought and changes in land use. A decrease in flow through the system will result in longer traveltimes than those predicted for a greater flow. Because the interpretation of the model was limited to flow on a larger scale, and did not consider individual wells or well fields, the interpretations were not seriously limited by the discretization of well discharge. The interpretations made from this model also were limited by the discretization of the major discharge areas. Near discharge areas, pathlines might not be representative at the resolution of the grid. Most improvement in the estimates of ground-waterflow directions and travelt

  11. Peptide and RNA contributions to iron-sulphur chemical gardens as life's first inorganic compartments, catalysts, capacitors and condensers.

    PubMed

    McGlynn, Shawn E; Kanik, Isik; Russell, Michael J

    2012-06-28

    Hydrothermal chimneys and compartments comprising transition metal sulphides and associated minerals have been proposed as likely locations for the beginnings of life. In laboratory simulations of off-axis alkaline springs, it is shown that the interaction of a simulated alkaline sulphide-bearing submarine vent solution with a primeval anoxic iron-bearing ocean leads to the formation of chimney structures reminiscent of chemical gardens. These chimneys display periodicity in their deposition and exhibit diverse morphologies and mineralogies, affording the possibilities of catalysis and molecular sequestration. The addition of peptides and RNA to the alkaline solution modifies the elemental stoichiometry of the chimneys-perhaps indicating the very initial stage of the organic takeover on the way to living cells by charged organic polymers potentially synthesized in this same environment.

  12. Air-displacement plethysmography pediatric option in 2-6 years old using the four-compartment model as a criterion method.

    PubMed

    Fields, David A; Allison, David B

    2012-08-01

    The objective of this study was to determine the accuracy, precision, bias, and reliability of percent fat (%fat) determined by air-displacement plethysmography (ADP) with the pediatric option against the four-compartment model in 31 children (4.1 ± 1.2 years, 103.3 ± 10.2 cm, 17.5 ± 3.4 kg). %Fat was determined by (BOD POD Body Composition System; COSMED USA, Concord, CA) with the pediatric option. Total body water (TBW) was determined by isotope dilution ((2)H(2)O; 0.2 g/kg) while bone mineral was determined by dual-energy X-ray absorptiometry (DXA) (Lunar iDXA v13.31; GE, Fairfield, CT and analyzed using enCore 2010 software). The four-compartment model by Lohman was used as the criterion measure of %fat. The regression for %fat by ADP vs. %fat by the four-compartment model did not deviate from the line of identity where: y = 0.849(x) + 4.291. ADP explained 75.2% of the variance in %fat by the four-compartment model while the standard error of the estimate (SEE) was 2.09 %fat. The Bland-Altman analysis showed %fat by ADP did not exhibit any bias across the range of fatness (r = 0.04; P = 0.81). The reliability of ADP was assessed by the coefficient of variation (CV), within-subject SD, and Cronbach's α. The CV was 3.5%, within-subject SD was 0.9%, and Cronbach's α was 0.95. In conclusion, ADP with the pediatric option is accurate, precise, reliable, and without bias in estimating %fat in children 2-6 years old.

  13. Dynamic phenotypic restructuring of the CD4 and CD8 T-cell subsets with age in healthy humans: a compartmental model analysis.

    PubMed

    Jackola, D R; Hallgren, H M

    1998-11-16

    In healthy humans, phenotypic restructuring occurs with age within the CD3+ T-lymphocyte complement. This is characterized by a non-linear decrease of the percentage of 'naive' (CD45RA+) cells and a corresponding non-linear increase of the percentage of 'memory' (CD45R0+) cells among both the CD4+ and CD8+ T-cell subsets. We devised a simple compartmental model to study the age-dependent kinetics of phenotypic restructuring. We also derived differential equations whose parameters determined yearly gains minus losses of the percentage and absolute numbers of circulating naive cells, yearly gains minus losses of the percentage and absolute numbers of circulating memory cells, and the yearly rate of conversion of naive to memory cells. Solutions of these evaluative differential equations demonstrate the following: (1) the memory cell complement 'resides' within its compartment for a longer time than the naive cell complement within its compartment for both CD4 and CD8 cells; (2) the average, annual 'turnover rate' is the same for CD4 and CD8 naive cells. In contrast, the average, annual 'turnover rate' for memory CD8 cells is 1.5 times that of memory CD4 cells; (3) the average, annual conversion rate of CD4 naive cells to memory cells is twice that of the CD8 conversion rate; (4) a transition in dynamic restructuring occurs during the third decade of life that is due to these differences in turnover and conversion rates, between and from naive to memory cells.

  14. Modelling dimercaptosuccinic acid (DMSA) plasma kinetics in humans.

    PubMed

    van Eijkeren, Jan C H; Olie, J Daniël N; Bradberry, Sally M; Vale, J Allister; de Vries, Irma; Meulenbelt, Jan; Hunault, Claudine C

    2016-11-01

    No kinetic models presently exist which simulate the effect of chelation therapy on lead blood concentrations in lead poisoning. Our aim was to develop a kinetic model that describes the kinetics of dimercaptosuccinic acid (DMSA; succimer), a commonly used chelating agent, that could be used in developing a lead chelating model. This was a kinetic modelling study. We used a two-compartment model, with a non-systemic gastrointestinal compartment (gut lumen) and the whole body as one systemic compartment. The only data available from the literature were used to calibrate the unknown model parameters. The calibrated model was then validated by comparing its predictions with measured data from three different experimental human studies. The model predicted total DMSA plasma and urine concentrations measured in three healthy volunteers after ingestion of DMSA 10 mg/kg. The model was then validated by using data from three other published studies; it predicted concentrations within a factor of two, representing inter-human variability. A simple kinetic model simulating the kinetics of DMSA in humans has been developed and validated. The interest of this model lies in the future potential to use it to predict blood lead concentrations in lead-poisoned patients treated with DMSA.

  15. A compartmental model of uranium in human hair for protracted ingestion of natural uranium in drinking water.

    PubMed

    Li, W B; Karpas, Z; Salonen, L; Kurttio, P; Muikku, M; Wahl, W; Höllriegl, V; Hoeschen, C; Oeh, U

    2009-06-01

    To predict uranium in human hair due to chronic exposure through drinking water, a compartment representing human hair was added into the uranium biokinetic model developed by the International Commission on Radiological Protection (ICRP). The hair compartmental model was used to predict uranium excretion in human hair as a bioassay indicator due to elevated uranium intakes. Two excretion pathways, one starting from the compartment of plasma and the other from the compartment of intermediate turnover soft tissue, are assumed to transfer uranium to the compartment of hair. The transfer rate was determined from reported uranium contents in urine and in hair, taking into account the hair growth rate of 0.1 g d(-1). The fractional absorption in the gastrointestinal tract of 0.6% was found to fit best to describe the measured uranium levels among the users of drilled wells in Finland. The ingestion dose coefficient for (238)U, which includes its progeny of (234)Th, (234m)Pa, and (234)Pa, was calculated equal to 1.3 x 10(-8) Sv Bq(-1) according to the hair compartmental model. This estimate is smaller than the value of 4.5 x 10(-8) Sv Bq(-1) published by ICRP for the members of the public. In this new model, excretion of uranium through urine is better represented when excretion to the hair compartment is accounted for and hair analysis can provide a means for assessing the internal body burden of uranium. The model is applicable for chronic exposure as well as for an acute exposure incident. In the latter case, the hair sample can be collected and analyzed even several days after the incident, whereas urinalysis requires sample collection shortly after the exposure. The model developed in this study applies to ingestion intakes of uranium.

  16. Physiologicomathematical model for studying human exposure to organic solvents: kinetics of blood/tissue n-hexane concentrations and of 2,5-hexanedione in urine.

    PubMed Central

    Perbellini, L; Mozzo, P; Brugnone, F; Zedde, A

    1986-01-01

    The physiologicomathematical model with eight compartments described allows the simulation of the absorbtion, distribution, biotransformation, excretion of an organic solvent, and the kinetics of its metabolites. The usual compartments of the human organism (vessel rich group, muscle group, and fat group) are integrated with the lungs, the metabolising tissues, and three other compartments dealing with the metabolic kinetics (biotransformation, water, and urinary compartments). The findings obtained by mathematical simulation of exposure to n-hexane were compared with data previously reported. The concentrations of n-hexane in alveolar air and in venous blood described both in experimental and occupational exposures provided a substantial validation for the data obtained by mathematical simulation. The results of the urinary excretion of 2,5-hexanedione given by the model were in good agreement with data already reported. The simulation of an exposure to n-hexane repeated five days a week suggested that the solvent accumulates in the fat tissue. The half life of n-hexane in fat tissue equalled 64 hours. The kinetics of 2,5-hexanedione resulting from the model suggest that occupational exposure results in the presence of large amounts of 2,5-hexanedione in the body for the whole working week. PMID:3790456

  17. Organic Pollutant Penetration through Fruit Polyester Skin: A Modified Three-compartment Diffusion Model

    PubMed Central

    Li, Yungui; Li, Qingqing; Chen, Baoliang

    2016-01-01

    The surface of plants is covered by a continuous but heterogeneous cuticular membrane (CM). Serving as the first protective barrier, the uptake and transport behavior of organic pollutants at this interface continue to engage the research efforts of environmental chemist. To date, the contributions of cuticular components as a defense against the organic pollutants penetration remain unresolved. In this study, the unsteady-state penetration characteristics of phenanthrene (PHE) through isolated fruit CM was investigated. PHE penetration was differentiated by three cuticular compartments: epicuticular waxes (EW), cuticle proper (CP) and cuticular layer (CL). The driving force for PHE penetration was ascribed to the sharp concentration gradient built up endogenously by cuticular compartments with different lipophilic affinities. A modified penetration model was established and verified in terms of its general suitability for the hydrophobic chemicals and CMs of various plant species (apple, tomato and potato). The new three-compartment model demonstrates much higher accuracy in characterizing the uptake and transport behavior of semivolatile chemicals with fewer limitations in terms of environmental conditions and complexity (e.g., coexisting contaminants and temperature). This model could contribute to a more comprehensive understanding on the role of polymeric lipids in the organic pollutant sorption and transport into plants. PMID:27009902

  18. Neutral dynamics and cell renewal of colonic crypts in homeostatic regime

    NASA Astrophysics Data System (ADS)

    Fendrik, A. J.; Romanelli, L.; Rotondo, E.

    2018-05-01

    The self renewal process in colonic crypts is the object of several studies. We present here a new compartment model with the following characteristics: (a) we distinguish different classes of cells: stem cells, six generations of transit amplifying cells and the differentiated cells; (b) in order to take into account the monoclonal character of crypts in homeostatic regimes we include symmetric divisions of the stem cells. We first consider the dynamic differential equations that describe the evolution of the mean values of the populations, but the small observed value of the total number of cells involved plus the huge dispersion of experimental data found in the literature leads us to study the stochastic discrete process. This analysis allows us to study fluctuations, the neutral drift that leads to monoclonality, and the effects of the fixation of mutant clones.

  19. Coupled effect of chemotaxis and growth on microbial distributions in organic-amended aquifer sediments: Observations from laboratory and field studies

    USGS Publications Warehouse

    Wang, M.; Ford, R.M.; Harvey, R.W.

    2008-01-01

    The inter-relationship of growth and chemotactic response exhibited by two common soil-inhabiting bacteria was investigated to determine its impact on bacterial migration. Filter-chambers were used to simulate aquifer sediments characterized by vertical gradients of organic contaminants in both artificial groundwater flow systems in the laboratory and within the screened intervals of observation wells in a sandy aquifer. A labile model contaminant (acetate) was added to the top compartments of the three-part chambers, whereas bacteria with a demonstrated propensity to grow on and chemotactically respond to acetate were introduced to the lower compartments, The motility and chemotactic response of Pseudomonas putida F1 resulted in 40 to 110% greater abundances in the upper compartments and concomitant 22 to 70% depletions in the lower compartments relative to the nonchemotactic controls over 2 days. Bacteria were in greatest abundance within the sand plug that separated the upper and lower compartments where sharp acetate gradients induced a strong chemotactic response. This observation was consistent with predictions from a mathematical model. In agreement with the laboratory results, the down-well filter-chamber incubations with Pseudomonas stutzeri in the aquifer indicated that 91% fewer bacteria resided in the lower compartment than the control experiment without acetate at 15 h. The combination of chemotaxis and growth greatly accelerated the migration of bacteria toward and subsequent abundance at the higher acetate concentration. ?? 2008 American Chemical Society.

  20. Systems Models for Transportation Problems : Volume 3. A Computable Command-Control System for a Social System.

    DOT National Transportation Integrated Search

    1976-03-01

    The spectral characteristics of the urban center -- at the level of the family, the functional organized units of society, and the essential compartment balances of the urban center -- are spelled out in greater detail. These compartments are food, m...

  1. Trailer microclimate and calf welfare during fall-run transportation of beef calves in Alberta.

    PubMed

    Goldhawk, C; Janzen, E; González, L A; Crowe, T; Kastelic, J; Pajor, E; Schwartzkopf-Genswein, K S

    2014-11-01

    Twenty-four commercial loads of beef calves (BW 300 ± 52 kg, mean ± SD) were evaluated for associations among transportation factors, in-transit microclimate, and calf welfare. Transport factors evaluated included vehicle speed, space allowance, compartment within trailer, and transit duration. Calves were transported for 7 h 44 min ± 4 h 15 min, with space allowances ranging from 0.56 to 1.17 m(2)/animal. Compartment within trailer, space allowance, and vehicle speed did not affect the difference between compartment ceiling-level and ambient temperatures during a 30-min period of steady-state microclimate. During the steady-state period, a 1°C increase in ambient temperature above the mean of 5.6°C was associated with a 0.62°C decrease in the difference between ceiling-level and ambient temperature (P < 0.01). Ceiling-level temperature and humidity during the first 400 min of transport could be predicted by ambient conditions and vehicle speed (pseudo-r(2) of 0.91 and 0.82 for temperature and humidity ratio; P < 0.01). Events when animal-level temperature-humidity index (THI) was classified as above the "danger" level lasted for 10.2 ± 4.1 consecutive minutes. Ambient and ceiling-level THI values were not classified as above "danger" for 90.0 and 84.9% of animal-level events. Ambient and ceiling-level THI were 5.0 ± 2.1 and 4.7 ± 2.0° Flower than animal-level THI during periods of disagreement, respectively. The majority of calves arrived in good condition and biochemical indicators of calf welfare were within reference ranges for healthy cattle. Within the study population, high pre-transport cortisol and hematocrit were associated with elevated post-transport values (P < 0.01). A 1% increase in shrink during the weaning to loading interval (24 or 48 h) decreased transportation shrink by 0.26 ± 0.04% when average animal-level temperature was greater than 5°C and decreased transportation shrink by 0.11 ± 0.04% when average animal-level temperature was less than 5°C (P < 0.01). We inferred that the study results support future investigation of the extension of in-transit microclimate as a risk factor for post-transport treatment for disease. The study also provided correction factors for estimating in-transit microclimate that could assist in evaluation of transportation management and decisions affecting profitability and calf welfare.

  2. ASEI-SEIR model with vaccination for dengue control in Shah Alam, Malaysia

    NASA Astrophysics Data System (ADS)

    Tay, Chai Jian; Teh, Su Yean; Koh, Hock Lye

    2018-03-01

    Epidemiology modelling provides an understanding of the underlying mechanisms that influence the spread of dengue disease. The most common mathematical models used are the compartment models abbreviated by ASI-SIR, ASEI-SIR and ASEI-SEIR. This paper starts with a discussion of these common models, followed by the derivation of the basic reproduction number (Ro) of each model. The value of Ro in ASI-SIR model is higher than that in ASEI-SIR and ASEI-SEIR models due to the exclusion of exposed adult mosquito in ASI-SIR model. Further, sensitivity analysis on Ro indicates that natural mortality and biting rate of adult mosquito have significant effects on dengue transmission dynamics. Next, an in-house mathematical model named MOSSEIR is developed, based upon the ASEI-SEIR compartment model, in which both mosquito and human populations are considered. The mosquito population is divided into four compartments consisting of aquatic mosquito, susceptible, exposed and infected adult mosquito; while the human population is classified into four compartments comprising susceptible, exposed, infected and recovered human. MOSSEIR is then used to replicate the number of dengue cases in 2010 for Shah Alam, a capital city of Selangor with high incidence of dengue fever. Finally, effectiveness of control strategies, including mosquito breeding sites control, fogging and vaccination, are evaluated for Shah Alam. Simulation results indicate that these three control strategies can significantly reduce dengue transmission, in theory. In reality, the effectiveness of traditional control methods such as elimination of mosquito breeding sites and fogging is below expectation due to non-compliance. Therefore, the adoption of a safe, effective and affordable vaccine remains the best prospect for controlling dengue.

  3. Compartmental and Spatial Rule-Based Modeling with Virtual Cell.

    PubMed

    Blinov, Michael L; Schaff, James C; Vasilescu, Dan; Moraru, Ion I; Bloom, Judy E; Loew, Leslie M

    2017-10-03

    In rule-based modeling, molecular interactions are systematically specified in the form of reaction rules that serve as generators of reactions. This provides a way to account for all the potential molecular complexes and interactions among multivalent or multistate molecules. Recently, we introduced rule-based modeling into the Virtual Cell (VCell) modeling framework, permitting graphical specification of rules and merger of networks generated automatically (using the BioNetGen modeling engine) with hand-specified reaction networks. VCell provides a number of ordinary differential equation and stochastic numerical solvers for single-compartment simulations of the kinetic systems derived from these networks, and agent-based network-free simulation of the rules. In this work, compartmental and spatial modeling of rule-based models has been implemented within VCell. To enable rule-based deterministic and stochastic spatial simulations and network-free agent-based compartmental simulations, the BioNetGen and NFSim engines were each modified to support compartments. In the new rule-based formalism, every reactant and product pattern and every reaction rule are assigned locations. We also introduce the rule-based concept of molecular anchors. This assures that any species that has a molecule anchored to a predefined compartment will remain in this compartment. Importantly, in addition to formulation of compartmental models, this now permits VCell users to seamlessly connect reaction networks derived from rules to explicit geometries to automatically generate a system of reaction-diffusion equations. These may then be simulated using either the VCell partial differential equations deterministic solvers or the Smoldyn stochastic simulator. Copyright © 2017 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  4. Influence of the fire location and the size of a compartment on the heat and smoke flow out of the compartment

    NASA Astrophysics Data System (ADS)

    Wegrzyński, Wojciech; Konecki, Marek

    2018-01-01

    This paper presents results of CFD and scale modelling of the flow of heat and smoke inside and outside of a compartment, in case of fire. Estimation of mass flow out of a compartment is critical, as it is the boundary condition in further considerations related to the exhaust of the smoke from a building - also in analysis related to the performance of natural ventilation in wind conditions. Both locations of the fire and the size of compartment were addressed as possible variables, which influence the mass and the temperature of smoke that leaves the room engulfed in fire. Results of the study show small to none influence of both size of the compartment and the location of the fire, on the mass flow of smoke exiting the room. On the same time, both of these parameters influence the temperature of the smoke - in larger compartments lower average temperatures of the smoke layer, but higher maximum values were observed. Results of this study may be useful also in the determination of the worst case scenarios for structural analysis, or in the investiga tion of the spread of fire through the compartment. Based on the results presented in this study, researchers can attribute an expert judgement choice of fire location, as a single scenario that is representative of a larger amount of probable scenarios.

  5. Lumped Parameter Models of the Central Nervous System for VIIP Research

    NASA Technical Reports Server (NTRS)

    Vera, J.; Mulugeta, L.; Nelson, E. S.; Raykin, J.; Feola, A.; Gleason, R.; Samuels, B.; Myers, J. G.

    2015-01-01

    INTRODUCTION: Current long-duration missions to the International Space Station and future exploration-class missions beyond low-Earth orbit, such as to Mars and asteroids, expose astronauts to increased risk of Visual Impairment and Intracranial Pressure (VIIP) syndrome [1]. It has been hypothesized that the headward shift of cerebral spinal fluid (CSF) and blood in microgravity may cause significant elevation of intracranial pressure (ICP), which in turn induces VIIP syndrome through biomechanical pathways [1, 2]. However, there is insufficient evidence to confirm this hypothesis. In this light, we are developing lumped-parameter models of fluid transport in the central nervous system (CNS) as a means to simulate the influence of microgravity on ICP. The CNS models will also be used in concert with the lumped parameter and finite element models of the eye described in the realted IWS abstracts submitted by Nelson et al., Feola et al. and Ethier et al. METHODS: We have developed a nine compartment CNS model (Figure 1) capable of both time-dependent and steady state fluid transport simulations, based on the works of Stevens et al. [3]. The breakdown of compartments within the model includes: vascular (3), CSF (2), brain (1) and extracranial (3). The boundary pressure in the Central Arteries [A] node is prescribed using an oscillating pressure function PA(t) simulating the carotid pulsatile pressure wave as developed by Linninger et al. [4]. For each time step, pressures are integrated through time using an adaptive-timestep 4th and 5th order Runga-Kutta solver. Once pressures are found, constitutive equations are used to solve for flowrates (Q) between each compartment. In addition to fluid flow between the different compartments, compliance (C) interactions between neighboring compartments are represented. We are also developing a second CNS model based on the works of Linninger et al. [4] which takes a more granular approach to represent the interactions of the intracranial and spinal compartments with the inclusion of arteries, arterioles, capillaries, venules, veins, venous sinus, and ventricles. The flow through the arteries, veins and CSF compartments are governed by continuity, momentum and distensibility balance equations. Furthermore, unlike the Stevens et al. approach, the Monro-Kellie doctrine of constant cranial volume and the bi-phasic nature of the brain parenchyma are implemented. These features appear to be more consistent with the physiologic and anatomical behavior of the CNS, and follow a modeling philosophy similar to the lumped parameter eye model that is intended to be integrated with the CNS model. However, Linninger’s approach has never been implemented to include hydrostatic gradient and microgravity simulation capabilities. Therefore, we aim at implement this modeling approach for spaceflight simulations and assess its overall applicability to VIIP research. OBJECTIVES: We will present verification and validation test results for both models, as well as head-to-head comparison to explore their strengths and limitations with respect to mathematical implementation and physiological significance for VIIP research. In doing so, we hope to provide some guidance to the HRP research community on how to appropriately leverage lumped parameter models for space biomedical research.

  6. Membrane order in the plasma membrane and endocytic recycling compartment.

    PubMed

    Iaea, David B; Maxfield, Frederick R

    2017-01-01

    The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the biophysical properties of membranes. While the properties of model or isolated membranes have been extensively studied, there has been little evaluation of internal membranes in living cells. Here, we use a Nile Red based probe, NR12S, and ratiometric live cell imaging, to analyze the membrane order of the plasma membrane and endocytic recycling compartment. We find that after a brief incubation to allow endocytosis, NR12S is distributed between the plasma membrane and the endocytic recycling compartment. The NR12S reports that the endocytic recycling compartment is more highly ordered than the plasma membrane. We also find that the plasma membrane and the endocytic recycling compartment are differentially affected by altering cellular cholesterol levels. The membrane order of the plasma membrane, but not the endocytic recycling compartment, is altered significantly when cellular cholesterol content is increased or decreased by 20%. These results demonstrate that changes in cellular cholesterol differentially alter membrane order within different organelles.

  7. Membrane order in the plasma membrane and endocytic recycling compartment

    PubMed Central

    Iaea, David B.; Maxfield, Frederick R.

    2017-01-01

    The cholesterol content of membranes plays an important role in organizing membranes for signal transduction and protein trafficking as well as in modulating the biophysical properties of membranes. While the properties of model or isolated membranes have been extensively studied, there has been little evaluation of internal membranes in living cells. Here, we use a Nile Red based probe, NR12S, and ratiometric live cell imaging, to analyze the membrane order of the plasma membrane and endocytic recycling compartment. We find that after a brief incubation to allow endocytosis, NR12S is distributed between the plasma membrane and the endocytic recycling compartment. The NR12S reports that the endocytic recycling compartment is more highly ordered than the plasma membrane. We also find that the plasma membrane and the endocytic recycling compartment are differentially affected by altering cellular cholesterol levels. The membrane order of the plasma membrane, but not the endocytic recycling compartment, is altered significantly when cellular cholesterol content is increased or decreased by 20%. These results demonstrate that changes in cellular cholesterol differentially alter membrane order within different organelles. PMID:29125865

  8. Dynamic and nucleolin-dependent localization of human cytomegalovirus UL84 to the periphery of viral replication compartments and nucleoli.

    PubMed

    Bender, Brian J; Coen, Donald M; Strang, Blair L

    2014-10-01

    Protein-protein and protein-nucleic acid interactions within subcellular compartments are required for viral genome replication. To understand the localization of the human cytomegalovirus viral replication factor UL84 relative to other proteins involved in viral DNA synthesis and to replicating viral DNA in infected cells, we created a recombinant virus expressing a FLAG-tagged version of UL84 (UL84FLAG) and used this virus in immunofluorescence assays. UL84FLAG localization differed at early and late times of infection, transitioning from diffuse distribution throughout the nucleus to exclusion from the interior of replication compartments, with some concentration at the periphery of replication compartments with newly labeled DNA and the viral DNA polymerase subunit UL44. Early in infection, UL84FLAG colocalized with the viral single-stranded DNA binding protein UL57, but colocalization became less prominent as infection progressed. A portion of UL84FLAG also colocalized with the host nucleolar protein nucleolin at the peripheries of both replication compartments and nucleoli. Small interfering RNA (siRNA)-mediated knockdown of nucleolin resulted in a dramatic elimination of UL84FLAG from replication compartments and other parts of the nucleus and its accumulation in the cytoplasm. Reciprocal coimmunoprecipitation of viral proteins from infected cell lysates revealed association of UL84, UL44, and nucleolin. These results indicate that UL84 localization during infection is dynamic, which is likely relevant to its functions, and suggest that its nuclear and subnuclear localization is highly dependent on direct or indirect interactions with nucleolin. Importance: The protein-protein interactions among viral and cellular proteins required for replication of the human cytomegalovirus (HCMV) DNA genome are poorly understood. We sought to understand how an enigmatic HCMV protein critical for virus replication, UL84, localizes relative to other viral and cellular proteins required for HCMV genome replication and replicating viral DNA. We found that UL84 localizes with viral proteins, viral DNA, and the cellular nucleolar protein nucleolin in the subnuclear replication compartments in which viral DNA replication occurs. Unexpectedly, we also found localization of UL84 with nucleolin in nucleoli and showed that the presence of nucleolin is involved in localization of UL84 to the nucleus. These results add to previous work showing the importance of nucleolin in replication compartment architecture and viral DNA synthesis and are relevant to understanding UL84 function. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  9. Classical Michaelis-Menten and system theory approach to modeling metabolite formation kinetics.

    PubMed

    Popović, Jovan

    2004-01-01

    When single doses of drug are administered and kinetics are linear, techniques, which are based on the compartment approach and the linear system theory approach, in modeling the formation of the metabolite from the parent drug are proposed. Unlike the purpose-specific compartment approach, the methodical, conceptual and computational uniformity in modeling various linear biomedical systems is the dominant characteristic of the linear system approach technology. Saturation of the metabolic reaction results in nonlinear kinetics according to the Michaelis-Menten equation. The two compartment open model with Michaelis-Menten elimination kinetics is theorethicaly basic when single doses of drug are administered. To simulate data or to fit real data using this model, one must resort to numerical integration. A biomathematical model for multiple dosage regimen calculations of nonlinear metabolic systems in steady-state and a working example with phenytoin are presented. High correlation between phenytoin steady-state serum levels calculated from individual Km and Vmax values in the 15 adult epileptic outpatients and the observed levels at the third adjustment of phenytoin daily dose (r=0.961, p<0.01) were found.

  10. Topologically-associating domains are stable units of replication-timing regulation

    PubMed Central

    Pope, Benjamin D.; Ryba, Tyrone; Dileep, Vishnu; Yue, Feng; Wu, Weisheng; Denas, Olgert; Vera, Daniel L.; Wang, Yanli; Hansen, R. Scott; Canfield, Theresa K.; Thurman, Robert E.; Cheng, Yong; Gülsoy, Günhan; Dennis, Jonathan H.; Snyder, Michael P.; Stamatoyannopoulos, John A.; Taylor, James; Hardison, Ross C.; Kahveci, Tamer; Ren, Bing; Gilbert, David M.

    2014-01-01

    Summary Eukaryotic chromosomes replicate in a temporal order known as the replication-timing program1. During mammalian development, at least half the genome changes replication timing, primarily in units of 400–800 kb (“replication domains”; RDs), whose positions are preserved in different cell types, conserved between species, and appear to confine long-range effects of chromosome rearrangements2–7. Early and late replication correlate strongly with open and closed chromatin compartments identified by high-resolution chromosome conformation capture (Hi-C), and, to a lesser extent, lamina-associated domains (LADs)4,5,8,9. Recent Hi-C mapping has unveiled a substructure of topologically-associating domains (TADs) that are largely conserved in their positions between cell types and are similar in size to RDs8,10. However, TADs can be further sub-stratified into smaller domains, challenging the significance of structures at any particular scale11,12. Moreover, attempts to reconcile TADs and LADs to replication-timing data have not revealed a common, underlying domain structure8,9,13. Here, we localize boundaries of RDs to the early-replicating border of replication-timing transitions and map their positions in 18 human and 13 mouse cell types. We demonstrate that, collectively, RD boundaries share a near one-to-one correlation with TAD boundaries, whereas within a cell type, adjacent TADs that replicate at similar times obscure RD boundaries, largely accounting for the previously reported lack of alignment. Moreover, cell-type specific replication timing of TADs partitions the genome into two large-scale sub-nuclear compartments revealing that replication-timing transitions are indistinguishable from late-replicating regions in chromatin composition and lamina association and accounting for the reduced correlation of replication timing to LADs and heterochromatin. Our results reconcile cell type specific sub-nuclear compartmentalization with developmentally stable chromosome domains and offer a unified model for large-scale chromosome structure and function. PMID:25409831

  11. Mapping the transition from catalyst-pool to bamboo-like growth-mechanism in vertically-aligned free-standing films of carbon nanotubes filled with Fe3C: The key role of water

    NASA Astrophysics Data System (ADS)

    Boi, Filippo S.; Wang, Shanling; He, Yi

    2016-08-01

    The control of carbon nanotube growth has challenged researchers for more than a decade due to the complex parameters-control necessary in the commonly used CVD approaches. Here we show that a direct transition from the catalyst-pool growth mechanism characterized by graphene-caps in the direction of growth to a bamboo-shaped mechanism characterized by the repetition of periodic elongated graphitic compartments is present when controlled quantities of water are added to ferrocene/dichlorobenzene. Our results suggest that water-addition allows enhancing the level of stress accumulated under the graphitic nanotubes-cap.

  12. 76 FR 10476 - Special Conditions: Boeing Model 787-8 Airplane; Overhead Crew-Rest Compartment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-02-25

    ...\\ in interior volume, the design must ensure the ability to contain a fire likely to occur within the... or unusual design features associated with installation of an overhead crew-rest (OCR) compartment... this design feature. These special conditions contain the additional safety standards that the...

  13. Protein-crystal growth experiment (planned)

    NASA Technical Reports Server (NTRS)

    Fujita, S.; Asano, K.; Hashitani, T.; Kitakohji, T.; Nemoto, H.; Kitamura, S.

    1988-01-01

    To evaluate the effectiveness of a microgravity environment on protein crystal growth, a system was developed using 5 cubic feet Get Away Special payload canister. In the experiment, protein (myoglobin) will be simultaneously crystallized from an aqueous solution in 16 crystallization units using three types of crystallization methods, i.e., batch, vapor diffusion, and free interface diffusion. Each unit has two compartments: one for the protein solution and the other for the ammonium sulfate solution. Compartments are separated by thick acrylic or thin stainless steel plates. Crystallization will be started by sliding out the plates, then will be periodically recorded up to 120 hours by a still camera. The temperature will be passively controlled by a phase transition thermal storage component and recorded in IC memory throughout the experiment. Microgravity environment can then be evaluated for protein crystal growth by comparing crystallization in space with that on Earth.

  14. Studies on Manfred Eigen's model for the self-organization of information processing.

    PubMed

    Ebeling, W; Feistel, R

    2018-05-01

    In 1971, Manfred Eigen extended the principles of Darwinian evolution to chemical processes, from catalytic networks to the emergence of information processing at the molecular level, leading to the emergence of life. In this paper, we investigate some very general characteristics of this scenario, such as the valuation process of phenotypic traits in a high-dimensional fitness landscape, the effect of spatial compartmentation on the valuation, and the self-organized transition from structural to symbolic genetic information of replicating chain molecules. In the first part, we perform an analysis of typical dynamical properties of continuous dynamical models of evolutionary processes. In particular, we study the mapping of genotype to continuous phenotype spaces following the ideas of Wright and Conrad. We investigate typical features of a Schrödinger-like dynamics, the consequences of the high dimensionality, the leading role of saddle points, and Conrad's extra-dimensional bypass. In the last part, we discuss in brief the valuation of compartment models and the self-organized emergence of molecular symbols at the beginning of life.

  15. Influence of biophase distribution and P-glycoprotein interaction on pharmacokinetic-pharmacodynamic modelling of the effects of morphine on the EEG

    PubMed Central

    Groenendaal, D; Freijer, J; de Mik, D; Bouw, M R; Danhof, M; de Lange, E C M

    2007-01-01

    Background and purpose: The aim was to investigate the influence of biophase distribution including P-glycoprotein (Pgp) function on the pharmacokinetic-pharmacodynamic correlations of morphine's actions in rat brain. Experimental approach: Male rats received a 10-min infusion of morphine as 4 mg kg−1, combined with a continuous infusion of the Pgp inhibitor GF120918 or vehicle, 10 or 40 mg kg−1. EEG signals were recorded continuously and blood samples were collected. Key results: Profound hysteresis was observed between morphine blood concentrations and effects on the EEG. Only the termination of the EEG effect was influenced by GF120918. Biophase distribution was best described with an extended catenary biophase distribution model, with a sequential transfer and effect compartment. The rate constant for transport through the transfer compartment (k1e) was 0.038 min−1, being unaffected by GF120918. In contrast, the rate constant for the loss from the effect compartment (keo) decreased 60% after GF120918. The EEG effect was directly related to concentrations in the effect compartment using the sigmoidal Emax model. The values of the pharmacodynamic parameters E0, Emax, EC50 and Hill factor were 45.0 μV, 44.5 μV, 451 ng ml−1 and 2.3, respectively. Conclusions and implications: The effects of GF120918 on the distribution kinetics of morphine in the effect compartment were consistent with the distribution in brain extracellular fluid (ECF) as estimated by intracerebral microdialysis. However, the time-course of morphine concentrations at the site of action in the brain, as deduced from the biophase model, is distinctly different from the brain ECF concentrations. PMID:17471181

  16. Population pharmacokinetics of telapristone (CDB-4124) and its active monodemethylated metabolite CDB-4453, with a mixture model for total clearance.

    PubMed

    Morris, Denise; Podolski, Joseph; Kirsch, Alan; Wiehle, Ronald; Fleckenstein, Lawrence

    2011-12-01

    Telapristone is a selective progesterone antagonist that is being developed for the long-term treatment of symptoms associated with endometriosis and uterine fibroids. The population pharmacokinetics of telapristone (CDB-4124) and CDB-4453 was investigated using nonlinear mixed-effects modeling. Data from two clinical studies (n = 32) were included in the analysis. A two-compartment (parent) one compartment (metabolite) mixture model (with two populations for apparent clearance) with first-order absorption and elimination adequately described the pharmacokinetics of telapristone and CDB-4453. Telapristone was rapidly absorbed with an absorption rate constant (Ka) of 1.26 h(-1). Moderate renal impairment resulted in a 74% decrease in Ka. The population estimates for oral clearance (CL/F) for the two populations were 11.6 and 3.34 L/h, respectively, with 25% of the subjects being allocated to the high-clearance group. Apparent volume of distribution for the central compartment (V2/F) was 37.4 L, apparent inter-compartmental clearance (Q/F) was 21.9 L/h, and apparent peripheral volume of distribution for the parent (V4/F) was 120 L. The ratio of the fraction of telapristone converted to CDB-4453 to the distribution volume of CDB-4453 (Fmet(est)) was 0.20/L. Apparent volume of distribution of the metabolite compartment (V3/F) was fixed to 1 L and apparent clearance of the metabolite (CLM/F) was 2.43 L/h. A two-compartment parent-metabolite model adequately described the pharmacokinetics of telapristone and CDB-4453. The clearance of telapristone was separated into two populations and could be the result of metabolism via polymorphic CYP3A5.

  17. Simulation of a proposed emergency outlet from Devils Lake, North Dakota

    USGS Publications Warehouse

    Vecchia, Aldo V.

    2002-01-01

    From 1993 to 2001, Devils Lake rose more than 25 feet, flooding farmland, roads, and structures around the lake and causing more than $400 million in damages in the Devils Lake Basin. In July 2001, the level of Devils Lake was at 1,448.0 feet above sea level1, which was the highest lake level in more than 160 years. The lake could continue to rise to several feet above its natural spill elevation to the Sheyenne River (1,459 feet above sea level) in future years, causing extensive additional flooding in the basin and, in the event of an uncontrolled natural spill, downstream in the Red River of the North Basin as well. The outlet simulation model described in this report was developed to determine the potential effects of various outlet alternatives on the future lake levels and water quality of Devils Lake.Lake levels of Devils Lake are controlled largely by precipitation on the lake surface, evaporation from the lake surface, and surface inflow. For this study, a monthly water-balance model was developed to compute the change in total volume of Devils Lake, and a regression model was used to estimate monthly water-balance data on the basis of limited recorded data. Estimated coefficients for the regression model indicated fitted precipitation on the lake surface was greater than measured precipitation in most months, fitted evaporation from the lake surface was less than estimated evaporation in most months, and ungaged inflow was about 2 percent of gaged inflow in most months. Dissolved sulfate was considered to be the key water-quality constituent for evaluating the effects of a proposed outlet on downstream water quality. Because large differences in sulfate concentrations existed among the various bays of Devils Lake, monthly water-balance data were used to develop detailed water and sulfate mass-balance models to compute changes in sulfate load for each of six major storage compartments in response to precipitation, evaporation, inflow, and outflow from each compartment. The storage compartments--five for Devils Lake and one for Stump Lake--were connected by bridge openings, culverts, or natural channels that restricted mixing between compartments. A numerical algorithm was developed to calculate inflow and outflow from each compartment. Sulfate loads for the storage compartments first were calculated using the assumptions that no interaction occurred between the bottom sediments and the water column and no wind- or buoyancy-induced mixing occurred between compartments. However, because the fitted sulfate loads did not agree with the estimated sulfate loads, which were obtained from recorded sulfate concentrations, components were added to the sulfate mass-balance model to account for the flux of sulfate between bottom sediments and the lake and for mixing between storage compartments. Mixing between compartments can occur during periods of open water because of wind and during periods of ice cover because of water-density differences between compartments. Sulfate loads calculated using the sulfate mass-balance model with sediment interaction and mixing between compartments closely matched sulfate loads computed from historical concentrations. The water and sulfate mass-balance models were used to calculate potential future lake levels and sulfate concentrations for Devils Lake and Stump Lake given potential future values of monthly precipitation, evaporation, and inflow. Potential future inputs were generated using a scenario approach and a stochastic approach. In the scenario approach, historical values of precipitation, evaporation, and inflow were repeated in the future for a particular sequence of historical years. In the stochastic approach, a statistical time-series model was developed to randomly generate potential future inputs. The scenario approach was used to evaluate the effectiveness of various outlet alternatives, and the stochastic approach was used to evaluate the hydrologic and water-quality effects of the potential outlet alternatives that were selected on the basis of the scenario analysis. Given potential future lake levels and sulfate concentrations generated using either the scenario or stochastic approach and potential future ambient flows and sulfate concentrations for the Sheyenne River receiving waters, daily outlet discharges could be calculated for virtually any outlet alternative. For the scenario approach, future ambient flows and sulfate concentrations for the Sheyenne River were generated using the same sequence of years used for generating water-balance data for Devils Lake. For the stochastic approach, a procedure was developed for generating daily Sheyenne River flows and sulfate concentrations that were "in-phase" with the generated water-balance data for Devils Lake. Simulation results for the scenario approach indicated that neither of the West Bay outlet alternatives provided effective flood-damage reduction without exceeding downstream water-quality constraints. However, both Pelican Lake outlet alternatives provided significant flood-damage reduction with only minor downstream water-quality changes. The most effective alternative for controlling rising lake levels was a Pelican Lake outlet with a 480-cubic-foot-per-second pump capacity and a 250-milligram-per-liter downstream sulfate constraint. However, this plan is costly because of the high pump capacity and the requirement of a control structure on Highway 19 to control the level of Pelican Lake. A less costly, though less effective for flood-damage reduction, plan is a Pelican Lake outlet with a 300-cubic-foot-per-second pump capacity and a 250-milligram-per-liter downstream sulfate constraint. The plan is less costly because the pump capacity is smaller and because the control structure on Highway 19 is not required. The less costly Pelican Lake alternative with a 450-milligramper- liter downstream sulfate constraint rather than a 250-milligram-per-liter downstream sulfate constraint was identified by the U.S. Army Corps of Engineers as the preferred alternative for detailed design and engineering analysis. Simulation results for the stochastic approach indicated that the geologic history of lake-level fluctuations of Devils Lake for the past 2,500 years was consistent with a climatic history that consisted of two climate states--a wet state, similar to conditions during 1980-99, and a normal state, similar to conditions during 1950-78. The transition times between the wet and normal climatic periods occurred randomly. The average duration of the wet climatic periods was 20 years, and the average duration of the normal climatic periods was 120 years. The stochastic approach was used to generate 10,000 independent sequences of lake levels and sulfate concentrations for Devils Lake for water years 2001-50. Each trace began with the same starting conditions, and the duration of the current wet cycle was generated randomly for each trace. Each trace was generated for the baseline (natural) condition and for the Pelican Lake outlet with a 300-cubic-foot-per-second pump capacity and a 450-milligram-per-liter downstream sulfate constraint. The outlet significantly lowered the probabilities of future lake-level increases within the next 50 years and did not substantially increase the probabilities of reaching low lake levels or poor water-quality conditions during the same period.

  18. Performance of an image analysis processing system for hen tracking in an environmental preference chamber.

    PubMed

    Kashiha, Mohammad Amin; Green, Angela R; Sales, Tatiana Glogerley; Bahr, Claudia; Berckmans, Daniel; Gates, Richard S

    2014-10-01

    Image processing systems have been widely used in monitoring livestock for many applications, including identification, tracking, behavior analysis, occupancy rates, and activity calculations. The primary goal of this work was to quantify image processing performance when monitoring laying hens by comparing length of stay in each compartment as detected by the image processing system with the actual occurrences registered by human observations. In this work, an image processing system was implemented and evaluated for use in an environmental animal preference chamber to detect hen navigation between 4 compartments of the chamber. One camera was installed above each compartment to produce top-view images of the whole compartment. An ellipse-fitting model was applied to captured images to detect whether the hen was present in a compartment. During a choice-test study, mean ± SD success detection rates of 95.9 ± 2.6% were achieved when considering total duration of compartment occupancy. These results suggest that the image processing system is currently suitable for determining the response measures for assessing environmental choices. Moreover, the image processing system offered a comprehensive analysis of occupancy while substantially reducing data processing time compared with the time-intensive alternative of manual video analysis. The above technique was used to monitor ammonia aversion in the chamber. As a preliminary pilot study, different levels of ammonia were applied to different compartments while hens were allowed to navigate between compartments. Using the automated monitor tool to assess occupancy, a negative trend of compartment occupancy with ammonia level was revealed, though further examination is needed. ©2014 Poultry Science Association Inc.

  19. N-acetyltransferase genotypes and the pharmacokinetics and tolerability of para-aminosalicylic acid in patients with drug-resistant pulmonary tuberculosis.

    PubMed

    Sy, Sherwin K B; de Kock, Lizanne; Diacon, Andreas H; Werely, Cedric J; Xia, Huiming; Rosenkranz, Bernd; van der Merwe, Lize; Donald, Peter R

    2015-07-01

    The aim of this study was to examine the relationships between N-acetyltransferase genotypes, pharmacokinetics, and tolerability of granular slow-release para-aminosalicylic acid (GSR-PAS) in tuberculosis patients. The study was a randomized, two-period, open-label, crossover design wherein each patient received 4 g GSR-PAS twice daily or 8 g once daily alternately. The PAS concentration-time profiles were modeled by a one-compartment disposition model with three transit compartments in series to describe its absorption. Patients' NAT1 and NAT2 genotypes were determined by sequencing and restriction enzyme analysis, respectively. The number of daily vomits was modeled by a Poisson probability mass function. Comparisons of other tolerability measures by regimens, gender, and genotypes were evaluated by a linear mixed-effects model. The covariate effects associated with efavirenz, gender, and NAT1*3, NAT1*14, and NAT2*5 alleles corresponded to 25, 37, -17, -48, and -27% changes, respectively, in oral clearance of PAS. The NAT1*10 allele did not influence drug clearance. The time above the MIC of 1 mg/liter was significantly different between the two regimens but not influenced by the NAT1 or NAT2 genotypes. The occurrence and intensity of intolerance differed little between regimens. Four grams of GSR-PAS twice daily but not 8 g once daily ensured concentrations exceeding the MIC (1 mg/liter) throughout the dosing interval; PAS intolerance was not related to maximum PAS concentrations over the doses studied and was not more frequent after once-daily dosing. We confirm that the slow phenotype conferred by the NAT1*14 and NAT1*3 alleles resulted in higher PAS exposure but found no evidence of increased activity of the NAT1*10 allele. Copyright © 2015, American Society for Microbiology. All Rights Reserved.

  20. The impact of genetic polymorphisms on the pharmacokinetics of efavirenz in African children.

    PubMed

    Bienczak, Andrzej; Cook, Adrian; Wiesner, Lubbe; Olagunju, Adeniyi; Mulenga, Veronica; Kityo, Cissy; Kekitiinwa, Addy; Owen, Andrew; Walker, A Sarah; Gibb, Diana M; McIlleron, Helen; Burger, David; Denti, Paolo

    2016-07-01

    Using a model-based approach, the efavirenz steady-state pharmacokinetics in African children is characterized, quantifying demographic and genotypic effects on the drug's disposition. Simulations are also conducted allowing prediction of optimized doses of efavirenz in this population. We modelled the steady-state population pharmacokinetics of efavirenz in Ugandan and Zambian children using nonlinear mixed-effects modelling. Individual mid-dose efavirenz concentrations were derived and simulations explored genotype-based dose optimization strategies. A two-compartment model with absorption through transit compartments well described 2086 concentration-time points in 169 children. The combined effect of single nucleotide polymorphisms (SNPs) 516G>T and 983T>C explained 44.5% and 14.7% of the variability in efavirenz clearance and bioavailability, respectively. The detected frequencies of composite CYP2B6 genotype were 0.33 for 516GG|983TT, 0.35 for 516GT|983TT, 0.06 for 516GG|983TC, 0.18 for 516TT|983TT, 0.07 516GT|983TC and 0.01 for 516GG|983CC. The corresponding estimated clearance rates were 6.94, 4.90, 3.93, 1.92, 1.36, and 0.74 l h(-1) for a 15.4 kg child and median (95% CI) observed mid-dose concentrations 1.55 (0.51-2.94), 2.20 (0.97-4.40), 2.03 (1.19-4.53), 7.55 (2.40-14.74), 7.79 (3.66-24.59) and 18.22 (11.84-22.76) mg l(-1) , respectively. Simulations showed that wild-type individuals had exposures at the bottom of therapeutic range, while slower metabolizers were overexposed. Dosage guidelines for African children should take into consideration the combined effect of SNPs CYP2B6 516G>T and 983T>C. © 2016 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of The British Pharmacological Society.

  1. Applicability of the Proposed Japanese Model for the Classification of Gastric Cancer Location: The "PROTRADIST" Retrospective Study.

    PubMed

    Marano, Luigi; Petrillo, Marianna; Pezzella, Modestino; Patriti, Alberto; Braccio, Bartolomeo; Esposito, Giuseppe; Grassia, Michele; Romano, Angela; Torelli, Francesco; De Luca, Raffaele; Fabozzi, Alessio; Falco, Giuseppe; Di Martino, Natale

    2017-06-01

    The extension of lymphadenectomy for surgical treatment of gastric cancer remains discordant among European and Japanese surgeons. Kinami et al. (Kinami S, Fujimura T, Ojima E, et al. PTD classification: proposal for a new classification of gastric cancer location based on physiological lymphatic flow. Int. J. Clin. Oncol. 2008;13:320-329) proposed a new experimental classification, the "Proximal zone, Transitional zone, Distal zone" (PTD) classification, based on the physiological lymphatic flow of gastric cancer site. The aim of the present retrospective study is to assess the applicability of PTD Japanese model in gastric cancer patients of our Western surgical department. Two groups of patients with histologically documented adenocarcinoma of the stomach were retrospectively obtained: In the first group were categorized 89 patients with T1a-T1b tumor invasion; and in the second group were 157 patients with T2-T3 category. The data collected were then categorized according to the PTD classification. In the T1a-T1b group there were no lymph node metastases within the r-GA or r-GEA compartments for tumors located in the P portion, and similarly there were no lymphatic metastases within the l-GEA or p-GA compartments for tumors located in the D portion. On the contrary, in the T2-T3 group the lymph node metastases presented a diffused spreading with no statistical significance between the two classification models. Our results show that the PTD classification based on physiological lymphatic flow of the gastric cancer site is a more physiological and clinical version than the Upper, Medium And Lower classification. It represents a valuable and applicable model of cancer location that could be a guide to a tailored surgical approach in Italian patients with neoplasm confined to submucosa. Nevertheless, in order to confirm our findings, larger and prospective studies are needed.

  2. Interstitial diffusion and the relationship between compartment modelling and multi-scale spatial-temporal modelling of (18)F-FLT tumour uptake dynamics.

    PubMed

    Liu, Dan; Chalkidou, Anastasia; Landau, David B; Marsden, Paul K; Fenwick, John D

    2014-09-07

    Tumour cell proliferation can be imaged via positron emission tomography of the radiotracer 3'-deoxy-3'-18F-fluorothymidine (18F-FLT). Conceptually, the number of proliferating cells might be expected to correlate more closely with the kinetics of 18F-FLT uptake than with uptake at a fixed time. Radiotracer uptake kinetics are standardly visualized using parametric maps of compartment model fits to time-activity-curves (TACs) of individual voxels. However the relationship between the underlying spatiotemporal accumulation of FLT and the kinetics described by compartment models has not yet been explored. In this work tumour tracer uptake is simulated using a mechanistic spatial-temporal model based on a convection-diffusion-reaction equation solved via the finite difference method. The model describes a chain of processes: the flow of FLT between the spatially heterogeneous tumour vasculature and interstitium; diffusion and convection of FLT within the interstitium; transport of FLT into cells; and intracellular phosphorylation. Using values of model parameters estimated from the biological literature, simulated FLT TACs are generated with shapes and magnitudes similar to those seen clinically. Results show that the kinetics of the spatial-temporal model can be recovered accurately by fitting a 3-tissue compartment model to FLT TACs simulated for those tumours or tumour sub-volumes that can be viewed as approximately closed, for which tracer diffusion throughout the interstitium makes only a small fractional change to the quantity of FLT they contain. For a single PET voxel of width 2.5-5 mm we show that this condition is roughly equivalent to requiring that the relative difference in tracer uptake between the voxel and its neighbours is much less than one.

  3. Regulation of Glutathione in a Rat Diploid Hepatic Epithelial Cell Line

    DTIC Science & Technology

    1990-06-01

    supporting the contention that they are not pre-neoplastic (60). Metabolic cooperation by gap- junctional intercellular communication has been demonstrated...counted. The resulting population statistics allowed calculation and display of cycle-specific cell characteristics and compartment transit times (see...was repeated in chinese hamster V79 cells to see if the effect is idiosyncratic. It is not - V79 cells respond to CYC in the same fashion as WB344(s) if

  4. Steady state phosphorus mass balance model during hemodialysis based on a pseudo one-compartment kinetic model.

    PubMed

    Leypoldt, John K; Agar, Baris U; Akonur, Alp; Gellens, Mary E; Culleton, Bruce F

    2012-11-01

    Mathematical models of phosphorus kinetics and mass balance during hemodialysis are in early development. We describe a theoretical phosphorus steady state mass balance model during hemodialysis based on a novel pseudo one-compartment kinetic model. The steady state mass balance model accounted for net intestinal absorption of phosphorus and phosphorus removal by both dialysis and residual kidney function. Analytical mathematical solutions were derived to describe time-dependent intradialytic and interdialytic serum phosphorus concentrations assuming hemodialysis treatments were performed symmetrically throughout a week. Results from the steady state phosphorus mass balance model are described for thrice weekly hemodialysis treatment prescriptions only. The analysis predicts 1) a minimal impact of dialyzer phosphorus clearance on predialysis serum phosphorus concentration using modern, conventional hemodialysis technology, 2) variability in the postdialysis-to-predialysis phosphorus concentration ratio due to differences in patient-specific phosphorus mobilization, and 3) the importance of treatment time in determining the predialysis serum phosphorus concentration. We conclude that a steady state phosphorus mass balance model can be developed based on a pseudo one-compartment kinetic model and that predictions from this model are consistent with previous clinical observations. The predictions from this mass balance model are theoretical and hypothesis-generating only; additional prospective clinical studies will be required for model confirmation.

  5. Dual-input two-compartment pharmacokinetic model of dynamic contrast-enhanced magnetic resonance imaging in hepatocellular carcinoma.

    PubMed

    Yang, Jian-Feng; Zhao, Zhen-Hua; Zhang, Yu; Zhao, Li; Yang, Li-Ming; Zhang, Min-Ming; Wang, Bo-Yin; Wang, Ting; Lu, Bao-Chun

    2016-04-07

    To investigate the feasibility of a dual-input two-compartment tracer kinetic model for evaluating tumorous microvascular properties in advanced hepatocellular carcinoma (HCC). From January 2014 to April 2015, we prospectively measured and analyzed pharmacokinetic parameters [transfer constant (Ktrans), plasma flow (Fp), permeability surface area product (PS), efflux rate constant (kep), extravascular extracellular space volume ratio (ve), blood plasma volume ratio (vp), and hepatic perfusion index (HPI)] using dual-input two-compartment tracer kinetic models [a dual-input extended Tofts model and a dual-input 2-compartment exchange model (2CXM)] in 28 consecutive HCC patients. A well-known consensus that HCC is a hypervascular tumor supplied by the hepatic artery and the portal vein was used as a reference standard. A paired Student's t-test and a nonparametric paired Wilcoxon rank sum test were used to compare the equivalent pharmacokinetic parameters derived from the two models, and Pearson correlation analysis was also applied to observe the correlations among all equivalent parameters. The tumor size and pharmacokinetic parameters were tested by Pearson correlation analysis, while correlations among stage, tumor size and all pharmacokinetic parameters were assessed by Spearman correlation analysis. The Fp value was greater than the PS value (FP = 1.07 mL/mL per minute, PS = 0.19 mL/mL per minute) in the dual-input 2CXM; HPI was 0.66 and 0.63 in the dual-input extended Tofts model and the dual-input 2CXM, respectively. There were no significant differences in the kep, vp, or HPI between the dual-input extended Tofts model and the dual-input 2CXM (P = 0.524, 0.569, and 0.622, respectively). All equivalent pharmacokinetic parameters, except for ve, were correlated in the two dual-input two-compartment pharmacokinetic models; both Fp and PS in the dual-input 2CXM were correlated with Ktrans derived from the dual-input extended Tofts model (P = 0.002, r = 0.566; P = 0.002, r = 0.570); kep, vp, and HPI between the two kinetic models were positively correlated (P = 0.001, r = 0.594; P = 0.0001, r = 0.686; P = 0.04, r = 0.391, respectively). In the dual input extended Tofts model, ve was significantly less than that in the dual input 2CXM (P = 0.004), and no significant correlation was seen between the two tracer kinetic models (P = 0.156, r = 0.276). Neither tumor size nor tumor stage was significantly correlated with any of the pharmacokinetic parameters obtained from the two models (P > 0.05). A dual-input two-compartment pharmacokinetic model (a dual-input extended Tofts model and a dual-input 2CXM) can be used in assessing the microvascular physiopathological properties before the treatment of advanced HCC. The dual-input extended Tofts model may be more stable in measuring the ve; however, the dual-input 2CXM may be more detailed and accurate in measuring microvascular permeability.

  6. Analytical solutions to compartmental indoor air quality models with application to environmental tobacco smoke concentrations measured in a house.

    PubMed

    Ott, Wayne R; Klepeis, Neil E; Switzer, Paul

    2003-08-01

    This paper derives the analytical solutions to multi-compartment indoor air quality models for predicting indoor air pollutant concentrations in the home and evaluates the solutions using experimental measurements in the rooms of a single-story residence. The model uses Laplace transform methods to solve the mass balance equations for two interconnected compartments, obtaining analytical solutions that can be applied without a computer. Environmental tobacco smoke (ETS) sources such as the cigarette typically emit pollutants for relatively short times (7-11 min) and are represented mathematically by a "rectangular" source emission time function, or approximated by a short-duration source called an "impulse" time function. Other time-varying indoor sources also can be represented by Laplace transforms. The two-compartment model is more complicated than the single-compartment model and has more parameters, including the cigarette or combustion source emission rate as a function of time, room volumes, compartmental air change rates, and interzonal air flow factors expressed as dimensionless ratios. This paper provides analytical solutions for the impulse, step (Heaviside), and rectangular source emission time functions. It evaluates the indoor model in an unoccupied two-bedroom home using cigars and cigarettes as sources with continuous measurements of carbon monoxide (CO), respirable suspended particles (RSP), and particulate polycyclic aromatic hydrocarbons (PPAH). Fine particle mass concentrations (RSP or PM3.5) are measured using real-time monitors. In our experiments, simultaneous measurements of concentrations at three heights in a bedroom confirm an important assumption of the model-spatial uniformity of mixing. The parameter values of the two-compartment model were obtained using a "grid search" optimization method, and the predicted solutions agreed well with the measured concentration time series in the rooms of the home. The door and window positions in each room had considerable effect on the pollutant concentrations observed in the home. Because of the small volumes and low air change rates of most homes, indoor pollutant concentrations from smoking activity in a home can be very high and can persist at measurable levels indoors for many hours.

  7. Understanding tumor heterogeneity as functional compartments - superorganisms revisited

    PubMed Central

    2011-01-01

    Compelling evidence broadens our understanding of tumors as highly heterogeneous populations derived from one common progenitor. In this review we portray various stages of tumorigenesis, tumor progression, self-seeding and metastasis in analogy to the superorganisms of insect societies to exemplify the highly complex architecture of a neoplasm as a system of functional "castes." Accordingly, we propose a model in which clonal expansion and cumulative acquisition of genetic alterations produce tumor compartments each equipped with distinct traits and thus distinct functions that cooperate to establish clinically apparent tumors. This functional compartment model also suggests mechanisms for the self-construction of tumor stem cell niches. Thus, thinking of a tumor as a superorganism will provide systemic insight into its functional compartmentalization and may even have clinical implications. PMID:21619636

  8. Near-Infrared Monitoring of Model Chronic Compartment Syndrome In Exercising Skeletal Muscle

    NASA Technical Reports Server (NTRS)

    Hargens, Alan R.; Breit, G. A.; Gross, J. H.; Watenpaugh, D. E.; Chance, B.

    1995-01-01

    Chronic compartment syndrome (CCS) is characterized by muscle ischemia, usually in the anterior oompartment of the leg, caused by high intramuscular pressure during exercise. Dual-wave near-infrared (NIR) spectroscopy is an optical technique that allows noninvasive tracking of variations in muscle tissue oxygenation (Chance et al., 1988). We hypothesized that with a model CCS, muscle tissue oxygenation will show a greater decline during exercise and a slower recovery post-exercise than under normal conditions.

  9. Blind identification of the kinetic parameters in three-compartment models

    NASA Astrophysics Data System (ADS)

    Riabkov, Dmitri Y.; Di Bella, Edward V. R.

    2004-03-01

    Quantified knowledge of tissue kinetic parameters in the regions of the brain and other organs can offer information useful in clinical and research applications. Dynamic medical imaging with injection of radioactive or paramagnetic tracer can be used for this measurement. The kinetics of some widely used tracers such as [18F]2-fluoro-2-deoxy-D-glucose can be described by a three-compartment physiological model. The kinetic parameters of the tissue can be estimated from dynamically acquired images. Feasibility of estimation by blind identification, which does not require knowledge of the blood input, is considered analytically and numerically in this work for the three-compartment type of tissue response. The non-uniqueness of the two-region case for blind identification of kinetic parameters in three-compartment model is shown; at least three regions are needed for the blind identification to be unique. Numerical results for the accuracy of these blind identification methods in different conditions were considered. Both a separable variables least-squares (SLS) approach and an eigenvector-based algorithm for multichannel blind deconvolution approach were used. The latter showed poor accuracy. Modifications for non-uniform time sampling were also developed. Also, another method which uses a model for the blood input was compared. Results for the macroparameter K, which reflects the metabolic rate of glucose usage, using three regions with noise showed comparable accuracy for the separable variables least squares method and for the input model-based method, and slightly worse accuracy for SLS with the non-uniform sampling modification.

  10. W3MAMCAT: a world wide web based tool for mammillary and catenary compartmental modeling and expert system distinguishability.

    PubMed

    Russell, Solomon; Distefano, Joseph J

    2006-07-01

    W(3)MAMCAT is a new web-based and interactive system for building and quantifying the parameters or parameter ranges of n-compartment mammillary and catenary model structures, with input and output in the first compartment, from unstructured multiexponential (sum-of-n-exponentials) models. It handles unidentifiable as well as identifiable models and, as such, provides finite parameter interval solutions for unidentifiable models, whereas direct parameter search programs typically do not. It also tutorially develops the theory of model distinguishability for same order mammillary versus catenary models, as did its desktop application predecessor MAMCAT+. This includes expert system analysis for distinguishing mammillary from catenary structures, given input and output in similarly numbered compartments. W(3)MAMCAT provides for universal deployment via the internet and enhanced application error checking. It uses supported Microsoft technologies to form an extensible application framework for maintaining a stable and easily updatable application. Most important, anybody, anywhere, is welcome to access it using Internet Explorer 6.0 over the internet for their teaching or research needs. It is available on the Biocybernetics Laboratory website at UCLA: www.biocyb.cs.ucla.edu.

  11. 75 FR 81 - Special Conditions: Boeing Model 787-8 Airplane; Overhead Flightcrew Rest Compartment Occupiable...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-04

    ..., explain the reason for any recommended change, and include supporting data. We ask that you send us two... changes to the approved OFCR compartment configuration that affect crewmember emergency egress or any other procedures affecting safety of the occupying crewmembers or related emergency training will...

  12. 75 FR 75 - Special Conditions: Boeing Model 787-8 Airplane; Overhead Crew Rest Compartment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-01-04

    ..., explain the reason for any recommended change, and include supporting data. We ask that you send us two...-site operational evaluation. Any changes to the approved OCR compartment configuration that affect crewmember emergency egress or any other procedures affecting safety of the occupying crewmembers or related...

  13. 78 FR 25846 - Special Conditions: Airbus, Model A340-600 Series Airplanes; Lower Deck Crew Rest Compartments

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-05-03

    ... significantly delay issuance of the design approval and thus delivery of the affected aircraft. In addition, the... specific portion of the special conditions, explain the reason for any recommended change, and include... compartment configuration that affect crew member emergency egress or any other procedures affecting the...

  14. The biodistribution and dosimetry of {sup 117m}Sn DTPA with special emphasis on active marrow absorbed doses

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Stubbs, J.; Atkins, H.

    1999-01-01

    {sup 117m}Sn(4+) DTPA is a new radiopharmaceutical for the palliation of pain associated with metastatic bone cancer. Recently, the Phase 2 clinical trials involving 47 patients were completed. These patients received administered activities in the range 6.7--10.6 MBq/kg of body mass. Frequent collections of urine were acquired over the first several hours postadministration and daily cumulative collections were obtained for the next 4--10 days. Anterior/posterior gamma camera images were obtained frequently over the initial 10 days. Radiation dose estimates were calculated for 8 of these patients. Each patient`s biodistribution data were mathematically simulated using a multicompartmental model. The model consistedmore » of the following compartments: central, bone, kidney, other tissues, and cumulative urine. The measured cumulative urine data were used as references for the cumulative urine excretion compartment. The total-body compartment (sum of the bone surfaces, central, kidney, and other tissues compartments) was reference to all activity not excreted in the urine.« less

  15. APPL endosomes are not obligatory endocytic intermediates but act as stable cargo-sorting compartments

    PubMed Central

    Kalaidzidis, Inna; Miaczynska, Marta; Brewińska-Olchowik, Marta; Hupalowska, Anna; Ferguson, Charles; Parton, Robert G.; Kalaidzidis, Yannis

    2015-01-01

    Endocytosis allows cargo to enter a series of specialized endosomal compartments, beginning with early endosomes harboring Rab5 and its effector EEA1. There are, however, additional structures labeled by the Rab5 effector APPL1 whose role in endocytic transport remains unclear. It has been proposed that APPL1 vesicles are transport intermediates that convert into EEA1 endosomes. Here, we tested this model by analyzing the ultrastructural morphology, kinetics of cargo transport, and stability of the APPL1 compartment over time. We found that APPL1 resides on a tubulo-vesicular compartment that is capable of sorting cargo for recycling or degradation and that displays long lifetimes, all features typical of early endosomes. Fitting mathematical models to experimental data rules out maturation of APPL1 vesicles into EEA1 endosomes as a primary mechanism for cargo transport. Our data suggest instead that APPL1 endosomes represent a distinct population of Rab5-positive sorting endosomes, thus providing important insights into the compartmental organization of the early endocytic pathway. PMID:26459602

  16. Biokinetic modelling development and analysis of arsenic dissolution into the gastrointestinal tract using SAAM II

    NASA Astrophysics Data System (ADS)

    Perama, Yasmin Mohd Idris; Siong, Khoo Kok

    2018-04-01

    A mathematical model comprising 8 compartments were designed to describe the kinetic dissolution of arsenic (As) from water leach purification (WLP) waste samples ingested into the gastrointestinal system. A totally reengineered software system named Simulation, Analysis and Modelling II (SAAM II) was employed to aid in the experimental design and data analysis. As a powerful tool that creates, simulate and analyze data accurately and rapidly, SAAM II computationally creates a system of ordinary differential equations according to the specified compartmental model structure and simulates the solutions based upon the parameter and model inputs provided. The experimental design of in vitro DIN approach was applied to create an artificial gastric and gastrointestinal fluids. These synthetic fluids assay were produced to determine the concentrations of As ingested into the gastrointestinal tract. The model outputs were created based upon the experimental inputs and the recommended fractional transfer rates parameter. As a result, the measured and predicted As concentrations in gastric fluids were much similar against the time of study. In contrast, the concentrations of As in the gastrointestinal fluids were only similar during the first hour and eventually started decreasing until the fifth hours of study between the measured and predicted values. This is due to the loss of As through the fractional transfer rates of q2 compartment to corresponding compartments of q3 and q5 which are involved with excretion and distribution to the whole body, respectively. The model outputs obtained after best fit to the data were influenced significantly by the fractional transfer rates between each compartment. Therefore, a series of compartmental model created with the association of fractional transfer rates parameter with the aid of SAAM II provides better estimation that simulate the kinetic behavior of As ingested into the gastrointestinal system.

  17. Hepatic sinusoid is not well-stirred: estimation of the degree of axial mixing by analysis of lobular concentration gradients formed during uptake of thyroxine by the perfused rat liver

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Weisiger, R.A.; Mendel, C.M.; Cavalieri, R.R.

    1986-03-01

    Two general models have been proposed for predicting the effects of metabolism, protein binding, and plasma flow on the removal of drugs by the liver. These models differ in the degree of plasma mixing assumed to exist within each hepatic sinusoid. The venous equilibrium model treats the sinusoid as a single well-stirred compartment, whereas the sinusoidal model effectively breaks up the sinusoid into a large number of sequentially perfused compartments which do not exchange their contents except through plasma flow. As a consequence, the sinusoidal model, but not the venous equilibrium model, predicts that the concentration of highly extracted drugsmore » will decline as the plasma flows through the hepatic lobule. To determine which of these alternative models best describes the hepatic uptake process, we looked for evidence that concentration gradients are formed during the uptake of (/sup 125/I)thyroxine by the perfused rat liver. Autoradiography of tissue slices after perfusion of the portal vein at physiologic flow rates with protein-free buffer containing (/sup 125/I)thyroxine demonstrated a rapid exponential fall in grain density with distance from the portal venule, declining by half for each 8% of the mean length of the sinusoid. Reversing the direction of perfusate flow reversed the direction of the autoradiographic gradients, indicating that they primarily reflect differences in the concentration of thyroxine within the hepatic sinusoids rather than differences in the uptake capacity of portal and central hepatocytes. Analysis of the data using models in which each sinusoid was represented by different numbers of sequentially perfused compartments (1-20) indicated that at least eight compartments were necessary to account for the magnitude of the gradients seen.« less

  18. Orthopaedic Perspective on Barefoot and Minimalist Running.

    PubMed

    Roth, Jonathan; Neumann, Julie; Tao, Matthew

    2016-03-01

    In recent years, there has been a movement toward barefoot and minimalist running. Advocates assert that a lack of cushion and support promotes a forefoot or midfoot strike rather than a rearfoot strike, decreasing the impact transient and stress on the hip and knee. Although the change in gait is theorized to decrease injury risk, this concept has not yet been fully elucidated. However, research has shown diminished symptoms of chronic exertional compartment syndrome and anterior knee pain after a transition to minimalist running. Skeptics are concerned that, because of the effects of the natural environment and the lack of a standardized transition program, barefoot running could lead to additional, unforeseen injuries. Studies have shown that, with the transition to minimalist running, there is increased stress on the foot and ankle and risk of repetitive stress injuries. Nonetheless, despite the large gap of evidence-based knowledge on minimalist running, the potential benefits warrant further research and consideration.

  19. Bioelectrical impedance analysis. What does it measure?

    NASA Technical Reports Server (NTRS)

    Schoeller, D. A.

    2000-01-01

    Bioelectrical impedance analysis (BIA) has been proposed for measuring fat-free mass, total body water, percent fat, body cell mass, intracellular water, and extracellular water: a veritable laboratory in a box. Although it is unlikely that BIA is quite this versatile, correlations have been demonstrated between BIA and all of these body compartments. At the same time, it is known that all of the compartments are correlated among themselves. Because of this, it is difficult to determine whether BIA is specific for any or all of these compartments. To investigate this question, we induced acute changes in total body water and its compartments over a 3-h period. Using this approach, we demonstrated that multifrequency BIA, using the Cole-Cole model to calculate the zero frequency and infinite frequency resistance, measures extracellular and intracellular water.

  20. Analysis of space radiation exposure levels at different shielding configurations by ray-tracing dose estimation method

    NASA Astrophysics Data System (ADS)

    Kartashov, Dmitry; Shurshakov, Vyacheslav

    2018-03-01

    A ray-tracing method to calculate radiation exposure levels of astronauts at different spacecraft shielding configurations has been developed. The method uses simplified shielding geometry models of the spacecraft compartments together with depth-dose curves. The depth-dose curves can be obtained with different space radiation environment models and radiation transport codes. The spacecraft shielding configurations are described by a set of geometry objects. To calculate the shielding probability functions for each object its surface is composed from a set of the disjoint adjacent triangles that fully cover the surface. Such description can be applied for any complex shape objects. The method is applied to the space experiment MATROSHKA-R modeling conditions. The experiment has been carried out onboard the ISS from 2004 to 2016. Dose measurements were realized in the ISS compartments with anthropomorphic and spherical phantoms, and the protective curtain facility that provides an additional shielding on the crew cabin wall. The space ionizing radiation dose distributions in tissue-equivalent spherical and anthropomorphic phantoms and for an additional shielding installed in the compartment are calculated. There is agreement within accuracy of about 15% between the data obtained in the experiment and calculated ones. Thus the calculation method used has been successfully verified with the MATROSHKA-R experiment data. The ray-tracing radiation dose calculation method can be recommended for estimation of dose distribution in astronaut body in different space station compartments and for estimation of the additional shielding efficiency, especially when exact compartment shielding geometry and the radiation environment for the planned mission are not known.

  1. The estimation of the rates of lead exchange between body compartments of smelter employees.

    PubMed

    Behinaein, Sepideh; Chettle, David R; Egden, Lesley M; McNeill, Fiona E; Norman, Geoff; Richard, Norbert; Stever, Susan

    2014-07-01

    The overwhelming proportion of the mass of lead (Pb) is stored in bone and the residence time of Pb in bone is much longer than that in other tissues. Hence, in a metabolic model that we used to solve the differential equations governing the transfer of lead between body compartments, three main compartments are involved: blood (as a transfer compartment), cortical bone (tibia), and trabecular bone (calcaneus). There is a bidirectional connection between blood and the other two compartments. A grid search chi-squared minimization method was used to estimate the initial values of lead transfer rate values from tibia (λTB) and calcaneus (λCB) to blood of 209 smelter employees whose bone lead measurements are available from 1994, 1999, and 2008, and their blood lead level from 1967 onwards (depending on exposure history from once per month to once per year), and then the initial values of kinematic parameters were used to develop multivariate models in order to express λTB and λCB as a function of employment time, age, body lead contents and their interaction. We observed a significant decrease in the transfer rate of lead from bone to blood with increasing body lead contents. The model was tested by calculating the bone lead concentration in 1999 and 2008, and by comparing those values with the measured ones. A good agreement was found between the calculated and measured tibia/calcaneus lead values. Also, we found that the transfer rate of lead from tibia to blood can be expressed solely as a function of cumulative blood lead index.

  2. Evolution of a mini-scale biphasic dissolution model: Impact of model parameters on partitioning of dissolved API and modelling of in vivo-relevant kinetics.

    PubMed

    Locher, Kathrin; Borghardt, Jens M; Frank, Kerstin J; Kloft, Charlotte; Wagner, Karl G

    2016-08-01

    Biphasic dissolution models are proposed to have good predictive power for the in vivo absorption. The aim of this study was to improve our previously introduced mini-scale dissolution model to mimic in vivo situations more realistically and to increase the robustness of the experimental model. Six dissolved APIs (BCS II) were tested applying the improved mini-scale biphasic dissolution model (miBIdi-pH-II). The influence of experimental model parameters including various excipients, API concentrations, dual paddle and its rotation speed was investigated. The kinetics in the biphasic model was described applying a one- and four-compartment pharmacokinetic (PK) model. The improved biphasic dissolution model was robust related to differing APIs and excipient concentrations. The dual paddle guaranteed homogenous mixing in both phases; the optimal rotation speed was 25 and 75rpm for the aqueous and the octanol phase, respectively. A one-compartment PK model adequately characterised the data of fully dissolved APIs. A four-compartment PK model best quantified dissolution, precipitation, and partitioning also of undissolved amounts due to realistic pH profiles. The improved dissolution model is a powerful tool for investigating the interplay between dissolution, precipitation and partitioning of various poorly soluble APIs (BCS II). In vivo-relevant PK parameters could be estimated applying respective PK models. Copyright © 2016 Elsevier B.V. All rights reserved.

  3. The Effects of Capillary Transit Time Heterogeneity (CTH) on the Cerebral Uptake of Glucose and Glucose Analogs: Application to FDG and Comparison to Oxygen Uptake

    PubMed Central

    Angleys, Hugo; Jespersen, Sune N.; Østergaard, Leif

    2016-01-01

    Glucose is the brain's principal source of ATP, but the extent to which cerebral glucose consumption (CMRglc) is coupled with its oxygen consumption (CMRO2) remains unclear. Measurements of the brain's oxygen-glucose index OGI = CMRO2/CMRglc suggest that its oxygen uptake largely suffices for oxidative phosphorylation. Nevertheless, during functional activation and in some disease states, brain tissue seemingly produces lactate although cerebral blood flow (CBF) delivers sufficient oxygen, so-called aerobic glycolysis. OGI measurements, in turn, are method-dependent in that estimates based on glucose analog uptake depend on the so-called lumped constant (LC) to arrive at CMRglc. Capillary transit time heterogeneity (CTH), which is believed to change during functional activation and in some disease states, affects the extraction efficacy of oxygen from blood. We developed a three-compartment model of glucose extraction to examine whether CTH also affects glucose extraction into brain tissue. We then combined this model with our previous model of oxygen extraction to examine whether differential glucose and oxygen extraction might favor non-oxidative glucose metabolism under certain conditions. Our model predicts that glucose uptake is largely unaffected by changes in its plasma concentration, while changes in CBF and CTH affect glucose and oxygen uptake to different extents. Accordingly, functional hyperemia facilitates glucose uptake more than oxygen uptake, favoring aerobic glycolysis during enhanced energy demands. Applying our model to glucose analogs, we observe that LC depends on physiological state, with a risk of overestimating relative increases in CMRglc during functional activation by as much as 50%. PMID:27790110

  4. Growth hormone distribution kinetics are markedly reduced in adults with growth hormone deficiency.

    PubMed

    Catalina, Pablo F; Páramo, Concepción; Andrade, Maria Amalia; Mallo, Federico

    2007-03-01

    Growth hormone (GH) circulating levels are highly dependent not only on GH secretion rate from the pituitary, but also on the hormone distribution in the compartments of the body and elimination phenomena. In adult GH-deficient patients these factors become critical nowadays, especially when recombinant human GH (rhGH) is available for replacement therapy. In the present study, we assess the influence of both distribution and elimination phenomena on GH pharmacokinetics in adult GH-deficient patients. We used a four-step methodology following a compartmental approach after an intravenous bolus of recombinant GH in adult GH-deficient patients. We found that GH kinetics are clearly explained by a bi-exponential, two-compartmental model in GH-deficient patients, similarly than in normal or diabetic subjects, as previously shown. We have also observed a marked delay in the whole GH elimination process in GH-deficient patients compared to normal adult subjects, as revealed by metabolic clearance ratio (MCR), elimination constant from central compartment (k(10)), and mean resident time in the body (MRT). Interestingly, such a delay appear to be caused by deep changes in the distribution phase (Mtt(1)- mean transit time-1; T(1/2alpha)- GH half-life at distribution phase), while the elimination phenomenon remains unaltered. Our results emphasize the relevance of distribution phenomena in GH pharmacokinetics, and indicates that studies avoiding data from the GH distribution phase, such as those carried out in steady-state conditions, or those using noncompartmental models, could easily miss relevant information. Our data should be taken into consideration when establishing the appropriate dosage for GH replacement treatments in GH-deficient patients, and calculations should include GH distribution kinetics.

  5. Loss of BMP signaling through BMPR1A in osteoblasts leads to greater collagen cross-link maturation and material-level mechanical properties in mouse femoral trabecular compartments

    PubMed Central

    Zhang, Yanshuai; McNerny, Erin Gatenby; Terajima, Masahiko; Raghavan, Mekhala; Romanowicz, Genevieve; Zhang, Zhanpeng; Zhang, Honghao; Kamiya, Nobuhiro; Tantillo, Margaret; Zhu, Peizhi; Scott, Gregory J.; Ray, Manas K.; Lynch, Michelle; Ma, Peter X.; Morris, Michael D.; Yamauchi, Mitsuo; Kohn, David H.; Mishina, Yuji

    2016-01-01

    Bone morphogenetic protein (BMP) signaling pathways play critical roles in skeletal development and new bone formation. Our previous study, however, showed a negative impact of BMP signaling on bone mass because of the osteoblast-specific loss of a BMP receptor (i.e. BMPR1A) showing increased trabecular bone volume and mineral density in mice. Here, we investigated the bone quality and biomechanical properties of the higher bone mass associated with BMPR1A deficiency using the osteoblast-specific Bmpr1a conditional knockout (cKO) mouse model. Collagen biochemical analysis revealed greater levels of the mature cross-link pyridinoline in the cKO bones, in parallel with upregulation of collagen modifying enzymes. Raman spectroscopy distinguished increases in the mature to immature cross-link ratio and mineral to matrix ratio in the trabecular compartments of cKO femora, but not in the cortical compartments. The mineral crystallinity was unchanged in the cKO in either the trabecular or cortical compartments. Further, we tested the intrinsic material properties by nanoindentation and found significantly higher hardness and elastic modulus in the cKO trabecular compartments, but not in the cortical compartments. Four point bending tests of cortical compartments showed lower structural biomechanical properties (i.e. strength and stiffness) in the cKO bones due to the smaller cortical areas. However, there were no significant differences in biomechanical performance at the material level, which was consistent with the nanoindentation test results on the cortical compartment. These studies emphasize the pivotal role of BMPR1A in the determination of bone quality and mechanical integrity under physiological conditions, with different impact on femoral cortical and trabecular compartments. PMID:27113526

  6. Environmental and Genetic Factors Regulating Localization of the Plant Plasma Membrane H+-ATPase.

    PubMed

    Haruta, Miyoshi; Tan, Li Xuan; Bushey, Daniel B; Swanson, Sarah J; Sussman, Michael R

    2018-01-01

    A P-type H + -ATPase is the primary transporter that converts ATP to electrochemical energy at the plasma membrane of higher plants. Its product, the proton-motive force, is composed of an electrical potential and a pH gradient. Many studies have demonstrated that this proton-motive force not only drives the secondary transporters required for nutrient uptake, but also plays a direct role in regulating cell expansion. Here, we have generated a transgenic Arabidopsis ( Arabidopsis thaliana ) plant expressing H + -ATPase isoform 2 (AHA2) that is translationally fused with a fluorescent protein and examined its cellular localization by live-cell microscopy. Using a 3D imaging approach with seedlings grown for various times under a variety of light intensities, we demonstrate that AHA2 localization at the plasma membrane of root cells requires light. In dim light conditions, AHA2 is found in intracellular compartments, in addition to the plasma membrane. This localization profile was age-dependent and specific to cell types found in the transition zone located between the meristem and elongation zones. The accumulation of AHA2 in intracellular compartments is consistent with reduced H + secretion near the transition zone and the suppression of root growth. By examining AHA2 localization in a knockout mutant of a receptor protein kinase, FERONIA, we found that the intracellular accumulation of AHA2 in the transition zone is dependent on a functional FERONIA-dependent inhibitory response in root elongation. Overall, this study provides a molecular underpinning for understanding the genetic, environmental, and developmental factors influencing root growth via localization of the plasma membrane H + -ATPase. © 2018 American Society of Plant Biologists. All Rights Reserved.

  7. Environmental and Genetic Factors Regulating Localization of the Plant Plasma Membrane H+-ATPase1[OPEN

    PubMed Central

    Tan, Li Xuan; Bushey, Daniel B.; Swanson, Sarah J.

    2018-01-01

    A P-type H+-ATPase is the primary transporter that converts ATP to electrochemical energy at the plasma membrane of higher plants. Its product, the proton-motive force, is composed of an electrical potential and a pH gradient. Many studies have demonstrated that this proton-motive force not only drives the secondary transporters required for nutrient uptake, but also plays a direct role in regulating cell expansion. Here, we have generated a transgenic Arabidopsis (Arabidopsis thaliana) plant expressing H+-ATPase isoform 2 (AHA2) that is translationally fused with a fluorescent protein and examined its cellular localization by live-cell microscopy. Using a 3D imaging approach with seedlings grown for various times under a variety of light intensities, we demonstrate that AHA2 localization at the plasma membrane of root cells requires light. In dim light conditions, AHA2 is found in intracellular compartments, in addition to the plasma membrane. This localization profile was age-dependent and specific to cell types found in the transition zone located between the meristem and elongation zones. The accumulation of AHA2 in intracellular compartments is consistent with reduced H+ secretion near the transition zone and the suppression of root growth. By examining AHA2 localization in a knockout mutant of a receptor protein kinase, FERONIA, we found that the intracellular accumulation of AHA2 in the transition zone is dependent on a functional FERONIA-dependent inhibitory response in root elongation. Overall, this study provides a molecular underpinning for understanding the genetic, environmental, and developmental factors influencing root growth via localization of the plasma membrane H+-ATPase. PMID:29042459

  8. Perpetual Motion with Maxwell's Demon

    NASA Astrophysics Data System (ADS)

    Gordon, Lyndsay G. M.

    2002-11-01

    A method for producing a temperature gradient by Brownian motion in an equilibrated isolated system composed of two fluid compartments and a separating adiabatic membrane is discussed. This method requires globular protein molecules, partially embedded in the membrane, to alternate between two conformations which lie on opposite sides of the membrane. The greater part of each conformer is bathed by one of the fluids and rotates in Brownian motion around its axis, perpendicular to the membrane. Rotational energy is transferred through the membrane during conformational changes. Angular momentum is conserved during the transitions. The energy flow becomes asymmetrical when the conformational changes of the protein are sterically hindered by two of its side-chains, the positions of which are affected by the angular velocity of the rotor. The heat flow increases the temperature gradient in contravention of the Second Law. A second hypothetical model which illustrates solute transfer at variance with the Second Law is also discussed.

  9. Perithecium morphogenesis in Sordaria macrospora.

    PubMed

    Lord, Kathryn M; Read, Nick D

    2011-04-01

    The perithecium of the self-fertile ascomycete Sordaria macrospora provides an excellent model in which to analyse fungal multicellular development. This study provides a detailed analysis of perithecium morphogenesis in the wild type and eight developmental mutants of S. macrospora, using a range of correlative microscopical techniques. Fundamentally, perithecia and other complex multicellular structures produced by fungi arise by hyphal aggregation and adhesion, and these processes are followed by specialization and septation of hyphal compartments within the aggregates. Perithecial morphogenesis can be divided into the ascogonial, protoperithecial, and perithecial stages of development. At least 13 specialized, morphologically distinct cell-types are involved in perithecium morphogenesis, and these fall into three basic classes: hyphae, conglutinate cells and spores. Conglutinate cells arise from hyphal adhesion and certain perithecial hyphae develop from conglutinate cells. Various hypha-conglutinate cell transitions play important roles during the development of the perithecial wall and neck. Copyright © 2010. Published by Elsevier Inc.

  10. Anxiolytic-like effects of noribogaine in zebrafish.

    PubMed

    Kalueff, Allan V; Kaluyeva, Aleksandra; Maillet, Emeline L

    2017-07-14

    Noribogaine is the main psychoactive metabolite of the hallucinogenic drug ibogaine, and is a particularly interesting compound potentially useful to treat dependence and various psychiatric disorders. Here, we report the effects of noribogaine on anxiety and locomotion in zebrafish (Danio rerio), a new promising model organism in neurobehavioral and psychopharmacological research. Adult zebrafish were subjected to the 5min novel tank test (NTT) following an acute, 20-min drug immersion in 1, 5 and 10mg/L noribogaine. Overall, noribogaine produced robust anxiolytic-like behavior in zebrafish (increasing the time spent and transitions to the top half compartment and reducing freezing bouts) without overt effects on fish locomotion. Taken together, these results indicate that noribogaine modulates the components of the acute stress response related to emotionality and anxiety behaviors, implicating this drug as a potentially useful non-sedative anxiolytic agent. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. A Dynamic Model for Nitrogen‐stressed Lettuce

    PubMed Central

    SEGINER, IDO

    2003-01-01

    A previously developed dynamic lettuce model, designed to predict growth and nitrate content under the normal range of glasshouse environmental conditions, has been extended to cover high nitrogen‐stress situations. Under severe shortage of nitrogen, lettuce has been observed to grow at a very slow rate, as well as to have abnormally low water content, low reduced‐nitrogen content and negligible nitrate content. The new model mimics these observations by adding to the original model a storage compartment for ‘excess’ carbon. The resulting model has three compartments: (1) ‘vacuole’, where the soluble non‐structural material is stored, and the nitrate : carbon ratio may vary as needed to maintain a constant osmotic potential; (2) ‘structure’, a metabolically active compartment with fixed chemical composition; and (3) ‘excess‐carbon’, which serves as a long‐term storage of ‘waterless’ carbohydrates. Simulations with the model illustrate its ability to predict the effect of light, temperature and nitrogen in the nutrient solution on the long‐term growth and composition of lettuce. They also illustrate the effects of plant size, and the associated relative growth rate, on the characteristic times of transient responses resulting from step changes in the environment. PMID:12714361

  12. Assessment of turkey vehicle container microclimate on transit during summer season conditions

    NASA Astrophysics Data System (ADS)

    Carvalho, Rafael H.; Honorato, Danielle C. B.; Guarnieri, Paulo D.; Soares, Adriana L.; Pedrão, Mayka R.; Oba, Alexandre; Paião, Fernanda G.; Ida, Elza I.; Shimokomaki, Massami

    2018-06-01

    This study evaluated the formed microclimate commercial truck transport practices effects on the turkeys' welfare by measuring Dead on Arrival (DOA) index and pale, soft, and exudative (PSE-like) meat occurrence. The experimental design was entirely randomized in a 6 × 2 factorial arrangements (two truck container compartments × six water shower groups) with birds positioned at superior front (SF), inferior front (IF), superior middle (SM), inferior middle (IM), superior rear (SR), and inferior rear (IR) and two bath treatments: with water shower (WiS) and without water shower (WoS) with eight replications for each treatment. The animals were transported for 95 min' journey from the farm to the slaughterhouse under hot-humidity conditions. The results shown herein indicated the formation of a thermal core at the inferior middle and rear truck container regions, because the heat produced by the birds and the influence of developed microclimate consisting of temperature, relative humidity, and air ventilation. The IM and IR container compartments under the WoS treatment presented the highest ( P < 0.01) numbers of PSE-like meat incidence and DOA index values compared with those located at the front under WiS treatment as the consequence of the altered to birds unbearable conditions within the container microclimate in transit. The formed microclimate during the commercial transport practices under hot-humidity conditions affected the bird's welfare consequently turkey meat qualities.

  13. Assessment of turkey vehicle container microclimate on transit during summer season conditions

    NASA Astrophysics Data System (ADS)

    Carvalho, Rafael H.; Honorato, Danielle C. B.; Guarnieri, Paulo D.; Soares, Adriana L.; Pedrão, Mayka R.; Oba, Alexandre; Paião, Fernanda G.; Ida, Elza I.; Shimokomaki, Massami

    2018-01-01

    This study evaluated the formed microclimate commercial truck transport practices effects on the turkeys' welfare by measuring Dead on Arrival (DOA) index and pale, soft, and exudative (PSE-like) meat occurrence. The experimental design was entirely randomized in a 6 × 2 factorial arrangements (two truck container compartments × six water shower groups) with birds positioned at superior front (SF), inferior front (IF), superior middle (SM), inferior middle (IM), superior rear (SR), and inferior rear (IR) and two bath treatments: with water shower (WiS) and without water shower (WoS) with eight replications for each treatment. The animals were transported for 95 min' journey from the farm to the slaughterhouse under hot-humidity conditions. The results shown herein indicated the formation of a thermal core at the inferior middle and rear truck container regions, because the heat produced by the birds and the influence of developed microclimate consisting of temperature, relative humidity, and air ventilation. The IM and IR container compartments under the WoS treatment presented the highest (P < 0.01) numbers of PSE-like meat incidence and DOA index values compared with those located at the front under WiS treatment as the consequence of the altered to birds unbearable conditions within the container microclimate in transit. The formed microclimate during the commercial transport practices under hot-humidity conditions affected the bird's welfare consequently turkey meat qualities.

  14. Assessment of turkey vehicle container microclimate on transit during summer season conditions.

    PubMed

    Carvalho, Rafael H; Honorato, Danielle C B; Guarnieri, Paulo D; Soares, Adriana L; Pedrão, Mayka R; Oba, Alexandre; Paião, Fernanda G; Ida, Elza I; Shimokomaki, Massami

    2018-06-01

    This study evaluated the formed microclimate commercial truck transport practices effects on the turkeys' welfare by measuring Dead on Arrival (DOA) index and pale, soft, and exudative (PSE-like) meat occurrence. The experimental design was entirely randomized in a 6 × 2 factorial arrangements (two truck container compartments × six water shower groups) with birds positioned at superior front (SF), inferior front (IF), superior middle (SM), inferior middle (IM), superior rear (SR), and inferior rear (IR) and two bath treatments: with water shower (WiS) and without water shower (WoS) with eight replications for each treatment. The animals were transported for 95 min' journey from the farm to the slaughterhouse under hot-humidity conditions. The results shown herein indicated the formation of a thermal core at the inferior middle and rear truck container regions, because the heat produced by the birds and the influence of developed microclimate consisting of temperature, relative humidity, and air ventilation. The IM and IR container compartments under the WoS treatment presented the highest (P < 0.01) numbers of PSE-like meat incidence and DOA index values compared with those located at the front under WiS treatment as the consequence of the altered to birds unbearable conditions within the container microclimate in transit. The formed microclimate during the commercial transport practices under hot-humidity conditions affected the bird's welfare consequently turkey meat qualities.

  15. 75 FR 6092 - Special Conditions: Model C-27J Airplane; Class E Cargo Compartment Lavatory

    Federal Register 2010, 2011, 2012, 2013, 2014

    2010-02-08

    ... waste-receptacle design-and-material standards. (g) Section 25.854, lavatory smoke-detector and fire... lavatory, and the oxygen-supply system in the lavatory, in the event of a smoke-detector alarm in the cargo... system that shuts off power to the lavatory following a lavatory or cargo-compartment smoke-detector...

  16. Modeling malware propagation using a carrier compartment

    NASA Astrophysics Data System (ADS)

    Hernández Guillén, J. D.; Martín del Rey, A.

    2018-03-01

    The great majority of mathematical models proposed to simulate malware spreading are based on systems of ordinary differential equations. These are compartmental models where the devices are classified according to some types: susceptible, exposed, infectious, recovered, etc. As far as we know, there is not any model considering the special class of carrier devices. This type is constituted by the devices whose operative systems is not targeted by the malware (for example, iOS devices for Android malware). In this work a novel mathematical model considering this new compartment is considered. Its qualitative study is presented and a detailed analysis of the efficient control measures is shown by studying the basic reproductive number.

  17. Design of vaccination and fumigation on Host-Vector Model by input-output linearization method

    NASA Astrophysics Data System (ADS)

    Nugraha, Edwin Setiawan; Naiborhu, Janson; Nuraini, Nuning

    2017-03-01

    Here, we analyze the Host-Vector Model and proposed design of vaccination and fumigation to control infectious population by using feedback control especially input-output liniearization method. Host population is divided into three compartments: susceptible, infectious and recovery. Whereas the vector population is divided into two compartment such as susceptible and infectious. In this system, vaccination and fumigation treat as input factors and infectious population as output result. The objective of design is to stabilize of the output asymptotically tend to zero. We also present the examples to illustrate the design model.

  18. A Model for the Estimation of Hepatic Insulin Extraction After a Meal.

    PubMed

    Piccinini, Francesca; Dalla Man, Chiara; Vella, Adrian; Cobelli, Claudio

    2016-09-01

    Quantitative assessment of hepatic insulin extraction (HE) after an oral glucose challenge, e.g., a meal, is important to understand the regulation of carbohydrate metabolism. The aim of the current study is to develop a model of system for estimating HE. Nine different models, of increasing complexity, were tested on data of 204 normal subjects, who underwent a mixed meal tolerance test, with frequent measurement of plasma glucose, insulin, and C-peptide concentrations. All these models included a two-compartment model of C-peptide kinetics, an insulin secretion model, a compartmental model of insulin kinetics (with number of compartments ranging from one to three), and different HE descriptions, depending on plasma glucose and insulin. Model performances were compared on the basis of data fit, precision of parameter estimates, and parsimony criteria. The three-compartment model of insulin kinetics, coupled with HE depending on glucose concentration, showed the best fit and a good ability to precisely estimate the parameters. In addition, the model calculates basal and total indices of HE ( HE b and HE tot , respectively), and provides an index of HE sensitivity to glucose ( S G HE ). A new physiologically based HE model has been developed, which allows an improved quantitative description of glucose regulation. The use of the new model provides an in-depth description of insulin kinetics, thus enabling a better understanding of a given subject's metabolic state.

  19. A COMPREHENSIVE INSIGHT ON OCULAR PHARMACOKINETICS

    PubMed Central

    Agrahari, Vibhuti; Mandal, Abhirup; Agrahari, Vivek; Trinh, Hoang My; Joseph, Mary; Ray, Animikh; Hadji, Hicheme; Mitra, Ranjana; Pal, Dhananjay; Mitra, Ashim K.

    2017-01-01

    Eye is a distinctive organ with protective anatomy and physiology. Several pharmacokinetics compartment model of ocular drug delivery has been developed for describing the absorption, distribution and elimination of ocular drugs in the eye. Determining pharmacokinetics parameters in ocular tissues is a major challenge because of the complex anatomy and dynamic physiological barrier of the eye. In this review, pharmacokinetics of these compartments exploring different drugs, delivery systems and routes of administration are discussed including factors affecting intraocular bioavailability. Factors such as pre-corneal fluid drainage, drug binding to tear proteins, systemic drug absorption, corneal factors, melanin binding, drug metabolism renders ocular delivery challenging and elaborated in this manuscript. Several compartment models are discussed those are developed in ocular drug delivery to study the pharmacokinetics parameters. There are several transporters present in both anterior and posterior segments of the eye which play a significant role in ocular pharmacokinetics and summarized briefly. Moreover, several ocular pharmacokinetics animal models and relevant studies are reviewed and discussed in addition to the pharmacokinetics of various ocular formulations. PMID:27798766

  20. The Decompression Sickness and Venous Gas Emboli Consequences of Air Breaks During 100% Oxygen Prebreathe

    NASA Technical Reports Server (NTRS)

    Conkin, J.; Gernhardt, M. L.; Powell, M. R.

    2004-01-01

    Not enough is known about the increased risk of hypobaric decompression sickness (DCS) and production of venous (VGE) and arterial (AGE) gas emboli following an air break in an otherwise normal 100% resting oxygen (O2) prebreathe (PB), and certainly a break in PB when exercise is used to accelerate nitrogen (N2) elimination from the tissues. Current Aeromedical Flight Rules at the Johnson Space Center about additional PB payback times are untested, possibly too conservative, and therefore not optimized for operational use. A 10 min air break at 90 min into a 120 min PB that includes initial dual-cycle ergometry for 10 min will show a measurable increase in the risk of DCS and VGE after ascent to 4.3 psia compared to a 10 min break at 15 min into the PB, or when there is no break in PB. Data collection with humans begins in 2005, but here we first evaluate the hypothesis using three models of tissue N2 kinetics: Model I is a simple single half-time compartment exponential model, Model II is a three compartment half-time exponential model, and Model III is a variable half-time compartment model where the percentage of maximum O2 consumption for the subject during dual-cycle ergometry exercise defines the half-time compartment. Model I with large rate constants to simulate an exercise effect always showed a late break in PB had the greatest consequence. Model II showed an early break had the greatest consequence. Model III showed there was no difference between early or late break in exercise PB. Only one of these outcomes will be observed when humans are tested. Our results will favor one of these models, and so advance our understanding of tissue N2 kinetics, and of altitude DCS after an air break in PB.

  1. Dictyostelium LvsB has a regulatory role in endosomal vesicle fusion

    PubMed Central

    Falkenstein, Kristin; De Lozanne, Arturo

    2014-01-01

    ABSTRACT Defects in human lysosomal-trafficking regulator (Lyst) are associated with the lysosomal disorder Chediak–Higashi syndrome. The absence of Lyst results in the formation of enlarged lysosome-related compartments, but the mechanism for how these compartments arise is not well established. Two opposing models have been proposed to explain Lyst function. The fission model describes Lyst as a positive regulator of fission from lysosomal compartments, whereas the fusion model identifies Lyst as a negative regulator of fusion between lysosomal vesicles. Here, we used assays that can distinguish between defects in vesicle fusion versus fission. We compared the phenotype of Dictyostelium discoideum cells defective in LvsB, the ortholog of Lyst, with that of two known fission defect mutants (μ3- and WASH-null mutants). We found that the temporal localization characteristics of the post-lysosomal marker vacuolin, as well as vesicular acidity and the fusion dynamics of LvsB-null cells are distinct from those of both μ3- and WASH-null fission defect mutants. These distinctions are predicted by the fusion defect model and implicate LvsB as a negative regulator of vesicle fusion. PMID:25086066

  2. Lowering transit crime may save energy

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Not Available

    Shifting travelers from less-energy-efficient automobiles to more-energy-efficient transit vehicles is an essential energy conservation measure. During peak travel periods the average auto carries 1.4 persons and consumes 16 times more fuel per passenger mile than an urban bus carrying an average of 75 passengers. Today's travelers are using transit for less than 3 percent of their urban trips. Travelers reject transit because its costs--in terms of time, money, and quality of service--are higher than those for the auto. One element of the higher cost of using transit is the increased exposure to crime which occurs when a traveler shifts frommore » his private car to mass transit. The increased exposure is the result of the additional time transit travelers spend getting to and waiting at transit stops, as well as the additional time spent riding, and the lack of privacy while on transit. Furthermore, transit travelers have no control over their route, which may go through high-crime areas. In contrast, traveling by auto not only eliminates the time getting to and waiting at transit stops, but it also provides a secure compartment which can be locked. Traveling companions can be chosen to limit exposure to crime. In addition, auto travel provides the opportunity to select the safest and shortest route. Between the two extremes of high exposure to crime presented by public transit and low exposure to crime offered by private autos lies para-transit, such as taxis, carpools, and jitneys (small buses that carry passengers over a regular route according to a flexible schedule). (MCW)« less

  3. SMAS Fusion Zones Determine the Subfascial and Subcutaneous Anatomy of the Human Face: Fascial Spaces, Fat Compartments, and Models of Facial Aging.

    PubMed

    Pessa, Joel E

    2016-05-01

    Fusion zones between superficial fascia and deep fascia have been recognized by surgical anatomists since 1938. Anatomical dissection performed by the author suggested that additional superficial fascia fusion zones exist. A study was performed to evaluate and define fusion zones between the superficial and the deep fascia. Dissection of fresh and minimally preserved cadavers was performed using the accepted technique for defining anatomic spaces: dye injection combined with cross-sectional anatomical dissection. This study identified bilaminar membranes traveling from deep to superficial fascia at consistent locations in all specimens. These membranes exist as fusion zones between superficial and deep fascia, and are referred to as SMAS fusion zones. Nerves, blood vessels and lymphatics transition between the deep and superficial fascia of the face by traveling along and within these membranes, a construct that provides stability and minimizes shear. Bilaminar subfascial membranes continue into the subcutaneous tissues as unilaminar septa on their way to skin. This three-dimensional lattice of interlocking horizontal, vertical, and oblique membranes defines the anatomic boundaries of the fascial spaces as well as the deep and superficial fat compartments of the face. This information facilitates accurate volume augmentation; helps to avoid facial nerve injury; and provides the conceptual basis for understanding jowls as a manifestation of enlargement of the buccal space that occurs with age. © 2016 The American Society for Aesthetic Plastic Surgery, Inc. Reprints and permission: journals.permissions@oup.com.

  4. Stochastic models to study the impact of mixing on a fed-batch culture of Saccharomyces cerevisiae.

    PubMed

    Delvigne, F; Lejeune, A; Destain, J; Thonart, P

    2006-01-01

    The mechanisms of interaction between microorganisms and their environment in a stirred bioreactor can be modeled by a stochastic approach. The procedure comprises two submodels: a classical stochastic model for the microbial cell circulation and a Markov chain model for the concentration gradient calculus. The advantage lies in the fact that the core of each submodel, i.e., the transition matrix (which contains the probabilities to shift from a perfectly mixed compartment to another in the bioreactor representation), is identical for the two cases. That means that both the particle circulation and fluid mixing process can be analyzed by use of the same modeling basis. This assumption has been validated by performing inert tracer (NaCl) and stained yeast cells dispersion experiments that have shown good agreement with simulation results. The stochastic model has been used to define a characteristic concentration profile experienced by the microorganisms during a fermentation test performed in a scale-down reactor. The concentration profiles obtained in this way can explain the scale-down effect in the case of a Saccharomyces cerevisiae fed-batch process. The simulation results are analyzed in order to give some explanations about the effect of the substrate fluctuation dynamics on S. cerevisiae.

  5. Measurement of regional cerebral blood flow with copper-62-PTSM and a three-compartment model.

    PubMed

    Okazawa, H; Yonekura, Y; Fujibayashi, Y; Mukai, T; Nishizawa, S; Magata, Y; Ishizu, K; Tamaki, N; Konishi, J

    1996-07-01

    We evaluated quantitatively 62Cu-labeled pyruvaldehyde bis(N4-methylthiosemicarbazone) copper II (62Cu-PTSM) as a brain perfusion tracer for positron emission tomography (PET). For quantitative measurement, the octanol extraction method is needed to correct for arterial radioactivity in estimating the lipophilic input function, but the procedure is not practical for clinical studies. To measure regional cerebral blood flow (rCBF) by 62Cu-PTSM with simple arterial blood sampling, a standard curve of the octanol extraction ratio and a three-compartment model were applied. We performed both 15O-labeled water PET and 62 Cu-PTSM PET with dynamic data acquisition and arterial sampling in six subjects. Data obtained in 10 subjects studied previously were used for the standard octanol extraction curve. Arterial activity was measured and corrected to obtain the true input function using the standard curve. Graphical analysis (Gjedde-Patlak plot) with the data for each subject fitted by a straight regression line suggested that 62Cu-PTSM can be analyzed by the three-compartment model with negligible K4. Using this model, K1-K3 were estimated from curve fitting of the cerebral time-activity curve and the corrected input function. The fractional uptake of 62Cu-PTSM was corrected to rCBF with the individual extraction at steady state calculated from K1-K3. The influx rates (Ki) obtained from three-compartment model and graphical analyses were compared for the validation of the model. A comparison of rCBF values obtained from 62Cu-PTSM and 150-water studies demonstrated excellent correlation. The results suggest the potential feasibility of quantitation of cerebral perfusion with 62Cu-PTSM accompanied by dynamic PET and simple arterial sampling.

  6. Population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (recombinant exendin-4, rE-4) in Chinese patients with type 2 diabetes mellitus
.

    PubMed

    Zang, Yan-Nan; Zhang, Min-Jie; Wang, Yi-Tong; Wang, Chen; Wang, Qian; Zheng, Qing-Shan; Ji, Li-Nong; Guo, Wei; Fang, Yi

    2017-08-01

    To investigate the population pharmacokinetics of lyophilized recombinant glucagon-like peptide-1 receptor agonist (rE-4) in Chinese patients with type 2 diabetes mellitus (T2DM) for plasma concentration estimation and individualized treatment. Twelve patients with T2DM were enrolled to receive subcutaneous injections of rE-4 at 5 µg twice daily for 84 days. Administration dosage was adjusted from 5 µg to 10 µg twice daily at day 29 in case of glycated albumin (GA) ≥ 17%. The population pharmacokinetic model was developed in the nonlinear mixed-effects modeling software NONMEM. The data were best described by a two-compartment model with first-order absorption and elimination. The outcome parameters were as follows: apparent clearance (CL/F) 6.67 L/h, apparent distribution volume of central compartment (Vc/F) 19.4 L, absorption rate constant (Ka) 1.39 h-1, apparent distribution volume of peripheral compartment (Vp/F) 22.6 L, intercompartmental clearance (Q/F) 1.28 L/h. The interindividual variabilities for CL/F, Vc/F, Ka, and Q/F were 64.4%, 57.7%, 45.5%, and 153.3%, respectively. The intra-individual variability of proportional error model was 41.7%. No covariate was screened out that showed significant influence on the model parameters. The established two-compartment model with first-order absorption and elimination successfully described the pharmacokinetic characteristics of rE-4 in Chinese patients with T2DM.
.

  7. Kernel Regression Estimation of Fiber Orientation Mixtures in Diffusion MRI

    PubMed Central

    Cabeen, Ryan P.; Bastin, Mark E.; Laidlaw, David H.

    2016-01-01

    We present and evaluate a method for kernel regression estimation of fiber orientations and associated volume fractions for diffusion MR tractography and population-based atlas construction in clinical imaging studies of brain white matter. This is a model-based image processing technique in which representative fiber models are estimated from collections of component fiber models in model-valued image data. This extends prior work in nonparametric image processing and multi-compartment processing to provide computational tools for image interpolation, smoothing, and fusion with fiber orientation mixtures. In contrast to related work on multi-compartment processing, this approach is based on directional measures of divergence and includes data-adaptive extensions for model selection and bilateral filtering. This is useful for reconstructing complex anatomical features in clinical datasets analyzed with the ball-and-sticks model, and our framework’s data-adaptive extensions are potentially useful for general multi-compartment image processing. We experimentally evaluate our approach with both synthetic data from computational phantoms and in vivo clinical data from human subjects. With synthetic data experiments, we evaluate performance based on errors in fiber orientation, volume fraction, compartment count, and tractography-based connectivity. With in vivo data experiments, we first show improved scan-rescan reproducibility and reliability of quantitative fiber bundle metrics, including mean length, volume, streamline count, and mean volume fraction. We then demonstrate the creation of a multi-fiber tractography atlas from a population of 80 human subjects. In comparison to single tensor atlasing, our multi-fiber atlas shows more complete features of known fiber bundles and includes reconstructions of the lateral projections of the corpus callosum and complex fronto-parietal connections of the superior longitudinal fasciculus I, II, and III. PMID:26691524

  8. Definition of compartment-based radical surgery in uterine cancer: modified radical hysterectomy in intermediate/high-risk endometrial cancer using peritoneal mesometrial resection (PMMR) by M Höckel translated to robotic surgery.

    PubMed

    Kimmig, Rainer; Aktas, Bahriye; Buderath, Paul; Wimberger, Pauline; Iannaccone, Antonella; Heubner, Martin

    2013-08-16

    The technique of compartment-based radical hysterectomy was originally described by M Höckel as total mesometrial resection (TMMR) for standard treatment of stage I and II cervical cancer. However, with regard to the ontogenetically-defined compartments of tumor development (Müllerian) and lymph drainage (Müllerian and mesonephric), compartments at risk may also be defined consistently in endometrial cancer. This is the first report in the literature on the compartment-based surgical approach to endometrial cancer. Peritoneal mesometrial resection (PMMR) with therapeutic lymphadenectomy (tLNE) as an ontogenetic, compartment-based oncologic surgery could be beneficial for patients in terms of surgical radicalness as well as complication rates; it can be standardized for compartment-confined tumors. Supported by M Höckel, PMMR was translated to robotic surgery (rPMMR) and described step-by-step in comparison to robotic TMMR (rTMMR). Patients (n = 42) were treated by rPMMR (n = 39) or extrafascial simple hysterectomy (n = 3) with/without bilateral pelvic and/or periaortic robotic therapeutic lymphadenectomy (rtLNE) for stage I to III endometrial cancer, according to International Federation of Gynecology and Obstetrics (FIGO) classification. Tumors were classified as intermediate/high-risk in 22 out of 40 patients (55%) and low-risk in 18 out of 40 patients (45%), and two patients showed other uterine malignancies. In 11 patients, no adjuvant external radiotherapy was performed, but chemotherapy was applied. No transition to open surgery was necessary. There were no intraoperative complications. The postoperative complication rate was 12% with venous thromboses, (n = 2), infected pelvic lymph cyst (n = 1), transient aphasia (n = 1) and transient dysfunction of micturition (n = 1). The mean difference in perioperative hemoglobin concentrations was 2.4 g/dL (± 1.2 g/dL) and one patient (2.4%) required transfusion. During follow-up (median 17 months), one patient experienced distant recurrence and one patient distant/regional recurrence of endometrial cancer (4.8%), but none developed isolated locoregional recurrence. There were two deaths from endometrial cancer during the observation period (4.8%). We conclude that rPMMR and rtLNE are feasible and safe with regard to perioperative morbidity, thus, it seems promising for the treatment of intermediate/high-risk endometrial cancer in terms of surgical radicalness and complication rates. This could be particularly beneficial for morbidly obese and seriously ill patients.

  9. Before the Endless Forms: Embodied Model of Transition from Single Cells to Aggregates to Ecosystem Engineering

    PubMed Central

    Solé, Ricard V.; Valverde, Sergi

    2013-01-01

    The emergence of complex multicellular systems and their associated developmental programs is one of the major problems of evolutionary biology. The advantages of cooperation over individuality seem well known but it is not clear yet how such increase of complexity emerged from unicellular life forms. Current multicellular systems display a complex cell-cell communication machinery, often tied to large-scale controls of body size or tissue homeostasis. Some unicellular life forms are simpler and involve groups of cells cooperating in a tissue-like fashion, as it occurs with biofilms. However, before true gene regulatory interactions were widespread and allowed for controlled changes in cell phenotypes, simple cellular colonies displaying adhesion and interacting with their environments were in place. In this context, models often ignore the physical embedding of evolving cells, thus leaving aside a key component. The potential for evolving pre-developmental patterns is a relevant issue: how far a colony of evolving cells can go? Here we study these pre-conditions for morphogenesis by using CHIMERA, a physically embodied computational model of evolving virtual organisms in a pre-Mendelian world. Starting from a population of identical, independent cells moving in a fluid, the system undergoes a series of changes, from spatial segregation, increased adhesion and the development of generalism. Eventually, a major transition occurs where a change in the flow of nutrients is triggered by a sub-population. This ecosystem engineering phenomenon leads to a subsequent separation of the ecological network into two well defined compartments. The relevance of these results for evodevo and its potential ecological triggers is discussed. PMID:23596506

  10. Population Pharmacokinetics of Rifampin in Pregnant Women with Tuberculosis and HIV Coinfection in Soweto, South Africa

    PubMed Central

    Denti, Paolo; Martinson, Neil; Cohn, Silvia; Mashabela, Fildah; Hoffmann, Jennifer; Msandiwa, Reginah; Castel, Sandra; Wiesner, Lubbe; Chaisson, Richard E.; McIlleron, Helen

    2015-01-01

    Effective treatment of tuberculosis during pregnancy is essential for preventing maternal and fetal mortality, but little is known about the effects of pregnancy on the disposition of antituberculosis drugs. We explored the effects of pregnancy on the pharmacokinetics of rifampin, the key sterilizing drug in tuberculosis treatment, in Tshepiso, a prospective cohort study involving pregnant HIV-infected women with or without tuberculosis in Soweto, South Africa. Participants receiving standard first-line tuberculosis treatment underwent sparse sampling for rifampin at 37 weeks' gestation or delivery and then postpartum. Cord blood was collected when possible. A population pharmacokinetic model was developed to investigate the effects of pregnancy on rifampin pharmacokinetics. Among the 48 participants, median age and weight were 28 years and 67 kg, respectively. A one-compartment model with first-order elimination, transit compartment absorption, and allometric scaling described the data well. Pregnancy reduced rifampin clearance by 14%. The median (interquartile range) model-estimated rifampin area under the concentration-time curve over 24 h (AUC0–24) during pregnancy or intrapartum was 40.8 h · mg/liter (27.1 to 54.2 h · mg/liter) compared to 37.4 h · mg/liter (26.8 to 50.3 h · mg/liter) postpartum. The maximum concentrations were similar during pregnancy and postpartum. Rifampin was detectable in 36% (8/22) of cord blood samples, and 88% (42/48) of the women had successful treatment outcomes. There was one case of perinatal tuberculosis. In conclusion, rifampin clearance is modestly reduced during the last trimester of pregnancy. Exposures are only slightly increased, so dose adjustment during pregnancy is not needed. Rifampin was detected in cord blood samples when delivery occurred soon after dosing. The consequences of exposure to this potent inducer of metabolizing enzymes among HIV-exposed infants are unclear. PMID:26643345

  11. 76 FR 26949 - Special Conditions: Boeing Model 747-8 Series Airplanes; Overhead Flight Attendant Rest Compartment

    Federal Register 2010, 2011, 2012, 2013, 2014

    2011-05-10

    ... comments on this proposal, include with your comments a pre-addressed, stamped postcard on which the docket number appears. We will stamp the date on the postcard and mail it back to you. Background On November 4... pots), other than a conventional lavatory or kitchenette hot water heater, within the OFAR compartment...

  12. Comparison of different blood compartments for the detection of circulating DNA using a rat model of Pneumocystis pneumonia.

    PubMed

    Fréalle, E; Gantois, N; Aliouat-Denis, C M; Leroy, S; Zawadzki, C; Perkhofer, S; Aliouat, E M; Dei-Cas, E

    2015-09-01

    Pneumocystis is mostly found in the alveolar spaces, but circulation of viable organisms also occurs and suggests that the detection of DNA in blood could be used as a noninvasive procedure to improve the diagnosis of Pneumocystis pneumonia (PcP). In order to determine the optimal compartment for Pneumocystis DNA detection, we used a rat model of PcP and tested the presence of Pneumocystis with a quantitative mtLSU targeting real-time PCR in four blood compartments: whole blood, clot, serum and Platelet-Rich-Plasma (PRP). All samples from 4 Pneumocystis-free control rats were negative. Pneumocystis was detected in 79, 64, 57, and 57% of samples from 14 PcP rats, respectively, but DNA release was not related to pulmonary loads. These data confirm the potential usefulness of Pneumocystis DNA detection in the blood for PcP diagnosis and suggest that whole blood could be the most appropriate compartment for Pneumocystis detection. © The Author 2015. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  13. Comparison of eight logger layouts for monitoring animal-level temperature and humidity during commercial feeder cattle transport.

    PubMed

    Goldhawk, C; Crowe, T; González, L A; Janzen, E; Kastelic, J; Pajor, E; Schwartzkopf-Genswein, K

    2014-09-01

    Measuring animal-level conditions during transit provides information regarding the true risk of environmental challenges to cattle welfare during transportation. However, due to constraints on placing loggers at the animal level, there is a need to identify appropriate proxy locations. The objective was to evaluate 8 distributions of ceiling-level loggers in the deck and belly compartments of pot-belly trailers for assessing animal-level temperature and humidity during 5 to 18 h commercial transportation of feeder cattle. Ambient conditions during transportation ranged from 3.6 to 45.2°C (20.3 ± 7.61°C, mean ± SD). When considering the entire journey, average differences between ceiling and animal-level temperatures were similar among logger layouts (P > 0.05). The uncertainty in the difference in temperature and humidity between locations was high relative to the magnitude of the difference between animal- and ceiling-level conditions. Single-logger layouts required larger adjustments to predict animal-level conditions within either compartment, during either the entire journey or when the trailer was stationary (P < 0.05). Within certain logger layouts, there were small but significant differences in the ability of regression equations to predict animal-level conditions that were associated with cattle weight and available space relative to body size. Furthermore, evaluation of logger layouts based solely on the entire journey without consideration of stationary periods did not adequately capture variability in layout performance. In conclusion, to adequately monitor animal-level temperature and humidity, 10 loggers distributed throughout the compartment was recommended over single-logger layouts within both the deck and belly compartments of pot-belly trailers transporting feeder cattle in warm weather.

  14. Assessment of mouse anxiety-like behavior in the light-dark box and open-field arena: role of equipment and procedure.

    PubMed

    Kulesskaya, Natalia; Voikar, Vootele

    2014-06-22

    Light-dark box and open field are conventional tests for assessment of anxiety-like behavior in the laboratory mice, based on approach-avoidance conflict. However, except the basic principles, variations in the equipment and procedures are very common. Therefore, contribution of certain methodological issues in different settings was investigated. Three inbred strains (C57BL/6, 129/Sv, DBA/2) and one outbred stock (ICR) of mice were used in the experiments. An effect of initial placement of mice either in the light or dark compartment was studied in the light-dark test. Moreover, two tracking systems were applied - position of the animals was detected either by infrared sensors in square box (1/2 dark) or by videotracking in rectangular box (1/3 dark). Both approaches revealed robust and consistent strain differences in the exploratory behavior. In general, C57BL/6 and ICR mice showed reduced anxiety-like behavior as compared to 129/Sv and DBA/2 strains. However, the latter two strains differed markedly in their behavior. DBA/2 mice displayed high avoidance of the light compartment accompanied by thigmotaxis, whereas the hypoactive 129 mice spent a significant proportion of time in risk-assessment behavior at the opening between two compartments. Starting from the light side increased the time spent in the light compartment and reduced the latency to the first transition. In the open field arena, black floor promoted exploratory behavior - increased time and distance in the center and increased rearing compared to white floor. In conclusion, modifications of the apparatus and procedure had significant effects on approach-avoidance behavior in general whereas the strain rankings remained unaffected. Copyright © 2014 Elsevier Inc. All rights reserved.

  15. A Kinase Inhibitor Screen Reveals Protein Kinase C-dependent Endocytic Recycling of ErbB2 in Breast Cancer Cells*

    PubMed Central

    Bailey, Tameka A.; Luan, Haitao; Tom, Eric; Bielecki, Timothy Alan; Mohapatra, Bhopal; Ahmad, Gulzar; George, Manju; Kelly, David L.; Natarajan, Amarnath; Raja, Srikumar M.; Band, Vimla; Band, Hamid

    2014-01-01

    ErbB2 overexpression drives oncogenesis in 20–30% cases of breast cancer. Oncogenic potential of ErbB2 is linked to inefficient endocytic traffic into lysosomes and preferential recycling. However, regulation of ErbB2 recycling is incompletely understood. We used a high-content immunofluorescence imaging-based kinase inhibitor screen on SKBR-3 breast cancer cells to identify kinases whose inhibition alters the clearance of cell surface ErbB2 induced by Hsp90 inhibitor 17-AAG. Less ErbB2 clearance was observed with broad-spectrum PKC inhibitor Ro 31-8220. A similar effect was observed with Go 6976, a selective inhibitor of classical Ca2+-dependent PKCs (α, β1, βII, and γ). PKC activation by PMA promoted surface ErbB2 clearance but without degradation, and ErbB2 was observed to move into a juxtanuclear compartment where it colocalized with PKC-α and PKC-δ together with the endocytic recycling regulator Arf6. PKC-α knockdown impaired the juxtanuclear localization of ErbB2. ErbB2 transit to the recycling compartment was also impaired upon PKC-δ knockdown. PMA-induced Erk phosphorylation was reduced by ErbB2 inhibitor lapatinib, as well as by knockdown of PKC-δ but not that of PKC-α. Our results suggest that activation of PKC-α and -δ mediates a novel positive feedback loop by promoting ErbB2 entry into the endocytic recycling compartment, consistent with reported positive roles for these PKCs in ErbB2-mediated tumorigenesis. As the endocytic recycling compartment/pericentrion has emerged as a PKC-dependent signaling hub for G-protein-coupled receptors, our findings raise the possibility that oncogenesis by ErbB2 involves previously unexplored PKC-dependent endosomal signaling. PMID:25225290

  16. Structural Design Strategies for Improved Small Overlap Crashworthiness Performance.

    PubMed

    Mueller, Becky C; Brethwaite, Andrew S; Zuby, David S; Nolan, Joseph M

    2014-11-01

    In 2012, the Insurance Institute for Highway Safety (IIHS) began a 64 km/h small overlap frontal crash test consumer information test program. Thirteen automakers already have redesigned models to improve test performance. One or more distinct strategies are evident in these redesigns: reinforcement of the occupant compartment, use of energy-absorbing fender structures, and the addition of engagement structures to induce vehicle lateral translation. Each strategy influences vehicle kinematics, posing additional challenges for the restraint systems. The objective of this two-part study was to examine how vehicles were modified to improve small overlap test performance and then to examine how these modifications affect dummy response and restraint system performance. Among eight models tested before and after design changes, occupant compartment intrusion reductions ranged from 6 cm to 45 cm, with the highest reductions observed in models with the largest number of modifications. All redesigns included additional occupant compartment reinforcement, one-third added structures to engage the barrier, and two modified a shotgun load path. Designs with engagement structures produced greater glance-off from the barrier and exhibited lower delta Vs but experienced more lateral outboard motion of the dummy. Designs with heavy reinforcement of the occupant compartment had higher vehicle accelerations and delta V. In three cases, these apparent trade-offs were not well addressed by concurrent changes in restraint systems and resulted in increased injury risk compared with the original tests. Among the 36 models tested after design changes, the extent of design changes correlated to structural performance. Half of the vehicles with the lowest intrusion levels incorporated aspects of all three design strategies. Vehicle kinematics and dummy and restraint system characteristics were similar to those observed in the before/after pairs. Different combinations of structural improvement strategies for improving small overlap test performance were found to be effective in reducing occupant compartment intrusion and improving dummy kinematics in the IIHS small overlap test with modest weight increase.

  17. Evaluation of an I-box wind tunnel model for assessment of behavioral responses of blow flies.

    PubMed

    Moophayak, Kittikhun; Sukontason, Kabkaew L; Kurahashi, Hiromu; Vogtsberger, Roy C; Sukontason, Kom

    2013-11-01

    The behavioral response of flies to olfactory cues remains the focus of many investigations, and wind tunnels have sometimes been employed for assessment of this variable in the laboratory. In this study, our aim was to design, construct, and operate a new model of I-box wind tunnel with improved efficacy, highlighting the use of a new wind tunnel model to investigate the behavioral response of the medically important blow fly, Chrysomya megacephala (Fabricius). The I-box dual-choice wind tunnel designed for this study consists of seven conjoined compartments that resulted in a linear apparatus with clear glass tunnel of 30 × 30 × 190 cm ended both sides with wooden "fan compartments" which are equipped with adjustable fans as wind source. The clear glass tunnel consisted of two "stimulus compartments" with either presence or absence (control) of bait; two "trap compartments" where flies were attracted and allowed to reside; and one central "release compartment" where flies were introduced. Wind tunnel experiments were carried out in a temperature-controlled room, with a room light as a light source and a room-ventilated fan as odor-remover from tunnel out. Evaluation of testing parameters revealed that the highest attractive index was achieved with the use of 300 g of 1-day tainted pork scrap (pork meat mixed with offal) as bait in wind tunnel settings wind speed of 0.58 m/s, during 1.00-5.00 PM with light intensity of 341.33 lux from vertical light and 135.93 lux from horizontal light for testing a group of 60 flies. In addition, no significant response of well-fed and 24 h staved flies to this bait under these conditions was found. Results of this study supported this new wind tunnel model as a suitable apparatus for investigation of behavioral response of blow flies to bait chemical cues in the laboratory.

  18. Integrated Aircraft Fuel Tank Inerting and Compartment Fire Suppression System. Volume 2. Evaluation of Nitrogen-Enriched Air as a Fire Suppressant

    DTIC Science & Technology

    1983-04-01

    transition sections on the basis of its strength, ductility, and corrosion H resistance. In addition, austenitic stainless steels , such as 304, retain their...desirable mechanical properties at both cryogenic and elevated temperatures (approaching low red heat or 650C), and since both extremes were likely... temperature incoming air combined with a fuel spray would create the effect of escaping bleed air in the test chamber, with velocities low enough to

  19. Numerical Modeling of Ophthalmic Response to Space

    NASA Technical Reports Server (NTRS)

    Nelson, E. S.; Myers, J. G.; Mulugeta, L.; Vera, J.; Raykin, J.; Feola, A.; Gleason, R.; Samuels, B.; Ethier, C. R.

    2015-01-01

    To investigate ophthalmic changes in spaceflight, we would like to predict the impact of blood dysregulation and elevated intracranial pressure (ICP) on Intraocular Pressure (IOP). Unlike other physiological systems, there are very few lumped parameter models of the eye. The eye model described here is novel in its inclusion of the human choroid and retrobulbar subarachnoid space (rSAS), which are key elements in investigating the impact of increased ICP and ocular blood volume. Some ingenuity was required in modeling the blood and rSAS compartments due to the lack of quantitative data on essential hydrodynamic quantities, such as net choroidal volume and blood flowrate, inlet and exit pressures, and material properties, such as compliances between compartments.

  20. Morphological elucidation of basal ganglia circuits contributing reward prediction

    PubMed Central

    Fujiyama, Fumino; Takahashi, Susumu; Karube, Fuyuki

    2015-01-01

    Electrophysiological studies in monkeys have shown that dopaminergic neurons respond to the reward prediction error. In addition, striatal neurons alter their responsiveness to cortical or thalamic inputs in response to the dopamine signal, via the mechanism of dopamine-regulated synaptic plasticity. These findings have led to the hypothesis that the striatum exhibits synaptic plasticity under the influence of the reward prediction error and conduct reinforcement learning throughout the basal ganglia circuits. The reinforcement learning model is useful; however, the mechanism by which such a process emerges in the basal ganglia needs to be anatomically explained. The actor–critic model has been previously proposed and extended by the existence of role sharing within the striatum, focusing on the striosome/matrix compartments. However, this hypothesis has been difficult to confirm morphologically, partly because of the complex structure of the striosome/matrix compartments. Here, we review recent morphological studies that elucidate the input/output organization of the striatal compartments. PMID:25698913

  1. The development of the MELiSSA Pilot Plant Facility

    NASA Astrophysics Data System (ADS)

    Godia, Francesc; Dussap, Claude-Gilles; Dixon, Mike; Peiro, Enrique; Fossen, Arnaud; Lamaze, Brigitte; Brunet, Jean; Demey, Dries; Mas-Albaigès, Joan L.

    MELiSSA (Micro-Ecological Life Support System Alternative) is a closed artificial ecosystem intended as a tool for the development of a bio-regenerative life support system for longterm manned missions. The MELiSSA loop is formed by five interconnected compartments, organized in three different loops (solid, liquid and gas). This compartments are microbial bioreactors and higher plant chambers. The MELiSSA Pilot Plant facility has been designed to achieve the preliminary terrestrial demonstration of the MELiSSA concept at pilot scale, using animals as a model for the crew compartent. The experience gained in the operation of such a facility will be highly relevant for planning future life support systems in Space. In this communication, the latests developments in the MELiSSA Pilot Plant will be reported. Particularly, the completion of the design phase and instalation of all the different compartments will be discussed in detail. Each of the compartments had to be designed and constructed according to very specific characteristics, associated to the biological systems to be cultured, as part of the complete MELiSSA loop (anerobic, oxygenic, thermophilic, heterotrophic, autotrophic, axenic, photosynthetic, etc.). Additionally, the sizing of each reactor (ranging from 8 to 100 Liters, depending of each particular compartment) should compile with the global integration scenario proposed, and with the final goal of connection of all compartments to provide a demonstration of the MELiSSA concept, and generate data for the design and operation of future biological life support systems.

  2. [Effect of the ISS Russian segment configuration on the service module radiation environment].

    PubMed

    Mitrikas, V G

    2011-01-01

    Mathematical modeling of variations in the Service module radiation environment as a function of ISS Russian segment configuration was carried out using models of the RS modules and a spherical humanoid phantom. ISS reconfiguration impacted significantly only the phantom brought into the transfer compartment (ExT). The Radiation Safety Service prohibition for cosmonauts to stay in this compartment during solar flare events remains valid. In all other instances, error of dose estimation is higher as compared to dose value estimation with consideration for ISS RS reconfiguration.

  3. GLUT4 Retention in Adipocytes Requires Two Intracellular Insulin-regulated Transport Steps

    PubMed Central

    Zeigerer, Anja; Lampson, Michael A.; Karylowski, Ola; Sabatini, David D.; Adesnik, Milton; Ren, Mindong; McGraw, Timothy E.

    2002-01-01

    Insulin regulates glucose uptake into fat and muscle by modulating the distribution of the GLUT4 glucose transporter between the surface and interior of cells. The GLUT4 trafficking pathway overlaps with the general endocytic recycling pathway, but the degree and functional significance of the overlap are not known. In this study of intact adipocytes, we demonstrate, by using a compartment-specific fluorescence-quenching assay, that GLUT4 is equally distributed between two intracellular pools: the transferrin receptor-containing endosomes and a specialized compartment that excludes the transferrin receptor. These pools of GLUT4 are in dynamic communication with one another and with the cell surface. Insulin-induced redistribution of GLUT4 to the surface requires mobilization of both pools. These data establish a role for the general endosomal system in the specialized, insulin-regulated trafficking of GLUT4. Trafficking through the general endosomal system is regulated by rab11. Herein, we show that rab11 is required for the transport of GLUT4 from endosomes to the specialized compartment and for the insulin-induced translocation to the cell surface, emphasizing the importance of the general endosomal pathway in the specialized trafficking of GLUT4. Based on these findings we propose a two-step model for GLUT4 trafficking in which the general endosomal recycling compartment plays a specialized role in the insulin-regulated traffic of GLUT4. This compartment-based model provides the framework for understanding insulin-regulated trafficking at a molecular level. PMID:12134080

  4. GLUT4 retention in adipocytes requires two intracellular insulin-regulated transport steps.

    PubMed

    Zeigerer, Anja; Lampson, Michael A; Karylowski, Ola; Sabatini, David D; Adesnik, Milton; Ren, Mindong; McGraw, Timothy E

    2002-07-01

    Insulin regulates glucose uptake into fat and muscle by modulating the distribution of the GLUT4 glucose transporter between the surface and interior of cells. The GLUT4 trafficking pathway overlaps with the general endocytic recycling pathway, but the degree and functional significance of the overlap are not known. In this study of intact adipocytes, we demonstrate, by using a compartment-specific fluorescence-quenching assay, that GLUT4 is equally distributed between two intracellular pools: the transferrin receptor-containing endosomes and a specialized compartment that excludes the transferrin receptor. These pools of GLUT4 are in dynamic communication with one another and with the cell surface. Insulin-induced redistribution of GLUT4 to the surface requires mobilization of both pools. These data establish a role for the general endosomal system in the specialized, insulin-regulated trafficking of GLUT4. Trafficking through the general endosomal system is regulated by rab11. Herein, we show that rab11 is required for the transport of GLUT4 from endosomes to the specialized compartment and for the insulin-induced translocation to the cell surface, emphasizing the importance of the general endosomal pathway in the specialized trafficking of GLUT4. Based on these findings we propose a two-step model for GLUT4 trafficking in which the general endosomal recycling compartment plays a specialized role in the insulin-regulated traffic of GLUT4. This compartment-based model provides the framework for understanding insulin-regulated trafficking at a molecular level.

  5. Statistical Exposé of a Multiple-Compartment Anaerobic Reactor Treating Domestic Wastewater.

    PubMed

    Pfluger, Andrew R; Hahn, Martha J; Hering, Amanda S; Munakata-Marr, Junko; Figueroa, Linda

    2018-06-01

      Mainstream anaerobic treatment of domestic wastewater is a promising energy-generating treatment strategy; however, such reactors operated in colder regions are not well characterized. Performance data from a pilot-scale, multiple-compartment anaerobic reactor taken over 786 days were subjected to comprehensive statistical analyses. Results suggest that chemical oxygen demand (COD) was a poor proxy for organics in anaerobic systems as oxygen demand from dissolved inorganic material, dissolved methane, and colloidal material influence dissolved and particulate COD measurements. Additionally, univariate and functional boxplots were useful in visualizing variability in contaminant concentrations and identifying statistical outliers. Further, significantly different dissolved organic removal and methane production was observed between operational years, suggesting that anaerobic reactor systems may not achieve steady-state performance within one year. Last, modeling multiple-compartment reactor systems will require data collected over at least two years to capture seasonal variations of the major anaerobic microbial functions occurring within each reactor compartment.

  6. Stochastic Model of Vesicular Sorting in Cellular Organelles

    NASA Astrophysics Data System (ADS)

    Vagne, Quentin; Sens, Pierre

    2018-02-01

    The proper sorting of membrane components by regulated exchange between cellular organelles is crucial to intracellular organization. This process relies on the budding and fusion of transport vesicles, and should be strongly influenced by stochastic fluctuations, considering the relatively small size of many organelles. We identify the perfect sorting of two membrane components initially mixed in a single compartment as a first passage process, and we show that the mean sorting time exhibits two distinct regimes as a function of the ratio of vesicle fusion to budding rates. Low ratio values lead to fast sorting but result in a broad size distribution of sorted compartments dominated by small entities. High ratio values result in two well-defined sorted compartments but sorting is exponentially slow. Our results suggest an optimal balance between vesicle budding and fusion for the rapid and efficient sorting of membrane components and highlight the importance of stochastic effects for the steady-state organization of intracellular compartments.

  7. A semi-mechanistic model of CP-690,550-induced reduction in neutrophil counts in patients with rheumatoid arthritis.

    PubMed

    Gupta, Pankaj; Friberg, Lena E; Karlsson, Mats O; Krishnaswami, Sriram; French, Jonathan

    2010-06-01

    CP-690,550, a selective inhibitor of the Janus kinase family, is being developed as an oral disease-modifying antirheumatic drug for the treatment of rheumatoid arthritis (RA). A semi-mechanistic model was developed to characterize the time course of drug-induced absolute neutrophil count (ANC) reduction in a phase 2a study. Data from 264 RA patients receiving 6-week treatment (placebo, 5, 15, 30 mg bid) followed by a 6-week off-treatment period were analyzed. The model included a progenitor cell pool, a maturation chain comprising transit compartments, a circulation pool, and a feedback mechanism. The model was adequately described by system parameters (BASE(h), ktr(h), gamma, and k(circ)), disease effect parameters (DIS), and drug effect parameters (k(off) and k(D)). The disease manifested as an increase in baseline ANC and reduced maturation time due to increased demand from the inflammation site. The drug restored the perturbed system parameters to their normal values via an indirect mechanism. ANC reduction due to a direct myelosuppressive drug effect was not supported. The final model successfully described the dose- and time-dependent changes in ANC and predicted the incidence of neutropenia at different doses reasonably well.

  8. 2D hydrodynamic simulations of a variable length gas target for density down-ramp injection of electrons into a laser wakefield accelerator

    NASA Astrophysics Data System (ADS)

    Kononenko, O.; Lopes, N. C.; Cole, J. M.; Kamperidis, C.; Mangles, S. P. D.; Najmudin, Z.; Osterhoff, J.; Poder, K.; Rusby, D.; Symes, D. R.; Warwick, J.; Wood, J. C.; Palmer, C. A. J.

    2016-09-01

    In this work, two-dimensional (2D) hydrodynamic simulations of a variable length gas cell were performed using the open source fluid code OpenFOAM. The gas cell was designed to study controlled injection of electrons into a laser-driven wakefield at the Astra Gemini laser facility. The target consists of two compartments: an accelerator and an injector section connected via an aperture. A sharp transition between the peak and plateau density regions in the injector and accelerator compartments, respectively, was observed in simulations with various inlet pressures. The fluid simulations indicate that the length of the down-ramp connecting the sections depends on the aperture diameter, as does the density drop outside the entrance and the exit cones. Further studies showed, that increasing the inlet pressure leads to turbulence and strong fluctuations in density along the axial profile during target filling, and consequently, is expected to negatively impact the accelerator stability.

  9. A Temporal Model of Cofilin Regulation and the Early Peak of Actin Barbed Ends in Invasive Tumor Cells

    PubMed Central

    Tania, Nessy; Prosk, Erin; Condeelis, John; Edelstein-Keshet, Leah

    2011-01-01

    Cofilin is an important regulator of actin polymerization, cell migration, and chemotaxis. Recent experimental data on mammary carcinoma cells reveal that stimulation by epidermal growth factor (EGF) generates a pool of active cofilin that results in a peak of actin filament barbed ends on the timescale of 1 min. Here, we present results of a mathematical model for the dynamics of cofilin and its transition between several pools in response to EGF stimulation. We describe the interactions of phospholipase C, membrane lipids (PIP2), and cofilin bound to PIP2 and to F-actin, as well as diffusible cofilin in active G-actin-monomer-bound or phosphorylated states. We consider a simplified representation in which the thin cell edge (lamellipod) and the cell interior are represented by two compartments that are linked by diffusion. We demonstrate that a high basal level of active cofilin stored by binding to PIP2, as well as the highly enriched local milieu of F-actin at the cell edge, is essential to capture the EGF-induced barbed-end amplification observed experimentally. PMID:21504724

  10. Effect of methanol extract of Trigonella foenum-graecum L. seeds on anxiety, sedation and motor coordination.

    PubMed

    Assad, Tahira; Khan, Rafeeq Alam

    2017-04-01

    Currently available anxiolytics cause numerous adverse effects and show craving and tolerance during long term treatment. Currently traditional medicines have been re-evaluated widely through work on various plant species. Numerous plants in traditional system show pharmacological activity with unlimited prospective for therapeutic use. Hence we planned to evaluate the effect of methanol extract of T. foenum-graecum L. seeds on anxiety, sedation and motor coordination in mice at different doses following 15 days of oral feeding. Effect on anxiety was assessed by Hole board test and Light and Dark transition models.Phenobarbitone induced sleeping time and Rota rod test were performed to assess effect on sedation and motor coordination. In Hole board test, T. foenum-graecum L. seeds decreased the number of head dips in mice at all the three doses. In Light and Dark transition model, T. foenum-graecum L. seeds increased the period spent in the light box and the number of moves among the two compartments at 100 and 200 mg/kg as compared to control animals. In phenobarbitone induced sleeping time, T. foenum-graecum L. seeds did not reveal any sedative effect. In Rota rod test, extract exhibited significant skeletal muscle relaxant effect at 200 mg/kg (at 90 min) as compared to the control animals. Results of our study shows significant antianxiety effects of T. foenum-graecum L. seeds and may also recommend improved adverse effect profile as compared to diazepam.

  11. Hydrological modelling in forested systems | Science ...

    EPA Pesticide Factsheets

    This chapter provides a brief overview of forest hydrology modelling approaches for answering important global research and management questions. Many hundreds of hydrological models have been applied globally across multiple decades to represent and predict forest hydrological processes. The focus of this chapter is on process-based models and approaches, specifically 'forest hydrology models'; that is, physically based simulation tools that quantify compartments of the forest hydrological cycle. Physically based models can be considered those that describe the conservation of mass, momentum and/or energy. The purpose of this chapter is to provide a brief overview of forest hydrology modeling approaches for answering important global research and management questions. The focus of this chapter is on process-based models and approaches, specifically “forest hydrology models”, i.e., physically-based simulation tools that quantify compartments of the forest hydrological cycle.

  12. Effects of 3,4-methylenedioxy-methamphetamine (MDMA) on anxiety in mice tested in the light-dark box.

    PubMed

    Maldonado, E; Navarro, J F

    2000-04-01

    1. The effects of acute administration of 3,4-methylenedioxymethamphetamine (MDMA; "ecstasy") on anxiety tested in the light/dark box were examined in albino male mice of the OF.1 strain. 2. Animals were evaluated in the light/dark test 30 min after injection of MDMA (1, 8, and 15 mg/kg, i.p) or saline. The following parameters were recorded (for 5 min); (a) number of exploratory rearings in the light and dark sections; (b) number of transitions between the lit and dark areas; (c) time spent in the light and dark areas; (d) latency of the initial movement from the light to the dark area, and (e) locomotor activity in light area. 3. MDMA (8 and 15 mg/kg) produced a significant reduction in exploratory activity (rearings and transitions), without decreasing motility, in comparison with saline-treated mice. However, time spent in lit/dark compartments was not significantly affected by the drug, which could be a consequence of the anti-exploratory properties of MDMA. 4. Overall, the behavioral profile found in the light/dark test indicates an anxiogenic-like activity of MDMA in mice. It is suggested, however, that animal models of anxiety which emphasize a social interaction could be more sensitive to the effects of this substance.

  13. 77 FR 29331 - Publication of the Petition for Waiver From Sanyo E&E Corporation From the Department of Energy...

    Federal Register 2010, 2011, 2012, 2013, 2014

    2012-05-17

    ... these hybrid models is cable of achieving temperatures at or below 38 [deg]F, the wine storage compartment of these single-cabinet units can only achieve a minimum temperature of 45 [deg]F. As a result, it... energy consumption be measured when each compartment temperature is set at 38 [deg]F. In order to...

  14. Analysis of blind identification methods for estimation of kinetic parameters in dynamic medical imaging

    NASA Astrophysics Data System (ADS)

    Riabkov, Dmitri

    Compartment modeling of dynamic medical image data implies that the concentration of the tracer over time in a particular region of the organ of interest is well-modeled as a convolution of the tissue response with the tracer concentration in the blood stream. The tissue response is different for different tissues while the blood input is assumed to be the same for different tissues. The kinetic parameters characterizing the tissue responses can be estimated by blind identification methods. These algorithms use the simultaneous measurements of concentration in separate regions of the organ; if the regions have different responses, the measurement of the blood input function may not be required. In this work it is shown that the blind identification problem has a unique solution for two-compartment model tissue response. For two-compartment model tissue responses in dynamic cardiac MRI imaging conditions with gadolinium-DTPA contrast agent, three blind identification algorithms are analyzed here to assess their utility: Eigenvector-based Algorithm for Multichannel Blind Deconvolution (EVAM), Cross Relations (CR), and Iterative Quadratic Maximum Likelihood (IQML). Comparisons of accuracy with conventional (not blind) identification techniques where the blood input is known are made as well. The statistical accuracies of estimation for the three methods are evaluated and compared for multiple parameter sets. The results show that the IQML method gives more accurate estimates than the other two blind identification methods. A proof is presented here that three-compartment model blind identification is not unique in the case of only two regions. It is shown that it is likely unique for the case of more than two regions, but this has not been proved analytically. For the three-compartment model the tissue responses in dynamic FDG PET imaging conditions are analyzed with the blind identification algorithms EVAM and Separable variables Least Squares (SLS). A method of identification that assumes that FDG blood input in the brain can be modeled as a function of time and several parameters (IFM) is analyzed also. Nonuniform sampling SLS (NSLS) is developed due to the rapid change of the FDG concentration in the blood during the early postinjection stage. Comparisons of accuracy of EVAM, SLS, NSLS and IFM identification techniques are made.

  15. 3D architecture modeling of reservoir compartments in a Shingled Turbidite Reservoir using high-resolution seismic data and sparse well control, example from Mars {open_quotes}Pink{close_quotes} reservoir, Mississippi Canyon Area, Gulf of Mexico

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chapin, M.A.; Mahaffie, M.J.; Tiller, G.M.

    1996-12-31

    Economics of most deep-water development projects require large reservoir volumes to be drained with relatively few wells. The presence of reservoir compartments must therefore be detected and planned for in a pre-development stage. We have used 3-D seismic data to constrain large-scale, deterministic reservoir bodies in a 3-D architecture model of Pliocene-turbidite sands of the {open_quotes}E{close_quotes} or {open_quotes}Pink{close_quotes} reservoir, Prospect Mars, Mississippi Canyon Areas 763 and 807, Gulf of Mexico. Reservoir compartmentalization is influenced by stratigraphic shingling, which in turn is caused by low accommodation space predentin the upper portion of a ponded seismic sequence within a salt withdrawal mini-basin.more » The accumulation is limited by updip onlap onto a condensed section marl, and by lateral truncation by a large scale submarine erosion surface. Compartments were suggested by RFT pressure variations and by geochemical analysis of RFT fluid samples. A geological interpretation derived from high-resolution 3-D seismic and three wells was linked to 3-D architecture models through seismic inversion, resulting in a reservoir all available data. Distinguishing subtle stratigraphical shingles from faults was accomplished by detailed, loop-level mapping, and was important to characterize the different types of reservoir compartments. Seismic inversion was used to detune the seismic amplitude, adjust sandbody thickness, and update the rock properties. Recent development wells confirm the architectural style identified. This modeling project illustrates how high-quality seismic data and architecture models can be combined in a pre-development phase of a prospect, in order to optimize well placement.« less

  16. 3D architecture modeling of reservoir compartments in a Shingled Turbidite Reservoir using high-resolution seismic data and sparse well control, example from Mars [open quotes]Pink[close quotes] reservoir, Mississippi Canyon Area, Gulf of Mexico

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Chapin, M.A.; Mahaffie, M.J.; Tiller, G.M.

    1996-01-01

    Economics of most deep-water development projects require large reservoir volumes to be drained with relatively few wells. The presence of reservoir compartments must therefore be detected and planned for in a pre-development stage. We have used 3-D seismic data to constrain large-scale, deterministic reservoir bodies in a 3-D architecture model of Pliocene-turbidite sands of the [open quotes]E[close quotes] or [open quotes]Pink[close quotes] reservoir, Prospect Mars, Mississippi Canyon Areas 763 and 807, Gulf of Mexico. Reservoir compartmentalization is influenced by stratigraphic shingling, which in turn is caused by low accommodation space predentin the upper portion of a ponded seismic sequence withinmore » a salt withdrawal mini-basin. The accumulation is limited by updip onlap onto a condensed section marl, and by lateral truncation by a large scale submarine erosion surface. Compartments were suggested by RFT pressure variations and by geochemical analysis of RFT fluid samples. A geological interpretation derived from high-resolution 3-D seismic and three wells was linked to 3-D architecture models through seismic inversion, resulting in a reservoir all available data. Distinguishing subtle stratigraphical shingles from faults was accomplished by detailed, loop-level mapping, and was important to characterize the different types of reservoir compartments. Seismic inversion was used to detune the seismic amplitude, adjust sandbody thickness, and update the rock properties. Recent development wells confirm the architectural style identified. This modeling project illustrates how high-quality seismic data and architecture models can be combined in a pre-development phase of a prospect, in order to optimize well placement.« less

  17. A Multi-Compartment 3-D Finite Element Model of Rectocele and Its Interaction with Cystocele

    PubMed Central

    Luo, Jiajia; Chen, Luyun; Fenner, Dee E.; Ashton-Miller, James A.; DeLancey, John O. L.

    2015-01-01

    We developed a subject-specific 3-D finite element model to understand the mechanics underlying formation of female pelvic organ prolapse, specifically a rectocele and its interaction with a cystocele. The model was created from MRI 3-D geometry of a healthy 45 year-old multiparous woman. It included anterior and posterior vaginal walls, levator ani muscle, cardinal and uterosacral ligaments, anterior and posterior arcus tendineus fascia pelvis, arcus tendineus levator ani, perineal body, perineal membrane and anal sphincter. Material properties were mostly from the literature. Tissue impairment was modeled as decreased tissue stiffness based on previous clinical studies. Model equations were solved using Abaqus v 6.11. The sensitivity of anterior and posterior vaginal wall geometry was calculated for different combinations tissue impairments under increasing intraabdominal pressure. Prolapse size was reported as POP-Q point at point Bp for rectocele and point Ba for cystocele. Results show that a rectocele resulted from impairments of the levator ani and posterior compartment support. For 20% levator and 85% posterior support impairments, simulated rectocele size (at POP-Q point: Bp) increased 0.29 mm/cm H2O without apical impairment and 0.36 mm/cm H2O with 60% apical impairment, as intraabdominal pressures increased from 0 to 150 cm H2O. Apical support impairment could result in the development of either a cystocele or rectocele. Simulated repair of posterior compartment support decreased rectocele but increased a preexisting cystocele. We conclude that development of rectocele and cystocele depend on the presence of anterior, posterior, levator and/or or apical support impairments, as well as the interaction of the prolapse with the opposing compartment. PMID:25757664

  18. Population Pharmacokinetic Model for Vancomycin Used in Open Heart Surgery: Model-Based Evaluation of Standard Dosing Regimens.

    PubMed

    Alqahtani, Saeed A; Alsultan, Abdullah S; Alqattan, Hussain M; Eldemerdash, Ahmed; Albacker, Turki B

    2018-04-23

    The purpose of this study was to investigate the population pharmacokinetics of vancomycin in patients undergoing open heart surgery. In this observational pharmacokinetic study, multiple blood samples were drawn over a 48-h period of intravenous vancomycin in patients who were undergoing open heart surgery. Blood samples were analysed using the Architect i4000SR Immunoassay Analyzer. Population pharmacokinetic models were developed using Monolix 4.4 software. Pharmacokinetic-pharmacodynamic (PK-PD) simulations were performed to explore the ability of different dosage regimens to achieve the pharmacodynamic targets. One-hundred and sixty-eight blood samples were analysed from 28 patients. The pharmacokinetics of vancomycin was best described by a two-compartment model with between-subject variability in CL, V of the central compartment, and V of the peripheral compartment. CL and central compartment V of vancomycin were related to CL CR , body weight, and albumin concentration. Dosing simulations showed that standard dosing regimens of 1 and 1.5 g failed to achieve the PK-PD target of AUC 0--24 /MIC > 400 for an MIC of 1 mg/L, while high weight-based dosing regimens were able to achieve the PK-PD target. In summary, administration of standard doses of 1 and 1.5 g of vancomycin two times daily provided inadequate antibiotic prophylaxis in patients undergoing open heart surgery. The same findings were obtained when 15 mg/kg and 20 mg/kg doses of vancomycin were administered. Achieving the PK-PD target required higher doses (25 mg/kg and 30 mg/kg) of vancomycin. Copyright © 2018 American Society for Microbiology.

  19. A closed-loop model of the respiratory system: focus on hypercapnia and active expiration.

    PubMed

    Molkov, Yaroslav I; Shevtsova, Natalia A; Park, Choongseok; Ben-Tal, Alona; Smith, Jeffrey C; Rubin, Jonathan E; Rybak, Ilya A

    2014-01-01

    Breathing is a vital process providing the exchange of gases between the lungs and atmosphere. During quiet breathing, pumping air from the lungs is mostly performed by contraction of the diaphragm during inspiration, and muscle contraction during expiration does not play a significant role in ventilation. In contrast, during intense exercise or severe hypercapnia forced or active expiration occurs in which the abdominal "expiratory" muscles become actively involved in breathing. The mechanisms of this transition remain unknown. To study these mechanisms, we developed a computational model of the closed-loop respiratory system that describes the brainstem respiratory network controlling the pulmonary subsystem representing lung biomechanics and gas (O2 and CO2) exchange and transport. The lung subsystem provides two types of feedback to the neural subsystem: a mechanical one from pulmonary stretch receptors and a chemical one from central chemoreceptors. The neural component of the model simulates the respiratory network that includes several interacting respiratory neuron types within the Bötzinger and pre-Bötzinger complexes, as well as the retrotrapezoid nucleus/parafacial respiratory group (RTN/pFRG) representing the central chemoreception module targeted by chemical feedback. The RTN/pFRG compartment contains an independent neural generator that is activated at an increased CO2 level and controls the abdominal motor output. The lung volume is controlled by two pumps, a major one driven by the diaphragm and an additional one activated by abdominal muscles and involved in active expiration. The model represents the first attempt to model the transition from quiet breathing to breathing with active expiration. The model suggests that the closed-loop respiratory control system switches to active expiration via a quantal acceleration of expiratory activity, when increases in breathing rate and phrenic amplitude no longer provide sufficient ventilation. The model can be used for simulation of closed-loop control of breathing under different conditions including respiratory disorders.

  20. The usage of a three-compartment model to investigate the metabolic differences between hepatic reductase null and wild-type mice.

    PubMed

    Hill, Lydia; Chaplain, Mark A J; Wolf, Roland; Kapelyukh, Yury

    2017-03-01

    The Cytochrome P450 (CYP) system is involved in 90% of the human body's interactions with xenobiotics and due to this, it has become an area of avid research including the creation of transgenic mice. This paper proposes a three-compartment model which is used to explain the drug metabolism in the Hepatic Reductase Null (HRN) mouse developed by the University of Dundee (Henderson, C. J., Otto, D. M. E., Carrie, D., Magnuson, M. A., McLaren, A. W., Rosewell, I. and Wolf, C. R. (2003) Inactivation of the hepatic cytochrome p450 system by conditional deletion of hepatic cytochrome p450 reductase. J. Biol. Chem. , 13480-13486). The model is compared with a two-compartment model using experimental data from studies using wild-type and HRN mice. This comparison allowed for metabolic differences between the two types of mice to be isolated. The three sets of drug data (Gefitinib, Midazolam and Thalidomide) showed that the transgenic mouse has a decreased rate of metabolism. © The authors 2015. Published by Oxford University Press on behalf of the Institute of Mathematics and its Applications. All rights reserved.

  1. Numerical cell model investigating cellular carbon fluxes in Emiliania huxleyi.

    PubMed

    Holtz, Lena-Maria; Wolf-Gladrow, Dieter; Thoms, Silke

    2015-01-07

    Coccolithophores play a crucial role in the marine carbon cycle and thus it is interesting to know how they will respond to climate change. After several decades of research the interplay between intracellular processes and the marine carbonate system is still not well understood. On the basis of experimental findings given in literature, a numerical cell model is developed that describes inorganic carbon fluxes between seawater and the intracellular sites of calcite precipitation and photosynthetic carbon fixation. The implemented cell model consists of four compartments, for each of which the carbonate system is resolved individually. The four compartments are connected to each other via H(+), CO2, and HCO3(-) fluxes across the compartment-confining membranes. For CO2 accumulation around RubisCO, an energy-efficient carbon concentrating mechanism is proposed that relies on diffusive CO2 uptake. At low external CO2 concentrations and high light intensities, CO2 diffusion does not suffice to cover the carbon demand of photosynthesis and an additional uptake of external HCO3(-) becomes essential. The model is constrained by data of Emiliania huxleyi, the numerically most abundant coccolithophore species in the present-day ocean. Copyright © 2014 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. Modeling the dynamic volatile fatty acids profiles with pH and hydraulic retention time in an anaerobic baffled reactor during the startup period.

    PubMed

    Shi, En; Li, Jianzheng; Leu, Shao-Yuan; Antwi, Philip

    2016-12-01

    To predict the dynamic profiles in volatile fatty acids (VFAs) with pH and hydraulic retention time (HRT) during the startup of a 4-compartment ABR, a mathematical model was constructed by introducing pH and thermodynamic inhibition functions into the biochemical processes derived from the ADM1. The calibration of inhibition parameter for propionate uptake effectively improved the prediction accuracy of VFAs. The developed model could simulate the VFAs profiles very well no matter the observable change of pH or/and HRT. The simulation results indicated that both H 2 -producing acetogenesis and methanogenesis in the ABR would be inhibited with a pH less than 4.61, and the propionate oxidation could be thermodynamically restricted even with a neutral pH. A decreased HRT would enhanced the acidogenesis and H 2 -producing acetogenesis in the first 3 compartments, but no observable increase in effluent VFAs could be found due to the synchronously enhanced methanogenesis in the last compartment. Copyright © 2016 Elsevier Ltd. All rights reserved.

  3. Comparison of recirculation configurations for biological nutrient removal in a membrane bioreactor.

    PubMed

    Bekir Ersu, Cagatayhan; Ong, Say Kee; Arslankaya, Ertan; Brown, Patrick

    2008-03-01

    A 12-L lab-scale membrane bioreactor (MBR), consisting of an anaerobic and anoxic compartment followed by an oxic plate-frame membrane compartment, was evaluated for carbonaceous and nutrient removals by varying the recirculation of mixed liquor and permeate. The hydraulic retention times (HRTs) for the anaerobic, anoxic, and oxic compartments were 2, 2, and 8h, respectively. The solids residence time (SRT) for the oxic compartment was 25 days. Five different recirculation configurations were tested by recirculating mixed liquor and/or permeate recirculation equal to the influent flow rate (identified as 100%) into different locations of the anaerobic and anoxic compartments. Of the five configurations, the configuration with 100% mixed liquor recirculation to the anaerobic compartment and 100% permeate recirculation to the anoxic compartment gave the highest percentage removal with an average 92.3+/-0.5% soluble chemical oxygen demand (sCOD), 75.6+/-0.4% total nitrogen (TN), and 62.4+/-1.3% total phosphorus (TP) removal. When the mixed liquor and permeate recirculation rates were varied for the same configuration, the highest TP removal was obtained for 300% mixed liquor recirculation and 100% permeate recirculation (300%/100%) with a TP removal of 88.1+/-1.3% while the highest TN removal (90.3+/-0.3%) was obtained for 200%/300% recirculation. TN and TP concentrations as low as 4.2+/-0.1 and 1.4+/-0.2mg/L respectively were obtained. Mass loading rates were generally low in the range of 0.11-0.22kgCOD/kgMLSS/d due to high biomass concentrations within the oxic reactor (approx. 8000mg/L). The BioWin model was calibrated against one set of the experimental data and was found to predict the experimental data of effluent TN, TP, and NO(3)(-)-N but over-predicted sCOD and NH(3)-N for various recirculation rates. The anoxic heterotrophic yield for the calibrated model was 0.2kg biomass COD/kg COD utilized while the maximum growth rates were found to be 0.45day(-1) for mu(max-autotroph), 3.2day(-1) for mu(max-heterotroph), and 1.5day(-1) for mu(max-PAO).

  4. The signal transducer NPH3 integrates the phototropin1 photosensor with PIN2-based polar auxin transport in Arabidopsis root phototropism.

    PubMed

    Wan, Yinglang; Jasik, Jan; Wang, Li; Hao, Huaiqing; Volkmann, Dieter; Menzel, Diedrik; Mancuso, Stefano; Baluška, František; Lin, Jinxing

    2012-02-01

    Under blue light (BL) illumination, Arabidopsis thaliana roots grow away from the light source, showing a negative phototropic response. However, the mechanism of root phototropism is still unclear. Using a noninvasive microelectrode system, we showed that the BL sensor phototropin1 (phot1), the signal transducer NONPHOTOTROPIC HYPOCOTYL3 (NPH3), and the auxin efflux transporter PIN2 were essential for BL-induced auxin flux in the root apex transition zone. We also found that PIN2-green fluorescent protein (GFP) localized to vacuole-like compartments (VLCs) in dark-grown root epidermal and cortical cells, and phot1/NPH3 mediated a BL-initiated pathway that caused PIN2 redistribution to the plasma membrane. When dark-grown roots were exposed to brefeldin A (BFA), PIN2-GFP remained in VLCs in darkness, and BL caused PIN2-GFP disappearance from VLCs and induced PIN2-GFP-FM4-64 colocalization within enlarged compartments. In the nph3 mutant, both dark and BL BFA treatments caused the disappearance of PIN2-GFP from VLCs. However, in the phot1 mutant, PIN2-GFP remained within VLCs under both dark and BL BFA treatments, suggesting that phot1 and NPH3 play different roles in PIN2 localization. In conclusion, BL-induced root phototropism is based on the phot1/NPH3 signaling pathway, which stimulates the shootward auxin flux by modifying the subcellular targeting of PIN2 in the root apex transition zone.

  5. A mathematical model for CTL effect on a latently infected cell inclusive HIV dynamics and treatment

    NASA Astrophysics Data System (ADS)

    Tarfulea, N. E.

    2017-10-01

    This paper investigates theoretically and numerically the effect of immune effectors, such as the cytotoxic lymphocyte (CTL), in modeling HIV pathogenesis (via a newly developed mathematical model); our results suggest the significant impact of the immune response on the control of the virus during primary infection. Qualitative aspects (including positivity, boundedness, stability, uncertainty, and sensitivity analysis) are addressed. Additionally, by introducing drug therapy, we analyze numerically the model to assess the effect of treatment consisting of a combination of several antiretroviral drugs. Our results show that the inclusion of the CTL compartment produces a higher rebound for an individual's healthy helper T-cell compartment than drug therapy alone. Furthermore, we quantitatively characterize successful drugs or drug combination scenarios.

  6. Random intermittent search and the tug-of-war model of motor-driven transport

    NASA Astrophysics Data System (ADS)

    Newby, Jay; Bressloff, Paul C.

    2010-04-01

    We formulate the 'tug-of-war' model of microtubule cargo transport by multiple molecular motors as an intermittent random search for a hidden target. A motor complex consisting of multiple molecular motors with opposing directional preference is modeled using a discrete Markov process. The motors randomly pull each other off of the microtubule so that the state of the motor complex is determined by the number of bound motors. The tug-of-war model prescribes the state transition rates and corresponding cargo velocities in terms of experimentally measured physical parameters. We add space to the resulting Chapman-Kolmogorov (CK) equation so that we can consider delivery of the cargo to a hidden target at an unknown location along the microtubule track. The target represents some subcellular compartment such as a synapse in a neuron's dendrites, and target delivery is modeled as a simple absorption process. Using a quasi-steady-state (QSS) reduction technique we calculate analytical approximations of the mean first passage time (MFPT) to find the target. We show that there exists an optimal adenosine triphosphate (ATP) concentration that minimizes the MFPT for two different cases: (i) the motor complex is composed of equal numbers of kinesin motors bound to two different microtubules (symmetric tug-of-war model) and (ii) the motor complex is composed of different numbers of kinesin and dynein motors bound to a single microtubule (asymmetric tug-of-war model).

  7. Geometric approach to segmentation and protein localization in cell culture assays.

    PubMed

    Raman, S; Maxwell, C A; Barcellos-Hoff, M H; Parvin, B

    2007-01-01

    Cell-based fluorescence imaging assays are heterogeneous and require the collection of a large number of images for detailed quantitative analysis. Complexities arise as a result of variation in spatial nonuniformity, shape, overlapping compartments and scale (size). A new technique and methodology has been developed and tested for delineating subcellular morphology and partitioning overlapping compartments at multiple scales. This system is packaged as an integrated software platform for quantifying images that are obtained through fluorescence microscopy. Proposed methods are model based, leveraging geometric shape properties of subcellular compartments and corresponding protein localization. From the morphological perspective, convexity constraint is imposed to delineate and partition nuclear compartments. From the protein localization perspective, radial symmetry is imposed to localize punctate protein events at submicron resolution. Convexity constraint is imposed against boundary information, which are extracted through a combination of zero-crossing and gradient operator. If the convexity constraint fails for the boundary then positive curvature maxima are localized along the contour and the entire blob is partitioned into disjointed convex objects representing individual nuclear compartment, by enforcing geometric constraints. Nuclear compartments provide the context for protein localization, which may be diffuse or punctate. Punctate signal are localized through iterative voting and radial symmetries for improved reliability and robustness. The technique has been tested against 196 images that were generated to study centrosome abnormalities. Corresponding computed representations are compared against manual counts for validation.

  8. Evaluation of pharmacokinetic models for perfusion imaging with dynamic contrast-enhanced magnetic resonance imaging in porcine skeletal muscle using low-molecular-weight contrast agents.

    PubMed

    Hindel, Stefan; Papanastasiou, Giorgos; Wust, Peter; Maaß, Marc; Söhner, Anika; Lüdemann, Lutz

    2018-06-01

    Pharmacokinetic models for perfusion quantification with a low-molecular-weight contrast agent (LMCA) in skeletal muscle using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were evaluated. Tissue perfusion was measured in seven regions of interest (ROIs) placed in the total hind leg supplied by the femoral artery in seven female pigs. DCE-MRI was performed using a 3D gradient echo sequence with k-space sharing. The sequence was acquired twice, first after LMCA and then after blood pool contrast agent injection. Blood flow was augmented by continuous infusion of the vasodilator adenosine into the femoral artery, resulting in up to four times increased blood flow. The results obtained with several LMCA models were compared with those of a two-compartment blood pool model (2CBPM) consisting of a capillary and an arteriolar compartment. Measurements performed with a Doppler flow probe placed at the femoral artery served as ground truth. The two-compartment exchange model extended by an arteriolar compartment (E2CXM) showed the highest fit quality of all LMCA models and the most significant correlation with the Doppler measurements, r = 0.78 (P < 0.001). The best correspondence between the capillary perfusion measurements of the LMCA models and those of the 2CBPM was found with the E2CXM (slope of the regression line equal to 1, r = 0.85, P < 0.001). The results for the clinical patient data corresponded very well with the results obtained in the animal experiments. Double-contrast agent DCE-MRI in combination with the E2CXM yields the most reliable results and can be used in clinical routine. Magn Reson Med 79:3154-3162, 2018. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  9. Mathematical modelling of the influenced of diffusion rate on macro nutrient availability in paddy field

    NASA Astrophysics Data System (ADS)

    Renny; Supriyanto

    2018-04-01

    Nutrition is the chemical compounds that needed by the organism for the growth process. In plants, nutrients are organic or inorganic compounds that are absorbed from the roots of the soil. It consist of macro and micro nutrient. Macro nutrients are nutrition that needed by plants in large quantities, such as, nitrogen, calcium, pottacium, magnesium, and sulfur. The total soil nutrient is the difference between the input nutrient and the output nutrients. Input nutrients are nutrient that derived from the decomposition of organic substances. Meanwhile, the output nutrient consists of the nutrients that absorbed by plant roots (uptake), the evaporated nutrients (volatilized) and leached nutrients. The nutrient transport can be done through diffusion process. The diffusion process is essential in removing the nutrient from one place to the root surface. It will cause the rate of absorption of nutrient by the roots will be greater. Nutrient concept in paddy filed can be represented into a mathematical modelling, by making compartment models. The rate of concentration change in the compartment model forms a system of homogeneous linear differential equations. In this research, we will use Laplaces transformation to solve the compartment model and determined the dynamics of macro nutrition due to diffusion process.

  10. Dynamic contrast-enhanced CT of head and neck tumors: perfusion measurements using a distributed-parameter tracer kinetic model. Initial results and comparison with deconvolution-based analysis

    NASA Astrophysics Data System (ADS)

    Bisdas, Sotirios; Konstantinou, George N.; Sherng Lee, Puor; Thng, Choon Hua; Wagenblast, Jens; Baghi, Mehran; San Koh, Tong

    2007-10-01

    The objective of this work was to evaluate the feasibility of a two-compartment distributed-parameter (DP) tracer kinetic model to generate functional images of several physiologic parameters from dynamic contrast-enhanced CT data obtained of patients with extracranial head and neck tumors and to compare the DP functional images to those obtained by deconvolution-based DCE-CT data analysis. We performed post-processing of DCE-CT studies, obtained from 15 patients with benign and malignant head and neck cancer. We introduced a DP model of the impulse residue function for a capillary-tissue exchange unit, which accounts for the processes of convective transport and capillary-tissue exchange. The calculated parametric maps represented blood flow (F), intravascular blood volume (v1), extravascular extracellular blood volume (v2), vascular transit time (t1), permeability-surface area product (PS), transfer ratios k12 and k21, and the fraction of extracted tracer (E). Based on the same regions of interest (ROI) analysis, we calculated the tumor blood flow (BF), blood volume (BV) and mean transit time (MTT) by using a modified deconvolution-based analysis taking into account the extravasation of the contrast agent for PS imaging. We compared the corresponding values by using Bland-Altman plot analysis. We outlined 73 ROIs including tumor sites, lymph nodes and normal tissue. The Bland-Altman plot analysis revealed that the two methods showed an accepted degree of agreement for blood flow, and, thus, can be used interchangeably for measuring this parameter. Slightly worse agreement was observed between v1 in the DP model and BV but even here the two tracer kinetic analyses can be used interchangeably. Under consideration of whether both techniques may be used interchangeably was the case of t1 and MTT, as well as for measurements of the PS values. The application of the proposed DP model is feasible in the clinical routine and it can be used interchangeably for measuring blood flow and vascular volume with the commercially available reference standard of the deconvolution-based approach. The lack of substantial agreement between the measurements of vascular transit time and permeability-surface area product may be attributed to the different tracer kinetic principles employed by both models and the detailed capillary tissue exchange physiological modeling of the DP technique.

  11. A probabilistic approach to assess antibiotic resistance development risks in environmental compartments and its application to an intensive aquaculture production scenario.

    PubMed

    Rico, Andreu; Jacobs, Rianne; Van den Brink, Paul J; Tello, Alfredo

    2017-12-01

    Estimating antibiotic pollution and antibiotic resistance development risks in environmental compartments is important to design management strategies that advance our stewardship of antibiotics. In this study we propose a modelling approach to estimate the risk of antibiotic resistance development in environmental compartments and demonstrate its application in aquaculture production systems. We modelled exposure concentrations for 12 antibiotics used in Vietnamese Pangasius catfish production using the ERA-AQUA model. Minimum selective concentration (MSC) distributions that characterize the selective pressure of antibiotics on bacterial communities were derived from the European Committee on Antimicrobial Susceptibility Testing (EUCAST) Minimum Inhibitory Concentration dataset. The antibiotic resistance development risk (RDR) for each antibiotic was calculated as the probability that the antibiotic exposure distribution exceeds the MSC distribution representing the bacterial community. RDRs in pond sediments were nearly 100% for all antibiotics. Median RDR values in pond water were high for the majority of the antibiotics, with rifampicin, levofloxacin and ampicillin having highest values. In the effluent mixing area, RDRs were low for most antibiotics, with the exception of amoxicillin, ampicillin and trimethoprim, which presented moderate risks, and rifampicin and levofloxacin, which presented high risks. The RDR provides an efficient means to benchmark multiple antibiotics and treatment regimes in the initial phase of a risk assessment with regards to their potential to develop resistance in different environmental compartments, and can be used to derive resistance threshold concentrations. Copyright © 2017 Elsevier Ltd. All rights reserved.

  12. Multiphoton fluorescence lifetime imaging of chemotherapy distribution in solid tumors

    NASA Astrophysics Data System (ADS)

    Carlson, Marjorie; Watson, Adrienne L.; Anderson, Leah; Largaespada, David A.; Provenzano, Paolo P.

    2017-11-01

    Doxorubicin is a commonly used chemotherapeutic employed to treat multiple human cancers, including numerous sarcomas and carcinomas. Furthermore, doxorubicin possesses strong fluorescent properties that make it an ideal reagent for modeling drug delivery by examining its distribution in cells and tissues. However, while doxorubicin fluorescence and lifetime have been imaged in live tissue, its behavior in archival samples that frequently result from drug and treatment studies in human and animal patients, and murine models of human cancer, has to date been largely unexplored. Here, we demonstrate imaging of doxorubicin intensity and lifetimes in archival formalin-fixed paraffin-embedded sections from mouse models of human cancer with multiphoton excitation and multiphoton fluorescence lifetime imaging microscopy (FLIM). Multiphoton excitation imaging reveals robust doxorubicin emission in tissue sections and captures spatial heterogeneity in cells and tissues. However, quantifying the amount of doxorubicin signal in distinct cell compartments, particularly the nucleus, often remains challenging due to strong signals in multiple compartments. The addition of FLIM analysis to display the spatial distribution of excited state lifetimes clearly distinguishes between signals in distinct compartments such as the cell nuclei versus cytoplasm and allows for quantification of doxorubicin signal in each compartment. Furthermore, we observed a shift in lifetime values in the nuclei of transformed cells versus nontransformed cells, suggesting a possible diagnostic role for doxorubicin lifetime imaging to distinguish normal versus transformed cells. Thus, data here demonstrate that multiphoton FLIM is a highly sensitive platform for imaging doxorubicin distribution in normal and diseased archival tissues.

  13. Convergence of methods for coupling of microscopic and mesoscopic reaction-diffusion simulations

    NASA Astrophysics Data System (ADS)

    Flegg, Mark B.; Hellander, Stefan; Erban, Radek

    2015-05-01

    In this paper, three multiscale methods for coupling of mesoscopic (compartment-based) and microscopic (molecular-based) stochastic reaction-diffusion simulations are investigated. Two of the three methods that will be discussed in detail have been previously reported in the literature; the two-regime method (TRM) and the compartment-placement method (CPM). The third method that is introduced and analysed in this paper is called the ghost cell method (GCM), since it works by constructing a "ghost cell" in which molecules can disappear and jump into the compartment-based simulation. Presented is a comparison of sources of error. The convergent properties of this error are studied as the time step Δt (for updating the molecular-based part of the model) approaches zero. It is found that the error behaviour depends on another fundamental computational parameter h, the compartment size in the mesoscopic part of the model. Two important limiting cases, which appear in applications, are considered: Δt → 0 and h is fixed; Δt → 0 and h → 0 such that √{ Δt } / h is fixed. The error for previously developed approaches (the TRM and CPM) converges to zero only in the limiting case (ii), but not in case (i). It is shown that the error of the GCM converges in the limiting case (i). Thus the GCM is superior to previous coupling techniques if the mesoscopic description is much coarser than the microscopic part of the model.

  14. Physiological Intracellular Crowdedness is Defined by the Perimeter-to-Area Ratio of Sub-Cellular Compartments

    PubMed Central

    Hiroi, Noriko; Okuhara, Takahiro; Kubojima, Takeshi; Iba, Keisuke; Tabira, Akito; Yamashita, Shuji; Okada, Yasunori; Kobayashi, Tetsuya J.; Funahashi, Akira

    2012-01-01

    The intracellular environment is known to be a crowded and inhomogeneous space. Such an in vivo environment differs from a well-diluted, homogeneous environment for biochemical reactions. However, the effects of both crowdedness and the inhomogeneity of environment on the behavior of a mobile particle have not yet been investigated sufficiently. As described in this paper, we constructed artificial reaction spaces with fractal models, which are assumed to be non-reactive solid obstacles in a reaction space with crevices that function as operating ranges for mobile particles threading the space. Because of the homogeneity of the structures of artificial reaction spaces, the models succeeded in reproducing the physiological fractal dimension of solid structures with a smaller number of non-reactive obstacles than in the physiological condition. This incomplete compatibility was mitigated when we chose a suitable condition of a perimeter-to-area ratio of the operating range to our model. Our results also show that a simulation space is partitioned into convenient reaction compartments as an in vivo environment with the exact amount of solid structures estimated from TEM images. The characteristics of these compartments engender larger mean square displacement of a mobile particle than that of particles in smaller compartments. Subsequently, the particles start to show confined particle-like behavior. These results are compatible with our previously presented results, which predicted that a physiological environment would produce quick response and slow exhaustion reactions. PMID:22936917

  15. Study the Seasonal Variability of Plankton and Forage Fish in the Gulf of Khambhat Using Npzfd Model

    NASA Astrophysics Data System (ADS)

    Kumar, V.; Kumar, S.

    2016-02-01

    Numerical modelling of marine ecology exploits several assumptions and it is indeed quite challenging to include marine ecological phenomena into a mathematical framework with too many unknown parameters. The governing ordinary differential equations represent the interaction of the biological and chemical processes in a marine environment. The key concern in the development of a numerical models are parameterizations based on output, viz., mathematical modelling of ecological system mainly depends on parameters and its variations. Almost, all constituents of each trophic level of marine food web are depended on phytoplankton, which are mostly influenced by initial slope of P-I curve and nutrient stock in the study domain. Whereas, the earlier plankton dynamic models rarely include a compartment of small fish and as an agent in zooplankton mortality, which is most important for the modelling of higher trophic level of marine species. A compartment of forage fish in the modelling of plankton dynamics has been given more realistic mortality rates of plankton, viz., they feed upon phytoplankton and zooplankton. The inclusion of an additional compartment increases complexity of earlier plankton dynamics model as it introduces additional unknown parameters, which has been specified for performing the numerical simulations.As a case study we applied our analysis to explain the aquatic ecology of Gulf of Khambhat (19o 48' N - 22o20' N, 65o E - 72o40' E), west coast of India, which has rich bio-diversity and a high productive area in the form of plankton and forage fish. It has elevated turbidity and varying geography location, viz., one of the regions among world's ocean with high biological productivity.The model presented in this study is able to bring out the essential features of the observed data; that includes the bimodal oscillations in the observed data, monthly mean chlorophyll-a in the SeaWiFs/MODIS Aqua data and in-situ data of plankton. The additional compartment of forage fish and detritus in NPZFD model represents a major structural difference from the earlier NPZ model.

  16. Estimating and mapping forest biomass using regression models and Spot-6 images (case study: Hyrcanian forests of north of Iran).

    PubMed

    Motlagh, Mohadeseh Ghanbari; Kafaky, Sasan Babaie; Mataji, Asadollah; Akhavan, Reza

    2018-05-21

    Hyrcanian forests of North of Iran are of great importance in terms of various economic and environmental aspects. In this study, Spot-6 satellite images and regression models were applied to estimate above-ground biomass in these forests. This research was carried out in six compartments in three climatic (semi-arid to humid) types and two altitude classes. In the first step, ground sampling methods at the compartment level were used to estimate aboveground biomass (Mg/ha). Then, by reviewing the results of other studies, the most appropriate vegetation indices were selected. In this study, three indices of NDVI, RVI, and TVI were calculated. We investigated the relationship between the vegetation indices and aboveground biomass measured at sample-plot level. Based on the results, the relationship between aboveground biomass values and vegetation indices was a linear regression with the highest level of significance for NDVI in all compartments. Since at the compartment level the correlation coefficient between NDVI and aboveground biomass was the highest, NDVI was used for mapping aboveground biomass. According to the results of this study, biomass values were highly different in various climatic and altitudinal classes with the highest biomass value observed in humid climate and high-altitude class.

  17. Ratios of transfer coefficients for radiocesium transport in ruminants

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Assimakopoulos, P.A.; Ioannides, K.G.; Karamanis, D.

    1995-09-01

    A corollary of the multiple-compartment model for the transport of trace elements through animals was tested for cows, goats, and sheep. According to this corollary, for a given body {open_quotes}compartment{close_quotes} k of the animal (soft tissue, lung, liver, etc.), the ratio a(k)=f(k)/f(blood) of the transfer coefficients f, should exhibit similar values for physiologically similar animals. In order to verify this prediction, two experiments were performed at the Agricultural Research Station of Ioannina and at the facilities of Ria Pripyat in Pripyat, Ukranine. Eight animals in the first experiment and eighteen in the second were housed in individual pens and weremore » artificially contaminated with a constant daily dose of radiocesium until equilibrium was reached. the animals were then sacrificed and transfer coefficients f(k) to twelve body {open_quotes}compartments{close_quotes} k were measured. These data were used to calculate the ratios a(k). The results were in accordance with predictions of the model and average values of a(k) were extracted for ruminants. It is concluded that these values may be employed for the prediction of animal contamination in any body compartment through the measurement of blood samples. 7 refs., 8 tabs.« less

  18. [Influence of combined vitamin deficiency on unconditioned reflexes and learning in growing rats].

    PubMed

    Vrzhesinskaya, O A; Kodentsova, V M; Beketova, N A; Pereverzeva, O G; Kosheleva, O V; Sidorova, Yu S; Zorin, S N; Mazo, V K

    2015-01-01

    The aim of this study was to investigate the effect of combined deficiency of all vitamins on the manifestation of unconditioned reflex and learning (in response to an electric current) in growing Wistar rats with initial body weight 53.4 ± 1.2 g (45.5-62.0 g). 20 of 46 tested male rats (latent period of transition from the illuminated chamber to the dark compartment did not exceed 60 s) were included in the experiment. Rats were randomly divided into 2 groups (control and experimental) for the duration of the latent period and body mass. Within 23 days the rats of the control group received a complete semisynthetic diet. Combined vitamin deficiency in tested rats was caused by 5-fold diet decrease of the amount of vitamin mixture without vitamin E. On the 12th day the second phase of testing was performed, during which the rat received electrocutaneous irritation on paws (current 0.4 mA, 8 seconds) after transition to the dark compartment of the chamber. Preservation of the conducted reflex was performed 24 h and 9 days after training. On the 23rd day pre-anesthetized with ether rats were taken out from the experiment by decapitation. The content of vitamin A (retinol and retinol palmitate) and E (tocopherols) in plasma and liver and in the sunflower oil was analyzed by HPLC, the level of vitamins B1 and B2 in liver and casein by fluorimetric method, blood serum malondialdehyde content--by spectrophotometric method. Reducing of vitamin mixture amount of the diet lead to significant reduction in liver vitamin A, E, B1, and B2 level and in blood plasma vitamin A and E concentration by the end of the experiment, but had no effect on blood plasma MDA concentration. On the 12th day of vitamin deficiency in rats manifestation of unconditioned reflex (photophobia) has been deteriorated, as evidenced by the significant 3,2-fold increase of latent period of transition to the dark compartment compared with animals fed a complete diet (47.8 ± 15.8 vs 14.8 ± 3.6 sec), but their ability to learn hadn't been effected. Based on the data that vitamin deficiency, especially of vitamin-antioxidants, causes oxidative stress, and that increase of corticosterone level in hippocampus during aging significantly inhibits the function of the brain, we can assume that increasing of corticosterone level may be one of the cause of the detected cognitive impairment, as isolated vitamin A deficiency in rats increases tissue corticosterone levels.

  19. Kinetic characteristic of phenanthrene sorption in aged soil amended with biochar

    NASA Astrophysics Data System (ADS)

    Kim, Chanyang; Kim, Yong-Seong; Hyun, Seunghun

    2015-04-01

    Biochar has been recently highlighted as an amendment that affects yield of the crops by increasing pH, cation exchange capacity and water retention, and reduces the lability of contaminants by increasing sorption capacity in the soil system. Biochar's physico-chemical properties, high CEC, surfaces containing abundant micropores and macropores, and various types of functional groups, play important roles in enhancing sorption capacity of contaminants. Aging through a natural weathering process might change physico-chemical properties of biochar amended in soils, which can affect the sorption behavior of contaminants. Thus, in this study, the sorption characteristics of phenanthrene (PHE) on biochar-amended soils were studied with various types of chars depending on aging time. To do this, 1) soil was amended with sludge waste char (SWC), wood char (WC), and municipal waste char (MWC) during 0, 6, and 12 month. Chars were applied to soil at 1% and 2.5% (w/w) ratio. 2) Several batch kinetic and equilibrium studies were conducted. One-compartment first order and two-compartment first order model apportioning the fraction of fast and slow sorbing were selected for kinetic models. Where, qt is PHE concentration in biochar-amended soils at each time t, qeis PHE concentration in biochar-amended soils at equilibrium. ff is fastly sorbing fraction and (1-ff) is slowly sorbing fraction. k is sorption rate constant from one-compartment first order model, k1 and k2 are sorption rate constant from two-compartment first order model, t is time (hr). The equilibrium sorption data were fitted with Fruendlich and Langmuir equation. 3) Change in physico-chemical properties of biochar-amended soils was investigated with aging time. Batch equilibrium sorption results suggested that sorbed amount of PHE on WC was greater than SWC and MWC. The more char contents added to soil, the greater sorption capacity of PHE. Sorption equilibrium was reached after 4 hours and equilibrium pH ranged from 6.5 to 8.0. Sorption capacity was reduced with aging time. From kinetic results, two-compartment first order model was more suitable than one-compartment first order model. Fast sorption site of biochar-amended soils dominated total sorption process (i.e., Fraction of fast sorption site ranged from 0.55 to 0.96). Reduced sorption capacity with aging time could be attributed to changes in physico-chemical properties of biochar-amended soils (e.g., reduced pores and increased hydrophilic carboxyl and carbonyl functional groups). Verification is FI-IR and SSA. It is assumed that biochar is a suitable material for PHE contaminated soil in order to reduce the lability of PHE. However, aging effects would lessen biochar benefit for reducing the sorption capacity of PHE by forming hydrophilic functional group and reducing pores.

  20. Three-dimensional whole-brain perfusion quantification using pseudo-continuous arterial spin labeling MRI at multiple post-labeling delays: accounting for both arterial transit time and impulse response function.

    PubMed

    Qin, Qin; Huang, Alan J; Hua, Jun; Desmond, John E; Stevens, Robert D; van Zijl, Peter C M

    2014-02-01

    Measurement of the cerebral blood flow (CBF) with whole-brain coverage is challenging in terms of both acquisition and quantitative analysis. In order to fit arterial spin labeling-based perfusion kinetic curves, an empirical three-parameter model which characterizes the effective impulse response function (IRF) is introduced, which allows the determination of CBF, the arterial transit time (ATT) and T(1,eff). The accuracy and precision of the proposed model were compared with those of more complicated models with four or five parameters through Monte Carlo simulations. Pseudo-continuous arterial spin labeling images were acquired on a clinical 3-T scanner in 10 normal volunteers using a three-dimensional multi-shot gradient and spin echo scheme at multiple post-labeling delays to sample the kinetic curves. Voxel-wise fitting was performed using the three-parameter model and other models that contain two, four or five unknown parameters. For the two-parameter model, T(1,eff) values close to tissue and blood were assumed separately. Standard statistical analysis was conducted to compare these fitting models in various brain regions. The fitted results indicated that: (i) the estimated CBF values using the two-parameter model show appreciable dependence on the assumed T(1,eff) values; (ii) the proposed three-parameter model achieves the optimal balance between the goodness of fit and model complexity when compared among the models with explicit IRF fitting; (iii) both the two-parameter model using fixed blood T1 values for T(1,eff) and the three-parameter model provide reasonable fitting results. Using the proposed three-parameter model, the estimated CBF (46 ± 14 mL/100 g/min) and ATT (1.4 ± 0.3 s) values averaged from different brain regions are close to the literature reports; the estimated T(1,eff) values (1.9 ± 0.4 s) are higher than the tissue T1 values, possibly reflecting a contribution from the microvascular arterial blood compartment. Copyright © 2013 John Wiley & Sons, Ltd.

  1. The role of backward cell migration in two-hit mutants' production in the stem cell niche.

    PubMed

    Bollas, Audrey; Shahriyari, Leili

    2017-01-01

    It has been discovered that there are two stem cell groups in the intestinal crypts: central stem cells (CeSCs), which are at the very bottom of the crypt, and border stem cells (BSCs), which are located between CeSCs and transit amplifying cells (TAs). Moreover, backward cell migration from BSCs to CeSCs has been observed. Recently, a bi-compartmental stochastic model, which includes CeSCs and BSCs, has been developed to investigate the probability of two-hit mutant production in the stem cell niche. In this project, we improve this stochastic model by adding the probability of backward cell migration to the model. The model suggests that the probability of two-hit mutant production increases when the frequency of backward cell migration increases. Furthermore, a small non-zero probability of backward cell migration leads to the largest range of optimal values for the frequency of symmetric divisions and the portion of divisions at each stem cell compartment in terms of delaying 2-hit mutant production. Moreover, the probability of two-hit mutant production is more sensitive to the probability of symmetric divisions than to the rate of backward cell migrations. The highest probability of two-hit mutant production corresponds to the case when all stem cell's divisions are asymmetric.

  2. The role of backward cell migration in two-hit mutants’ production in the stem cell niche

    PubMed Central

    Bollas, Audrey

    2017-01-01

    It has been discovered that there are two stem cell groups in the intestinal crypts: central stem cells (CeSCs), which are at the very bottom of the crypt, and border stem cells (BSCs), which are located between CeSCs and transit amplifying cells (TAs). Moreover, backward cell migration from BSCs to CeSCs has been observed. Recently, a bi-compartmental stochastic model, which includes CeSCs and BSCs, has been developed to investigate the probability of two-hit mutant production in the stem cell niche. In this project, we improve this stochastic model by adding the probability of backward cell migration to the model. The model suggests that the probability of two-hit mutant production increases when the frequency of backward cell migration increases. Furthermore, a small non-zero probability of backward cell migration leads to the largest range of optimal values for the frequency of symmetric divisions and the portion of divisions at each stem cell compartment in terms of delaying 2-hit mutant production. Moreover, the probability of two-hit mutant production is more sensitive to the probability of symmetric divisions than to the rate of backward cell migrations. The highest probability of two-hit mutant production corresponds to the case when all stem cell’s divisions are asymmetric. PMID:28931019

  3. Population pharmacokinetic-pharmacodynamic modelling of mycophenolic acid in paediatric renal transplant recipients in the early post-transplant period.

    PubMed

    Dong, Min; Fukuda, Tsuyoshi; Cox, Shareen; de Vries, Marij T; Hooper, David K; Goebel, Jens; Vinks, Alexander A

    2014-11-01

    The purpose of this study was to develop a population pharmacokinetic and pharmacodynamic (PK-PD) model for mycophenolic acid (MPA) in paediatric renal transplant recipients in the early post-transplant period. A total of 214 MPA plasma concentrations-time data points from 24 patients were available for PK model development. In 17 out of a total of 24 patients, inosine monophosphate dehydrogenase (IMPDH) enzyme activity measurements (n = 97) in peripheral blood mononuclear cells were available for PK-PD modelling. The PK-PD model was developed using non-linear mixed effects modelling sequentially by 1) developing a population PK model and 2) incorporating IMPDH activity into a PK-PD model using post hoc Bayesian PK parameter estimates. Covariate analysis included patient demographics, co-medication and clinical laboratory data. Non-parametric bootstrapping and prediction-corrected visual predictive checks were performed to evaluate the final models. A two compartment model with a transit compartment absorption best described MPA PK. A non-linear relationship between dose and MPA exposure was observed and was described by a power function in the model. The final population PK parameter estimates (and their 95% confidence intervals) were CL/F, 22 (14.8, 25.2) l h(-1) 70 kg(-1) ; Vc /F, 45.4 (29.6, 55.6) l; Vp /F, 411 (152.6, 1472.6)l; Q/F, 22.4 (16.0, 32.5) l h(-1) ; Ka , 2.5 (1.45, 4.93) h(-1) . Covariate analysis in the PK study identified body weight to be significantly correlated with CL/F. A simplified inhibitory Emax model adequately described the relationship between MPA concentration and IMPDH activity. The final population PK-PD parameter estimates (and their 95% confidence intervals) were: E0 , 3.45 (2.61, 4.56) nmol h(-1)  mg(-1) protein and EC50 , 1.73 (1.16, 3.01) mg l(-1) . Emax was fixed to 0. There were two African-American patients in our study cohorts and both had low IMPDH baseline activities (E0 ) compared with Caucasian patients (mean value 2.13 mg l(-1) vs. 3.86 mg l(-1) ). An integrated population PK-PD model of MPA has been developed in paediatric renal transplant recipients. The current model provides information that will facilitate future studies and may be implemented in a Bayesian algorithm to allow a PK-PD guided therapeutic drug monitoring strategy. © 2014 The British Pharmacological Society.

  4. Population Pharmacokinetics and Dosing Regimen Optimization of Meropenem in Cerebrospinal Fluid and Plasma in Patients with Meningitis after Neurosurgery

    PubMed Central

    Lu, Cheng; Zhang, Yuyi; Chen, Mingyu; Zhong, Ping; Chen, Yuancheng; Yu, Jicheng; Wu, Xiaojie; Wu, Jufang

    2016-01-01

    Meropenem is used to manage postneurosurgical meningitis, but its population pharmacokinetics (PPK) in plasma and cerebrospinal fluid (CSF) in this patient group are not well-known. Our aims were to (i) characterize meropenem PPK in plasma and CSF and (ii) recommend favorable dosing regimens in postneurosurgical meningitis patients. Eighty-two patients were enrolled to receive meropenem infusions of 2 g every 8 h (q8h), 1 g q8h, or 1 g q6h for at least 3 days. Serial blood and CSF samples were collected, and concentrations were determined and analyzed via population modeling. Probabilities of target attainment (PTA) were predicted via Monte Carlo simulations, using the target of unbound meropenem concentrations above the MICs for at least 40% of dosing intervals in plasma and at least of 50% or 100% of dosing intervals in CSF. A two-compartment model plus another CSF compartment best described the data. The central, intercentral/peripheral, and intercentral/CSF compartment clearances were 22.2 liters/h, 1.79 liters/h, and 0.01 liter/h, respectively. Distribution volumes of the central and peripheral compartments were 17.9 liters and 3.84 liters, respectively. The CSF compartment volume was fixed at 0.13 liter, with its clearance calculated by the observed drainage amount. The multiplier for the transfer from the central to the CSF compartment was 0.172. Simulation results show that the PTAs increase as infusion is prolonged and as the daily CSF drainage volume decreases. A 4-hour infusion of 2 g q8h with CSF drainage of less than 150 ml/day, which provides a PTA of >90% for MICs of ≤8 mg/liter in blood and of ≤0.5 mg/liter or 0.25 mg/liter in CSF, is recommended. (This study has been registered at ClinicalTrials.gov under identifier NCT02506686.) PMID:27572392

  5. A Stochastic Model For Extracting Sediment Delivery Timescales From Sediment Budgets

    NASA Astrophysics Data System (ADS)

    Pizzuto, J. E.; Benthem, A.; Karwan, D. L.; Keeler, J. J.; Skalak, K.

    2015-12-01

    Watershed managers need to quantify sediment storage and delivery timescales to understand the time required for best management practices to improve downstream water quality. To address this need, we route sediment downstream using a random walk through a series of valley compartments spaced at 1 km intervals. The probability of storage within each compartment, q, is specified from a sediment budget and is defined as the ratio of the volume deposited to the annual sediment flux. Within each compartment, the probability of sediment moving directly downstream without being stored is p=1-q. If sediment is stored within a compartment, its "resting time" is specified by a stochastic exponential waiting time distribution with a mean of 10 years. After a particle's waiting time is over, it moves downstream to the next compartment by fluvial transport. Over a distance of "n" compartments, a sediment particle may be stored from 0 to n times with the probability of each outcome (store or not store) specified by the binomial distribution. We assign q = 0.02, a stream velocity of 0.5 m/s, an event "intermittency "of 0.01, and assume a balanced sediment budget. Travel time probability density functions have a steep peak at the shortest times, representing rapid transport in the channel of the fraction of sediment that moves downstream without being stored. However, the probability of moving downstream "n" km without storage is pn (0.90 for 5 km, 0.36 for 50 km, 0.006 for 250 km), so travel times are increasingly dominated by storage with increasing distance. Median travel times for 5, 50, and 250 km are 0.03, 4.4, and 46.5 years. After a distance of approximately 2/q or 100 km (2/0.02/km), the median travel time is determined by storage timescales, and active fluvial transport is irrelevant. Our model extracts travel time statistics from sediment budgets, and can be cast as a differential equation and solved numerically for more complex systems.

  6. Division of the intermediate compartment at the onset of mitosis provides a mechanism for Golgi inheritance.

    PubMed

    Marie, Michaël; Dale, Hege A; Kouprina, Nina; Saraste, Jaakko

    2012-11-15

    As mammalian cells prepare for mitosis, the Golgi ribbon is first unlinked into its constituent stacks and then transformed into spindle-associated, pleiomorphic membrane clusters in a process that remains enigmatic. Also, it remains unclear whether Golgi inheritance involves the incorporation of Golgi enzymes into a pool of coat protein I (COPI) vesicles, or their COPI-independent transfer to the endoplasmic reticulum (ER). Based on the observation that the intermediate compartment (IC) at the ER-Golgi boundary is connected to the centrosome, we examined its mitotic fate and possible role in Golgi breakdown. The use of multiple imaging techniques and markers revealed that the IC elements persist during the M phase, maintain their compositional and structural properties and remain associated with the mitotic spindle, forming circular arrays at the spindle poles. At G2/M transition, the movement of the pericentrosomal domain of the IC (pcIC) to the cell centre and its expansion coincide with the unlinking of the Golgi ribbon. At prophase, coupled to centrosome separation, the pcIC divides together with recycling endosomes, providing novel landmarks for mitotic entry. We provide evidence that the permanent IC elements function as way stations during the COPI-dependent dispersal of Golgi components at prometa- and metaphase, indicating that they correspond to the previously described Golgi clusters. In addition, they continue to communicate with the vesicular 'Golgi haze' and thus are likely to provide templates for Golgi reassembly. These results implicate the IC in mitotic Golgi inheritance, resulting in a model that integrates key features of the two previously proposed pathways.

  7. Proposal of a calculation method to determine the structural components' contribution on the deceleration of a passenger compartment based on the energy-derivative method.

    PubMed

    Nagasaka, Kei; Mizuno, Koji; Ito, Daisuke; Saida, Naoya

    2017-05-29

    In car crashes, the passenger compartment deceleration significantly influences the occupant loading. Hence, it is important to consider how each structural component deforms in order to control the passenger compartment deceleration. In frontal impact tests, the passenger compartment deceleration depends on the energy absorption property of the front structures. However, at this point in time there are few papers describing the components' quantitative contributions on the passenger compartment deceleration. Generally, the cross-sectional force is used to examine each component's contribution to passenger compartment deceleration. However, it is difficult to determine each component's contribution based on the cross-sectional forces, especially within segments of the individual members itself such as the front rails, because the force is transmitted continuously and the cross-sectional forces remain the same through the component. The deceleration of a particle can be determined from the derivative of the kinetic energy. Using this energy-derivative method, the contribution of each component on the passenger compartment deceleration can be determined. Using finite element (FE) car models, this method was applied for full-width and offset impact tests. This method was also applied to evaluate the deceleration of the powertrain. The finite impulse response (FIR) coefficient of the vehicle deceleration (input) and the driver chest deceleration (output) was calculated from Japan New Car Assessment Program (JNCAP) tests. These were applied to the component's contribution on the vehicle deceleration in FE analysis, and the component's contribution to the deceleration of the driver's chest was determined. The sum of the contribution of each component coincides with the passenger compartment deceleration in all types of impacts; therefore, the validity of this method was confirmed. In the full-width impact, the contribution of the crush box was large in the initial phases, and the contribution of the passenger compartment was large in the final phases. For the powertrain deceleration, the crush box had a positive contribution and the passenger compartment had a negative contribution. In the offset test, the contribution of the honeycomb and the passenger compartment deformation to the passenger compartment deceleration was large. Based on the FIR analysis, the passenger compartment deformation contributed the most to the chest deceleration of the driver dummy in the full-width impact. Based on the energy-derivative method, the contribution of the components' deformation to deceleration of the passenger compartment can be calculated for various types of crash configurations more easily, directly, and quantitatively than by using conventional methods. In addition, by combining the energy-derivative method and FIR, each structure's contribution to the occupant deceleration can be obtained. The energy-derivative method is useful in investigating how the deceleration develops from component deformations and also in designing deceleration curves for various impact configurations.

  8. Photoelectrodialytic cell

    DOEpatents

    Murphy, George W.

    1983-01-01

    A multicompartment photoelectrodialytic demineralization cell is provided with a buffer compartment interposed between the product compartment and a compartment containing an electrolyte solution. Semipermeable membranes separate the buffer compartment from the product and electrolyte compartments. The buffer compartment is flushed to prevent leakage of the electrolyte compartment from entering the product compartment.

  9. A tracer kinetic model for 18F-FHBG for quantitating herpes simplex virus type 1 thymidine kinase reporter gene expression in living animals using PET.

    PubMed

    Green, Leeta Alison; Nguyen, Khoi; Berenji, Bijan; Iyer, Meera; Bauer, Eileen; Barrio, Jorge R; Namavari, Mohammad; Satyamurthy, Nagichettiar; Gambhir, Sanjiv S

    2004-09-01

    Reporter probe 9-(4-18F-fluoro-3-[hydroxymethyl]butyl)guanine (18F-FHBG) and reporter gene mutant herpes simplex virus type 1 thymidine kinase (HSV1-sr39tk) have been used for imaging reporter gene expression with PET. Current methods for quantitating the images using the percentage injected dose per gram of tissue do not distinguish between the effects of probe transport and subsequent phosphorylation. We therefore investigated tracer kinetic models for 18F-FHBG dynamic microPET data and noninvasive methods for determining blood time-activity curves in an adenoviral gene delivery model in mice. 18F-FHBG (approximately 7.4 MBq [approximately 200 microCi]) was injected into 4 mice; 18F-FHBG concentrations in plasma and whole blood were measured from mouse heart left ventricle (LV) direct sampling. Replication-incompetent adenovirus (0-2 x 10(9) plaque-forming units) with the E1 region deleted (n = 8) or replaced by HSV1-sr39tk (n = 18) was tail-vein injected into mice. Mice were dynamically scanned using microPET (approximately 7.4 MBq [approximately 200 microCi] 18F-FHBG) over 1 h; regions of interest were drawn on images of the heart and liver. Serial whole blood 18F-FHBG concentrations were measured in 6 of the mice by LV sampling, and 1 least-squares ratio of the heart image to the LV time-activity curve was calculated for all 6 mice. For 2 control mice and 9 mice expressing HSV1-sr39tk, heart image (input function) and liver image time-activity curves (tissue curves) were fit to 2- and 3-compartment models using Levenberg-Marquardt nonlinear regression. The models were compared using an F statistic. HSV1-sr39TK enzyme activity was determined from liver samples and compared with model parameter estimates. For another 3 control mice and 6 HSV1-sr39TK-positive mice, the model-predicted relative percentage of metabolites was compared with high-performance liquid chromatography analysis. The ratio of 18F-FHBG in plasma to whole blood was 0.84 +/- 0.05 (mean +/- SE) by 30 s after injection. The least-squares ratio of the heart image time-activity curve to the LV time-activity curve was 0.83 +/- 0.02, consistent with the recovery coefficient for the partial-volume effect (0.81) based on independent measures of heart geometry. A 3-compartment model best described 18F-FHBG kinetics in mice expressing HSV1-sr39tk in the liver; a 2-compartment model best described the kinetics in control mice. The 3-compartment model parameter, k3, correlated well with the HSV1-sr39TK enzyme activity (r2 = 0.88). 18F-FHBG equilibrates rapidly between plasma and whole blood in mice. Heart image time-activity curves corrected for partial-volume effects well approximate LV time-activity curves and can be used as input functions for 2- and 3-compartment models. The model parameter k3 from the 3-compartment model can be used as a noninvasive estimate for HSV1-sr39TK reporter protein activity and can predict the relative percentage of metabolites.

  10. Allothermal steam gasification of biomass in cyclic multi-compartment bubbling fluidized-bed gasifier/combustor - new reactor concept.

    PubMed

    Iliuta, Ion; Leclerc, Arnaud; Larachi, Faïçal

    2010-05-01

    A new reactor concept of allothermal cyclic multi-compartment fluidized bed steam biomass gasification is proposed and analyzed numerically. The concept combines space and time delocalization to approach an ideal allothermal gasifier. Thermochemical conversion of biomass in periodic time and space sequences of steam biomass gasification and char/biomass combustion is simulated in which the exothermic combustion compartments provide heat into an array of interspersed endothermic steam gasification compartments. This should enhance unit heat integration and thermal efficiency and procure N(2)-free biosyngas with recourse neither to oxygen addition in steam gasification nor contact between flue and syngas. The dynamic, one-dimensional, multi-component, non-isothermal model developed for this concept accounts for detailed solid and gas flow dynamics whereupon gasification/combustion reaction kinetics, thermal effects and freeboard-zone reactions were tied. Simulations suggest that allothermal operation could be achieved with switch periods in the range of a minute supporting practical feasibility for portable small-scale gasification units. Copyright 2009 Elsevier Ltd. All rights reserved.

  11. Photoelectrodialytic cell

    DOEpatents

    Murphy, G.W.

    1983-09-13

    A multicompartment photoelectrodialytic demineralization cell is provided with a buffer compartment interposed between the product compartment and a compartment containing an electrolyte solution. Semipermeable membranes separate the buffer compartment from the product and electrolyte compartments. The buffer compartment is flushed to prevent leakage of the electrolyte compartment from entering the product compartment. 3 figs.

  12. Assessment of hemoglobin responsiveness to epoetin alfa in patients on hemodialysis using a population pharmacokinetic pharmacodynamic model.

    PubMed

    Wu, Liviawati; Mould, Diane R; Perez Ruixo, Juan Jose; Doshi, Sameer

    2015-10-01

    A population pharmacokinetic pharmacodynamic (PK/PD) model describing the effect of epoetin alfa on hemoglobin (Hb) response in hemodialysis patients was developed. Epoetin alfa pharmacokinetics was described using a linear 2-compartment model. PK parameter estimates were similar to previously reported values. A maturation-structured cytokinetic model consisting of 5 compartments linked in a catenary fashion by first-order cell transfer rates following a zero-order input process described the Hb time course. The PD model described 2 subpopulations, one whose Hb response reflected epoetin alfa dosing and a second whose response was unrelated to epoetin alfa dosing. Parameter estimates from the PK/PD model were physiologically reasonable and consistent with published reports. Numerical and visual predictive checks using data from 2 studies were performed. The PK and PD of epoetin alfa were well described by the model. © 2015, The American College of Clinical Pharmacology.

  13. Effect of Posterior Horn Medial Meniscus Root Tear on In Vivo Knee Kinematics.

    PubMed

    Marsh, Chelsea A; Martin, Daniel E; Harner, Christopher D; Tashman, Scott

    2014-07-01

    Medial meniscus root tear (MMRT) is a recently recognized yet frequently missed meniscal tear pattern that biomechanically creates an environment approaching meniscal deficiency. The purpose of this study was to assess the effect of MMRT on tibiofemoral kinematics and arthrokinematics during daily activities by comparing the injured knees of subjects with isolated MMRT to their uninjured contralateral knees. The hypothesis was that the injured knee will demonstrate significantly more lateral tibial translation and adduction than the uninjured knee, and that the medial compartment will exhibit significantly different arthrokinematics than the lateral compartment in the affected limb. Cross-sectional study; Level of evidence, 3. Seven subjects with isolated MMRT were recruited and volumetric, density-based 3-dimensional models of their distal femurs and proximal tibia were created from computed tomography scans. High-speed, biplane radiographs were obtained of both their affected and unaffected knees. Moving 3-dimensional models of tibiofemoral kinematics were calculated using model-based tracking to assess overall kinematic variables and specific measures of tibiofemoral joint contact. The affected knees of the subjects were then compared to their unaffected contralateral knees. Affected knees demonstrated significantly more lateral tibial translation than the uninjured contralateral limb in all dynamic activities. Additionally, the medial compartment displayed greater amounts of mobility than the lateral compartment in the injured limbs. This study suggests that MMRT causes significant changes in in vivo knee kinematics and arthrokinematics and that the magnitude of these changes is influenced by dynamic task difficulty. Medial meniscus root tears lead to significant changes in joint arthrokinematics, with increased lateral tibial translation and greater medial compartment excursion. With complete root tears, essentially 100% of circumferential fibers are lost. This study will further our knowledge of meniscal deficiency and osteoarthritis and provide a baseline for more common forms of medial meniscal injuries (vertical, horizontal, radial), with various degrees of circumferential fiber function remaining.

  14. Simulation of radiofrequency ablation in real human anatomy.

    PubMed

    Zorbas, George; Samaras, Theodoros

    2014-12-01

    The objective of the current work was to simulate radiofrequency ablation treatment in computational models with realistic human anatomy, in order to investigate the effect of realistic geometry in the treatment outcome. The body sites considered in the study were liver, lung and kidney. One numerical model for each body site was obtained from Duke, member of the IT'IS Virtual Family. A spherical tumour was embedded in each model and a single electrode was inserted into the tumour. The same excitation voltage was used in all cases to underline the differences in the resulting temperature rise, due to different anatomy at each body site investigated. The same numerical calculations were performed for a two-compartment model of the tissue geometry, as well as with the use of an analytical approximation for a single tissue compartment. Radiofrequency ablation (RFA) therapy appears efficient for tumours in liver and lung, but less efficient in kidney. Moreover, the time evolution of temperature for a realistic geometry differs from that for a two-compartment model, but even more for an infinite homogenous tissue model. However, it appears that the most critical parameters of computational models for RFA treatment planning are tissue properties rather than tissue geometry. Computational simulations of realistic anatomy models show that the conventional technique of a single electrode inside the tumour volume requires a careful choice of both the excitation voltage and treatment time in order to achieve effective treatment, since the ablation zone differs considerably for various body sites.

  15. Population Pharmacokinetic Modeling as a Tool To Characterize the Decrease in Ciprofloxacin Free Interstitial Levels Caused by Pseudomonas aeruginosa Biofilm Lung Infection in Wistar Rats

    PubMed Central

    Torres, Bruna G. S.; Helfer, Victória E.; Bernardes, Priscila M.; Macedo, Alexandre José; Nielsen, Elisabet I.; Friberg, Lena E.

    2017-01-01

    ABSTRACT Biofilm formation plays an important role in the persistence of pulmonary infections, for example, in cystic fibrosis patients. So far, little is known about the antimicrobial lung disposition in biofilm-associated pneumonia. This study aimed to evaluate, by microdialysis, ciprofloxacin (CIP) penetration into the lungs of healthy and Pseudomonas aeruginosa biofilm-infected rats and to develop a comprehensive model to describe the CIP disposition under both conditions. P. aeruginosa was immobilized into alginate beads and intratracheally inoculated 14 days before CIP administration (20 mg/kg of body weight). Plasma and microdialysate were sampled from different animal groups, and the observations were evaluated by noncompartmental analysis (NCA) and population pharmacokinetic (popPK) analysis. The final model that successfully described all data consisted of an arterial and a venous central compartment and two peripheral distribution compartments, and the disposition in the lung was modeled as a two-compartment model structure linked to the venous compartment. Plasma clearance was approximately 32% lower in infected animals, leading to a significantly higher level of plasma CIP exposure (area under the concentration-time curve from time zero to infinity, 27.3 ± 12.1 μg · h/ml and 13.3 ± 3.5 μg · h/ml in infected and healthy rats, respectively). Despite the plasma exposure, infected animals showed a four times lower tissue concentration/plasma concentration ratio (lung penetration factor = 0.44 and 1.69 in infected and healthy rats, respectively), and lung clearance (CLlung) was added to the model for these animals (CLlung = 0.643 liters/h/kg) to explain the lower tissue concentrations. Our results indicate that P. aeruginosa biofilm infection reduces the CIP free interstitial lung concentrations and increases plasma exposure, suggesting that plasma concentrations alone are not a good surrogate of lung concentrations. PMID:28461311

  16. Physiologic volume of phosphorus during hemodialysis: predictions from a pseudo one-compartment model.

    PubMed

    Leypoldt, John K; Akonur, Alp; Agar, Baris U; Culleton, Bruce F

    2012-10-01

    The kinetics of plasma phosphorus concentrations during hemodialysis (HD) are complex and cannot be described by conventional one- or two-compartment kinetic models. It has recently been shown by others that the physiologic (or apparent distribution) volume for phosphorus (Vr-P) increases with increasing treatment time and shows a large variation among patients treated by thrice weekly and daily HD. Here, we describe the dependence of Vr-P on treatment time and predialysis plasma phosphorus concentration as predicted by a novel pseudo one-compartment model. The kinetics of plasma phosphorus during conventional and six times per week daily HD were simulated as a function of treatment time per session for various dialyzer phosphate clearances and patient-specific phosphorus mobilization clearances (K(M)). Vr-P normalized to extracellular volume from these simulations were reported and compared with previously published empirical findings. Simulated results were relatively independent of dialyzer phosphate clearance and treatment frequency. In contrast, Vr-P was strongly dependent on treatment time per session; the increase in Vr-P with treatment time was larger for higher values of K(M). Vr-P was inversely dependent on predialysis plasma phosphorus concentration. There was significant variation among predicted Vr-P values, depending largely on the value of K(M). We conclude that a pseudo one-compartment model can describe the empirical dependence of the physiologic volume of phosphorus on treatment time and predialysis plasma phosphorus concentration. Further, the variation in physiologic volume of phosphorus among HD patients is largely due to differences in patient-specific phosphorus mobilization clearance. © 2012 The Authors. Hemodialysis International © 2012 International Society for Hemodialysis.

  17. Tracing compartment exchange by NMR diffusometry: Water in lithium-exchanged low-silica X zeolites

    NASA Astrophysics Data System (ADS)

    Lauerer, A.; Kurzhals, R.; Toufar, H.; Freude, D.; Kärger, J.

    2018-04-01

    The two-region model for analyzing signal attenuation in pulsed field gradient (PFG) NMR diffusion studies with molecules in compartmented media implies that, on their trajectory, molecules get from one region (one type of compartment) into the other one with a constant (i.e. a time-invariant) probability. This pattern has proved to serve as a good approach for considering guest diffusion in beds of nanoporous host materials, with the two regions ("compartments") identified as the intra- and intercrystalline pore spaces. It is obvious, however, that the requirements of the application of the two-region model are not strictly fulfilled given the correlation between the covered diffusion path lengths in the intracrystalline pore space and the probability of molecular "escape" from the individual crystallites. On considering water diffusion in lithium-exchanged low-silica X zeolite, we are now assuming a different position since this type of material is known to offer "traps" in the trajectories of the water molecules. Now, on attributing the water molecules in the traps and outside of the traps to these two types of regions, we perfectly comply with the requirements of the two-region model. We do, moreover, benefit from the option of high-resolution measurements owing to the combination of magic angle spinning (MAS) with PFG NMR. Data analysis via the two-region model under inclusion of the influence of nuclear magnetic relaxation yields satisfactory agreement between experimental evidence and theoretical estimates. Limitations in accuracy are shown to result from the fact that mass transfer outside of the traps is too complicated for being adequately reflected by simple Fick's laws with but one diffusivity.

  18. PET Pharmacokinetic Modelling

    NASA Astrophysics Data System (ADS)

    Müller-Schauenburg, Wolfgang; Reimold, Matthias

    Positron Emission Tomography is a well-established technique that allows imaging and quantification of tissue properties in-vivo. The goal of pharmacokinetic modelling is to estimate physiological parameters, e.g. perfusion or receptor density from the measured time course of a radiotracer. After a brief overview of clinical application of PET, we summarize the fundamentals of modelling: distribution volume, Fick's principle of local balancing, extraction and perfusion, and how to calculate equilibrium data from measurements after bolus injection. Three fundamental models are considered: (i) the 1-tissue compartment model, e.g. for regional cerebral blood flow (rCBF) with the short-lived tracer [15O]water, (ii) the 2-tissue compartment model accounting for trapping (one exponential + constant), e.g. for glucose metabolism with [18F]FDG, (iii) the reversible 2-tissue compartment model (two exponentials), e.g. for receptor binding. Arterial blood sampling is required for classical PET modelling, but can often be avoided by comparing regions with specific binding with so called reference regions with negligible specific uptake, e.g. in receptor imaging. To estimate the model parameters, non-linear least square fits are the standard. Various linearizations have been proposed for rapid parameter estimation, e.g. on a pixel-by-pixel basis, for the prize of a bias. Such linear approaches exist for all three models; e.g. the PATLAK-plot for trapping substances like FDG, and the LOGAN-plot to obtain distribution volumes for reversibly binding tracers. The description of receptor modelling is dedicated to the approaches of the subsequent lecture (chapter) of Millet, who works in the tradition of Delforge with multiple-injection investigations.

  19. A physiologically based toxicokinetic model for methylmercury in female American kestrels

    USGS Publications Warehouse

    Nichols, J.W.; Bennett, R.S.; Rossmann, R.; French, J.B.; Sappington, K.G.

    2010-01-01

    A physiologically based toxicokinetic (PBTK) model was developed to describe the uptake, distribution, and elimination of methylmercury (CH 3Hg) in female American kestrels. The model consists of six tissue compartments corresponding to the brain, liver, kidney, gut, red blood cells, and remaining carcass. Additional compartments describe the elimination of CH3Hg to eggs and growing feathers. Dietary uptake of CH 3Hg was modeled as a diffusion-limited process, and the distribution of CH3Hg among compartments was assumed to be mediated by the flow of blood plasma. To the extent possible, model parameters were developed using information from American kestrels. Additional parameters were based on measured values for closely related species and allometric relationships for birds. The model was calibrated using data from dietary dosing studies with American kestrels. Good agreement between model simulations and measured CH3Hg concentrations in blood and tissues during the loading phase of these studies was obtained by fitting model parameters that control dietary uptake of CH 3Hg and possible hepatic demethylation. Modeled results tended to underestimate the observed effect of egg production on circulating levels of CH3Hg. In general, however, simulations were consistent with observed patterns of CH3Hg uptake and elimination in birds, including the dominant role of feather molt. This model could be used to extrapolate CH 3Hg kinetics from American kestrels to other bird species by appropriate reassignment of parameter values. Alternatively, when combined with a bioenergetics-based description, the model could be used to simulate CH 3Hg kinetics in a long-term environmental exposure. ?? 2010 SETAC.

  20. Using Rising Limb Analysis to Estimate Uptake of Reactive Solutes in Advective and Transient Storage Sub-compartments of Stream Ecosystems

    NASA Astrophysics Data System (ADS)

    Thomas, S. A.; Valett, H.; Webster, J. R.; Mulholland, P. J.; Dahm, C. N.

    2001-12-01

    Identifying the locations and controls governing solute uptake is a recent area of focus in studies of stream biogeochemistry. We introduce a technique, rising limb analysis (RLA), to estimate areal nitrate uptake in the advective and transient storage (TS) zones of streams. RLA is an inverse approach that combines nutrient spiraling and transient storage modeling to calculate total uptake of reactive solutes and the fraction of uptake occurring within the advective sub-compartment of streams. The contribution of the transient storage zones to solute loss is determined by difference. Twelve-hour coinjections of conservative (Cl-) and reactive (15NO3) tracers were conducted seasonally in several headwater streams among which AS/A ranged from 0.01 - 2.0. TS characteristics were determined using an advection-dispersion model modified to include hydrologic exchange with a transient storage compartment. Whole-system uptake was determined by fitting the longitudinal pattern of NO3 to first-order, exponential decay model. Uptake in the advective sub-compartment was determined by collecting a temporal sequence of samples from a single location beginning with the arrival of the solute front and concluding with the onset of plateau conditions (i.e. the rising limb). Across the rising limb, 15NO3:Cl was regressed against the percentage of water that had resided in the transient storage zone (calculated from the TS modeling). The y-intercept thus provides an estimate of the plateau 15NO3:Cl ratio in the absence of NO3 uptake within the transient storage zone. Algebraic expressions were used to calculate the percentage of NO3 uptake occurring in the advective and transient storage sub-compartments. Application of RLA successfully estimated uptake coefficients for NO3 in the subsurface when the physical dimensions of that habitat were substantial (AS/A > 0.2) and when plateau conditions at the sampling location consisted of waters in which at least 25% had resided in the transient storage zone. In those cases, the TS zone accounted for 8 - 47 % of overall NO3 uptake and uptake rates within the subsurface ranged from 0.7 - 14.3 mg N m-2 d-1.

  1. Optimization Parameters of Air-conditioning and Heat Insulation Systems of a Pressurized Cabins of Long-distance Airplanes

    NASA Astrophysics Data System (ADS)

    Gusev, Sergey A.; Nikolaev, Vladimir N.

    2018-01-01

    The method for determination of an aircraft compartment thermal condition, based on a mathematical model of a compartment thermal condition was developed. Development of solution techniques for solving heat exchange direct and inverse problems and for determining confidence intervals of parametric identification estimations was carried out. The required performance of air-conditioning, ventilation systems and heat insulation depth of crew and passenger cabins were received.

  2. Fasciotomy Reduces Compartment Pressures and Improves Recovery in a Porcine Model of Extremity Vascular Injury and Ischemia/Reperfusion

    DTIC Science & Technology

    2012-10-01

    the study. Ill. ~Ut’i.Jt.t.;l I 1:111V1~ Vascular injury, Extremity\\ Ischemia-rcperfusion, Therapeutic reperfusion, Statin \\ Recovery\\ Neuromuscular...Health Sciences, Bethesda, Maryland Keywords: Vascular injury, Extremity, Ischemia-reperfusion, Therapeutic reperfusion, Statin , Recovery...compartment pressure (pɘ.05) which were directly related to degree of muscle degeneration (pɘ.05) and inversely related to nerve recovery (p<.05

  3. Estimating changes in mean body temperature for humans during exercise using core and skin temperatures is inaccurate even with a correction factor.

    PubMed

    Jay, Ollie; Reardon, Francis D; Webb, Paul; Ducharme, Michel B; Ramsay, Tim; Nettlefold, Lindsay; Kenny, Glen P

    2007-08-01

    Changes in mean body temperature (DeltaT(b)) estimated by the traditional two-compartment model of "core" and "shell" temperatures and an adjusted two-compartment model incorporating a correction factor were compared with values derived by whole body calorimetry. Sixty participants (31 men, 29 women) cycled at 40% of peak O(2) consumption for 60 or 90 min in the Snellen calorimeter at 24 or 30 degrees C. The core compartment was represented by esophageal, rectal (T(re)), and aural canal temperature, and the shell compartment was represented by a 12-point mean skin temperature (T(sk)). Using T(re) and conventional core-to-shell weightings (X) of 0.66, 0.79, and 0.90, mean DeltaT(b) estimation error (with 95% confidence interval limits in parentheses) for the traditional model was -95.2% (-83.0, -107.3) to -76.6% (-72.8, -80.5) after 10 min and -47.2% (-40.9, -53.5) to -22.6% (-14.5, -30.7) after 90 min. Using T(re), X = 0.80, and a correction factor (X(0)) of 0.40, mean DeltaT(b) estimation error for the adjusted model was +9.5% (+16.9, +2.1) to -0.3% (+11.9, -12.5) after 10 min and +15.0% (+27.2, +2.8) to -13.7% (-4.2, -23.3) after 90 min. Quadratic analyses of calorimetry DeltaT(b) data was subsequently used to derive best-fitting values of X for both models and X(0) for the adjusted model for each measure of core temperature. The most accurate model at any time point or condition only accounted for 20% of the variation observed in DeltaT(b) for the traditional model and 56% for the adjusted model. In conclusion, throughout exercise the estimation of DeltaT(b) using any measure of core temperature together with mean skin temperature irrespective of weighting is inaccurate even with a correction factor customized for the specific conditions.

  4. Dynamics of an SAITS alcoholism model on unweighted and weighted networks

    NASA Astrophysics Data System (ADS)

    Huo, Hai-Feng; Cui, Fang-Fang; Xiang, Hong

    2018-04-01

    A novel SAITS alcoholism model on networks is introduced, in which alcoholics are divided into light problem alcoholics and heavy problem alcoholics. Susceptible individuals can enter into the compartment of heavy problem alcoholics directly by contacting with light problem alcoholics or heavy problem alcoholics and the heavy problem alcoholics who receive treatment can relapse into the compartment of heavy problem alcoholics are also considered. First, the dynamics of our model on unweighted networks, including the basic reproduction number, existence and stability of equilibria are studied. Second, the models with fixed weighted and adaptive weighted networks are introduced and investigated. At last, some simulations are presented to illustrate and extend our results. Our results show that it is very important to treat alcoholics to quit the drinking.

  5. Insulin-like growth factor (IGF)-I controls prostate fibromuscular development: IGF-I inhibition prevents both fibromuscular and glandular development in eugonadal mice.

    PubMed

    Kleinberg, David L; Ruan, Weifeng; Yee, Douglas; Kovacs, Kalman T; Vidal, Sergio

    2007-03-01

    Although antiandrogen therapy has been shown effective in treating prostatic tumors, it is relatively ineffective in treating benign prostatic hyperplasia (BPH). In an attempt to understand better the role of androgens in the development of the normal prostate and BPH, we studied the relative effects of testosterone and IGF-I on the development of the two compartments of the prostate in castrated IGF-I((-/-)) male mice. Here we report that IGF-I stimulated the development of the fibromuscular compartment, but testosterone inhibited it (stromal epithelial ratio 2.17 vs. 0.83, respectively; P < 0.001). Testosterone also impaired IGF-I induced insulin receptor substrate-1 phosphorylation and cell division, and increased apoptosis in fibromuscular tissue. In sharp contrast IGF-I and testosterone both stimulated the development of the glandular compartment individually and together. The combined effects were either additive or synergistic on compartment size, cell division, insulin receptor substrate-1 phosphorylation, and probasin production. Together they also had a greater inhibitory effect on apoptosis in gland tissue. To determine whether IGF-I inhibition would inhibit both fibromuscular and glandular compartments, we tested the effect of IGF binding protein-1 on prostate development in two different models: castrated Ames dwarf mice and eugonadal normal male mice. IGF binding protein-1 blocked bovine GH-induced fibromuscular and glandular development in both. It also inhibited epithelial cell division and increased apoptosis in both prostate compartments in the eugonadal mice. The observed discordance between IGF-I and testosterone control of prostate compartment development might explain the relative failure of 5alpha-reductase inhibition in BPH and why testosterone inhibition might theoretically reduce gland volume but increase fibromuscular tissue. The work also provides a rationale for considering IGF-I inhibition as therapy for BPH to reduce the size of both prostate compartments.

  6. The Selector Gene apterous and Notch Are Required to Locally Increase Mechanical Cell Bond Tension at the Drosophila Dorsoventral Compartment Boundary

    PubMed Central

    Michel, Marcus; Aliee, Maryam; Rudolf, Katrin; Bialas, Lisa; Jülicher, Frank; Dahmann, Christian

    2016-01-01

    The separation of cells with distinct fates and functions is important for tissue and organ formation during animal development. Regions of different fates within tissues are often separated from another along straight boundaries. These compartment boundaries play a crucial role in tissue patterning and growth by stably positioning organizers. In Drosophila, the wing imaginal disc is subdivided into a dorsal and a ventral compartment. Cells of the dorsal, but not ventral, compartment express the selector gene apterous. Apterous expression sets in motion a gene regulatory cascade that leads to the activation of Notch signaling in a few cell rows on either side of the dorsoventral compartment boundary. Both Notch and apterous mutant clones disturb the separation of dorsal and ventral cells. Maintenance of the straight shape of the dorsoventral boundary involves a local increase in mechanical tension at cell bonds along the boundary. The mechanisms by which cell bond tension is locally increased however remain unknown. Here we use a combination of laser ablation of cell bonds, quantitative image analysis, and genetic mutants to show that Notch and Apterous are required to increase cell bond tension along the dorsoventral compartment boundary. Moreover, clonal expression of the Apterous target gene capricious results in cell separation and increased cell bond tension at the clone borders. Finally, using a vertex model to simulate tissue growth, we find that an increase in cell bond tension at the borders of cell clones, but not throughout the cell clone, can lead to cell separation. We conclude that Apterous and Notch maintain the characteristic straight shape of the dorsoventral compartment boundary by locally increasing cell bond tension. PMID:27552097

  7. Scanning number and brightness yields absolute protein concentrations in live cells: a crucial parameter controlling functional bio-molecular interaction networks.

    PubMed

    Papini, Christina; Royer, Catherine A

    2018-02-01

    Biological function results from properly timed bio-molecular interactions that transduce external or internal signals, resulting in any number of cellular fates, including triggering of cell-state transitions (division, differentiation, transformation, apoptosis), metabolic homeostasis and adjustment to changing physical or nutritional environments, amongst many more. These bio-molecular interactions can be modulated by chemical modifications of proteins, nucleic acids, lipids and other small molecules. They can result in bio-molecular transport from one cellular compartment to the other and often trigger specific enzyme activities involved in bio-molecular synthesis, modification or degradation. Clearly, a mechanistic understanding of any given high level biological function requires a quantitative characterization of the principal bio-molecular interactions involved and how these may change dynamically. Such information can be obtained using fluctation analysis, in particular scanning number and brightness, and used to build and test mechanistic models of the functional network to define which characteristics are the most important for its regulation.

  8. Evaluation of Subchondral Bone Marrow Lipids of Acute Anterior Cruciate Ligament (ACL)-Injured Patients at 3 T

    PubMed Central

    Wang, Ligong; Salibi, Nouha; Chang, Gregory; Bencardino, Jenny T.; Babb, James S.; Rokito, Andrew; Jazrawi, Laith; Sherman, Orrin; Regatte, Ravinder R.

    2014-01-01

    Rationale and Objectives The objectives of this study were to investigate the changes in compartment-specific subchondral bone marrow lipids of femoral–tibial bone in acute anterior cruciate ligament (ACL)-injured patients compared to that of healthy volunteers and patients with osteoarthritis (OA) (Kellgren–Lawrence [KL] grade 2–3). Materials and Methods A total of 55 subjects were recruited in the study and subdivided into three subgroups: 17 healthy controls (4 females, 13 males; mean age = 41 ± 16, age range 24–78 years), 17 patients with acute ACL injury (3 females, 14 males; mean age = 30 ± 11, age range 18–61 years), and 21 patients with KL2–3 OA (12 females, 9 males; mean age = 65 ± 12, age range 44–89 years). Routine clinical proton density–weighted fast spin echo images in sagittal (without fat saturation), axial, and coronal (fat saturation) planes were acquired on a 3 T clinical scanner for cartilage morphology using Whole-Organ Magnetic Resonance Imaging Score grading. A voxel of 10 × 10 × 10 mm3 was positioned in the medial and lateral compartments of the tibia and femur for proton magnetic resonance spectroscopy measurements using the single voxel stimulated echo acquisition mode pulse sequence. All proton magnetic resonance data were processed with Java-based magnetic resonance user interface. Wilcoxon rank sum test and mixed model two-way analysis of variance were performed to determine significant differences between different compartments and examine the effect of ACL injury, OA grade and compartment, and their interactions. Results The index of unsaturation in lateral tibial compartment in ACL-injured patients was significantly higher (P < .05) than all compartments except lateral femoral in patients with KL2–3 OA. Significantly lower values (P < .05) were also identified in saturated lipids at 2.03 ppm in all compartments in ACL-injured patients than those of all compartments in patients with KL2–3 OA. Conclusions The preliminary results suggest that the indices of unsaturation in the lateral tibial compartment and the peaks of saturated lipids at 1.3 and 2.03 ppm in medial tibial compartment may be clinically useful to characterize subchondral bone marrow among healthy controls, acute ACL-injured patients, and patients with OA. PMID:24717549

  9. Evaluation of subchondral bone marrow lipids of acute anterior cruciate ligament (ACL)-injured patients at 3 T.

    PubMed

    Wang, Ligong; Salibi, Nouha; Chang, Gregory; Bencardino, Jenny T; Babb, James S; Rokito, Andrew; Jazrawi, Laith; Sherman, Orrin; Regatte, Ravinder R

    2014-06-01

    The objectives of this study were to investigate the changes in compartment-specific subchondral bone marrow lipids of femoral-tibial bone in acute anterior cruciate ligament (ACL)-injured patients compared to that of healthy volunteers and patients with osteoarthritis (OA) (Kellgren-Lawrence [KL] grade 2-3). A total of 55 subjects were recruited in the study and subdivided into three subgroups: 17 healthy controls (4 females, 13 males; mean age = 41 ± 16, age range 24-78 years), 17 patients with acute ACL injury (3 females, 14 males; mean age = 30 ± 11, age range 18-61 years), and 21 patients with KL2-3 OA (12 females, 9 males; mean age = 65 ± 12, age range 44-89 years). Routine clinical proton density-weighted fast spin echo images in sagittal (without fat saturation), axial, and coronal (fat saturation) planes were acquired on a 3 T clinical scanner for cartilage morphology using Whole-Organ Magnetic Resonance Imaging Score grading. A voxel of 10 × 10 × 10 mm(3) was positioned in the medial and lateral compartments of the tibia and femur for proton magnetic resonance spectroscopy measurements using the single voxel stimulated echo acquisition mode pulse sequence. All proton magnetic resonance data were processed with Java-based magnetic resonance user interface. Wilcoxon rank sum test and mixed model two-way analysis of variance were performed to determine significant differences between different compartments and examine the effect of ACL injury, OA grade and compartment, and their interactions. The index of unsaturation in lateral tibial compartment in ACL-injured patients was significantly higher (P < .05) than all compartments except lateral femoral in patients with KL2-3 OA. Significantly lower values (P < .05) were also identified in saturated lipids at 2.03 ppm in all compartments in ACL-injured patients than those of all compartments in patients with KL2-3 OA. The preliminary results suggest that the indices of unsaturation in the lateral tibial compartment and the peaks of saturated lipids at 1.3 and 2.03 ppm in medial tibial compartment may be clinically useful to characterize subchondral bone marrow among healthy controls, acute ACL-injured patients, and patients with OA. Copyright © 2014 AUR. Published by Elsevier Inc. All rights reserved.

  10. The association of magnetic resonance imaging (MRI)-detected structural pathology of the knee with crepitus in a population-based cohort with knee pain: the MoDEKO study.

    PubMed

    Crema, M D; Guermazi, A; Sayre, E C; Roemer, F W; Wong, H; Thorne, A; Singer, J; Esdaile, J M; Marra, M D; Kopec, J A; Nicolaou, S; Cibere, J

    2011-12-01

    Osteoarthritis (OA) is the most common arthropathy of the knee joint(1). Symptoms reported by patients and signs noted during physical examination guide clinicians in identifying subjects with knee OA(2-4). Pain is one of the most important symptoms reported by subjects with knee OA(2,3). Although very common, pain is a non-specific symptom, related to pathology in several structures within the knee joint, and includes synovitis(5), subchondral bone marrow lesions(6), and joint effusion(7). Further, pain is a subjective symptom that cannot be directly measured or assessed during physical examination. Crepitus or crepitation in association with arthritis is defined as a crackling or grinding sound on joint movement with a sensation in the joint. Crepitus may occur with or without pain and is a common finding during physical examination in subjects with knee OA(2-4,8,9). It is not known whether crepitus is related to pathology in various structures within the knee. The aim of our study was to determine the cross-sectional associations of structural pathologies within the knee with crepitus in a population-based cohort with knee pain, using magnetic resonance imaging (MRI). Subjects with knee pain were recruited as a random population sample, with crepitus assessed in each compartment of the knee using a validated and standardized approach during physical examination(10). MRI of the knee was performed to assess cartilage morphology, meniscal morphology, osteophytes, cruciate ligaments, and collateral ligaments. For both compartment-specific and whole-knee analyses, a multiple logistic regression analysis was performed to assess the associations of MRI-detected structural pathology with crepitus, adjusting for potential confounders. Variables were selected by backwards elimination within each compartment and in the overall knee models, and only statistically significant variables remained in the "selected" models; remaining variables in these models are adjusted for each other. An increased risk for compartment-specific crepitus was associated with osteophytes at the patellofemoral (PF) and lateral tibiofemoral (LTF) joints. Crepitus was associated with osteophytes and medial collateral ligament (MCL) pathology at the medial tibiofemoral (MTF) compartment, but cartilage damage was negatively associated with crepitus at this compartment. In the selected whole-knee model, only meniscal tears were associated with an increased risk for general crepitus. Thus, it seems that crepitus may be associated with pathology in several internal structures. Copyright © 2011 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

  11. A novel single compartment in vitro model for electrophysiological research using the perfluorocarbon FC-770.

    PubMed

    Choudhary, M; Clavica, F; van Mastrigt, R; van Asselt, E

    2016-06-20

    Electrophysiological studies of whole organ systems in vitro often require measurement of nerve activity and/or stimulation of the organ via the associated nerves. Currently two-compartment setups are used for such studies. These setups are complicated and require two fluids in two separate compartments and stretching the nerve across one chamber to the other, which may damage the nerves. We aimed at developing a simple single compartment setup by testing the electrophysiological properties of FC-770 (a perfluorocarbon) for in vitro recording of bladder afferent nerve activity and electrical stimulation of the bladder. Perflurocarbons are especially suitable for such a setup because of their high oxygen carrying capacity and insulating properties. In male Wistar rats, afferent nerve activity was recorded from postganglionic branches of the pelvic nerve in vitro, in situ and in vivo. The bladder was stimulated electrically via the efferent nerves. Organ viability was monitored by recording spontaneous contractions of the bladder. Additionally, histological examinations were done to test the effect of FC-770 on the bladder tissue. Afferent nerve activity was successfully recorded in a total of 11 rats. The bladders were stimulated electrically and high amplitude contractions were evoked. Histological examinations and monitoring of spontaneous contractions showed that FC-770 maintained organ viability and did not cause damage to the tissue. We have shown that FC-770 enables a simple, one compartment in vitro alternative for the generally used two compartment setups for whole organ electrophysiological studies.

  12. In vivo tibiofemoral cartilage-to-cartilage contact area of females with medial osteoarthritis under acute loading using MRI.

    PubMed

    Shin, Choongsoo S; Souza, Richard B; Kumar, Deepak; Link, Thomas M; Wyman, Bradley T; Majumdar, Sharmila

    2011-12-01

    To investigate the effect of acute loading on in vivo tibiofemoral contact area changes in both compartments, and to determine whether in vivo tibiofemoral contact area differs between subjects with medial knee osteoarthritis (OA) and healthy controls. Ten subjects with medial knee OA (KL3) and 11 control subjects (KL0) were tested. Coronal three-dimensional spoiled gradient-recalled (3D-SPGR) and T(2) -weighted fast spin-echo FSE magnetic resonance imaging (MRI) of the knee were acquired under both unloaded and loaded conditions. Tibiofemoral cartilage contact areas were measured using image-based 3D models. Tibiofemoral contact areas in both compartments significantly increased under loading (P < 0.001) and the increased contact area in the medial compartment was significantly larger than in the lateral compartment (P < 0.05). Medial compartment contact area was significantly larger in KL3 subjects than KL0 subjects, both at unloaded and loaded conditions (P < 0.05). Contact areas measured from 3D-SPGR and T(2) -weighted FSE images were strongly correlated (r = 0.904). Females with medial OA increased tibiofemoral contact area in the medial compartment compared to healthy subjects under both unloaded and loaded conditions. The contact area data presented in this study may provide a quantitative reference for further cartilage contact biomechanics such as contact stress analysis and cartilage biomechanical function difference between osteoarthritic and healthy knees. Copyright © 2011 Wiley Periodicals, Inc.

  13. Ecposure Related Dose Estimating Model

    EPA Science Inventory

    ERDEM is a physiologically based pharmacokinetic (PBPK) modeling system consisting of a general model and an associated front end. An actual model is defined when the user prepares an input command file. Such a command file defines the chemicals, compartments and processes that...

  14. Simulation, identification and statistical variation in cardiovascular analysis (SISCA) - A software framework for multi-compartment lumped modeling.

    PubMed

    Huttary, Rudolf; Goubergrits, Leonid; Schütte, Christof; Bernhard, Stefan

    2017-08-01

    It has not yet been possible to obtain modeling approaches suitable for covering a wide range of real world scenarios in cardiovascular physiology because many of the system parameters are uncertain or even unknown. Natural variability and statistical variation of cardiovascular system parameters in healthy and diseased conditions are characteristic features for understanding cardiovascular diseases in more detail. This paper presents SISCA, a novel software framework for cardiovascular system modeling and its MATLAB implementation. The framework defines a multi-model statistical ensemble approach for dimension reduced, multi-compartment models and focuses on statistical variation, system identification and patient-specific simulation based on clinical data. We also discuss a data-driven modeling scenario as a use case example. The regarded dataset originated from routine clinical examinations and comprised typical pre and post surgery clinical data from a patient diagnosed with coarctation of aorta. We conducted patient and disease specific pre/post surgery modeling by adapting a validated nominal multi-compartment model with respect to structure and parametrization using metadata and MRI geometry. In both models, the simulation reproduced measured pressures and flows fairly well with respect to stenosis and stent treatment and by pre-treatment cross stenosis phase shift of the pulse wave. However, with post-treatment data showing unrealistic phase shifts and other more obvious inconsistencies within the dataset, the methods and results we present suggest that conditioning and uncertainty management of routine clinical data sets needs significantly more attention to obtain reasonable results in patient-specific cardiovascular modeling. Copyright © 2017 Elsevier Ltd. All rights reserved.

  15. A physiologically based pharmacokinetic model for developmental exposure to BDE-47 in rats

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Emond, Claude, E-mail: claude.emond@umontreal.c; BioSimulation Consulting Inc., Newark, DE 19711; Raymer, James H.

    2010-02-01

    Polybrominated diphenyl ethers (PBDEs) are used commercially as additive flame retardants and have been shown to transfer into environmental compartments, where they have the potential to bioaccumulate in wildlife and humans. Of the 209 possible PBDEs, 2,2',4,4'-tetrabromodiphenyl ether (BDE-47) is usually the dominant congener found in human blood and milk samples. BDE-47 has been shown to have endocrine activity and produce developmental, reproductive, and neurotoxic effects. The objective of this study was to develop a physiologically based pharmacokinetic (PBPK) model for BDE-47 in male and female (pregnant and non-pregnant) adult rats to facilitate investigations of developmental exposure. This model consistsmore » of eight compartments: liver, brain, adipose tissue, kidney, placenta, fetus, blood, and the rest of the body. Concentrations of BDE-47 from the literature and from maternal-fetal pharmacokinetic studies conducted at RTI International were used to parameterize and evaluate the model. The results showed that the model simulated BDE-47 tissue concentrations in adult male, maternal, and fetal compartments within the standard deviations of the experimental data. The model's ability to estimate BDE-47 concentrations in the fetus after maternal exposure will be useful to design in utero exposure/effect studies. This PBPK model is the first one designed for any PBDE pharmaco/toxicokinetic description. The next steps will be to expand this model to simulate BDE-47 pharmacokinetics and distributions across species (mice), and then extrapolate it to humans. After mouse and human model development, additional PBDE congeners will be incorporated into the model and simulated as a mixture.« less

  16. Real-Time Kinetic Modeling of Voltage-Gated Ion Channels Using Dynamic Clamp

    PubMed Central

    Milescu, Lorin S.; Yamanishi, Tadashi; Ptak, Krzysztof; Mogri, Murtaza Z.; Smith, Jeffrey C.

    2008-01-01

    We propose what to our knowledge is a new technique for modeling the kinetics of voltage-gated ion channels in a functional context, in neurons or other excitable cells. The principle is to pharmacologically block the studied channel type, and to functionally replace it with dynamic clamp, on the basis of a computational model. Then, the parameters of the model are modified in real time (manually or automatically), with the objective of matching the dynamical behavior of the cell (e.g., action potential shape and spiking frequency), but also the transient and steady-state properties of the model (e.g., those derived from voltage-clamp recordings). Through this approach, one may find a model and parameter values that explain both the observed cellular dynamics and the biophysical properties of the channel. We extensively tested the method, focusing on Nav models. Complex Markov models (10–12 states or more) could be accurately integrated in real time at >50 kHz using the transition probability matrix, but not the explicit Euler method. The practicality of the technique was tested with experiments in raphe pacemaker neurons. Through automated real-time fitting, a Hodgkin-Huxley model could be found that reproduced well the action potential shape and the spiking frequency. Adding a virtual axonal compartment with a high density of Nav channels further improved the action potential shape. The computational procedure was implemented in the free QuB software, running under Microsoft Windows and featuring a friendly graphical user interface. PMID:18375511

  17. Definition of compartment-based radical surgery in uterine cancer: radical hysterectomy in cervical cancer as 'total mesometrial resection (TMMR)' by M Höckel translated to robotic surgery (rTMMR).

    PubMed

    Kimmig, Rainer; Wimberger, Pauline; Buderath, Paul; Aktas, Bahriye; Iannaccone, Antonella; Heubner, Martin

    2013-08-26

    Radical hysterectomy has been developed as a standard treatment in Stage I and II cervical cancers with and without adjuvant therapy. However, there have been several attempts to standardize the technique of radical hysterectomy required for different tumor extension with variable success. Total mesometrial resection as ontogenetic compartment-based oncologic surgery - developed by open surgery - can be standardized identically for all patients with locally defined tumors. It appears to be promising for patients in terms of radicalness as well as complication rates. Robotic surgery may additionally reduce morbidity compared to open surgery. We describe robotically assisted total mesometrial resection (rTMMR) step by step in cervical cancer and present feasibility data from 26 patients. Patients (n = 26) with the diagnosis of cervical cancer were included. Patients were treated by robotic total mesometrial resection (rTMMR) and pelvic or pelvic/periaortic robotic therapeutic lymphadenectomy (rtLNE) for FIGO stage IA-IIB cervical cancer. No transition to open surgery was necessary. No intraoperative complications were noted. The postoperative complication rate was 23%. Within follow-up time (mean: 18 months) we noted one distant but no locoregional recurrence of cervical cancer. There were no deaths from cervical cancer during the observation period. We conclude that rTMMR and rtLNE is a feasible and safe technique for the treatment of compartment-defined cervical cancer.

  18. Comparative Digestive Physiology

    PubMed Central

    Karasov, William H.; Douglas, Angela E.

    2015-01-01

    In vertebrates and invertebrates, morphological and functional features of gastrointestinal (GI) tracts generally reflect food chemistry, such as content of carbohydrates, proteins, fats, and material(s) refractory to rapid digestion (e.g., cellulose). The expression of digestive enzymes and nutrient transporters approximately matches the dietary load of their respective substrates, with relatively modest excess capacity. Mechanisms explaining differences in hydrolase activity between populations and species include gene copy number variations and single-nucleotide polymorphisms. Transcriptional and posttranscriptional adjustments mediate phenotypic changes in the expression of hydrolases and transporters in response to dietary signals. Many species respond to higher food intake by flexibly increasing digestive compartment size. Fermentative processes by symbiotic microorganisms are important for cellulose degradation but are relatively slow, so animals that rely on those processes typically possess special enlarged compartment(s) to maintain a microbiota and other GI structures that slow digesta flow. The taxon richness of the gut microbiota, usually identified by 16S rRNA gene sequencing, is typically an order of magnitude greater in vertebrates than invertebrates, and the interspecific variation in microbial composition is strongly influenced by diet. Many of the nutrient transporters are orthologous across different animal phyla, though functional details may vary (e.g., glucose and amino acid transport with K+ rather than Na+ as a counter ion). Paracellular absorption is important in many birds. Natural toxins are ubiquitous in foods and may influence key features such as digesta transit, enzymatic breakdown, microbial fermentation, and absorption PMID:23720328

  19. Survival, Physiology, and Lysis of Lactococcus lactis in the Digestive Tract

    PubMed Central

    Drouault, Sophie; Corthier, Gérard; Ehrlich, S. Dusko; Renault, Pierre

    1999-01-01

    The survival and the physiology of lactococcal cells in the different compartments of the digestive tracts of rats were studied in order to know better the fate of ingested lactic acid bacteria after oral administration. For this purpose, we used strains marked with reporter genes, the luxA-luxB gene of Vibrio harveyi and the gfp gene of Aequora victoria, that allowed us to differentiate the inoculated bacteria from food and the other intestinal bacteria. Luciferase was chosen to measure the metabolic activity of Lactococcus lactis in the digestive tract because it requires NADH, which is available only in metabolically active cells. The green fluorescent protein was used to assess the bacterial lysis independently of death. We report not only that specific factors affect the cell viability and integrity in some digestive tract compartments but also that the way bacteria are administrated has a dramatic impact. Lactococci which transit with the diet are quite resistant to gastric acidity (90 to 98% survival). In contrast, only 10 to 30% of bacteria survive in the duodenum. Viable cells are metabolically active in each compartment of the digestive tract, whereas most dead cells appear to be subject to rapid lysis. This property suggests that lactococci could be used as a vector to deliver specifically into the duodenum the proteins produced in the cytoplasm. This type of delivery vector would be particularly appropriate for targeting digestive enzymes such as lipase to treat pancreatic deficiencies. PMID:10543799

  20. Parameter estimation using weighted total least squares in the two-compartment exchange model.

    PubMed

    Garpebring, Anders; Löfstedt, Tommy

    2018-01-01

    The linear least squares (LLS) estimator provides a fast approach to parameter estimation in the linearized two-compartment exchange model. However, the LLS method may introduce a bias through correlated noise in the system matrix of the model. The purpose of this work is to present a new estimator for the linearized two-compartment exchange model that takes this noise into account. To account for the noise in the system matrix, we developed an estimator based on the weighted total least squares (WTLS) method. Using simulations, the proposed WTLS estimator was compared, in terms of accuracy and precision, to an LLS estimator and a nonlinear least squares (NLLS) estimator. The WTLS method improved the accuracy compared to the LLS method to levels comparable to the NLLS method. This improvement was at the expense of increased computational time; however, the WTLS was still faster than the NLLS method. At high signal-to-noise ratio all methods provided similar precisions while inconclusive results were observed at low signal-to-noise ratio. The proposed method provides improvements in accuracy compared to the LLS method, however, at an increased computational cost. Magn Reson Med 79:561-567, 2017. © 2017 International Society for Magnetic Resonance in Medicine. © 2017 International Society for Magnetic Resonance in Medicine.

  1. Simulating the effects of light intensity and carbonate system composition on particulate organic and inorganic carbon production in Emiliania huxleyi.

    PubMed

    Holtz, Lena-Maria; Wolf-Gladrow, Dieter; Thoms, Silke

    2015-05-07

    Coccolithophores play an important role in the marine carbon cycle. Variations in light intensity and external carbonate system composition alter intracellular carbon fluxes and therewith the production rates of particulate organic and inorganic carbon. Aiming to find a mechanistic explanation for the interrelation between dissolved inorganic carbon fluxes and particulate carbon production rates, we develop a numerical cell model for Emiliania huxleyi, one of the most abundant coccolithophore species. The model consists of four cellular compartments, for each of which the carbonate system is resolved dynamically. The compartments are connected to each other and to the external medium via substrate fluxes across the compartment-confining membranes. By means of the model we are able to explain several pattern observed in particulate organic and inorganic carbon production rates for different strains and under different acclimation conditions. Particulate organic and inorganic carbon production rates for instance decrease at very low external CO2 concentrations. Our model suggests that this effect is caused mainly by reduced HCO3(-) uptake rates, not by CO2 limitation. The often observed decrease in particulate inorganic carbon production rates under Ocean Acidification is explained by a downregulation of cellular HCO3(-) uptake. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

  2. DOE Office of Scientific and Technical Information (OSTI.GOV)

    Smith, Jordan N.; Hinderliter, Paul M.; Timchalk, Charles

    Sensitivity to chemicals in animals and humans are known to vary with age. Age-related changes in sensitivity to chlorpyrifos have been reported in animal models. A life-stage physiologically based pharmacokinetic and pharmacodynamic (PBPK/PD) model was developed to computationally predict disposition of CPF and its metabolites, chlorpyrifos-oxon (the ultimate toxicant) and 3,5,6-trichloro-2-pyridinol (TCPy), as well as B-esterase inhibition by chlorpyrifos-oxon in humans. In this model, age-dependent body weight was calculated from a generalized Gompertz function, and compartments (liver, brain, fat, blood, diaphragm, rapid, and slow) were scaled based on body weight from polynomial functions on a fractional body weight basis. Bloodmore » flows among compartments were calculated as a constant flow per compartment volume. The life-stage PBPK/PD model was calibrated and tested against controlled adult human exposure studies. Model simulations suggest age-dependent pharmacokinetics and response may exist. At oral doses ≥ 0.55 mg/kg of chlorpyrifos (significantly higher than environmental exposure levels), 6 mo old children are predicted to have higher levels of chlorpyrifos-oxon in blood and higher levels of red blood cell cholinesterase inhibition compared to adults from equivalent oral doses of chlorpyrifos. At lower doses that are more relevant to environmental exposures, the model predicts that adults will have slightly higher levels of chlorpyrifos-oxon in blood and greater cholinesterase inhibition. This model provides a computational framework for age-comparative simulations that can be utilized to predict CPF disposition and biological response over various postnatal life-stages.« less

  3. Impact of Trichodesmium Sp. on Pacific Primary production

    NASA Astrophysics Data System (ADS)

    Dutheil, C.; Menkes, C.; Aumont, O.; Shiozaki, T.; Bonnet, S.; Rodier, M.; Bopp, L.; Lorrain, A.

    2016-12-01

    Recent sea-experiments have suggested that the South Pacific is one of the world's hot spot for nitrogen fixation. In that region, diazotrophs Trichodesmium Sp. have been shown to be one of its major contributors. Here we assess the climatological impact of these diazotrophs in the Pacific by using a 1°x1° coupled model dynamical-biogeochemical model ROMS-PISCES in which an explicit a Trichodesmium compartment is implemented. Firstly, we validate our model on the main limiting components (phosphate, iron, and temperature) of Trichodesmium growth. Phosphate patterns show modelled values and structures in qualitatively good agreement with observations. Iron concentrations are in good agreement with the observations. We also validate our model on nitrogen fixation rates. The regional spatial patterns of strong fixation are coherent with the observations. In the South Pacific, the model is able to reproduce the strong east-west gradient. Secondly, we evaluate the climatological effects of Trichodesmium on the biogeochemical conditions of the Tropical Pacific by adding with the explicit Trichodesmium compartment. The implementation of this compartment improves the model ability to reproduce the observed chlorophyll fields in the South West Pacific and the northern hemisphere, especially around Hawaii. In regions where there are strong nitrogen fixation rates, we observe an increase in the primary production by more than 100%, and an increase by more than 60 % in the production due to nanophytoplankton and diatoms, between the simulation with trichodesmium and without nitrogen fixation.

  4. Starling forces drive intracranial water exchange during normal and pathological states.

    PubMed

    Linninger, Andreas A; Xu, Colin; Tangen, Kevin; Hartung, Grant

    2017-12-31

    To quantify the exchange of water between cerebral compartments, specifically blood, tissue, perivascular pathways, and cerebrospinal fluid-filled spaces, on the basis of experimental data and to propose a dynamic global model of water flux through the entire brain to elucidate functionally relevant fluid exchange phenomena. The mechanistic computer model to predict brain water shifts is discretized by cerebral compartments into nodes. Water and species flux is calculated between these nodes across a network of arcs driven by Hagen-Poiseuille flow (blood), Darcy flow (interstitial fluid transport), and Starling's Law (transmembrane fluid exchange). Compartment compliance is accounted for using a pressure-volume relationship to enforce the Monro-Kellie doctrine. This nonlinear system of differential equations is solved implicitly using MATLAB software. The model predictions of intraventricular osmotic injection caused a pressure rise from 10 to 22 mmHg, followed by a taper to 14 mmHg over 100 minutes. The computational results are compared to experimental data with R2=0.929. Moreover, simulated osmotic therapy of systemic (blood) injection reduced intracranial pressure from 25 to 10 mmHg. The modeled volume and intracranial pressure changes following cerebral edema agree with experimental trends observed in animal models with R2=0.997. The model successfully predicted time course and the efficacy of osmotic therapy for clearing cerebral edema. Furthermore, the mathematical model implicated the perivascular pathways as a possible conduit for water and solute exchange. This was a first step to quantify fluid exchange throughout the brain.

  5. Population pharmacokinetics of methadone hydrochloride after a single intramuscular administration in adult Japanese sika deer (Cervus nippon nippon).

    PubMed

    Scala, Christopher; Marsot, Amélie; Limoges, Marie-Josée; Locatelli, Yann; Simon, Nicolas; Alvarez, Jean-Claude

    2015-03-01

    To assess the population pharmacokinetics of methadone in deer. Prospective non-randomized experimental trial. Twelve healthy adult sika deer (nine males and three females). Deer received intramuscular administration of racemic methadone hydrochloride at 0.5 mg kg(-1) or 1 mg kg(-1) . Plasma methadone and its metabolite 2-Ethylidene-1,5-Dimethyl-3,3-Diphenyl-Pyrolidine (EDDP) concentrations were determined by validated liquid chromatography coupled to tandem mass spectrometry methods, at times 0, 30 minutes, 1, 2, 3, 4, 5, 6, 8, 12 and 24 hours. Population pharmacokinetics analysis was undertaken using a non-linear mixed effects modelling (NONMEM). A two-compartment linear disposition model best described observed time-concentration profiles of methadone and EDDP. Population parameter estimates of methadone were elimination clearance (17.3 L hour(-1) ), metabolic clearance (34.6 L hour(-1) ), volume of distribution of compartment 1 (216.0 L) and volume of distribution of compartment 2 (384.0 L). Population parameter estimates of EDDP were elimination clearance (121.0 L hour(-1) ), volume of distribution of compartment 3 (1.08 L) and volume of distribution of compartment 4 (499.5 L). The total clearance and total volume of distribution of methadone and EDDP were 51.9 L hour(-1) , 121.0 L hour (-1) , 600.0 L and 500.6 L, respectively. The methadone terminal elimination half-life was 8.19 hours. No adverse effects were observed after methadone administration. Following intramuscular injection, methadone was characterized by a large total volume of distribution, high systemic clearance and intermediate terminal half-life in sika deer. © 2014 Association of Veterinary Anaesthetists and the American College of Veterinary Anesthesia and Analgesia.

  6. Fractal pharmacokinetics.

    PubMed

    Pereira, Luis M

    2010-06-01

    Pharmacokinetics (PK) has been traditionally dealt with under the homogeneity assumption. However, biological systems are nowadays comprehensively understood as being inherently fractal. Specifically, the microenvironments where drug molecules interact with membrane interfaces, metabolic enzymes or pharmacological receptors, are unanimously recognized as unstirred, space-restricted, heterogeneous and geometrically fractal. Therefore, classical Fickean diffusion and the notion of the compartment as a homogeneous kinetic space must be revisited. Diffusion in fractal spaces has been studied for a long time making use of fractional calculus and expanding on the notion of dimension. Combining this new paradigm with the need to describe and explain experimental data results in defining time-dependent rate constants with a characteristic fractal exponent. Under the one-compartment simplification this strategy is straightforward. However, precisely due to the heterogeneity of the underlying biology, often at least a two-compartment model is required to address macroscopic data such as drug concentrations. This simple modelling step-up implies significant analytical and numerical complications. However, a few methods are available that make possible the original desideratum. In fact, exploring the full range of parametric possibilities and looking at different drugs and respective biological concentrations, it may be concluded that all PK modelling approaches are indeed particular cases of the fractal PK theory.

  7. [Analysis of parameters of serum concentration and pharmacokinetic of liposome and aqueous solution of toatal ginsenoside of ginseng stems and leaves in rats].

    PubMed

    Zha, Lin; Zhao, Yan; Zhu, Hong-Yan; Cai, En-Bo; Liu, Shuang-Li; Yang, He; Zhao, Ying; Gao, Yu-Gang; Zhang, Lian-Xue

    2017-05-01

    The experiment was aimed to investigate the difference of plasma concentration and pharmacokinetic parameters between liposome and aqueous solution of toatal ginsenoside of ginseng stems and leaves in rats, such as ginsenosides Rg₁, Re, Rf, Rb₁, Rg₂, Rc, Rb₂, Rb₃, Rd. After intravenous injection of liposome and aqueous solution in rats, the blood was taken from the femoral vein to detect the plasma concentration of the above 9 ginsenoside monomers in different time points by using HPLC. The concentration-time curve was obtained and 3p97 pharmacokinetic software was used to get the pharmacokinetic parameters. After the intravenous injection of ginsenosides to rats, nine ginsenosides were detected in plasma. In general, among these ginsenosides, the peak time of the aqueous solution was between 0.05 to 0.083 3 h, and the serum concentration peak of liposome usually appeared after 0.5 h. After software fitting, the aqueous solution of ginsenoside monomers Rg₁, Re, Rf, Rg₂, Rc, Rd, Rb₃ was two-compartment model, and the liposomes were one-compartment model; aqueous solution and liposome of ginsenoside monomers Rb₁ were three-compartment model; aqueous solution of ginsenoside monomers Rb₂ was three-compartment model, and its liposome was one-compartment model. Area under the drug time curve (AUC) of these 9 kinds of saponin liposomes was larger than that of aqueous solution, and the retention time of the liposomes was longer than that of the aqueous solution; the removal rate was slower than that of the aqueous solution, and the half-life was longer than that of the water solution. The results from the experiment showed that by intravenous administration, the pharmacokinetic parameters of two formulations were significantly different from each other; the liposomes could not only remain the drug for a longer time in vivo, but also reduce the elimination rate and increase the treatment efficacy. As compared with the traditional dosage forms, the total ginsenoside of ginseng stems and leaves can improve the sustained release of the drug, which is of great significance for the research and development of new dosage forms of ginsenosides in the future. Copyright© by the Chinese Pharmaceutical Association.

  8. Modeling Microgravity Induced Fluid Redistribution Autoregulatory and Hydrostatic Enhancements

    NASA Technical Reports Server (NTRS)

    Myers, J. G.; Werner, C.; Nelson, E. S.; Feola, A.; Raykin, J.; Samuels, B.; Ethier, C. R.

    2017-01-01

    Space flight induces a marked cephalad (headward) redistribution of blood and interstitial fluid potentially resulting in a loss of venous tone and reduction in heart muscle efficiency upon introduction into the microgravity environment. Using various types of computational models, we are investigating how this fluid redistribution may induce intracranial pressure changes, relevant to reported reductions in astronaut visual acuity, part of the Visual Impairment and Intracranial Pressure (VIIP) syndrome. Methods: We utilize a lumped parameter cardiovascular system (CVS) model, augmented by compartments comprising the cerebral spinal fluid (CSF) space, as the primary tool to describe how microgravity, and the associated lack of hydrostatic gradient, impacts fluid redistribution. Models of ocular fluid pressures and biomechanics then accept the output of the above model as boundary condition input to allow more detailed, local analysis (see IWS Abstract by Ethier et al.). Recently, we enhanced the capabilities our previously reported CVS model through the implementation of robust autoregulatory mechanisms and a more fundamental approach to the implementation of hydrostatic mechanisms. Modifying the approach of Blanco et al., we implemented auto-regulation in a quasi-static manner, as an averaged effect across the span of one heartbeat. This approach reduced the higher frequency perturbations from the regulatory mechanism and was intended to allow longer simulation times (days) than models that implement within-beat regulatory mechanisms (minutes). A more fundamental approach to hydrostatics was implemented by a quasi-1D approach, in which compartment descriptions include compartment length, orientation and relative position, allowed for modeling of body orientation, relative body positioning and, in the future, alternative gravity environments. At this time the inclusion of hydrostatic mechanisms supplies additional capabilities to train and validate the CVS model with terrestrial data. Results and Conclusions: With the implementation of auto-regulation and hydrostatic modeling capabilities, the model performs as expected in the maintaining the CA (Central Artery) compartment pressure when simulating orientations ranging from supine to standing. The model appears to generally overpredict heart rate and thus cardiac output, possibly indicating sensitivity to the nominal heart rate, which is used as an initial set point of the regulation mechanisms. Despite this sensitivity, the model performs consistently for many hours of simulation time, indicating the success of our quasi-static implementation approach.

  9. Assessment of disintegration of rapidly disintegrating tablets by a visiometric liquid jet-mediated disintegration apparatus.

    PubMed

    Desai, Parind M; Liew, Celine V; Heng, Paul W S

    2013-02-14

    The aim of this study was to develop a responsive disintegration test apparatus that is particularly suitable for rapidly disintegrating tablets (RDTs). The designed RDT disintegration apparatus consisted of disintegration compartment, stereomicroscope and high speed video camera. Computational fluid dynamics (CFD) was used to simulate 3 different designs of the compartment and to predict velocity and pressure patterns inside the compartment. The CFD preprocessor established the compartment models and the CFD solver determined the numerical solutions of the governing equations that described disintegration medium flow. Simulation was validated by good agreement between CFD and experimental results. Based on the results, the most suitable disintegration compartment was selected. Six types of commercial RDTs were used and disintegration times of these tablets were determined using the designed RDT disintegration apparatus and the USP disintegration apparatus. The results obtained using the designed apparatus correlated well to those obtained by the USP apparatus. Thus, the applied CFD approach had the potential to predict the fluid hydrodynamics for the design of optimal disintegration apparatus. The designed visiometric liquid jet-mediated disintegration apparatus for RDT provided efficient and precise determination of very short disintegration times of rapidly disintegrating dosage forms. Copyright © 2012 Elsevier B.V. All rights reserved.

  10. B Cell Development in the Bone Marrow Is Regulated by Homeostatic Feedback Exerted by Mature B Cells

    PubMed Central

    Shahaf, Gitit; Zisman-Rozen, Simona; Benhamou, David; Melamed, Doron; Mehr, Ramit

    2016-01-01

    Cellular homeostasis in the B cell compartment is strictly imposed to balance cell production and cell loss. However, it is not clear whether B cell development in the bone marrow is an autonomous process or subjected to regulation by the peripheral B cell compartment. To specifically address this question, we used mice transgenic for human CD20, where effective depletion of B lineage cells is obtained upon administration of mouse anti-human CD20 antibodies, in the absence of any effect on other cell lineages and/or tissues. We followed the kinetics of B cell return to equilibrium by BrdU labeling and flow cytometry and analyzed the resulting data by mathematical modeling. Labeling was much faster in depleted mice. Compared to control mice, B cell-depleted mice exhibited a higher proliferation rate in the pro-/pre-B compartment, and higher cell death and lower differentiation in the immature B cell compartment. We validated the first result by analysis of the expression of Ki67, the nuclear protein expressed in proliferating cells, and the second using Annexin V staining. Collectively, our results suggest that B lymphopoiesis is subjected to homeostatic feedback mechanisms imposed by mature B cells in the peripheral compartment. PMID:27047488

  11. Proceedings of the Annual Conference on Environmental Toxicology (5th) Held at Fairborn, OH on 24-26 September 1974

    DTIC Science & Technology

    1974-12-01

    259 Paul M. Newberne 19 - STATISTICAL MODELS FOR ESTIMATING CARCINOGENIC RISKS FROM ANIMAL DATA ................... 285 .David G. Hoel V AMRL-TR-74-125... Paul M., D. V. M., Ph. D. SHANK, Ronald C., Ph. D. Professor of Pathology Associate Professor of Toxicology Laboratory of Animal Pathology Departments of...significance for water quality management . Each compartment represents the concentration of a measurable constituent. Lines connecting compartments represent

  12. Emergent Chemical Behavior in Variable-Volume Protocells

    PubMed Central

    Shirt-Ediss, Ben; Solé, Ricard V.; Ruiz-Mirazo, Kepa

    2015-01-01

    Artificial protocellular compartments and lipid vesicles have been used as model systems to understand the origins and requirements for early cells, as well as to design encapsulated reactors for biotechnology. One prominent feature of vesicles is the semi-permeable nature of their membranes, able to support passive diffusion of individual solute species into/out of the compartment, in addition to an osmotic water flow in the opposite direction to the net solute concentration gradient. Crucially, this water flow affects the internal aqueous volume of the vesicle in response to osmotic imbalances, in particular those created by ongoing reactions within the system. In this theoretical study, we pay attention to this often overlooked aspect and show, via the use of a simple semi-spatial vesicle reactor model, that a changing solvent volume introduces interesting non-linearities into an encapsulated chemistry. Focusing on bistability, we demonstrate how a changing volume compartment can degenerate existing bistable reactions, but also promote emergent bistability from very simple reactions, which are not bistable in bulk conditions. One particularly remarkable effect is that two or more chemically-independent reactions, with mutually exclusive reaction kinetics, are able to couple their dynamics through the variation of solvent volume inside the vesicle. Our results suggest that other chemical innovations should be expected when more realistic and active properties of protocellular compartments are taken into account. PMID:25590570

  13. SIZE DEPENDENT MODEL OF HAZARDOUS SUBSTANCES IN Q AQUATIC FOOD CHAIN

    EPA Science Inventory

    A model of toxic substance accumulation is constructed that introduces organism size as an additional independent variable. The model represents an ecological continuum through size dependency; classical compartment analyses are therefore a special case of the continuous model. S...

  14. MELiSSA third compartment: Nitrosomonas europaea and Nitrobacter winogradskyi axenic cultures in bioreactors

    NASA Astrophysics Data System (ADS)

    Cruvellier, Nelly; Lasseur, Christophe; Poughon, Laurent; Creuly, Catherine; Dussap, Gilles

    Nitrogen is a key element for the life and its balance on Earth is regulated by the nitrogen cycle. This loop includes several steps among which nitrification that permits the transformation of the ammonium into nitrate. The MELiSSA loop is an artificial ecosystem designed for life support systems (LSS). It is based on the carbon and nitrogen cycles and the recycling of the non-edible part of the higher plants and the waste produced by the crew. In this order, all the wastes are collected in the first compartment to degrade them into organic acids and CO2. These compounds are joining the second compartment which is a photoheterotrophic compartment where at the outlet an organic-free medium containing ammonium is produced. This solution will be the substrate of the third compartment where nitrification is done. This compartment has to oxidize the ammonium into nitrate, and this biological reaction needs two steps. In the MELiSSA loop, the nitrification is carried out by two bacteria: Nitrosomonas europaea ATCC® 19718™ which is oxidizing ammonia into nitrite and Nitrobacter winogradskyi ATCC® 25391™ which is producing nitrate from nitrite in the third compartment. These two bacteria are growing in axenic conditions on a fixed bed bioreactor filled with Biostyr® beads. The nitrogen compounds are controlled by Ionic Chromatography and colorimetric titration for each sample. The work presented here deals with the culture of both bacteria in pure cultures and mixed cultures in stirred and aerated bioreactors of different volumes. The first aim of our work is the characterization of the bacteria growth in bioreactors and in the nitrifying fixed-bed column. The experimental results confirm that the growth is slow; the maximal growth rate in suspended cultures is 0.054h-1 for Nitrosomonas europaea and 0.022h-1 for Nitrobacter winogradskyi. Mixed cultures are difficult to control and operate but one could be done for more than 500 hours. The characterization of the bacteria will be used to calibrate the nitrification model which will be the basis of the control model for managing the nitrification process in the MELiSSA loop. The experimental results highlighted the use of online measurement of base addition and oxygen consumption as possible parameters for the control of the nitrification process. Keywords: Nitrosomonas europaea, Nitrobacter winogradskyi, MELiSSA, bioreactor

  15. The relationships between half-life (t1/2) and mean residence time (MRT) in the two-compartment open body model.

    PubMed

    Sobol, Eyal; Bialer, Meir

    2004-05-01

    In the one-compartment model following i.v. administration the mean residence time (MRT) of a drug is always greater than its half-life (t(1/2)). However, following i.v. administration, drug plasma concentration (C) versus time (t) is best described by a two-compartment model or a two exponential equation:C=Ae(-alpha t)+Be(-beta t), where A and B are concentration unit-coefficients and alpha and beta are exponential coefficients. The relationships between t(1/2) and MRT in the two-compartment model have not been explored and it is not clear whether in this model too MRT is always greater than t(1/2). In the current paper new equations have been developed that describe the relationships between the terminal t(1/2) (or t(1/2 beta)) and MRT in the two-compartment model following administration of i.v. bolus, i.v. infusion (zero order input) and oral administration (first order input). A critical value (CV) equals to the quotient of (1-ln2) and (1-beta/alpha) (CV=(1-ln2)/(1-beta/alpha)=0.307/(1-beta/alpha)) has been derived and was compared with the fraction (f(1)) of drug elimination or AUC (AUC-area under C vs t curve) associated with the first exponential term of the two-compartment equation (f(1)=A/alpha/AUC). Following i.v. bolus, CV ranges between a minimal value of 0.307 (1-ln2) and infinity. As long as f(1)t(1/2) and vice versa, and when f(1)=CV, then MRT=t(1/2). Following i.v. infusion and oral administration the denominator of the CV equation does not change but its numerator increases to (0.307+beta T/2) (T-infusion duration) and (0.307+beta/ka) (ka-absorption rate constant), respectively. Examples of various drugs are provided. For every drug that after i.v. bolus shows two-compartment disposition kinetics the following conclusions can be drawn (a) When f(1)<0.307, then f(1)t(1/2). (b) When beta/alpha>ln2, then CV>1>f(1) and thus(,) MRT>t(1/2). (c) When ln2>beta/alpha>(ln4-1), then 1>CV>0.5 and thus, in order for t(1/2)>MRT, f(1) has to be greater than its complementary fraction f(2) (f(1)>f(2)). (d) When beta/alpha<(ln4-1), it is possible that t(1/2)>MRT even when f(2)>f(1), as long as f(1)>CV. (e) As beta gets closer to alpha, CV approaches its maximal value (infinity) and therefore, the chances of MRT>t(1/2) are growing. (f) As beta becomes smaller compared with alpha, beta/alpha approaches zero, the denominator approaches unity and consequently, CV gets its minimal value and thus, the chances of t(1/2)>MRT are growing. (g) Following zero and first order input MRT increases compared with i.v. bolus and so does CV and thus, the chances of MRT>t(1/2) are growing. Copyright 2004 John Wiley & Sons, Ltd.

  16. The Signal Transducer NPH3 Integrates the Phototropin1 Photosensor with PIN2-Based Polar Auxin Transport in Arabidopsis Root Phototropism[C][W

    PubMed Central

    Wan, Yinglang; Jasik, Jan; Wang, Li; Hao, Huaiqing; Volkmann, Dieter; Menzel, Diedrik; Mancuso, Stefano; Baluška, František; Lin, Jinxing

    2012-01-01

    Under blue light (BL) illumination, Arabidopsis thaliana roots grow away from the light source, showing a negative phototropic response. However, the mechanism of root phototropism is still unclear. Using a noninvasive microelectrode system, we showed that the BL sensor phototropin1 (phot1), the signal transducer NONPHOTOTROPIC HYPOCOTYL3 (NPH3), and the auxin efflux transporter PIN2 were essential for BL-induced auxin flux in the root apex transition zone. We also found that PIN2-green fluorescent protein (GFP) localized to vacuole-like compartments (VLCs) in dark-grown root epidermal and cortical cells, and phot1/NPH3 mediated a BL-initiated pathway that caused PIN2 redistribution to the plasma membrane. When dark-grown roots were exposed to brefeldin A (BFA), PIN2-GFP remained in VLCs in darkness, and BL caused PIN2-GFP disappearance from VLCs and induced PIN2-GFP-FM4-64 colocalization within enlarged compartments. In the nph3 mutant, both dark and BL BFA treatments caused the disappearance of PIN2-GFP from VLCs. However, in the phot1 mutant, PIN2-GFP remained within VLCs under both dark and BL BFA treatments, suggesting that phot1 and NPH3 play different roles in PIN2 localization. In conclusion, BL-induced root phototropism is based on the phot1/NPH3 signaling pathway, which stimulates the shootward auxin flux by modifying the subcellular targeting of PIN2 in the root apex transition zone. PMID:22374399

  17. Two compartment model of diazepam biotransformation in an organotypical culture of primary human hepatocytes

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Acikgoez, Ali; Department of Surgery, Universitaet Leipzig, Liebig Str. 20, D-04103 Leipzig; Karim, Najibulla

    2009-01-15

    Drug biotransformation is one of the most important parameters of preclinical screening tests for the registration of new drug candidates. Conventional existing tests rely on nonhuman models which deliver an incomplete metabolic profile of drugs due to the lack of proper CYP450 expression as seen in human liver in vivo. In order to overcome this limitation, we used an organotypical model of human primary hepatocytes for the biotransformation of the drug diazepam with special reference to metabolites in both the cell matrix phase and supernatant and its interaction of three inducers (phenobarbital, dexamethasone, aroclor 1254) in different time responses (1,more » 2, 4, 8, 24 h). Phenobarbital showed the strongest inducing effect in generating desmethyldiazepam and induced up to a 150 fold increase in oxazepam-content which correlates with the increased availability of the precursor metabolites (temazepam and desmethyldiazepam). Aroclor 1254 and dexamethasone had the strongest inducing effect on temazepam and the second strongest on oxazepam. The strong and overlapping inductive role of phenobarbital strengthens the participation of CYP2B6 and CYP3A in diazepam N-demethylation and CYP3A in temazepam formation. Aroclor 1254 preferentially generated temazepam due to the interaction with CYP3A and potentially CYP2C19. In parallel we represented these data in the form of a mathematical model with two compartments explaining the dynamics of diazepam metabolism with the effect of these other inducers in human primary hepatocytes. The model consists of ten differential equations, with one for each concentration c{sub i,j} (i = diazepam, temazepam, desmethyldiazepam, oxazepam, other metabolites) and one for each compartment (j = cell matrix phase, supernatant), respectively. The parameters p{sub k} (k = 1, 2, 3, 4, 13) are rate constants describing the biotransformation of diazepam and its metabolites and the other parameters (k = 5, 6, 7, 8, 9, 10, 11, 12, 14, 15) explain the concentration changes in the two compartments.« less

  18. Membrane Compartmentalization Reducing the Mobility of Lipids and Proteins within a Model Plasma Membrane.

    PubMed

    Koldsø, Heidi; Reddy, Tyler; Fowler, Philip W; Duncan, Anna L; Sansom, Mark S P

    2016-09-01

    The cytoskeleton underlying cell membranes may influence the dynamic organization of proteins and lipids within the bilayer by immobilizing certain transmembrane (TM) proteins and forming corrals within the membrane. Here, we present coarse-grained resolution simulations of a biologically realistic membrane model of asymmetrically organized lipids and TM proteins. We determine the effects of a model of cytoskeletal immobilization of selected membrane proteins using long time scale coarse-grained molecular dynamics simulations. By introducing compartments with varying degrees of restraints within the membrane models, we are able to reveal how compartmentalization caused by cytoskeletal immobilization leads to reduced and anomalous diffusional mobility of both proteins and lipids. This in turn results in a reduced rate of protein dimerization within the membrane and of hopping of membrane proteins between compartments. These simulations provide a molecular realization of hierarchical models often invoked to explain single-molecule imaging studies of membrane proteins.

  19. Modeling intrinsic electrophysiology of AII amacrine cells: preliminary results.

    PubMed

    Apollo, Nick; Grayden, David B; Burkitt, Anthony N; Meffin, Hamish; Kameneva, Tatiana

    2013-01-01

    In patients who have lost their photoreceptors due to retinal degenerative diseases, it is possible to restore rudimentary vision by electrically stimulating surviving neurons. AII amacrine cells, which reside in the inner plexiform layer, split the signal from rod bipolar cells into ON and OFF cone pathways. As a result, it is of interest to develop a computational model to aid in the understanding of how these cells respond to the electrical stimulation delivered by a prosthetic implant. The aim of this work is to develop and constrain parameters in a single-compartment model of an AII amacrine cell using data from whole-cell patch clamp recordings. This model will be used to explore responses of AII amacrine cells to electrical stimulation. Single-compartment Hodgkin-Huxley-type neural models are simulated in the NEURON environment. Simulations showed successful reproduction of the potassium currentvoltage relationship and some of the spiking properties observed in vitro.

  20. Compositional shifts in root-associated bacterial and archaeal microbiota track the plant life cycle in field-grown rice

    PubMed Central

    Edwards, Joseph A.; Santos-Medellín, Christian M.; Liechty, Zachary S.; Nguyen, Bao; Lurie, Eugene; Eason, Shane; Phillips, Gregory

    2018-01-01

    Bacterial communities associated with roots impact the health and nutrition of the host plant. The dynamics of these microbial assemblies over the plant life cycle are, however, not well understood. Here, we use dense temporal sampling of 1,510 samples from root spatial compartments to characterize the bacterial and archaeal components of the root-associated microbiota of field grown rice (Oryza sativa) over the course of 3 consecutive growing seasons, as well as 2 sites in diverse geographic regions. The root microbiota was found to be highly dynamic during the vegetative phase of plant growth and then stabilized compositionally for the remainder of the life cycle. Bacterial and archaeal taxa conserved between field sites were defined as predictive features of rice plant age by modeling using a random forest approach. The age-prediction models revealed that drought-stressed plants have developmentally immature microbiota compared to unstressed plants. Further, by using genotypes with varying developmental rates, we show that shifts in the microbiome are correlated with rates of developmental transitions rather than age alone, such that different microbiota compositions reflect juvenile and adult life stages. These results suggest a model for successional dynamics of the root-associated microbiota over the plant life cycle. PMID:29474469

  1. Compositional shifts in root-associated bacterial and archaeal microbiota track the plant life cycle in field-grown rice.

    PubMed

    Edwards, Joseph A; Santos-Medellín, Christian M; Liechty, Zachary S; Nguyen, Bao; Lurie, Eugene; Eason, Shane; Phillips, Gregory; Sundaresan, Venkatesan

    2018-02-01

    Bacterial communities associated with roots impact the health and nutrition of the host plant. The dynamics of these microbial assemblies over the plant life cycle are, however, not well understood. Here, we use dense temporal sampling of 1,510 samples from root spatial compartments to characterize the bacterial and archaeal components of the root-associated microbiota of field grown rice (Oryza sativa) over the course of 3 consecutive growing seasons, as well as 2 sites in diverse geographic regions. The root microbiota was found to be highly dynamic during the vegetative phase of plant growth and then stabilized compositionally for the remainder of the life cycle. Bacterial and archaeal taxa conserved between field sites were defined as predictive features of rice plant age by modeling using a random forest approach. The age-prediction models revealed that drought-stressed plants have developmentally immature microbiota compared to unstressed plants. Further, by using genotypes with varying developmental rates, we show that shifts in the microbiome are correlated with rates of developmental transitions rather than age alone, such that different microbiota compositions reflect juvenile and adult life stages. These results suggest a model for successional dynamics of the root-associated microbiota over the plant life cycle.

  2. [Modelling of phosphorus transfers during haemodialysis].

    PubMed

    Chazot, Guillaume; Lemoine, Sandrine; Juillard, Laurent

    2017-04-01

    Chronic kidney disease causes hyperphosphatemia, which is associated with increased cardiovascular risk and mortality. In patients with end-stage renal disease, haemodialysis allows the control of hyperphosphatemia. During a 4-h haemodialysis session, between 600 and 700mg of phosphate are extracted from the plasma, whereas the latter contains only 90mg of inorganic phosphate. The precise origin of phosphates remains unknown. The modelling of phosphorus transfers allows to predict the outcome after changes in dialysis prescription (duration, frequency) with simple two-compartment models and to describe the transfers between the different body compartments with more complex models. Work using 31 P nuclear magnetic resonance spectroscopy performed in animals showed an increase in intracellular phosphate concentration and a decrease in intracellular ATP during a haemodialysis session suggesting an intracellular origin of phosphates. Copyright © 2017. Published by Elsevier Masson SAS.

  3. Oscillations in epidemic models with spread of awareness.

    PubMed

    Just, Winfried; Saldaña, Joan; Xin, Ying

    2018-03-01

    We study ODE models of epidemic spreading with a preventive behavioral response that is triggered by awareness of the infection. Previous studies of such models have mostly focused on the impact of the response on the initial growth of an outbreak and the existence and location of endemic equilibria. Here we study the question whether this type of response is sufficient to prevent future flare-ups from low endemic levels if awareness is assumed to decay over time. In the ODE context, such flare-ups would translate into sustained oscillations with significant amplitudes. Our results show that such oscillations are ruled out in Susceptible-Aware-Infectious-Susceptible models with a single compartment of aware hosts, but can occur if we consider two distinct compartments of aware hosts who differ in their willingness to alert other susceptible hosts.

  4. Hepatic function imaging using dynamic Gd-EOB-DTPA enhanced MRI and pharmacokinetic modeling.

    PubMed

    Ning, Jia; Yang, Zhiying; Xie, Sheng; Sun, Yongliang; Yuan, Chun; Chen, Huijun

    2017-10-01

    To determine whether pharmacokinetic modeling parameters with different output assumptions of dynamic contrast-enhanced MRI (DCE-MRI) using Gd-EOB-DTPA correlate with serum-based liver function tests, and compare the goodness of fit of the different output assumptions. A 6-min DCE-MRI protocol was performed in 38 patients. Four dual-input two-compartment models with different output assumptions and a published one-compartment model were used to calculate hepatic function parameters. The Akaike information criterion fitting error was used to evaluate the goodness of fit. Imaging-based hepatic function parameters were compared with blood chemistry using correlation with multiple comparison correction. The dual-input two-compartment model assuming venous flow equals arterial flow plus portal venous flow and no bile duct output better described the liver tissue enhancement with low fitting error and high correlation with blood chemistry. The relative uptake rate Kir derived from this model was found to be significantly correlated with direct bilirubin (r = -0.52, P = 0.015), prealbumin concentration (r = 0.58, P = 0.015), and prothrombin time (r = -0.51, P = 0.026). It is feasible to evaluate hepatic function by proper output assumptions. The relative uptake rate has the potential to serve as a biomarker of function. Magn Reson Med 78:1488-1495, 2017. © 2016 International Society for Magnetic Resonance in Medicine. © 2016 International Society for Magnetic Resonance in Medicine.

  5. Oscillation mechanics of the respiratory system.

    PubMed

    Bates, Jason H T; Irvin, Charles G; Farré, Ramon; Hantos, Zoltán

    2011-07-01

    The mechanical impedance of the respiratory system defines the pressure profile required to drive a unit of oscillatory flow into the lungs. Impedance is a function of oscillation frequency, and is measured using the forced oscillation technique. Digital signal processing methods, most notably the Fourier transform, are used to calculate impedance from measured oscillatory pressures and flows. Impedance is a complex function of frequency, having both real and imaginary parts that vary with frequency in ways that can be used empirically to distinguish normal lung function from a variety of different pathologies. The most useful diagnostic information is gained when anatomically based mathematical models are fit to measurements of impedance. The simplest such model consists of a single flow-resistive conduit connecting to a single elastic compartment. Models of greater complexity may have two or more compartments, and provide more accurate fits to impedance measurements over a variety of different frequency ranges. The model that currently enjoys the widest application in studies of animal models of lung disease consists of a single airway serving an alveolar compartment comprising tissue with a constant-phase impedance. This model has been shown to fit very accurately to a wide range of impedance data, yet contains only four free parameters, and as such is highly parsimonious. The measurement of impedance in human patients is also now rapidly gaining acceptance, and promises to provide a more comprehensible assessment of lung function than parameters derived from conventional spirometry. © 2011 American Physiological Society.

  6. Quantification of Dynamic 11C-Phenytoin PET Studies.

    PubMed

    Mansor, Syahir; Boellaard, Ronald; Froklage, Femke E; Bakker, Esther D M; Yaqub, Maqsood; Voskuyl, Rob A; Schwarte, Lothar A; Verbeek, Joost; Windhorst, Albert D; Lammertsma, Adriaan

    2015-09-01

    The overexpression of P-glycoprotein (Pgp) is thought to be an important mechanism of pharmacoresistance in epilepsy. Recently, (11)C-phenytoin has been evaluated preclinically as a tracer for Pgp. The aim of the present study was to assess the optimal plasma kinetic model for quantification of (11)C-phenytoin studies in humans. Dynamic (11)C-phenytoin PET scans of 6 healthy volunteers with arterial sampling were acquired twice on the same day and analyzed using single- and 2-tissue-compartment models with and without a blood volume parameter. Global and regional test-retest (TRT) variability was determined for both plasma to tissue rate constant (K1) and volume of distribution (VT). According to the Akaike information criterion, the reversible single-tissue-compartment model with blood volume parameter was the preferred plasma input model. Mean TRT variability ranged from 1.5% to 16.9% for K1 and from 0.5% to 5.8% for VT. Larger volumes of interest showed better repeatabilities than smaller regions. A 45-min scan provided essentially the same K1 and VT values as a 60-min scan. A reversible single-tissue-compartment model with blood volume seems to be a good candidate model for quantification of dynamic (11)C-phenytoin studies. Scan duration may be reduced to 45 min without notable loss of accuracy and precision of both K1 and VT, although this still needs to be confirmed under pathologic conditions. © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.

  7. Modeling the effects of exercise during 100% oxygen prebreathe on the risk of hypobaric decompression sickness

    NASA Technical Reports Server (NTRS)

    Loftin, K. C.; Conkin, J.; Powell, M. R.

    1997-01-01

    BACKGROUND: Several previous studies indicated that exercise during prebreathe with 100% O2 decreased the incidence of hypobaric decompression sickness (DCS). We report a meta-analysis of these investigations combined with a new study in our laboratory to develop a statistical model as a predictive tool for DCS. HYPOTHESIS: Exercise during prebreathe increases N2 elimination in a theoretical 360-min half-time compartment decreasing the incidence of DCS. METHODS: A dose-response probability tissue ratio (TR) model with 95% confidence limits was created for two groups, prebreathe with exercise (n = 113) and resting prebreathe (n = 113), using nonlinear regression analysis with maximum likelihood optimization. RESULTS: The model predicted that prebreathe exercise would reduce the residual N2 in a 360-min half-time compartment to a level analogous to that in a 180-min compartment. This finding supported the hypothesis. The incidence of DCS for the exercise prebreathe group was significantly decreased (Chi-Square = 17.1, p < 0.0001) from the resting prebreathe group. CONCLUSIONS: The results suggested that exercise during prebreathe increases tissue perfusion and N2 elimination approximately 2-fold and markedly lowers the risk of DCS. Based on the model, the prebreathe duration may be reduced from 240 min to a predicted 91 min for the protocol in our study, but this remains to be verified. The model provides a useful planning tool to develop and test appropriate prebreathe exercise protocols and to predict DCS risks for astronauts.

  8. The Influence of Articular Cartilage Thickness Reduction on Meniscus Biomechanics

    PubMed Central

    Łuczkiewicz, Piotr; Daszkiewicz, Karol; Chróścielewski, Jacek; Witkowski, Wojciech; Winklewski, Pawel J.

    2016-01-01

    Objective Evaluation of the biomechanical interaction between meniscus and cartilage in medial compartment knee osteoarthritis. Methods The finite element method was used to simulate knee joint contact mechanics. Three knee models were created on the basis of knee geometry from the Open Knee project. We reduced the thickness of medial cartilages in the intact knee model by approximately 50% to obtain a medial knee osteoarthritis (OA) model. Two variants of medial knee OA model with congruent and incongruent contact surfaces were analysed to investigate the influence of congruency. A nonlinear static analysis for one compressive load case was performed. The focus of the study was the influence of cartilage degeneration on meniscal extrusion and the values of the contact forces and contact areas. Results In the model with incongruent contact surfaces, we observed maximal compressive stress on the tibial plateau. In this model, the value of medial meniscus external shift was 95.3% greater, while the contact area between the tibial cartilage and medial meniscus was 50% lower than in the congruent contact surfaces model. After the non-uniform reduction of cartilage thickness, the medial meniscus carried only 48.4% of load in the medial compartment in comparison to 71.2% in the healthy knee model. Conclusions We have shown that the change in articular cartilage geometry may significantly reduce the role of meniscus in load transmission and the contact area between the meniscus and cartilage. Additionally, medial knee OA may increase the risk of meniscal extrusion in the medial compartment of the knee joint. PMID:27936066

  9. A temporal model of cofilin regulation and the early peak of actin barbed ends in invasive tumor cells.

    PubMed

    Tania, Nessy; Prosk, Erin; Condeelis, John; Edelstein-Keshet, Leah

    2011-04-20

    Cofilin is an important regulator of actin polymerization, cell migration, and chemotaxis. Recent experimental data on mammary carcinoma cells reveal that stimulation by epidermal growth factor (EGF) generates a pool of active cofilin that results in a peak of actin filament barbed ends on the timescale of 1 min. Here, we present results of a mathematical model for the dynamics of cofilin and its transition between several pools in response to EGF stimulation. We describe the interactions of phospholipase C, membrane lipids (PIP(2)), and cofilin bound to PIP(2) and to F-actin, as well as diffusible cofilin in active G-actin-monomer-bound or phosphorylated states. We consider a simplified representation in which the thin cell edge (lamellipod) and the cell interior are represented by two compartments that are linked by diffusion. We demonstrate that a high basal level of active cofilin stored by binding to PIP(2), as well as the highly enriched local milieu of F-actin at the cell edge, is essential to capture the EGF-induced barbed-end amplification observed experimentally. Copyright © 2011 Biophysical Society. Published by Elsevier Inc. All rights reserved.

  10. A generic biokinetic model for carbon-14 labelled compounds

    NASA Astrophysics Data System (ADS)

    Manger, Ryan Paul

    Carbon-14, a radioactive nuclide, is used in many industrial applications. Due to its wide range of uses in industry, many workers are at risk of accidental internal exposure to 14C. Being a low energy beta emitter, 14C is not a significant external radiation hazard, but the internal consequences posed by 14C are important, especially because of its long half life of 5730 years [46]. The current biokinetic model recommended by the International Commission on Radiological Protection (ICRP) is a conservative estimate of how radiocarbon is treated by the human body. The ICRP generic radiocarbon model consists of a single compartment representing the entire human body. This compartment has a biological half life of 40 days yielding an effective dose coefficient of 5.8x10-10 Sv B q-1 [44, 45, 49, 53, 54]. This overestimates the dose of all radiocarbon compounds that have been studied [96]. An improved model has been developed that includes and alimentary tract, a urinary bladder, CO2 model, and an "Other" compartment used to model systemic tissues. The model can be adapted to replicate any excretion curve and excretion pattern. In addition, the effective dose coefficient produced by the updated model is near the mean effective dose coefficient of carbon compounds that have been considered in this research. The major areas of improvement are: more anatomically significant, a less conservative dose coefficient, and the ability to manipulate the model for known excretion data. Due to the wide variety of carbon compounds, it is suggested that specific biokinetic models be implemented for known radiocarbon substances. If the source of radiocarbon is dietary, then the physiologically based model proposed by Whillans [102] that splits all ingested radiocarbon compounds into carbohydrates, fats, and proteins should be used.

  11. Mechanism-based pharmacokinetic-pharmacodynamic modeling of the antinociceptive effect of buprenorphine in healthy volunteers.

    PubMed

    Yassen, Ashraf; Olofsen, Erik; Romberg, Raymonda; Sarton, Elise; Danhof, Meindert; Dahan, Albert

    2006-06-01

    The objective of this investigation was to characterize the pharmacokinetic-pharmacodynamic relation of buprenorphine's antinociceptive effect in healthy volunteers. Data on the time course of the antinociceptive effect after intravenous administration of 0.05-0.6 mg/70 kg buprenorphine in healthy volunteers was analyzed in conjunction with plasma concentrations by nonlinear mixed-effects analysis. A three-compartment pharmacokinetic model best described the concentration time course. Four structurally different pharmacokinetic-pharmacodynamic models were evaluated for their appropriateness to describe the time course of buprenorphine's antinociceptive effect: (1) E(max) model with an effect compartment model, (2) "power" model with an effect compartment model, (3) receptor association-dissociation model with a linear transduction function, and (4) combined biophase equilibration/receptor association-dissociation model with a linear transduction function. The latter pharmacokinetic-pharmacodynamic model described the time course of effect best and was used to explain time dependencies in buprenorphine's pharmacodynamics. The model converged, yielding precise estimation of the parameters characterizing hysteresis and the relation between relative receptor occupancy and antinociceptive effect. The rate constant describing biophase equilibration (k(eo)) was 0.00447 min(-1) (95% confidence interval, 0.00299-0.00595 min(-1)). The receptor dissociation rate constant (k(off)) was 0.0785 min(-1) (95% confidence interval, 0.0352-0.122 min(-1)), and k(on) was 0.0631 ml . ng(-1) . min(-1) (95% confidence interval, 0.0390-0.0872 ml . ng(-1) . min(-1)). This is consistent with observations in rats, suggesting that the rate-limiting step in the onset and offset of the antinociceptive effect is biophase distribution rather than slow receptor association-dissociation. In the dose range studied, no saturation of receptor occupancy occurred explaining the lack of a ceiling effect for antinociception.

  12. Modeling the pharmacokinetics of extended release pharmaceutical systems

    NASA Astrophysics Data System (ADS)

    di Muria, Michela; Lamberti, Gaetano; Titomanlio, Giuseppe

    2009-03-01

    The pharmacokinetic (PK) models predict the hematic concentration of drugs after the administration. In compartment modeling, the body is described by a set of interconnected “vessels” or “compartments”; the modeling consisting of transient mass balances. Usually the orally administered drugs were considered as immediately available: this cannot describe the administration of extended-release systems. In this work we added to the traditional compartment models the ability to account for a delay in administration, relating this delay to in vitro data. Firstly, the method was validated, applying the model to the dosage of nicotine by chewing-gum; the model was tuned by in vitro/in vivo data of drugs (divalproex-sodium and diltiazem) with medium-rate release kinetics, then it was applied in describing in vivo evolutions due to the assumption of fast- and slow-release systems. The model reveals itself predictive, the same of a Level A in vitro/in vivo correlation, but being physically based, it is preferable to a purely statistical method.

  13. Finite element analysis of unicompartmental knee arthroplasty.

    PubMed

    Hopkins, Andrew R; New, Andrew M; Rodriguez-y-Baena, Ferdinando; Taylor, Mark

    2010-01-01

    Concerns over accelerated damage to the untreated compartment of the knee following unicompartmental knee arthroplasty (UKA), as well as the relatively poor success rates observed for lateral as opposed to the medial arthroplasty, remain issues for attention. Finite element analysis (FEA) was used to assess changes to the kinematics and potential for cartilage damage across the knee joint in response to the implantation of the Oxford Mobile Bearing UKA. FE models of lateral and medial compartment arthroplasty were developed, in addition to a healthy natural knee model, to gauge changes incurred through the arthroplasty. Varus-valgus misalignments were introduced to the femoral components to simulate surgical inaccuracy or over-correction. Boundary conditions from the Stanmore knee simulator during the stance phase of level gait were used. AP translations of the tibia in the medial UKA models were comparable to the behaviour of the natural knee models (+/-0.6mm deviation from pre-operative motion). Following lateral UKA, 4.1mm additional posterior translation of the tibia was recorded than predicted for the natural knee. IE rotations of the medial UKA models were less consistent with the pre-operative knee model than the lateral UKA models (7.7 degrees vs. 3.6 degrees deviation). Varus misalignment of the femoral prosthesis was more influential than valgus for medial UKA kinematics, whereas in lateral UKA, a valgus misalignment of the femoral prosthesis was most influential on the kinematics. Resection of the cartilage in the medial compartment reduced the overall risk of progressive OA in the knee, whereas removing the cartilage from the lateral compartment, and in particular introducing a valgus femoral misalignment, increased the overall risk of progressive OA in the knee. Based on these results, under the conditions tested herein, both medial and lateral UKA can be said to induce kinematics of the knee which could be considered broadly comparable to those of the natural knee, and that even a 10 degrees varus-valgus misalignment of the femoral component may not induce highly irregular kinematics. However, elevated posterior translation of the tibia in lateral UKA and large excursions of the insert may explain the higher incidence of bearing dislocation observed in some clinical studies. (c) 2009 IPEM. All rights reserved.

  14. Comparing models for perfluorooctanoic acid pharmacokinetics using Bayesian analysis

    EPA Science Inventory

    Selecting the appropriate pharmacokinetic (PK) model given the available data is investigated for perfluorooctanoic acid (PFOA), which has been widely analyzed with an empirical, one-compartment model. This research examined the results of experiments [Kemper R. A., DuPont Haskel...

  15. A PHYSIOLOGICALLY BASED TOXICOKINETIC MODEL FOR LAKE TROUT (SALVELINUS NAMAYCUSH)

    EPA Science Inventory

    A physiologically based toxicokinetic (PB-TK) model for fish, incorporating chemical exchange at the gill and accumulation in five tissue compartments, was used to examine the effect of natural variability in physiological, morphological, and physico-chemical parameters on model ...

  16. Inferring rules of lineage commitment in haematopoiesis.

    PubMed

    Pina, Cristina; Fugazza, Cristina; Tipping, Alex J; Brown, John; Soneji, Shamit; Teles, Jose; Peterson, Carsten; Enver, Tariq

    2012-02-19

    How the molecular programs of differentiated cells develop as cells transit from multipotency through lineage commitment remains unexplored. This reflects the inability to access cells undergoing commitment or located in the immediate vicinity of commitment boundaries. It remains unclear whether commitment constitutes a gradual process, or else represents a discrete transition. Analyses of in vitro self-renewing multipotent systems have revealed cellular heterogeneity with individual cells transiently exhibiting distinct biases for lineage commitment. Such systems can be used to molecularly interrogate early stages of lineage affiliation and infer rules of lineage commitment. In haematopoiesis, population-based studies have indicated that lineage choice is governed by global transcriptional noise, with self-renewing multipotent cells reversibly activating transcriptome-wide lineage-affiliated programs. We examine this hypothesis through functional and molecular analysis of individual blood cells captured from self-renewal cultures, during cytokine-driven differentiation and from primary stem and progenitor bone marrow compartments. We show dissociation between self-renewal potential and transcriptome-wide activation of lineage programs, and instead suggest that multipotent cells experience independent activation of individual regulators resulting in a low probability of transition to the committed state.

  17. Near Infra-Red Spectroscopy to Reduce Prophylactic Fasciotomies for and Missed Cases of Acute Compartment Syndrome in Soldiers Injured in OEF/OIF

    DTIC Science & Technology

    2013-10-01

    demonstrated that NIRS measurement of hemoglobin oxygen saturation in the tibial compartment provided reliable and sensitive correlation to increases...on 60 healthy participants. Our results indicated that NIRS was able to detect changes in oxygen saturation of muscle with exercise in all 60...Model 41 Introduction 42 Over the last two decades, tissue oxygenation saturation (StO2) measured by near infrared 43 spectroscopy (NIRS) has

  18. Reinforcing properties of the substance P C-fragment analog DiMe-C7 in Carassius auratus.

    PubMed

    Mattioli, R; Coelho, J; Martins, A

    1996-04-01

    The aim of the present study was to investigate whether two substance P (SP) fragments have reinforcing effects in Carassius auratus when the fish were tested in a place-preference experimental model. Fish were placed in a 3-compartment box in which one compartment gives access to two others that are not connected. The time spent in each compartment was recorded for 10 min in order to determine which one was preferred. Twenty-four hours later the fish were given one of the following ip treatments: 1) group VEH (N = 12), injected with teleost saline, 2) group DiMe-C7 (N = 12), injected with 33 micrograms/kg DiMe-C7, and 3) group SP1-7 (N = 12), injected with 167 micrograms/kg SP1-7. Immediately after treatment the fish were kept for 30 min in the compartment that was the least preferred on the day before and this procedure was repeated for 3 days. On the fifth day the fish were retested for 10 min to determine the time spent in each compartment. Two-way analysis of variance with treatments and testing as factors indicated a main effect (P < 0.0025) as well as a testing effect (P < 0.009). The post-hoc Scheffé multiple comparison test indicated that only the DiMe-C7 group presented an increase in the time spent in the paired compartment after treatment. We suggest that the C-terminal fragment of SP has reinforcing effects in Carassius auratus.

  19. Design/Development of Spacecraft and Module Crew Compartments

    NASA Technical Reports Server (NTRS)

    Goodman, Jerry R.

    2010-01-01

    This slide presentation reviews the design and development of crew compartments for spacecraft and for modules. The Crew Compartment or Crew Station is defined as the spacecraft interior and all other areas the crewman interfaces inside the cabin, or may potentially interface.It uses examples from all of the human rated spacecraft. It includes information about the process, significant drivers for the design, habitability, definitions of models, mockups, prototypes and trainers, including pictures of each stage in the development from Apollo, pictures of the space shuttle trainers, and International Space Station trainers. It further reviews the size and shape of the Space Shuttle orbiter crew compartment, and the Apollo command module and the lunar module. It also has a chart which reviews the International Space Station (ISS) internal volume by stage. The placement and use of windows is also discussed. Interestingly according to the table presented, the number 1 rated piece of equipment for recreation was viewing windows. The design of crew positions and restraints, crew translation aids and hardware restraints is shown with views of the restraints and handholds used from the Apollo program through the ISS.

  20. Morphological and quantitative changes in mitochondria, plastids, and peroxisomes during the log-to-stationary transition of the growth phase in cultured tobacco BY-2 cells.

    PubMed

    Toyooka, Kiminori; Sato, Mayuko; Wakazaki, Mayumi; Matsuoka, Ken

    2016-01-01

    We developed a wide-range and high-resolution transmission electron microscope acquisition system and obtained giga-pixel images of tobacco BY-2 cells during the log and stationary phases of cell growth. We demonstrated that the distribution and ultrastructure of compartments involved in membrane traffic (i.e., Golgi apparatus, multivesicular body, and vesicle cluster) change during the log-to-stationary transition. Mitochondria, peroxisomes, and plastids were also enumerated. Electron densities of mitochondria and peroxisomes were altered during the growth-phase shift, while their numbers were reduced by nearly half. Plastid structure dramatically changed from atypical to spherical with starch granules. Nearly the same number of plastids was observed in both log and stationary phases. These results indicate that mechanisms regulating organelle populations differ from organelle to organelle.

  1. Uncertainty quantification in flux balance analysis of spatially lumped and distributed models of neuron-astrocyte metabolism.

    PubMed

    Calvetti, Daniela; Cheng, Yougan; Somersalo, Erkki

    2016-12-01

    Identifying feasible steady state solutions of a brain energy metabolism model is an inverse problem that allows infinitely many solutions. The characterization of the non-uniqueness, or the uncertainty quantification of the flux balance analysis, is tantamount to identifying the degrees of freedom of the solution. The degrees of freedom of multi-compartment mathematical models for energy metabolism of a neuron-astrocyte complex may offer a key to understand the different ways in which the energetic needs of the brain are met. In this paper we study the uncertainty in the solution, using techniques of linear algebra to identify the degrees of freedom in a lumped model, and Markov chain Monte Carlo methods in its extension to a spatially distributed case. The interpretation of the degrees of freedom in metabolic terms, more specifically, glucose and oxygen partitioning, is then leveraged to derive constraints on the free parameters to guarantee that the model is energetically feasible. We demonstrate how the model can be used to estimate the stoichiometric energy needs of the cells as well as the household energy based on the measured oxidative cerebral metabolic rate of glucose and glutamate cycling. Moreover, our analysis shows that in the lumped model the net direction of lactate dehydrogenase (LDH) in the cells can be deduced from the glucose partitioning between the compartments. The extension of the lumped model to a spatially distributed multi-compartment setting that includes diffusion fluxes from capillary to tissue increases the number of degrees of freedom, requiring the use of statistical sampling techniques. The analysis of the distributed model reveals that some of the conclusions valid for the spatially lumped model, e.g., concerning the LDH activity and glucose partitioning, may no longer hold.

  2. Polarity and transport properties of rabbit kidney proximal tubule cells on collagen IV-coated porous membranes.

    PubMed

    Genestie, I; Morin, J P; Vannier, B; Lorenzon, G

    1995-07-01

    A high degree of functional polarity has been obtained in primary cultures of rabbit kidney proximal tubule cells grown on collagen IV-coated porous membranes. Tight confluency was attained 6 days after seeding and maintained for at least 6 more days, as shown by analysis of paracellular inulin diffusion. From day 6 onward, L-lactate, ammonia, and D-glucose concentration gradient and a pH difference of approximately 1 unit developed between the two nutrient medium compartments. Confluent monolayers expressed organic ion transport properties higher than those formerly reported for other cell models. Transcellular transport of 20 microM tetraethylammonium was directed from basal to apical compartment and was specifically inhibited by mepiperphenidol (1 mM). Unidirectional transport of 2.4 microM p-aminohippurate also occurred from basal to apical compartment, was saturable, and specifically inhibited by probenecid (1 mM). These results suggest that rabbit kidney proximal tubule cells, cultured under the experimental conditions described here, may be a useful model for the in vitro study of highly polarized renal transport processes.

  3. Comparison of multiple methods to measure maternal fat mass in late gestation12

    PubMed Central

    Marshall, Nicole E; Murphy, Elizabeth J; King, Janet C; Haas, E Kate; Lim, Jeong Y; Wiedrick, Jack; Thornburg, Kent L; Purnell, Jonathan Q

    2016-01-01

    Background: Measurements of maternal fat mass (FM) are important for studies of maternal and fetal health. Common methods of estimating FM have not been previously compared in pregnancy with measurements using more complete body composition models. Objectives: The goal of this pilot study was to compare multiple methods that estimate FM, including 2-, 3- and 4-compartment models in pregnant women at term, and to determine how these measures compare with FM by dual-energy X-ray absorptiometry (DXA) 2 wk postpartum. Design: Forty-one healthy pregnant women with prepregnancy body mass index (in kg/m2) 19 to 46 underwent skinfold thickness (SFT), bioelectrical impedance analysis (BIA), body density (Db) via air displacement plethysmography (ADP), and deuterium dilution of total body water (TBW) with and without adjustments for gestational age using van Raaij (VRJ) equations at 37–38 wk of gestation and 2 wk postpartum to derive 8 estimates of maternal FM. Deming regression analysis and Bland-Altman plots were used to compare methods of FM assessment. Results: Systematic differences in FM estimates were found. Methods for FM estimates from lowest to highest were 4-compartment, DXA, TBW(VRJ), 3-compartment, Db(VRJ), BIA, air displacement plethysmography body density, and SFT ranging from a mean ± SD of 29.5 ± 13.2 kg via 4-compartment to 39.1 ± 11.7 kg via SFT. Compared with postpartum DXA values, Deming regressions revealed no substantial departures from trend lines in maternal FM in late pregnancy for any of the methods. The 4-compartment method showed substantial negative (underestimating) constant bias, and the air displacement plethysmography body density and SFT methods showed positive (overestimating) constant bias. ADP via Db(VRJ) and 3-compartment methods had the highest precision; BIA had the lowest. Conclusions: ADP that uses gestational age-specific equations may provide a reasonable and practical measurement of maternal FM across a spectrum of body weights in late pregnancy. SFT would be acceptable for use in larger studies. This trial was registered at clinicaltrials.gov as NCT02586714. PMID:26888714

  4. Integrating microbial diversity in soil carbon dynamic models parameters

    NASA Astrophysics Data System (ADS)

    Louis, Benjamin; Menasseri-Aubry, Safya; Leterme, Philippe; Maron, Pierre-Alain; Viaud, Valérie

    2015-04-01

    Faced with the numerous concerns about soil carbon dynamic, a large quantity of carbon dynamic models has been developed during the last century. These models are mainly in the form of deterministic compartment models with carbon fluxes between compartments represented by ordinary differential equations. Nowadays, lots of them consider the microbial biomass as a compartment of the soil organic matter (carbon quantity). But the amount of microbial carbon is rarely used in the differential equations of the models as a limiting factor. Additionally, microbial diversity and community composition are mostly missing, although last advances in soil microbial analytical methods during the two past decades have shown that these characteristics play also a significant role in soil carbon dynamic. As soil microorganisms are essential drivers of soil carbon dynamic, the question about explicitly integrating their role have become a key issue in soil carbon dynamic models development. Some interesting attempts can be found and are dominated by the incorporation of several compartments of different groups of microbial biomass in terms of functional traits and/or biogeochemical compositions to integrate microbial diversity. However, these models are basically heuristic models in the sense that they are used to test hypotheses through simulations. They have rarely been confronted to real data and thus cannot be used to predict realistic situations. The objective of this work was to empirically integrate microbial diversity in a simple model of carbon dynamic through statistical modelling of the model parameters. This work is based on available experimental results coming from a French National Research Agency program called DIMIMOS. Briefly, 13C-labelled wheat residue has been incorporated into soils with different pedological characteristics and land use history. Then, the soils have been incubated during 104 days and labelled and non-labelled CO2 fluxes have been measured at ten sampling time in order to follow the dynamic of residue and soil organic matter mineralization. Diversity, structure and composition of microbial communities have been characterized before incubation time. The dynamic of carbon fluxes through CO2 emissions has been modelled through a simple model. Using statistical tools, relations between parameters of the model and microbial diversity indexes and/or pedological characteristics have been developed and integrated to the model. First results show that global diversity has an impact on the models parameters. Moreover, larger fungi diversity seems to lead to larger parameters representing decomposition rates and/or carbon use efficiencies than bacterial diversity. Classically, pedological factors such as soil pH and texture must also be taken into account.

  5. Developing a physiologically based approach for modeling plutonium decorporation therapy with DTPA.

    PubMed

    Kastl, Manuel; Giussani, Augusto; Blanchardon, Eric; Breustedt, Bastian; Fritsch, Paul; Hoeschen, Christoph; Lopez, Maria Antonia

    2014-11-01

    To develop a physiologically based compartmental approach for modeling plutonium decorporation therapy with the chelating agent Diethylenetriaminepentaacetic acid (Ca-DTPA/Zn-DTPA). Model calculations were performed using the software package SAAM II (©The Epsilon Group, Charlottesville, Virginia, USA). The Luciani/Polig compartmental model with age-dependent description of the bone recycling processes was used for the biokinetics of plutonium. The Luciani/Polig model was slightly modified in order to account for the speciation of plutonium in blood and for the different affinities for DTPA of the present chemical species. The introduction of two separate blood compartments, describing low-molecular-weight complexes of plutonium (Pu-LW) and transferrin-bound plutonium (Pu-Tf), respectively, and one additional compartment describing plutonium in the interstitial fluids was performed successfully. The next step of the work is the modeling of the chelation process, coupling the physiologically modified structure with the biokinetic model for DTPA. RESULTS of animal studies performed under controlled conditions will enable to better understand the principles of the involved mechanisms.

  6. Starling forces drive intracranial water exchange during normal and pathological states

    PubMed Central

    Linninger, Andreas A.; Xu, Colin; Tangen, Kevin; Hartung, Grant

    2017-01-01

    Aim To quantify the exchange of water between cerebral compartments, specifically blood, tissue, perivascular pathways, and cerebrospinal fluid-filled spaces, on the basis of experimental data and to propose a dynamic global model of water flux through the entire brain to elucidate functionally relevant fluid exchange phenomena. Methods The mechanistic computer model to predict brain water shifts is discretized by cerebral compartments into nodes. Water and species flux is calculated between these nodes across a network of arcs driven by Hagen-Poiseuille flow (blood), Darcy flow (interstitial fluid transport), and Starling’s Law (transmembrane fluid exchange). Compartment compliance is accounted for using a pressure-volume relationship to enforce the Monro-Kellie doctrine. This nonlinear system of differential equations is solved implicitly using MATLAB software. Results The model predictions of intraventricular osmotic injection caused a pressure rise from 10 to 22 mmHg, followed by a taper to 14 mmHg over 100 minutes. The computational results are compared to experimental data with R2 = 0.929. Moreover, simulated osmotic therapy of systemic (blood) injection reduced intracranial pressure from 25 to 10 mmHg. The modeled volume and intracranial pressure changes following cerebral edema agree with experimental trends observed in animal models with R2 = 0.997. Conclusion The model successfully predicted time course and the efficacy of osmotic therapy for clearing cerebral edema. Furthermore, the mathematical model implicated the perivascular pathways as a possible conduit for water and solute exchange. This was a first step to quantify fluid exchange throughout the brain. PMID:29308830

  7. Investigation of tDCS volume conduction effects in a highly realistic head model

    NASA Astrophysics Data System (ADS)

    Wagner, S.; Rampersad, S. M.; Aydin, Ü.; Vorwerk, J.; Oostendorp, T. F.; Neuling, T.; Herrmann, C. S.; Stegeman, D. F.; Wolters, C. H.

    2014-02-01

    Objective. We investigate volume conduction effects in transcranial direct current stimulation (tDCS) and present a guideline for efficient and yet accurate volume conductor modeling in tDCS using our newly-developed finite element (FE) approach. Approach. We developed a new, accurate and fast isoparametric FE approach for high-resolution geometry-adapted hexahedral meshes and tissue anisotropy. To attain a deeper insight into tDCS, we performed computer simulations, starting with a homogenized three-compartment head model and extending this step by step to a six-compartment anisotropic model. Main results. We are able to demonstrate important tDCS effects. First, we find channeling effects of the skin, the skull spongiosa and the cerebrospinal fluid compartments. Second, current vectors tend to be oriented towards the closest higher conducting region. Third, anisotropic WM conductivity causes current flow in directions more parallel to the WM fiber tracts. Fourth, the highest cortical current magnitudes are not only found close to the stimulation sites. Fifth, the median brain current density decreases with increasing distance from the electrodes. Significance. Our results allow us to formulate a guideline for volume conductor modeling in tDCS. We recommend to accurately model the major tissues between the stimulating electrodes and the target areas, while for efficient yet accurate modeling, an exact representation of other tissues is less important. Because for the low-frequency regime in electrophysiology the quasi-static approach is justified, our results should also be valid for at least low-frequency (e.g., below 100 Hz) transcranial alternating current stimulation.

  8. A Physiologically Based Model for Methylmercury in Female American Kestrels

    EPA Science Inventory

    A physiologically based toxicokinetic (PBTK) model was developed to describe the uptake, distribution, and elimination of methylmercury (CH3Hg) in female American kestrels. The model consists of six tissue compartments corresponding to the brain, liver, kidney, gut, red blood cel...

  9. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis.

    PubMed

    Loor, Gabriel; Kondapalli, Jyothisri; Schriewer, Jacqueline M; Chandel, Navdeep S; Vanden Hoek, Terry L; Schumacker, Paul T

    2010-12-15

    Low levels of reactive oxygen species (ROS) can function as redox-active signaling messengers, whereas high levels of ROS induce cellular damage. Menadione generates ROS through redox cycling, and high concentrations trigger cell death. Previous work suggests that menadione triggers cytochrome c release from mitochondria, whereas other studies implicate the activation of the mitochondrial permeability transition pore as the mediator of cell death. We investigated menadione-induced cell death in genetically modified cells lacking specific death-associated proteins. In cardiomyocytes, oxidant stress was assessed using the redox sensor RoGFP, expressed in the cytosol or the mitochondrial matrix. Menadione elicited rapid oxidation in both compartments, whereas it decreased mitochondrial potential and triggered cytochrome c redistribution to the cytosol. Cell death was attenuated by N-acetylcysteine and exogenous glutathione or by overexpression of cytosolic or mitochondria-targeted catalase. By contrast, no protection was observed in cells overexpressing Cu,Zn-SOD or Mn-SOD. Overexpression of antiapoptotic Bcl-X(L) protected against staurosporine-induced cell death, but it failed to confer protection against menadione. Genetic deletion of Bax and Bak, cytochrome c, cyclophilin D, or caspase-9 conferred no protection against menadione-induced cell death. However, cells lacking PARP-1 showed a significant decrease in menadione-induced cell death. Thus, menadione induces cell death through the generation of oxidant stress in multiple subcellular compartments, yet cytochrome c, Bax/Bak, caspase-9, and cyclophilin D are dispensable for cell death in this model. These studies suggest that multiple redundant cell death pathways are activated by menadione, but that PARP plays an essential role in mediating each of them. Copyright © 2010 Elsevier Inc. All rights reserved.

  10. Menadione triggers cell death through ROS-dependent mechanisms involving PARP activation without requiring apoptosis

    PubMed Central

    Loor, Gabriel; Kondapalli, Jyothisri; Schriewer, Jacqueline M.; Chandel, Navdeep S.; Vanden Hoek, Terry L.; Schumacker, Paul T.

    2010-01-01

    Low levels of reactive oxygen species (ROS) can function as redox-active signaling messengers, whereas high levels of ROS induce cellular damage. Menadione generates ROS through redox cycling, and high concentrations trigger cell death. Previous work suggests that menadione triggers cytochrome c release from mitochondria, while other studies implicate activation of the mitochondrial permeability transition poreas the mediator of cell death. We investigated menadione-induced cell death in genetically modified cells lacking specific death-associated proteins. In cardiomyocytes, oxidant stress was assessed using the redox sensor RoGFP, expressed in the cytosol or the mitochondrial matrix. Menadione elicited rapid oxidation in both compartments, while it decreased mitochondrial potential and triggered cytochrome c redistribution to the cytosol. Cell death was attenuated by N-acetyl cysteine and exogenous glutathione (GSH), or by over-expression of cytosolic or mitochondria-targeted catalase. By contrast, no protection was observed in cells over-expressing Cu, Zn-SOD or MnSOD. Over-expression of antiapoptotic Bcl-XLprotected against staurosporine-induced cell death, but it failed to confer protection against menadione. Genetic deletion of Bax and Bak, cytochrome c, cyclophilin D or caspase-9 conferred no protection against menadione-induced cell death. However, cells lacking PARP-1 showed a significant decrease in menadione-induced cell death. Thus, menadione induces cell death through the generation of oxidant stress in multiple subcellular compartments, yet cytochromec, Bax/Bak, caspase-9 and cyclophilin D are dispensable for cell death in this model. These studies suggest that multiple redundant cell death pathways are activated by menadione, but that PARP plays an essential role in mediating each of them. PMID:20937380

  11. Whole transcriptome profiling of patient-derived xenograft models as a tool to identify both tumor and stromal specific biomarkers.

    PubMed

    Bradford, James R; Wappett, Mark; Beran, Garry; Logie, Armelle; Delpuech, Oona; Brown, Henry; Boros, Joanna; Camp, Nicola J; McEwen, Robert; Mazzola, Anne Marie; D'Cruz, Celina; Barry, Simon T

    2016-04-12

    The tumor microenvironment is emerging as a key regulator of cancer growth and progression, however the exact mechanisms of interaction with the tumor are poorly understood. Whilst the majority of genomic profiling efforts thus far have focused on the tumor, here we investigate RNA-Seq as a hypothesis-free tool to generate independent tumor and stromal biomarkers, and explore tumor-stroma interactions by exploiting the human-murine compartment specificity of patient-derived xenografts (PDX).Across a pan-cancer cohort of 79 PDX models, we determine that mouse stroma can be separated into distinct clusters, each corresponding to a specific stromal cell type. This implies heterogeneous recruitment of mouse stroma to the xenograft independent of tumor type. We then generate cross-species expression networks to recapitulate a known association between tumor epithelial cells and fibroblast activation, and propose a potentially novel relationship between two hypoxia-associated genes, human MIF and mouse Ddx6. Assessment of disease subtype also reveals MMP12 as a putative stromal marker of triple-negative breast cancer. Finally, we establish that our ability to dissect recruited stroma from trans-differentiated tumor cells is crucial to identifying stem-like poor-prognosis signatures in the tumor compartment.In conclusion, RNA-Seq is a powerful, cost-effective solution to global analysis of human tumor and mouse stroma simultaneously, providing new insights into mouse stromal heterogeneity and compartment-specific disease markers that are otherwise overlooked by alternative technologies. The study represents the first comprehensive analysis of its kind across multiple PDX models, and supports adoption of the approach in pre-clinical drug efficacy studies, and compartment-specific biomarker discovery.

  12. An electrical description of the generation of slow waves in the antrum of the guinea-pig

    PubMed Central

    Edwards, FR; Hirst, GDS

    2005-01-01

    This paper provides an electrical description of the generation of slow waves in the guinea-pig gastric antrum. A short segment of a circular smooth muscle bundle with an attached network of myenteric interstitial cells of Cajal (ICC-MY) and longitudinal muscle sheet was modelled as three electrical compartments with resistive connexions between the ICC-MY compartment and each of the smooth muscle compartments. The circular smooth muscle layer contains a proportion of intramuscular interstitial cells of Cajal (ICC-IM), responsible for the regenerative component of the slow wave. Hence the equivalent cell representing the circular muscle layer incorporated a mechanism, modelled as a two stage reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley. A similar mechanism was incorporated into the equivalent cell describing the ICC-MY network. Spontaneous discrete transient depolarizations, termed unitary potentials, are detected in records taken from either bundles of circular smooth muscle containing ICC-IM or from ICC-MY. In the simulation the mean rate of discharge of unitary potentials was allowed to vary with the concentration of messenger according to a conventional dose–effect relationship. Such a mechanism, which describes regenerative potentials generated by the circular muscle layer, also simulated the plateau component of the pacemaker potential in the ICC-MY network. A voltage-sensitive membrane conductance was included in the ICC-MY compartment; this was used to describe the primary component of the pacemaker potential. The model generates a range of membrane potential changes with properties similar to those generated by the three cell types present in the intact tissue. PMID:15613372

  13. Neuromuscular partitioning in the extensor carpi radialis longus and brevis based on intramuscular nerve distribution patterns: A three-dimensional modeling study.

    PubMed

    Ravichandiran, Mayoorendra; Ravichandiran, Nisanthini; Ravichandiran, Kajeandra; McKee, Nancy H; Richardson, Denyse; Oliver, Michele; Agur, Anne M

    2012-04-01

    Differential activation of specific regions within a skeletal muscle has been linked to the presence of neuromuscular compartments. However, few studies have investigated the extra- or intramuscular innervation throughout the muscle volume of extensor carpi radialis longus (ECRL) and brevis (ECRB). The aim of this study was to determine the presence of neuromuscular partitions in ECRL and ECRB based on the extra- and intramuscular innervation using three-dimensional modeling. The extra- and intramuscular nerve distribution was digitized and reconstructed in 3D in all the muscle volumes using Autodesk Maya in seven formalin embalmed cadaveric specimens (mean age, 75.7 ± 15.2 years). The intramuscular nerve distribution was modeled in all the muscle volumes. ECRL was found to have two neuromuscular compartments, superficial and deep. One branch from the radial nerve proper was found to innervate ECRL. This branch was divided into anterior and posterior branches to the superficial and deep compartments, respectively. Five innervation patterns were identified in ECRB with partitioning of the muscle belly into two, three, or four compartments, in a proximal to distal direction depending on the number of nerve branches entering the muscle belly. The ECRL and ECRB both demonstrated neuromuscular compartmentalization based on intramuscular innervation. According to the partitioning hypothesis, a muscle may be differentially activated depending on the required function of the muscle, thus allowing multifunctional muscles to contribute to a variety of movements. Therefore, the increased number of neuromuscular partitions in ECRB when compared with ECRL could be due to the need for more differential recruitment in the ECRB depending on force requirements. Copyright © 2011 Wiley Periodicals, Inc.

  14. Multimedia fate modeling and risk assessment of a commonly used azole fungicide climbazole at the river basin scale in China.

    PubMed

    Zhang, Qian-Qian; Ying, Guang-Guo; Chen, Zhi-Feng; Liu, You-Sheng; Liu, Wang-Rong; Zhao, Jian-Liang

    2015-07-01

    Climbazole is an antidandruff active ingredient commonly used in personal care products, but little is known about its environmental fate. The aim of this study was to evaluate the fate of climbazole in water, sediment, soil and air compartments of the whole China by using a level III multimedia fugacity model. The usage of climbazole was calculated to be 345 t in the whole China according to the market research data, and after wastewater treatment a total emission of 245 t was discharged into the receiving environment with approximately 93% into the water compartment and 7% into the soil compartment. The developed fugacity model was successfully applied to estimate the contamination levels and mass inventories of climbazole in various environmental compartments of the river basins in China. The predicted environmental concentration ranges of climbazole were: 0.20-367 ng/L in water, and 0.009-25.2 ng/g dry weight in sediment. The highest concentration was mainly found in Haihe River basin and the lowest was in basins of Tibet and Xinjiang regions. The mass inventory of climbazole in the whole China was estimated to be 294 t, with 6.79% in water, 83.7% in sediment, 9.49% in soil, and 0.002% in air. Preliminary risk assessment showed high risks in sediment posed by climbazole in 2 out of 58 basins in China. The medium risks in water and sediment were mostly concentrated in north China. To the best of our knowledge, it is the first report on the emissions and multimedia fate of climbazole in the river basins of the whole China. Copyright © 2015 Elsevier B.V. All rights reserved.

  15. Image-based evaluations of distribution and cytotoxicity of Irinotecan (CPT-11) in a multi-compartment micro-cell coculture device.

    PubMed

    Nakayama, Hidenari; Kimura, Hiroshi; Fujii, Teruo; Sakai, Yasuyuki

    2014-06-01

    We recently developed a polydimethylsiloxane (PDMS)-based three-compartment microfluidic cocultivation device enabling real-time interactions of different cell populations as an advanced physiologically-relevant cell-based assay. This device had valves and small magnetic stirrer-based internal pumps for easy and flexible perfusion operations. In this study, we applied this device for the evaluation of Irinotecan (CPT-11) toxicity to the lung, because it is detoxified by the liver and accumulated in the fat in humans. We successfully cultured representative three different tissue model cells in each compartment under the individual culture conditions and also in entire perfusion. Growth inhibition of rat lung epithelial cell line L-2, was measured when administered with 50 μM CPT-11 under various cocultivation conditions with respect to the presences and absence of primary rat hepatocytes (liver tissue model) and adipocyte-like cells (fat tissue model) induced from a mouse fibroblast cell line, 3T3-L1. Although CPT-11 showed moderate toxicity to the pure culture of L-2 cells in the device after 72 h of perfusion culture, this was lowered mainly in the presence of the liver tissue. Inhibition of the L-2 cell growth agreed with the area under curve (AUC) values obtained from fluorescent image-based analyses in each compartment. These results demonstrate that developed simple and flexible microfluidic cocultivation device, with appropriate image-based analyses, can be used in evaluating toxicokinetic behaviors of drug candidates in systemic levels. Copyright © 2013 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.

  16. Population Pharmacokinetics and Exploratory Pharmacodynamics of Lorazepam in Pediatric Status Epilepticus.

    PubMed

    Gonzalez, Daniel; Chamberlain, James M; Guptill, Jeffrey T; Cohen-Wolkowiez, Michael; Harper, Barrie; Zhao, Jian; Capparelli, Edmund V

    2017-08-01

    Lorazepam is one of the preferred agents used for intravenous treatment of status epilepticus (SE). We combined data from two pediatric clinical trials to characterize the population pharmacokinetics of intravenous lorazepam in infants and children aged 3 months to 17 years with active SE or a history of SE. We developed a population pharmacokinetic model for lorazepam using the NONMEM software. We then assessed exploratory exposure-response relationships using the overall efficacy and safety study endpoints, and performed dosing simulations. A total of 145 patients contributed 439 pharmacokinetic samples. The median (range) age and dose were 5.4 years (0.3-17.8) and 0.10 mg/kg (0.02-0.18), respectively. A two-compartment pharmacokinetic model with allometric scaling described the data well. In addition to total body weight (WT), younger age was associated with slightly higher weight-normalized clearance (CL). The following relationships characterized the typical values for the central compartment volume (V1), CL, peripheral compartment volume (V2), and intercompartmental CL (Q), using individual subject WT (kg) and age (years): V1 (L) = 0.879*WT; CL (L/h) = 0.115*(Age/4.7) 0.133 *WT 0.75 ; V2 (L) = 0.542*V1; Q (L/h) = 1.45*WT 0.75 . No pharmacokinetic parameters were associated with clinical outcomes. Simulations suggest uniform pediatric dosing (0.1 mg/kg, to a maximum of 4 mg) can be used to achieve concentrations of 50-100 ng/mL in children with SE, which have been previously associated with effective seizure control. The population pharmacokinetics of lorazepam were successfully described using a sparse sampling approach and a two-compartment model in pediatric patients with active SE.

  17. Dynamic 99mTc-MAG3 renography: images for quality control obtained by combining pharmacokinetic modelling, an anthropomorphic computer phantom and Monte Carlo simulated scintillation camera imaging

    NASA Astrophysics Data System (ADS)

    Brolin, Gustav; Sjögreen Gleisner, Katarina; Ljungberg, Michael

    2013-05-01

    In dynamic renal scintigraphy, the main interest is the radiopharmaceutical redistribution as a function of time. Quality control (QC) of renal procedures often relies on phantom experiments to compare image-based results with the measurement setup. A phantom with a realistic anatomy and time-varying activity distribution is therefore desirable. This work describes a pharmacokinetic (PK) compartment model for 99mTc-MAG3, used for defining a dynamic whole-body activity distribution within a digital phantom (XCAT) for accurate Monte Carlo (MC)-based images for QC. Each phantom structure is assigned a time-activity curve provided by the PK model, employing parameter values consistent with MAG3 pharmacokinetics. This approach ensures that the total amount of tracer in the phantom is preserved between time points, and it allows for modifications of the pharmacokinetics in a controlled fashion. By adjusting parameter values in the PK model, different clinically realistic scenarios can be mimicked, regarding, e.g., the relative renal uptake and renal transit time. Using the MC code SIMIND, a complete set of renography images including effects of photon attenuation, scattering, limited spatial resolution and noise, are simulated. The obtained image data can be used to evaluate quantitative techniques and computer software in clinical renography.

  18. Exploration of optimal dosing regimens of haloperidol, a D2 Antagonist, via modeling and simulation analysis in a D2 receptor occupancy study.

    PubMed

    Lim, Hyeong-Seok; Kim, Su Jin; Noh, Yook-Hwan; Lee, Byung Chul; Jin, Seok-Joon; Park, Hyun Soo; Kim, Soohyeon; Jang, In-Jin; Kim, Sang Eun

    2013-03-01

    To evaluate the potential usage of D(2) receptor occupancy (D2RO) measured by positron emission tomography (PET) in antipsychotic development. In this randomized, parallel group study, eight healthy male volunteers received oral doses of 0.5 (n = 3), 1 (n = 2), or 3 mg (n = 3) of haloperidol once daily for 7 days. PET's were scanned before haloperidol, and on days 8, 12, with serial pharmacokinetic sampling on day 7. Pharmacokinetics and binding potential to D(2) receptor in putamen and caudate nucleus over time were analyzed using NONMEM, and simulations for the profiles of D2RO over time on various regimens of haloperidol were conducted to find the optimal dosing regimens. One compartment model with a saturable binding compartment, and inhibitory E(max) model in the effect compartment best described the data. Plasma haloperidol concentrations at half-maximal inhibition were 0.791 and 0.650 ng/ml, in putamen and caudate nucleus. Simulation suggested haloperidol 2 mg every 12 h is near the optimal dose. This study showed that sparse D2RO measurements in steady state pharmacodynamic design after multiple dosing could reveal the possibility of treatment effect of D(2) antagonist, and could identify the potential optimal doses for later clinical studies by modeling and simulation.

  19. Abdominal intra-compartment syndrome - a non-hydraulic model of abdominal compartment syndrome due to post-hepatectomy hemorrhage in a man with a localized frozen abdomen due to extensive adhesions: a case report.

    PubMed

    Bressan, Alexsander K; Kirkpatrick, Andrew W; Ball, Chad G

    2016-09-15

    Postoperative hemorrhage is a significant cause of morbidity and mortality following liver resection. It typically presents early within the postoperative period, and conservative management is possible in the majority of cases. We present a case of late post-hepatectomy hemorrhage associated with overt abdominal compartment syndrome resulting from a localized functional compartment within the abdomen. A 68-year-old white man was readmitted with sudden onset of upper abdominal pain, vomiting, and hemodynamic instability 8 days after an uneventful hepatic resection for metachronous colon cancer metastasis. A frozen abdomen with adhesions due to complicated previous abdominal surgeries was encountered at the first intervention, but the surgery itself and initial recovery were otherwise unremarkable. Prompt response to fluid resuscitation at admission was followed by a computed tomography of his abdomen that revealed active arterial hemorrhage in the liver resection site and hemoperitoneum (estimated volume <2 L). Selective arteriography successfully identified and embolized a small bleeding branch of his right hepatic artery. He remained hemodynamically stable, but eventually developed overt abdominal compartment syndrome. Surgical exploration confirmed a small volume of ascites and blood clots (1.2 L) under significant pressure in his supramesocolic region, restricted by his frozen lower abdomen, which we evacuated. Dramatic improvement in his ventilatory pressure was immediate. His abdomen was left open and a negative pressure device was placed for temporary abdominal closure. The fascia was formally closed after 48 hours. He was discharged home at postoperative day 6. Intra-abdominal pressure and radiologic findings of intra-abdominal hemorrhage should be carefully interpreted in patients with extensive intra-abdominal adhesions. A high index of suspicion and detailed understanding of abdominal compartment mechanics are paramount for the timely diagnosis of abdominal compartment syndrome in these patients. Clinicians should be aware that abnormal anatomy (such as adhesions) coupled with localized pathophysiology (such as hemorrhage) can create a so-named abdominal intra-compartment syndrome requiring extra vigilance to diagnose.

  20. Stochastic Pharmacokinetic-Pharmacodynamic Modeling for Assessing the Systemic Health Risk of Perfluorooctanoate (PFOA)

    PubMed Central

    Convertino, Matteo; Church, Timothy R; Olsen, Geary W; Liu, Yang; Doyle, Eddie; Elcombe, Clifford R; Barnett, Anna L; Samuel, Leslie M; Evans, Thomas R J

    2018-01-01

    Abstract A phase 1 dose-escalation trial assessed the chemotherapeutic potential of ammonium perfluorooctanoate (APFO). Forty-nine primarily solid-tumor cancer patients who failed standard therapy received weekly APFO doses (50–1200 mg) for 6 weeks. Clinical chemistries and plasma PFOA (anionic APFO) were measured predose and weekly thereafter. Several clinical measures including total cholesterol, high-density lipoproteins (HDLs), thyroid stimulating hormone (TSH), and free thyroxine (fT4), relative to PFOA concentrations were examined by: Standard statistical analyses using generalized estimating equations (GEE) and a probabilistic analysis using probability distribution functions (pdf) at various PFOA concentrations; and a 2-compartment pharmacokinetic/pharmacodynamic (PK/PD) model to directly estimate mean changes. Based on the GEE, the average rates of change in total cholesterol and fT4 associated with increasing PFOA were approximately −1.2×10−3 mmol/l/μM and 2.8×10−3 pmol/l/μM, respectively. The PK/PD model predicted more closely the trends observed in the data as well as the pdfs of biomarkers. A decline in total cholesterol was observed, with a clear transition in shape and range of the pdfs, manifested by the maximum value of the Kullback-Leibler (KL) divergence, that occurred at plasma PFOA between 420 and 565 μM (175 000–230 000 ng/ml). High-density lipoprotein was unchanged. An increase in fT4 was observed at a higher PFOA transition point, albeit TSH was unchanged. Our findings are consistent with some animal models and may motivate re-examination of the epidemiologic studies to PFOA at levels several orders of magnitude lower than this study. These observational studies have reported contrary associations, but currently understood biology does not support the existence of such conflicting effects. PMID:29462473

  1. Evaluation of conceptual models of natural organic matter (humus) from a consideration of the chemical and biochemical processes of humification

    USGS Publications Warehouse

    Wershaw, Robert L.

    2004-01-01

    Natural organic matter (NOM) has been studied for more than 200 years because of its importance in enhancing soil fertility, soil structure, and water-holding capacity and as a carbon sink in the global carbon cycle. Two different types of models have been proposed for NOM: (1) the humic polymer models and (2) the molecular aggregate models. In the humic polymer models, NOM molecules are depicted as large (humic) polymers that have unique chemical structures that are different from those of the precursor plant degradation products. In the molecular aggregate models, NOM is depicted as being composed of molecular aggregates (supramolecular aggregates) of plant degradation products held together by non-covalent bonds. The preponderance of evidence favors the supramolecular aggregate models. These models were developed by studying the properties of NOM extracted from soils and natural waters, and as such, they provide only a very generalized picture of the structure of NOM aggregates in soils and natural waters prior to extraction. A compartmental model, in which the structure of the NOM in each of the compartments is treated separately, should provide a more accurate representation of NOM in soil and sediment systems. The proposed NOM compartments are: (1) partially degraded plant tissue, (2) biomass from microorganisms, (3) organic coatings on mineral grains, (4) pyrolytic carbon, (5) organic precipitates, and (6) dissolved organic matter (DOM) in interstitial water. Within each of these compartments there are NOM supramolecular aggregates that will be dissolved by the solvent systems that are used by researchers for extraction of NOM from soils and sediments. In natural water systems DOM may be considered as existing in two subcompartments: (1) truly dissolved DOM and (2) colloidal DOM.

  2. Prediction of medial and lateral contact force of the knee joint during normal and turning gait after total knee replacement.

    PubMed

    Purevsuren, Tserenchimed; Dorj, Ariunzaya; Kim, Kyungsoo; Kim, Yoon Hyuk

    2016-04-01

    The computational modeling approach has commonly been used to predict knee joint contact forces, muscle forces, and ligament loads during activities of daily living. Knowledge of these forces has several potential applications, for example, within design of equipment to protect the knee joint from injury and to plan adequate rehabilitation protocols, although clinical applications of computational models are still evolving and one of the limiting factors is model validation. The objective of this study was to extend previous modeling technique and to improve the validity of the model prediction using publicly available data set of the fifth "Grand Challenge Competition to Predict In Vivo Knee Loads." A two-stage modeling approach, which combines conventional inverse dynamic analysis (the first stage) with a multi-body subject-specific lower limb model (the second stage), was used to calculate medial and lateral compartment contact forces. The validation was performed by direct comparison of model predictions and experimental measurement of medial and lateral compartment contact forces during normal and turning gait. The model predictions of both medial and lateral contact forces showed strong correlations with experimental measurements in normal gait (r = 0.75 and 0.71) and in turning gait trials (r = 0.86 and 0.72), even though the current technique over-estimated medial compartment contact forces in swing phase. The correlation coefficient, Sprague and Geers metrics, and root mean squared error indicated that the lateral contact forces were predicted better than medial contact forces in comparison with the experimental measurements during both normal and turning gait trials. © IMechE 2016.

  3. Stimulated echo diffusion tensor imaging and SPAIR T2-weighted imaging in Chronic Exertional Compartment Syndrome of the lower leg muscles

    PubMed Central

    Sigmund, Eric E.; Sui, Dabang; Ukpebor, Obehi; Baete, Steven; Fieremans, Els; Babb, James S.; Mechlin, Michael; Liu, Kecheng; Kwon, Jane; Mcgorty, KellyAnne; Hodnett, Phil; Bencardino, Jenny

    2013-01-01

    Purpose To evaluate the performance of diffusion tensor imaging (DTI) in the evaluation of chronic exertional compartment syndrome (CECS) as compared to T2-weighted imaging. Materials and Methods Using an IRB-approved HIPAA-compliant protocol, spectral adiabatic inversion recovery (SPAIR) T2-weighted imaging (T2w) and stimulated echo DTI were applied to 8 healthy volunteers and 14 suspected CECS patients before and after exertion. Longitudinal and transverse diffusion eigenvalues, mean diffusivity (MD), and fractional anisotropy (FA) were measured in 7 calf muscle compartments, which in patients were classified by their response on T2w: normal (<20% change), and CECS (>20% change). Mixed model analysis of variance compared subject groups and compartments in terms of response factors (post-/pre-exercise ratios) of DTI parameters. Results All diffusivities significantly increased (p<0.0001) and FA decreased (p=.0014) with exercise. Longitudinal diffusion responses were significantly smaller than transversal diffusion responses (p<0.0001). 19 of 98 patient compartments were classified as CECS on T2w. MD increased by 3.8±3.4% (volunteer), 7.4±4.2 % (normal), and 9.1±7.0% (CECS) with exercise. Conclusion DTI shows promise as an ancillary imaging method in the diagnosis and understanding of the pathophysiology in CECS. Future studies may explore its utility in predicting response to treatment. PMID:23440764

  4. Spatial Heterogeneity in Drug Concentrations Can Facilitate the Emergence of Resistance to Cancer Therapy

    PubMed Central

    Fu, Feng; Nowak, Martin A.; Bonhoeffer, Sebastian

    2015-01-01

    Acquired resistance is one of the major barriers to successful cancer therapy. The development of resistance is commonly attributed to genetic heterogeneity. However, heterogeneity of drug penetration of the tumor microenvironment both on the microscopic level within solid tumors as well as on the macroscopic level across metastases may also contribute to acquired drug resistance. Here we use mathematical models to investigate the effect of drug heterogeneity on the probability of escape from treatment and the time to resistance. Specifically we address scenarios with sufficiently potent therapies that suppress growth of all preexisting genetic variants in the compartment with the highest possible drug concentration. To study the joint effect of drug heterogeneity, growth rate, and evolution of resistance, we analyze a multi-type stochastic branching process describing growth of cancer cells in multiple compartments with different drug concentrations and limited migration between compartments. We show that resistance is likely to arise first in the sanctuary compartment with poor drug penetrations and from there populate non-sanctuary compartments with high drug concentrations. Moreover, we show that only below a threshold rate of cell migration does spatial heterogeneity accelerate resistance evolution, otherwise deterring drug resistance with excessively high migration rates. Our results provide new insights into understanding why cancers tend to quickly become resistant, and that cell migration and the presence of sanctuary sites with little drug exposure are essential to this end. PMID:25789469

  5. Pharmacokinetics of ketamine and its metabolite norketamine administered at a sub-anesthetic dose together with xylazine to calves prior to castration.

    PubMed

    Gehring, R; Coetzee, J F; Tarus-Sang, J; Apley, M D

    2009-04-01

    The objective of this study was to evaluate the plasma pharmacokinetics of ketamine and its active metabolite norketamine administered intravenously at a dose of 0.1 mg/kg together with xylazine (0.05 mg/kg) to control the pain associated with castration in calves. A two-compartment model with an additional metabolite compartment linked to the central compartment was used to simultaneously describe the time-concentration profiles of both ketamine and its major metabolite norketamine. Parameter values estimated from the time-concentration profiles observed in this study were volume of the central compartment (V(c) = 132.82 +/- 68.23 mL/kg), distribution clearance (CL(D) = 15.49 +/- 2.56 mL/min/kg), volume of the peripheral compartment (V(T) = 257.05 +/- 41.65 mL/kg), ketamine clearance by the formation of the norketamine metabolite (CL(2M) = 8.56 +/- 7.37 mL/kg/min) and ketamine clearance by other routes (CL(o) = 16.41 +/- 3.42 mL/kg/min). Previously published data from rats suggest that the metabolite norketamine contributes to the analgesic effect of ketamine, with a potency that is one-third of the parent drug. An understanding of the time-concentration relationships and the disposition of the parent drug and its metabolite is therefore important for a better understanding of the analgesic potential of ketamine in cattle.

  6. Advanced tissue engineering scaffold design for regeneration of the complex hierarchical periodontal structure.

    PubMed

    Costa, Pedro F; Vaquette, Cédryck; Zhang, Qiyi; Reis, Rui L; Ivanovski, Saso; Hutmacher, Dietmar W

    2014-03-01

    This study investigated the ability of an osteoconductive biphasic scaffold to simultaneously regenerate alveolar bone, periodontal ligament and cementum. A biphasic scaffold was built by attaching a fused deposition modelled bone compartment to a melt electrospun periodontal compartment. The bone compartment was coated with a calcium phosphate (CaP) layer for increasing osteoconductivity, seeded with osteoblasts and cultured in vitro for 6 weeks. The resulting constructs were then complemented with the placement of PDL cell sheets on the periodontal compartment, attached to a dentin block and subcutaneously implanted into athymic rats for 8 weeks. Scanning electron microscopy, X-ray diffraction, alkaline phosphatase and DNA content quantification, confocal laser microscopy, micro computerized tomography and histological analysis were employed to evaluate the scaffold's performance. The in vitro study showed that alkaline phosphatase activity was significantly increased in the CaP-coated samples and they also displayed enhanced mineralization. In the in vivo study, significantly more bone formation was observed in the coated scaffolds. Histological analysis revealed that the large pore size of the periodontal compartment permitted vascularization of the cell sheets, and periodontal attachment was achieved at the dentin interface. This work demonstrates that the combination of cell sheet technology together with an osteoconductive biphasic scaffold could be utilized to address the limitations of current periodontal regeneration techniques. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  7. Characterization of pH-sensitive molecular switches that trigger the structural transition of vesicular stomatitis virus glycoprotein from the postfusion state toward the prefusion state.

    PubMed

    Ferlin, Anna; Raux, Hélène; Baquero, Eduard; Lepault, Jean; Gaudin, Yves

    2014-11-01

    Vesicular stomatitis virus (VSV; the prototype rhabdovirus) fusion is triggered at low pH and mediated by glycoprotein G, which undergoes a low-pH-induced structural transition. A unique feature of rhabdovirus G is that its conformational change is reversible. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. The crystal structures of G pre- and postfusion states have been elucidated, leading to the identification of several acidic amino acid residues, clustered in the postfusion trimer, as potential pH-sensitive switches controlling the transition back toward the prefusion state. We mutated these residues and produced a panel of single and double mutants whose fusion properties, conformational change characteristics, and ability to pseudotype a virus lacking the glycoprotein gene were assayed. Some of these mutations were also introduced in the genome of recombinant viruses which were further characterized. We show that D268, located in the segment consisting of residues 264 to 273, which refolds into postfusion helix F during G structural transition, is the major pH sensor while D274, D395, and D393 have additional contributions. Furthermore, a single passage of recombinant virus bearing the mutation D268L (which was demonstrated to stabilize the G postfusion state) resulted in a pseudorevertant with a compensatory second mutation, L271P. This revealed that the propensity of the segment of residues 264 to 273 to refold into helix F has to be finely tuned since either an increase (mutation D268L alone) or a decrease (mutation L271P alone) of this propensity is detrimental to the virus. Vesicular stomatitis virus enters cells via endocytosis. Endosome acidification induces a structural transition of its unique glycoprotein (G), which mediates fusion between viral and endosomal membranes. G conformational change is reversible upon increases in pH. This allows G to recover its native prefusion state at the viral surface after its transport through the acidic Golgi compartments. We mutated five acidic residues, proposed to be pH-sensitive switches controlling the structural transition back toward the prefusion state. Our results indicate that residue D268 is the major pH sensor, while other acidic residues have additional contributions, and reveal that the propensity of the segment consisting of residues 264 to 273 to adopt a helical conformation is finely regulated. This segment might be a good target for antiviral compounds. Copyright © 2014, American Society for Microbiology. All Rights Reserved.

  8. RLC model of visco-elastic properties of the chest wall

    NASA Astrophysics Data System (ADS)

    Aliverti, Andrea; Ferrigno, Giancarlo

    1996-04-01

    The quantification of the visco-elastic properties (resistance (R), inertia (L) and compliance (C)) of the different chest wall compartments (pulmonary rib cage,diaphragmatic rib cage and abdomen) is important to study the status of the passive components of the respiratory system, particularly in selected pathologies. Applying the viscoelastic-electrical analogy to the chest wall, we used an identification method in order to estimate the R, L and C parameters of the different parts of the chest, basing on different models; the input and output measured data were constituted by the volume variations of the different chest wall compartments and by the nasal pressure during controlled intermittent positive pressure ventilation by nasal mask, while the parameters of the system (R, L and C of the different compartments) were to be estimated. Volumes were measured with a new method, recently validated, based on an opto-electronic motion analyzer, able to compute with high accuracy and null invasivity the absolute values and the time variations of the volumes of each of the three compartments. The estimation of the R, L and C parameters has been based on a least-squared criterion, and the minimization has been based on a robustified iterative Gauss-Newton algorithm. The validation of the estimation procedure (fitting) has ben performed computing the percentage root mean square value of the error between the output real data and the output estimated data. The method has been applied to 2 healthy subjects. Also preliminary results have been obtained from 20 subjects affected by neuromuscular diseases (Duchenne Muscular Dystrophy (DMD) and Spinal Muscle Atrophy (SMA)). The results show that: (a) the best-fitting electrical models of the respiratory system are made up by one or three parallel RLC branches supplied by a voltage generator (so considering inertial properties, particularly in the abdominal compartment, and not considering patient/machine connection); (b) there is a significant difference between DMD and SMA groups (the value of resistance and rigidity of the thorax is much higher in SMA patients); (c) the inclusion of the connection patient-ventilator make the models ill-conditioned. We conclude that this method allows a quantitative evaluation of rib cage and abdominal passive characteristics with a good accuracy and through a dynamic measurement and that it could give significant data in physiology and clinics.

  9. Dynamic model for the tissue concentration and oxygen saturation of hemoglobin in relation to blood volume, flow velocity, and oxygen consumption: Implications for functional neuroimaging and coherent hemodynamics spectroscopy (CHS).

    PubMed

    Fantini, Sergio

    2014-01-15

    This article presents a dynamic model that quantifies the temporal evolution of the concentration and oxygen saturation of hemoglobin in tissue, as determined by time-varying hemodynamic and metabolic parameters: blood volume, flow velocity, and oxygen consumption. This multi-compartment model determines separate contributions from arterioles, capillaries, and venules that comprise the tissue microvasculature, and treats them as a complete network, without making assumptions on the details of the architecture and morphology of the microvascular bed. A key parameter in the model is the effective blood transit time through the capillaries and its associated probability of oxygen release from hemoglobin to tissue, as described by a rate constant for oxygen diffusion. The solution of the model in the time domain predicts the signals measured by hemodynamic-based neuroimaging techniques such as functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) in response to brain activation. In the frequency domain, the model yields an analytical solution based on a phasor representation that provides a framework for quantitative spectroscopy of coherent hemodynamic oscillations. I term this novel technique coherent hemodynamics spectroscopy (CHS), and this article describes how it can be used for the assessment of cerebral autoregulation and the study of hemodynamic oscillations resulting from a variety of periodic physiological challenges, brain activation protocols, or physical maneuvers. Copyright © 2013 Elsevier Inc. All rights reserved.

  10. Dynamic model for the tissue concentration and oxygen saturation of hemoglobin in relation to blood volume, flow velocity, and oxygen consumption: Implications for functional neuroimaging and coherent hemodynamics spectroscopy (CHS)

    PubMed Central

    Fantini, Sergio

    2013-01-01

    This article presents a dynamic model that quantifies the temporal evolution of the concentration and oxygen saturation of hemoglobin in tissue, as determined by time-varying hemodynamic and metabolic parameters: blood volume, flow velocity, and oxygen consumption. This multi-compartment model determines separate contributions from arterioles, capillaries, and venules that comprise the tissue microvasculature, and treats them as a complete network, without making assumptions on the details of the architecture and morphology of the microvascular bed. A key parameter in the model is the effective blood transit time through the capillaries and its associated probability of oxygen release from hemoglobin to tissue, as described by a rate constant for oxygen diffusion. The solution of the model in the time domain predicts the signals measured by hemodynamic-based neuroimaging techniques such as functional near-infrared spectroscopy (fNIRS) and functional magnetic resonance imaging (fMRI) in response to brain activation. In the frequency domain, the model yields an analytical solution based on a phasor representation that provides a framework for quantitative spectroscopy of coherent hemodynamic oscillations. I term this novel technique coherent hemodynamics spectroscopy (CHS), and this article describes how it can be used for the assessment of cerebral autoregulation and the study of hemodynamic oscillations resulting from a variety of periodic physiological challenges, brain activation protocols, or physical maneuvers. PMID:23583744

  11. Physiologically based pharmacokinetic modeling using microsoft excel and visual basic for applications.

    PubMed

    Marino, Dale J

    2005-01-01

    Abstract Physiologically based pharmacokinetic (PBPK) models are mathematical descriptions depicting the relationship between external exposure and internal dose. These models have found great utility for interspecies extrapolation. However, specialized computer software packages, which are not widely distributed, have typically been used for model development and utilization. A few physiological models have been reported using more widely available software packages (e.g., Microsoft Excel), but these tend to include less complex processes and dose metrics. To ascertain the capability of Microsoft Excel and Visual Basis for Applications (VBA) for PBPK modeling, models for styrene, vinyl chloride, and methylene chloride were coded in Advanced Continuous Simulation Language (ACSL), Excel, and VBA, and simulation results were compared. For styrene, differences between ACSL and Excel or VBA compartment concentrations and rates of change were less than +/-7.5E-10 using the same numerical integration technique and time step. Differences using VBA fixed step or ACSL Gear's methods were generally <1.00E-03, although larger differences involving very small values were noted after exposure transitions. For vinyl chloride and methylene chloride, Excel and VBA PBPK model dose metrics differed by no more than -0.013% or -0.23%, respectively, from ACSL results. These differences are likely attributable to different step sizes rather than different numerical integration techniques. These results indicate that Microsoft Excel and VBA can be useful tools for utilizing PBPK models, and given the availability of these software programs, it is hoped that this effort will help facilitate the use and investigation of PBPK modeling.

  12. A microvascular compartment model validated using 11C-methylglucose liver PET in pigs

    NASA Astrophysics Data System (ADS)

    Munk, Ole L.; Keiding, Susanne; Baker, Charles; Bass, Ludvik

    2018-01-01

    The standard compartment model (CM) is widely used to analyse dynamic PET data. The CM is fitted to time-activity curves to estimate rate constants that describe the transport of a tracer between well-mixed compartments. The aim of this study was to develop and validate a more realistic microvascular compartment model (MCM) that includes capillary tracer concentration gradients, backflux from cells into the perfused capillaries and multiple re-uptakes during the passage through a capillary. The MCM incorporates only parameters with clear physiological meaning, it is easy to implement, and it does not require numerical solution. We compared the MCM and CM for the analysis of 3 min dynamic PET data of pig livers (N  =  5) following injection of 11C-methylglucose. During PET scans, the tracer concentrations in blood were measured in the abdominal aorta, portal vein and liver vein by manual sampling. We found that the MCM outperformed the CM and that dynamic PET data include information which cannot be extracted using standard CM. The MCM fitted dynamic PET data better than the CM (Akaike values were 46  ±  4 for best MCM fits, and 82  ±  8 for best CM fits; mean  ±  standard deviation) and extracted physiologically reasonable parameter estimates such as blood perfusion that were in agreement with independent measurements. The difference between model-independent perfusion estimates and the best MCM perfusion estimates was  -0.01  ±  0.05 ml/ml/min, whereas the difference was 0.30  ±  0.13 ml/ml/min using the CM. In addition, the MCM predicted the time course of concentrations in the liver vein, a prediction fundamentally unobtainable using the CM as it does not return tracer backflux from cells to capillary blood. The results demonstrate the benefit of using models that include more physiology and that models including concentration gradients should be preferred when analysing the blood-cell exchange of any tracer in any capillary bed.

  13. Forecasting impact injuries of unrestrained occupants in railway vehicle passenger compartments.

    PubMed

    Xie, Suchao; Zhou, Hui

    2014-01-01

    In order to predict the injury parameters of the occupants corresponding to different experimental parameters and to determine impact injury indices conveniently and efficiently, a model forecasting occupant impact injury was established in this work. The work was based on finite experimental observation values obtained by numerical simulation. First, the various factors influencing the impact injuries caused by the interaction between unrestrained occupants and the compartment's internal structures were collated and the most vulnerable regions of the occupant's body were analyzed. Then, the forecast model was set up based on a genetic algorithm-back propagation (GA-BP) hybrid algorithm, which unified the individual characteristics of the back propagation-artificial neural network (BP-ANN) model and the genetic algorithm (GA). The model was well suited to studies of occupant impact injuries and allowed multiple-parameter forecasts of the occupant impact injuries to be realized assuming values for various influencing factors. Finally, the forecast results for three types of secondary collision were analyzed using forecasting accuracy evaluation methods. All of the results showed the ideal accuracy of the forecast model. When an occupant faced a table, the relative errors between the predicted and experimental values of the respective injury parameters were kept within ± 6.0 percent and the average relative error (ARE) values did not exceed 3.0 percent. When an occupant faced a seat, the relative errors between the predicted and experimental values of the respective injury parameters were kept within ± 5.2 percent and the ARE values did not exceed 3.1 percent. When the occupant faced another occupant, the relative errors between the predicted and experimental values of the respective injury parameters were kept within ± 6.3 percent and the ARE values did not exceed 3.8 percent. The injury forecast model established in this article reduced repeat experiment times and improved the design efficiency of the internal compartment's structure parameters, and it provided a new way for assessing the safety performance of the interior structural parameters in existing, and newly designed, railway vehicle compartments.

  14. Development of guidelines for optimum baghouse fluid-dynamic-system design. Final report

    DOE Office of Scientific and Technical Information (OSTI.GOV)

    Eskinazi, D.; Gilbert, G.B.

    1982-06-01

    In recent years, the utility industry has turned to fabric filters as an alternative technology to electrostatic precipitators for particulate emission control from pulverized coal-fired power plants. One aspect of baghouse technology which appears to be of major importance in minimizing the size, cost, and operating pressure drop is the development of ductwork and compartment designs which achieve uniform gas and dust flow distribution to individual compartments and bags within a compartment. The objective of this project was to perform an experimental modeling program to develop design guidelines for optimizing the fluid mechanic performance of baghouses. Tasks included formulation ofmore » the appropriate modeling techniques for analysis of the flow of dust-laden gas through the collector system and extensive experimental analysis of fabric filter duct system design. A matrix of geometric configurations and operating conditions was experimentally investigated to establish the characteristics of an optimum system, to identify the level of fluid mechanic sophistication in current designs, and to experimentally develop new ideas and improved designs. Experimental results indicate that the design of the inlet and outlet manifolds, hopper entrance, hopper region below the tubesheet, and the compartment outlet have not been given sufficient attention. Unsteady flow patterns, poor velocity profiles, recirculation zones, and excessive pressure losses may be associated with these regions. It is evident from the results presented here that the fluid mechanic design of fabric filter systems can be improved significantly.« less

  15. Comparison of PrestoBlue® and plating method to evaluate antimicrobial activity of ascorbic acid, boric acid and curcumin in an in vitro gastrointestinal model.

    PubMed

    Hernandez-Patlan, D; Solis-Cruz, B; Méndez-Albores, A; Latorre, J D; Hernandez-Velasco, X; Tellez, G; López-Arellano, R

    2018-02-01

    To compare the conventional plating method vs a fluorometric method using PrestoBlue ® as a dye by determining the antimicrobial activity of two organic acids and curcumin (CUR) against Salmonella Enteritidis in an avian in vitro digestion model that simulates the crop, proventriculus and intestine. A concentration of 10 8  CFU per ml of S. Enteritidis was exposed to groups with different rates of ascorbic acid (AA), boric acid (BA) and CUR. Significant differences were observed when the means of the treatments were compared with the controls in the compartments that simulate the crop and intestine (P < 0·05). Ascorbic acid alone and high rates of AA in the mixtures were the most efficient treatments in the crop compartment. However, in the intestinal compartment BA alone and at different rates in the mixture BA-CUR (1 : 1) were the best treatments to decrease the concentration of S. Enteritidis. The results of this study suggest that there could be an antagonistic bactericidal effect between AA and CUR and AA and BA as well as a synergistic bactericidal effect between BA and CUR. These findings may contribute to the development of a formulation with microencapsulated compounds to liberate them in different compartments to combat S. Enteritidis infections in broiler chickens. © 2017 The Society for Applied Microbiology.

  16. Multi-Compartment T2 Relaxometry Using a Spatially Constrained Multi-Gaussian Model

    PubMed Central

    Raj, Ashish; Pandya, Sneha; Shen, Xiaobo; LoCastro, Eve; Nguyen, Thanh D.; Gauthier, Susan A.

    2014-01-01

    The brain’s myelin content can be mapped by T2-relaxometry, which resolves multiple differentially relaxing T2 pools from multi-echo MRI. Unfortunately, the conventional fitting procedure is a hard and numerically ill-posed problem. Consequently, the T2 distributions and myelin maps become very sensitive to noise and are frequently difficult to interpret diagnostically. Although regularization can improve stability, it is generally not adequate, particularly at relatively low signal to noise ratio (SNR) of around 100–200. The purpose of this study was to obtain a fitting algorithm which is able to overcome these difficulties and generate usable myelin maps from noisy acquisitions in a realistic scan time. To this end, we restrict the T2 distribution to only 3 distinct resolvable tissue compartments, modeled as Gaussians: myelin water, intra/extra-cellular water and a slow relaxing cerebrospinal fluid compartment. We also impose spatial smoothness expectation that volume fractions and T2 relaxation times of tissue compartments change smoothly within coherent brain regions. The method greatly improves robustness to noise, reduces spatial variations, improves definition of white matter fibers, and enhances detection of demyelinating lesions. Due to efficient design, the additional spatial aspect does not cause an increase in processing time. The proposed method was applied to fast spiral acquisitions on which conventional fitting gives uninterpretable results. While these fast acquisitions suffer from noise and inhomogeneity artifacts, our preliminary results indicate the potential of spatially constrained 3-pool T2 relaxometry. PMID:24896833

  17. Feasibility of Rapid Multitracer PET Tumor Imaging

    NASA Astrophysics Data System (ADS)

    Kadrmas, D. J.; Rust, T. C.

    2005-10-01

    Positron emission tomography (PET) can characterize different aspects of tumor physiology using various tracers. PET scans are usually performed using only one tracer since there is no explicit signal for distinguishing multiple tracers. We tested the feasibility of rapidly imaging multiple PET tracers using dynamic imaging techniques, where the signals from each tracer are separated based upon differences in tracer half-life, kinetics, and distribution. Time-activity curve populations for FDG, acetate, ATSM, and PTSM were simulated using appropriate compartment models, and noisy dual-tracer curves were computed by shifting and adding the single-tracer curves. Single-tracer components were then estimated from dual-tracer data using two methods: principal component analysis (PCA)-based fits of single-tracer components to multitracer data, and parallel multitracer compartment models estimating single-tracer rate parameters from multitracer time-activity curves. The PCA analysis found that there is information content present for separating multitracer data, and that tracer separability depends upon tracer kinetics, injection order and timing. Multitracer compartment modeling recovered rate parameters for individual tracers with good accuracy but somewhat higher statistical uncertainty than single-tracer results when the injection delay was >10 min. These approaches to processing rapid multitracer PET data may potentially provide a new tool for characterizing multiple aspects of tumor physiology in vivo.

  18. Chemometric strategy for modeling metabolic biological space along the gastrointestinal tract and assessing microbial influences.

    PubMed

    Martin, François-Pierre J; Montoliu, Ivan; Kochhar, Sunil; Rezzi, Serge

    2010-12-01

    Over the past decade, the analysis of metabolic data with advanced chemometric techniques has offered the potential to explore functional relationships among biological compartments in relation to the structure and function of the intestine. However, the employed methodologies, generally based on regression modeling techniques, have given emphasis to region-specific metabolic patterns, while providing only limited insights into the spatiotemporal metabolic features of the complex gastrointestinal system. Hence, novel approaches are needed to analyze metabolic data to reconstruct the metabolic biological space associated with the evolving structures and functions of an organ such as the gastrointestinal tract. Here, we report the application of multivariate curve resolution (MCR) methodology to model metabolic relationships along the gastrointestinal compartments in relation to its structure and function using data from our previous metabonomic analysis. The method simultaneously summarizes metabolite occurrence and contribution to continuous metabolic signatures of the different biological compartments of the gut tract. This methodology sheds new light onto the complex web of metabolic interactions with gut symbionts that modulate host cell metabolism in surrounding gut tissues. In the future, such an approach will be key to provide new insights into the dynamic onset of metabolic deregulations involved in region-specific gastrointestinal disorders, such as Crohn's disease or ulcerative colitis.

  19. A physiological pharmacokinetic model describing the disposition of lycopene in healthy men.

    PubMed

    Diwadkar-Navsariwala, Veda; Novotny, Janet A; Gustin, David M; Sosman, Jeffery A; Rodvold, Keith A; Crowell, James A; Stacewicz-Sapuntzakis, Maria; Bowen, Phyllis E

    2003-10-01

    A physiological pharmacokinetic model was developed to describe the disposition of lycopene, delivered as a tomato beverage formulation in five graded doses (10, 30, 60, 90, or 120 mg), for a phase I study in healthy male subjects (five per dose). Blood was collected before dose administration (0 h) and at scheduled intervals until 672 h. Serum concentrations of carotenoids and vitamins were measured by high performance liquid chromatography analysis. The model was comprised of seven compartments: gastrointestinal tract, enterocytes, chylomicrons, plasma lipoproteins, fast-turnover liver, slow-turnover tissues, and a delay compartment before the enterocytes. As predicted, the percent absorption at the 10 mg dose (33.9 +/- 8.1%) was significantly greater than at the higher doses; however, the amount of lycopene absorbed (mg) was not statistically different (mean: 4.69 +/- 0.55 mg) between doses, suggesting a possible saturation of absorptive mechanisms. The slow-turnover tissue compartment served as a slow-depleting reservoir for lycopene, and the liver represented the fast-turnover pool. Independent of dose, 80% of the subjects absorbed less than 6 mg of lycopene. This may have important implications for planning clinical trials with pharmacological doses of lycopene in cancer control and prevention if absorption saturation occurs at levels that are already being consumed in the population.

  20. Reprint of: A numerical modelling of gas exchange mechanisms between air and turbulent water with an aquarium chemical reaction

    NASA Astrophysics Data System (ADS)

    Nagaosa, Ryuichi S.

    2014-08-01

    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, A(g)⇌A(aq), with Henry's law constant H. The second is a first-order irreversible chemical reaction in turbulent water, A(aq)+H2O→B(aq)+H+ with a chemical reaction rate κA. 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 10(≈0) 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.

  1. Pharmacokinetics of topically applied pilocarpine in the albino rabbit eye.

    PubMed

    Makoid, M C; Robinson, J R

    1979-04-01

    The temporal and spatial pattern of [3H]-pilocarpine nitrate distribution in the albino rabbit eye following topical administration was determined. A four-compartment caternary chain model describing this disposition corresponds to the precorneal area, the cornea, the aqueous humor, and the lens and vitreous. Simultaneous computer fitting of data from tissue corresponding to some compartments in the model supported the proposed model. Additional support was provided by the excellent correlation between predicted and observed values in multiple-dosing studies. Several important aspects of ocular drug disposition are evident from the model. The extensive parallel elimination at the absorption site gives rise to an apparent absorption rate constant that is one to two orders of magnitude larger than the true absorption rate constant. In addition, aqueous flow accounts for most of the drug removal. Thus, major effects on absorption and elimination, independent of the drug structure, suggest the possibility of similar pharmacokinetics for vastly different drugs.

  2. Ultra-sensitive assay for paclitaxel in intracellular compartments of A549 cells using liquid chromatography-tandem mass spectrometry.

    PubMed

    Wang, Tingting; Ma, Wenxiao; Sun, Yantong; Yang, Yan; Zhang, Weiping; Fawcett, J Paul; Du, Hongwei; Gu, Jingkai

    2013-01-01

    A high-performance liquid chromatography-tandem mass spectrometric (LC-MS/MS) method for the determination of paclitaxel in intracellular compartments using docetaxel as internal standard (IS) has been developed and validated. A549 cancer cells (10(6)) were incubated with paclitaxel (2ng/mL) for up to 4h and then subjected to sequential extraction of cytosolic, membrane/organelle, nuclear and cytoskeleton soluble protein. Fractions were ultrasonicated to release protein bound paclitaxel after which drug was extracted using liquid-liquid extraction with diethyl ether:dichloromethane (2:1, v/v). Chromatographic separation was then carried out on an Ascentis Express C18 column (50mm×4.6mm, 2.7μm) with a mobile phase of acetonitrile:0.1% formic acid in water (50:50, v/v). Detection involved electrospray positive ionization followed by multiple reactions monitoring of the precursor-to-product ion transitions of paclitaxel at m/z 854.4→286.3 and docetaxel at m/z 808.6→226.1. Assay validation based on samples of total cell extract in the same buffer as protein fractions showed the assay was linear over the range 2-600pg/mL with intra- and inter-day precision (as relative standard deviation) and accuracy (as relative error) of <7% and <±12%, respectively. Recovery was approximately 70% and matrix effects were minimal. The distribution of paclitaxel in subcellular components of A549 cancer cells was mainly into the cytoskeletal compartment. Copyright © 2012 Elsevier B.V. All rights reserved.

  3. TEST OF A THEORETICAL COMMUTER EXPOSURE MODEL TO VEHICLE EXHAUST IN TRAFFIC

    EPA Science Inventory

    A theoretical model of commuter exposure is presented as a box or cell model with the automobile passenger compartment representing the microenvironment exposed to CO concentrations resulting from vehicle exhaust leaks and emissions from traffic. Equations which describe this sit...

  4. USE OF A PHYSIOLOGICALLY BASED TOXICOKINETIC MODEL TO SIMULATE CHRONIC DIETARY EXPOSURE IN FISH

    EPA Science Inventory

    A physiologically based toxicokinetic (PBTK) model was developed to describe dietary uptake of hydrophobic organic chemicals by fish. The GI tract was modeled as four compartments corresponding to the stomach, pyloric ceca, upper intestine, and lower intestine. Partitioning coeff...

  5. A PHYSIOLOGICALLY-BASED PHARMACOKINETIC MODEL FOR TRICHLOROETHYLENE WITH SPECIFICITY FOR THE LONG EVANS RAT

    EPA Science Inventory

    A PBPK model for TCE with specificity for the male LE rat that accurately predicts TCE tissue time-course data has not been developed, although other PBPK models for TCE exist. Development of such a model was the present aim. The PBPK model consisted of 5 compartments: fat; slowl...

  6. A biophysical observation model for field potentials of networks of leaky integrate-and-fire neurons.

    PubMed

    Beim Graben, Peter; Rodrigues, Serafim

    2012-01-01

    We present a biophysical approach for the coupling of neural network activity as resulting from proper dipole currents of cortical pyramidal neurons to the electric field in extracellular fluid. Starting from a reduced three-compartment model of a single pyramidal neuron, we derive an observation model for dendritic dipole currents in extracellular space and thereby for the dendritic field potential (DFP) that contributes to the local field potential (LFP) of a neural population. This work aligns and satisfies the widespread dipole assumption that is motivated by the "open-field" configuration of the DFP around cortical pyramidal cells. Our reduced three-compartment scheme allows to derive networks of leaky integrate-and-fire (LIF) models, which facilitates comparison with existing neural network and observation models. In particular, by means of numerical simulations we compare our approach with an ad hoc model by Mazzoni et al. (2008), and conclude that our biophysically motivated approach yields substantial improvement.

  7. Biothermal Model of Patient for Brain Hypothermia Treatment

    NASA Astrophysics Data System (ADS)

    Wakamatsu, Hidetoshi; Gaohua, Lu

    A biothermal model of patient is proposed and verified for the brain hypothermia treatment, since the conventionally applied biothermal models are inappropriate for their unprecedented application. The model is constructed on the basis of the clinical practice of the pertinent therapy and characterized by the mathematical relation with variable ambient temperatures, in consideration of the clinical treatments such as the vital cardiopulmonary regulation. It has geometrically clear representation of multi-segmental core-shell structure, database of physiological and physical parameters with a systemic state equation setting the initial temperature of each compartment. Its step response gives the time constant about 3 hours in agreement with clinical knowledge. As for the essential property of the model, the dynamic temperature of its face-core compartment is realized, which corresponds to the tympanic membrane temperature measured under the practical anesthesia. From the various simulations consistent with the phenomena of clinical practice, it is concluded that the proposed model is appropriate for the theoretical analysis and clinical application to the brain hypothermia treatment.

  8. On the influences of key modelling constants of large eddy simulations for large-scale compartment fires predictions

    NASA Astrophysics Data System (ADS)

    Yuen, Anthony C. Y.; Yeoh, Guan H.; Timchenko, Victoria; Cheung, Sherman C. P.; Chan, Qing N.; Chen, Timothy

    2017-09-01

    An in-house large eddy simulation (LES) based fire field model has been developed for large-scale compartment fire simulations. The model incorporates four major components, including subgrid-scale turbulence, combustion, soot and radiation models which are fully coupled. It is designed to simulate the temporal and fluid dynamical effects of turbulent reaction flow for non-premixed diffusion flame. Parametric studies were performed based on a large-scale fire experiment carried out in a 39-m long test hall facility. Several turbulent Prandtl and Schmidt numbers ranging from 0.2 to 0.5, and Smagorinsky constants ranging from 0.18 to 0.23 were investigated. It was found that the temperature and flow field predictions were most accurate with turbulent Prandtl and Schmidt numbers of 0.3, respectively, and a Smagorinsky constant of 0.2 applied. In addition, by utilising a set of numerically verified key modelling parameters, the smoke filling process was successfully captured by the present LES model.

  9. A biophysical observation model for field potentials of networks of leaky integrate-and-fire neurons

    PubMed Central

    beim Graben, Peter; Rodrigues, Serafim

    2013-01-01

    We present a biophysical approach for the coupling of neural network activity as resulting from proper dipole currents of cortical pyramidal neurons to the electric field in extracellular fluid. Starting from a reduced three-compartment model of a single pyramidal neuron, we derive an observation model for dendritic dipole currents in extracellular space and thereby for the dendritic field potential (DFP) that contributes to the local field potential (LFP) of a neural population. This work aligns and satisfies the widespread dipole assumption that is motivated by the “open-field” configuration of the DFP around cortical pyramidal cells. Our reduced three-compartment scheme allows to derive networks of leaky integrate-and-fire (LIF) models, which facilitates comparison with existing neural network and observation models. In particular, by means of numerical simulations we compare our approach with an ad hoc model by Mazzoni et al. (2008), and conclude that our biophysically motivated approach yields substantial improvement. PMID:23316157

  10. Electrolytic method to make alkali alcoholates using ion conducting alkali electrolyte/separator

    DOEpatents

    Joshi, Ashok V [Salt Lake City, UT; Balagopal, Shekar [Sandy, UT; Pendelton, Justin [Salt Lake City, UT

    2011-12-13

    Alkali alcoholates, also called alkali alkoxides, are produced from alkali metal salt solutions and alcohol using a three-compartment electrolytic cell. The electrolytic cell includes an anolyte compartment configured with an anode, a buffer compartment, and a catholyte compartment configured with a cathode. An alkali ion conducting solid electrolyte configured to selectively transport alkali ions is positioned between the anolyte compartment and the buffer compartment. An alkali ion permeable separator is positioned between the buffer compartment and the catholyte compartment. The catholyte solution may include an alkali alcoholate and alcohol. The anolyte solution may include at least one alkali salt. The buffer compartment solution may include a soluble alkali salt and an alkali alcoholate in alcohol.

  11. The impact of pH inhomogeneities on CHO cell physiology and fed-batch process performance - two-compartment scale-down modelling and intracellular pH excursion.

    PubMed

    Brunner, Matthias; Braun, Philipp; Doppler, Philipp; Posch, Christoph; Behrens, Dirk; Herwig, Christoph; Fricke, Jens

    2017-07-01

    Due to high mixing times and base addition from top of the vessel, pH inhomogeneities are most likely to occur during large-scale mammalian processes. The goal of this study was to set-up a scale-down model of a 10-12 m 3 stirred tank bioreactor and to investigate the effect of pH perturbations on CHO cell physiology and process performance. Short-term changes in extracellular pH are hypothesized to affect intracellular pH and thus cell physiology. Therefore, batch fermentations, including pH shifts to 9.0 and 7.8, in regular one-compartment systems are conducted. The short-term adaption of the cells intracellular pH are showed an immediate increase due to elevated extracellular pH. With this basis of fundamental knowledge, a two-compartment system is established which is capable of simulating defined pH inhomogeneities. In contrast to state-of-the-art literature, the scale-down model is included parameters (e.g. volume of the inhomogeneous zone) as they might occur during large-scale processes. pH inhomogeneity studies in the two-compartment system are performed with simulation of temporary pH zones of pH 9.0. The specific growth rate especially during the exponential growth phase is strongly affected resulting in a decreased maximum viable cell density and final product titer. The gathered results indicate that even short-term exposure of cells to elevated pH values during large-scale processes can affect cell physiology and overall process performance. In particular, it could be shown for the first time that pH perturbations, which might occur during the early process phase, have to be considered in scale-down models of mammalian processes. Copyright © 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

  12. MATHEMATICAL ANALYSIS OF STEADY-STATE SOLUTIONS IN COMPARTMENT AND CONTINUUM MODELS OF CELL POLARIZATION

    PubMed Central

    ZHENG, ZHENZHEN; CHOU, CHING-SHAN; YI, TAU-MU; NIE, QING

    2013-01-01

    Cell polarization, in which substances previously uniformly distributed become asymmetric due to external or/and internal stimulation, is a fundamental process underlying cell mobility, cell division, and other polarized functions. The yeast cell S. cerevisiae has been a model system to study cell polarization. During mating, yeast cells sense shallow external spatial gradients and respond by creating steeper internal gradients of protein aligned with the external cue. The complex spatial dynamics during yeast mating polarization consists of positive feedback, degradation, global negative feedback control, and cooperative effects in protein synthesis. Understanding such complex regulations and interactions is critical to studying many important characteristics in cell polarization including signal amplification, tracking dynamic signals, and potential trade-off between achieving both objectives in a robust fashion. In this paper, we study some of these questions by analyzing several models with different spatial complexity: two compartments, three compartments, and continuum in space. The step-wise approach allows detailed characterization of properties of the steady state of the system, providing more insights for biological regulations during cell polarization. For cases without membrane diffusion, our study reveals that increasing the number of spatial compartments results in an increase in the number of steady-state solutions, in particular, the number of stable steady-state solutions, with the continuum models possessing infinitely many steady-state solutions. Through both analysis and simulations, we find that stronger positive feedback, reduced diffusion, and a shallower ligand gradient all result in more steady-state solutions, although most of these are not optimally aligned with the gradient. We explore in the different settings the relationship between the number of steady-state solutions and the extent and accuracy of the polarization. Taken together these results furnish a detailed description of the factors that influence the tradeoff between a single correctly aligned but poorly polarized stable steady-state solution versus multiple more highly polarized stable steady-state solutions that may be incorrectly aligned with the external gradient. PMID:21936604

  13. Dermal, oral, and inhalation pharmacokinetics of methyl tertiary butyl ether (MTBE) in human volunteers.

    PubMed

    Prah, James; Ashley, David; Blount, Benjamin; Case, Martin; Leavens, Teresa; Pleil, Joachim; Cardinali, Frederick

    2004-02-01

    Methyl tertiary butyl ether (MTBE), a gasoline additive used to increase octane and reduce carbon monoxide emissions and ozone precursors, has contaminated drinking water and can lead to exposure by oral, inhalation, and dermal routes. To determine its dermal, oral, and inhalation kinetics, 14 volunteers were exposed to 51.3 microg/ml MTBE dermally in tap water for 1 h, drank 2.8 mg MTBE in 250 ml Gatorade(R), and inhaled 3.1 ppm. MTBE for 1 h. Blood and exhaled breath samples were then obtained. Blood MTBE peaked between 15 and 30 min following oral exposure, at the end of inhalation exposure, and ~5 min after dermal exposure. Elimination by each route was described well by a three-compartment model (Rsq >0.9). The Akaike Information Criterion for the three-compartment model was smaller than the two-compartment model, supporting it over the two-compartment model. One metabolite, tertiary butyl alcohol (TBA), measured in blood slowly increased and plateaued, but it did not return to the pre-exposure baseline at the 24-h follow-up. TBA is very water-soluble and has a blood:air partition ratio of 462, reducing elimination by exhalation. Oral exposure resulted in a significantly greater MTBE metabolism into TBA than by other routes based on a greater blood TBA:MTBE AUC ratio, implying significant first-pass metabolism. The slower TBA elimination may make it a better biomarker of MTBE exposure, though one must consider the exposure route when estimating MTBE exposure from TBA because of first-pass metabolism. Most subjects had a baseline blood TBA of 1-3 ppb. Because TBA is found in consumer products and can be used as a fuel additive, it is not a definitive marker of MTBE exposure. These data provide the risk assessment process of pharmacokinetic information relevant to the media through which most exposures occur-air and drinking water.

  14. Simple Kinematic Pathway Approach (KPA) to Catchment-scale Travel Time and Water Age Distributions

    NASA Astrophysics Data System (ADS)

    Soltani, S. S.; Cvetkovic, V.; Destouni, G.

    2017-12-01

    The distribution of catchment-scale water travel times is strongly influenced by morphological dispersion and is partitioned between hillslope and larger, regional scales. We explore whether hillslope travel times are predictable using a simple semi-analytical "kinematic pathway approach" (KPA) that accounts for dispersion on two levels of morphological and macro-dispersion. The study gives new insights to shallow (hillslope) and deep (regional) groundwater travel times by comparing numerical simulations of travel time distributions, referred to as "dynamic model", with corresponding KPA computations for three different real catchment case studies in Sweden. KPA uses basic structural and hydrological data to compute transient water travel time (forward mode) and age (backward mode) distributions at the catchment outlet. Longitudinal and morphological dispersion components are reflected in KPA computations by assuming an effective Peclet number and topographically driven pathway length distributions, respectively. Numerical simulations of advective travel times are obtained by means of particle tracking using the fully-integrated flow model MIKE SHE. The comparison of computed cumulative distribution functions of travel times shows significant influence of morphological dispersion and groundwater recharge rate on the compatibility of the "kinematic pathway" and "dynamic" models. Zones of high recharge rate in "dynamic" models are associated with topographically driven groundwater flow paths to adjacent discharge zones, e.g. rivers and lakes, through relatively shallow pathway compartments. These zones exhibit more compatible behavior between "dynamic" and "kinematic pathway" models than the zones of low recharge rate. Interestingly, the travel time distributions of hillslope compartments remain almost unchanged with increasing recharge rates in the "dynamic" models. This robust "dynamic" model behavior suggests that flow path lengths and travel times in shallow hillslope compartments are controlled by topography, and therefore application and further development of the simple "kinematic pathway" approach is promising for their modeling.

  15. Carbon fuel cells with carbon corrosion suppression

    DOEpatents

    Cooper, John F [Oakland, CA

    2012-04-10

    An electrochemical cell apparatus that can operate as either a fuel cell or a battery includes a cathode compartment, an anode compartment operatively connected to the cathode compartment, and a carbon fuel cell section connected to the anode compartment and the cathode compartment. An effusion plate is operatively positioned adjacent the anode compartment or the cathode compartment. The effusion plate allows passage of carbon dioxide. Carbon dioxide exhaust channels are operatively positioned in the electrochemical cell to direct the carbon dioxide from the electrochemical cell.

  16. Environmental Risk Assessment Strategy for Nanomaterials.

    PubMed

    Scott-Fordsmand, Janeck J; Peijnenburg, Willie J G M; Semenzin, Elena; Nowack, Bernd; Hunt, Neil; Hristozov, Danail; Marcomini, Antonio; Irfan, Muhammad-Adeel; Jiménez, Araceli Sánchez; Landsiedel, Robert; Tran, Lang; Oomen, Agnes G; Bos, Peter M J; Hund-Rinke, Kerstin

    2017-10-19

    An Environmental Risk Assessment (ERA) for nanomaterials (NMs) is outlined in this paper. Contrary to other recent papers on the subject, the main data requirements, models and advancement within each of the four risk assessment domains are described, i.e., in the: (i) materials, (ii) release, fate and exposure, (iii) hazard and (iv) risk characterisation domains. The material, which is obviously the foundation for any risk assessment, should be described according to the legislatively required characterisation data. Characterisation data will also be used at various levels within the ERA, e.g., exposure modelling. The release, fate and exposure data and models cover the input for environmental distribution models in order to identify the potential (PES) and relevant exposure scenarios (RES) and, subsequently, the possible release routes, both with regard to which compartment(s) NMs are distributed in line with the factors determining the fate within environmental compartment. The initial outcome in the risk characterisation will be a generic Predicted Environmental Concentration (PEC), but a refined PEC can be obtained by applying specific exposure models for relevant media. The hazard information covers a variety of representative, relevant and reliable organisms and/or functions, relevant for the RES and enabling a hazard characterisation. The initial outcome will be hazard characterisation in test systems allowing estimating a Predicted No-Effect concentration (PNEC), either based on uncertainty factors or on a NM adapted version of the Species Sensitivity Distributions approach. The risk characterisation will either be based on a deterministic risk ratio approach (i.e., PEC/PNEC) or an overlay of probability distributions, i.e., exposure and hazard distributions, using the nano relevant models.

  17. Environmental Risk Assessment Strategy for Nanomaterials

    PubMed Central

    Scott-Fordsmand, Janeck J.; Nowack, Bernd; Hunt, Neil; Hristozov, Danail; Marcomini, Antonio; Irfan, Muhammad-Adeel; Jiménez, Araceli Sánchez; Landsiedel, Robert; Tran, Lang; Oomen, Agnes G.; Bos, Peter M. J.

    2017-01-01

    An Environmental Risk Assessment (ERA) for nanomaterials (NMs) is outlined in this paper. Contrary to other recent papers on the subject, the main data requirements, models and advancement within each of the four risk assessment domains are described, i.e., in the: (i) materials, (ii) release, fate and exposure, (iii) hazard and (iv) risk characterisation domains. The material, which is obviously the foundation for any risk assessment, should be described according to the legislatively required characterisation data. Characterisation data will also be used at various levels within the ERA, e.g., exposure modelling. The release, fate and exposure data and models cover the input for environmental distribution models in order to identify the potential (PES) and relevant exposure scenarios (RES) and, subsequently, the possible release routes, both with regard to which compartment(s) NMs are distributed in line with the factors determining the fate within environmental compartment. The initial outcome in the risk characterisation will be a generic Predicted Environmental Concentration (PEC), but a refined PEC can be obtained by applying specific exposure models for relevant media. The hazard information covers a variety of representative, relevant and reliable organisms and/or functions, relevant for the RES and enabling a hazard characterisation. The initial outcome will be hazard characterisation in test systems allowing estimating a Predicted No-Effect concentration (PNEC), either based on uncertainty factors or on a NM adapted version of the Species Sensitivity Distributions approach. The risk characterisation will either be based on a deterministic risk ratio approach (i.e., PEC/PNEC) or an overlay of probability distributions, i.e., exposure and hazard distributions, using the nano relevant models. PMID:29048395

  18. Numerical Cerebrospinal System Modeling in Fluid-Structure Interaction.

    PubMed

    Garnotel, Simon; Salmon, Stéphanie; Balédent, Olivier

    2018-01-01

    Cerebrospinal fluid (CSF) stroke volume in the aqueduct is widely used to evaluate CSF dynamics disorders. In a healthy population, aqueduct stroke volume represents around 10% of the spinal stroke volume while intracranial subarachnoid space stroke volume represents 90%. The amplitude of the CSF oscillations through the different compartments of the cerebrospinal system is a function of the geometry and the compliances of each compartment, but we suspect that it could also be impacted be the cardiac cycle frequency. To study this CSF distribution, we have developed a numerical model of the cerebrospinal system taking into account cerebral ventricles, intracranial subarachnoid spaces, spinal canal and brain tissue in fluid-structure interactions. A numerical fluid-structure interaction model is implemented using a finite-element method library to model the cerebrospinal system and its interaction with the brain based on fluid mechanics equations and linear elasticity equations coupled in a monolithic formulation. The model geometry, simplified in a first approach, is designed in accordance with realistic volume ratios of the different compartments: a thin tube is used to mimic the high flow resistance of the aqueduct. CSF velocity and pressure and brain displacements are obtained as simulation results, and CSF flow and stroke volume are calculated from these results. Simulation results show a significant variability of aqueduct stroke volume and intracranial subarachnoid space stroke volume in the physiological range of cardiac frequencies. Fluid-structure interactions are numerous in the cerebrospinal system and difficult to understand in the rigid skull. The presented model highlights significant variations of stroke volumes under cardiac frequency variations only.

  19. Quantification of tumor perfusion using dynamic contrast-enhanced ultrasound: impact of mathematical modeling

    NASA Astrophysics Data System (ADS)

    Doury, Maxime; Dizeux, Alexandre; de Cesare, Alain; Lucidarme, Olivier; Pellot-Barakat, Claire; Bridal, S. Lori; Frouin, Frédérique

    2017-02-01

    Dynamic contrast-enhanced ultrasound has been proposed to monitor tumor therapy, as a complement to volume measurements. To assess the variability of perfusion parameters in ideal conditions, four consecutive test-retest studies were acquired in a mouse tumor model, using controlled injections. The impact of mathematical modeling on parameter variability was then investigated. Coefficients of variation (CV) of tissue blood volume (BV) and tissue blood flow (BF) based-parameters were estimated inside 32 sub-regions of the tumors, comparing the log-normal (LN) model with a one-compartment model fed by an arterial input function (AIF) and improved by the introduction of a time delay parameter. Relative perfusion parameters were also estimated by normalization of the LN parameters and normalization of the one-compartment parameters estimated with the AIF, using a reference tissue (RT) region. A direct estimation (rRTd) of relative parameters, based on the one-compartment model without using the AIF, was also obtained by using the kinetics inside the RT region. Results of test-retest studies show that absolute regional parameters have high CV, whatever the approach, with median values of about 30% for BV, and 40% for BF. The positive impact of normalization was established, showing a coherent estimation of relative parameters, with reduced CV (about 20% for BV and 30% for BF using the rRTd approach). These values were significantly lower (p  <  0.05) than the CV of absolute parameters. The rRTd approach provided the smallest CV and should be preferred for estimating relative perfusion parameters.

  20. Quantitative protein localization signatures reveal an association between spatial and functional divergences of proteins.

    PubMed

    Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

    2014-03-01

    Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein functions and how these functions were acquired in cells from different organisms or species. A public web interface of PLAST is available at http://plast.bii.a-star.edu.sg.

  1. Quantitative Protein Localization Signatures Reveal an Association between Spatial and Functional Divergences of Proteins

    PubMed Central

    Loo, Lit-Hsin; Laksameethanasan, Danai; Tung, Yi-Ling

    2014-01-01

    Protein subcellular localization is a major determinant of protein function. However, this important protein feature is often described in terms of discrete and qualitative categories of subcellular compartments, and therefore it has limited applications in quantitative protein function analyses. Here, we present Protein Localization Analysis and Search Tools (PLAST), an automated analysis framework for constructing and comparing quantitative signatures of protein subcellular localization patterns based on microscopy images. PLAST produces human-interpretable protein localization maps that quantitatively describe the similarities in the localization patterns of proteins and major subcellular compartments, without requiring manual assignment or supervised learning of these compartments. Using the budding yeast Saccharomyces cerevisiae as a model system, we show that PLAST is more accurate than existing, qualitative protein localization annotations in identifying known co-localized proteins. Furthermore, we demonstrate that PLAST can reveal protein localization-function relationships that are not obvious from these annotations. First, we identified proteins that have similar localization patterns and participate in closely-related biological processes, but do not necessarily form stable complexes with each other or localize at the same organelles. Second, we found an association between spatial and functional divergences of proteins during evolution. Surprisingly, as proteins with common ancestors evolve, they tend to develop more diverged subcellular localization patterns, but still occupy similar numbers of compartments. This suggests that divergence of protein localization might be more frequently due to the development of more specific localization patterns over ancestral compartments than the occupation of new compartments. PLAST enables systematic and quantitative analyses of protein localization-function relationships, and will be useful to elucidate protein functions and how these functions were acquired in cells from different organisms or species. A public web interface of PLAST is available at http://plast.bii.a-star.edu.sg. PMID:24603469

  2. Dynamic GLUT4 sorting through a syntaxin-6 compartment in muscle cells is derailed by insulin resistance-causing ceramide

    PubMed Central

    Foley, Kevin P.; Klip, Amira

    2014-01-01

    ABSTRACT GLUT4 constitutively recycles between the plasma membrane and intracellular depots. Insulin shifts this dynamic equilibrium towards the plasma membrane by recruiting GLUT4 to the plasma membrane from insulin-responsive vesicles. Muscle is the primary site for dietary glucose deposition; however, how GLUT4 sorts into insulin-responsive vesicles, and if and how insulin resistance affects this process, is unknown. In L6 myoblasts stably expressing myc-tagged GLUT4, we analyzed the intracellular itinerary of GLUT4 as it internalizes from the cell surface and examined if such sorting is perturbed by C2-ceramide, a lipid metabolite causing insulin resistance. Surface-labeled GLUT4myc that internalized for 30 min accumulated in a Syntaxin-6 (Stx6)- and Stx16-positive perinuclear sub-compartment devoid of furin or internalized transferrin, and displayed insulin-responsive re-exocytosis. C2-ceramide dispersed the Stx6-positive sub-compartment and prevented insulin-responsive re-exocytosis of internalized GLUT4myc, even under conditions not affecting insulin-stimulated signaling towards Akt. Microtubule disruption with nocodazole prevented pre-internalized GLUT4myc from reaching the Stx6-positive perinuclear sub-compartment and from undergoing insulin-responsive exocytosis. Removing nocodazole allowed both parameters to recover, suggesting that the Stx6-positive perinuclear sub-compartment was required for GLUT4 insulin-responsiveness. Accordingly, Stx6 knockdown inhibited by ∼50% the ability of internalized GLUT4myc to undergo insulin-responsive re-exocytosis without altering its overall perinuclear accumulation. We propose that Stx6 defines the insulin-responsive compartment in muscle cells. Our data are consistent with a model where ceramide could cause insulin resistance by altering intracellular GLUT4 sorting. PMID:24705014

  3. Mapping the parameter space of a T2-dependent model of water diffusion MR in brain tissue.

    PubMed

    Hansen, Brian; Vestergaard-Poulsen, Peter

    2006-10-01

    We present a new model for describing the diffusion-weighted (DW) proton nuclear magnetic resonance signal obtained from normal grey matter. Our model is analytical and, in some respects, is an extension of earlier model schemes. We model tissue as composed of three separate compartments with individual properties of diffusion and transverse relaxation. Our study assumes slow exchange between compartments. We attempt to take cell morphology into account, along with its effect on water diffusion in tissues. Using this model, we simulate diffusion-sensitive MR signals and compare model output to experimental data from human grey matter. In doing this comparison, we perform a global search for good fits in the parameter space of the model. The characteristic nonmonoexponential behavior of the signal as a function of experimental b value is reproduced quite well, along with established values for tissue-specific parameters such as volume fraction, tortuosity and apparent diffusion coefficient. We believe that the presented approach to modeling diffusion in grey matter adds new aspects to the treatment of a longstanding problem.

  4. The Dynamics of HPV Infection and Cervical Cancer Cells.

    PubMed

    Asih, Tri Sri Noor; Lenhart, Suzanne; Wise, Steven; Aryati, Lina; Adi-Kusumo, F; Hardianti, Mardiah S; Forde, Jonathan

    2016-01-01

    The development of cervical cells from normal cells infected by human papillomavirus into invasive cancer cells can be modeled using population dynamics of the cells and free virus. The cell populations are separated into four compartments: susceptible cells, infected cells, precancerous cells and cancer cells. The model system of differential equations also has a free virus compartment in the system, which infect normal cells. We analyze the local stability of the equilibrium points of the model and investigate the parameters, which play an important role in the progression toward invasive cancer. By simulation, we investigate the boundary between initial conditions of solutions, which tend to stable equilibrium point, representing controlled infection, and those which tend to unbounded growth of the cancer cell population. Parameters affected by drug treatment are varied, and their effect on the risk of cancer progression is explored.

  5. A SIMPLE MODEL FOR THE UPTAKE, TRANSLOCATION, AND ACCUMULATION OF PERCHLORATE IN TOBACCO PLANTS

    EPA Science Inventory

    A simple mathematical model is being developed to describe the uptake, translocation, and accumulation of perchlorate in tobacco plants. The model defines a plant as a set of compartments, consisting of mass balance differential equations and plant-specific physiological paramet...

  6. Optimal timing of oral fosfomycin administration for pre-prostate biopsy prophylaxis.

    PubMed

    Rhodes, Nathaniel J; Gardiner, Bradley J; Neely, Michael N; Grayson, M Lindsay; Ellis, Andrew G; Lawrentschuk, Nathan; Frauman, Albert G; Maxwell, Kelly M; Zembower, Teresa R; Scheetz, Marc H

    2015-07-01

    As the optimal administration time for fosfomycin peri-procedural prophylaxis is unclear, we sought to determine optimal administration times for fosfomycin peri-procedural prophylaxis. Plasma, peripheral zone and transition zone fosfomycin concentrations were obtained from 26 subjects undergoing transurethral resection of the prostate (TURP), following a single oral dose of 3 g of fosfomycin. Population pharmacokinetic modelling was completed with the Nonparametric Adaptive Grid (NPAG) algorithm (Pmetrics package for R), with a four-compartment model. Plasma and tissue concentrations were simulated during the first 24 h post-dose, comparing these with EUCAST susceptibility breakpoints for Escherichia coli, a common uropathogen. Non-compartmental-determined pharmacokinetic values in our population were similar to those reported in the package insert. Predicted plasma concentrations rapidly increased after the first hour, giving more than 90% population coverage for organisms with an MIC ≤4 mg/L over the first 12 h post-dose. Organisms with higher MICs fared much worse, with organisms at the EUCAST breakpoint being covered for <10% of the population at any time. Transitional zone prostate concentrations exceeded 4 mg/L for 90% of the population between hours 1 and 9. Peripheral zone prostate concentrations were much lower and only exceeded 4 mg/L for 70% of the population between hours 1 and 4. Until more precise plasma and tissue data are available, we recommend that fosfomycin prophylaxis be given 1-4 h prior to prostate biopsy. We do not recommend fosfomycin prophylaxis for subjects with known organisms with MICs >4 mg/L. © The Author 2015. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

  7. Posttranslational Amelogenin Processing and Changes in Matrix Assembly during Enamel Development

    PubMed Central

    Pandya, Mirali; Lin, Tiffani; Li, Leo; Allen, Michael J.; Jin, Tianquan; Luan, Xianghong; Diekwisch, Thomas G. H.

    2017-01-01

    The extracellular tooth enamel matrix is a unique, protein-rich environment that provides the structural basis for the growth of long and parallel oriented enamel crystals. Here we have conducted a series of in vivo and in vitro studies to characterize the changes in matrix shape and organization that take place during the transition from ameloblast intravesicular matrices to extracellular subunit compartments and pericrystalline sheath proteins, and correlated these changes with stages of amelogenin matrix protein posttranslational processing. Our transmission electron microscopic studies revealed a 2.5-fold difference in matrix subunit compartment dimensions between secretory vesicle and extracellular enamel protein matrix as well as conformational changes in matrix structure between vesicles, stippled materials, and pericrystalline matrix. Enamel crystal growth in organ culture demonstrated granular mineral deposits associated with the enamel matrix framework, dot-like mineral deposits along elongating initial enamel crystallites, and dramatic changes in enamel matrix configuration following the onset of enamel crystal formation. Atomic force micrographs provided evidence for the presence of both linear and hexagonal/ring-shaped full-length recombinant amelogenin protein assemblies on mica surfaces, while nickel-staining of the N-terminal amelogenin N92 His-tag revealed 20 nm diameter oval and globular amelogenin assemblies in N92 amelogenin matrices. Western blot analysis comparing loosely bound and mineral-associated protein fractions of developing porcine enamel organs, superficial and deep enamel layers demonstrated (i) a single, full-length amelogenin band in the enamel organ followed by 3 kDa cleavage upon entry into the enamel layer, (ii) a close association of 8–16 kDa C-terminal amelogenin cleavage products with the growing enamel apatite crystal surface, and (iii) a remaining pool of N-terminal amelogenin fragments loosely retained between the crystalline phases of the deep enamel layer. Together, our data establish a temporo-spatial correlation between amelogenin protein processing and the changes in enamel matrix configuration that take place during the transition from intracellular vesicle compartments to extracellular matrix assemblies and the formation of protein coats along elongating apatite crystal surfaces. In conclusion, our study suggests that enzymatic cleavage of the amelogenin enamel matrix protein plays a key role in the patterning of the organic matrix framework as it affects enamel apatite crystal growth and habit. PMID:29089900

  8. Posttranslational Amelogenin Processing and Changes in Matrix Assembly during Enamel Development.

    PubMed

    Pandya, Mirali; Lin, Tiffani; Li, Leo; Allen, Michael J; Jin, Tianquan; Luan, Xianghong; Diekwisch, Thomas G H

    2017-01-01

    The extracellular tooth enamel matrix is a unique, protein-rich environment that provides the structural basis for the growth of long and parallel oriented enamel crystals. Here we have conducted a series of in vivo and in vitro studies to characterize the changes in matrix shape and organization that take place during the transition from ameloblast intravesicular matrices to extracellular subunit compartments and pericrystalline sheath proteins, and correlated these changes with stages of amelogenin matrix protein posttranslational processing. Our transmission electron microscopic studies revealed a 2.5-fold difference in matrix subunit compartment dimensions between secretory vesicle and extracellular enamel protein matrix as well as conformational changes in matrix structure between vesicles, stippled materials, and pericrystalline matrix. Enamel crystal growth in organ culture demonstrated granular mineral deposits associated with the enamel matrix framework, dot-like mineral deposits along elongating initial enamel crystallites, and dramatic changes in enamel matrix configuration following the onset of enamel crystal formation. Atomic force micrographs provided evidence for the presence of both linear and hexagonal/ring-shaped full-length recombinant amelogenin protein assemblies on mica surfaces, while nickel-staining of the N-terminal amelogenin N92 His-tag revealed 20 nm diameter oval and globular amelogenin assemblies in N92 amelogenin matrices. Western blot analysis comparing loosely bound and mineral-associated protein fractions of developing porcine enamel organs, superficial and deep enamel layers demonstrated (i) a single, full-length amelogenin band in the enamel organ followed by 3 kDa cleavage upon entry into the enamel layer, (ii) a close association of 8-16 kDa C-terminal amelogenin cleavage products with the growing enamel apatite crystal surface, and (iii) a remaining pool of N-terminal amelogenin fragments loosely retained between the crystalline phases of the deep enamel layer. Together, our data establish a temporo-spatial correlation between amelogenin protein processing and the changes in enamel matrix configuration that take place during the transition from intracellular vesicle compartments to extracellular matrix assemblies and the formation of protein coats along elongating apatite crystal surfaces. In conclusion, our study suggests that enzymatic cleavage of the amelogenin enamel matrix protein plays a key role in the patterning of the organic matrix framework as it affects enamel apatite crystal growth and habit.

  9. Translating transitions – how to decipher peripheral human B cell development

    PubMed Central

    Bemark, Mats

    2015-01-01

    Abstract During the last two decades our understanding of human B cell differentiation has developed considerably. Our understanding of the human B cell compartment has advanced from a point where essentially all assays were based on the presence or not of class-switched antibodies to a level where a substantial diversity is appreciated among the cells involved. Several consecutive transitional stages that newly formed IgM expressing B cells go through after they leave the bone marrow, but before they are fully mature, have been described, and a significant complexity is also acknowledged within the IgM expressing and class-switched memory B cell compartments. It is possible to isolate plasma blasts in blood to follow the formation of plasma cells during immune responses, and the importance and uniqueness of the mucosal IgA system is now much more appreciated. Current data suggest the presence of at least one lineage of human innate-like B cells akin to B1 and/or marginal zone B cells in mice. In addition, regulatory B cells with the ability to produce IL-10 have been identified. Clinically, B cell depletion therapy is used for a broad range of conditions. The ability to define different human B cell subtypes using flow cytometry has therefore started to come into clinical use, but as our understanding of human B cell development further progresses, B cell subtype analysis will be of increasing importance in diagnosis, to measure the effect of immune therapy and to understand the underlying causes for diseases. In this review the diversity of human B cells will be discussed, with special focus on current data regarding their phenotypes and functions. PMID:26243514

  10. Experiments in a three-dimensional adaptive-wall wind tunnel

    NASA Technical Reports Server (NTRS)

    Schairer, E. T.

    1983-01-01

    Three dimensional adaptive-wall experiments were performed in the Ames Research Center (ARC) 25- by 13-cm indraft wind tunnel. A semispan wing model was mounted to one sidewall of a test section with solid sidewalls, and slotted top and bottom walls. The test section had separate top and bottom plenums which were divided into streamwise and cross-stream compartments. An iterative procedure was demonstrated for measuring wall interference and for adjusting the plenum compartment pressures to eliminate such interference. The experiments were conducted at a freestream Mach number of 0.60 and model angles of attack between 0 and 6 deg. Although in all the experiments wall interference was reduced after the plenum pressures were adjusted, interference could not be completely eliminated.

  11. Global, spatial, and temporal sensitivity analysis for a complex pesticide fate and transport model.

    EPA Science Inventory

    Background/Questions/Methods As one ofthe most heavily used exposure models by U.S. EPA, Pesticide Root Zone Model (PRZM) is a one-dimensional, dynamic, compartment model that predicts the fate and transport of a pesticide in the unsaturated soil system around a plant's root zo...

  12. Ultrasonic Apparatus and Method to Assess Compartment Syndrome

    NASA Technical Reports Server (NTRS)

    Yost, William T. (Inventor); Ueno, Toshiaki (Inventor); Hargens, Alan R. (Inventor)

    2009-01-01

    A process and apparatus for measuring pressure buildup in a body compartment that encases muscular tissue. The method includes assessing the body compartment configuration and identifying the effect of pulsatible components on compartment dimensions and muscle tissue characteristics. This process is used in preventing tissue necrosis, and in decisions of whether to perform surgery on the body compartment for prevention of Compartment Syndrome. An apparatus is used for measuring pressure build-up in the body compartment having components for imparting ultrasonic waves such as a transducer, placing the transducer to impart the ultrasonic waves, capturing the imparted ultrasonic waves, mathematically manipulating the captured ultrasonic waves and categorizing pressure build-up in the body compartment from the mathematical manipulations.

  13. Method and apparatus to assess compartment syndrome

    NASA Technical Reports Server (NTRS)

    Hargens, Alan R. (Inventor); Yost, William T. (Inventor); Ueno, Toshiaki (Inventor)

    2008-01-01

    A method and apparatus for measuring pressure buildup in a body compartment that encases muscular tissue. The method includes assessing the body compartment configuration and identifying the effect of pulsatile components on at least one compartment dimension. This process is used in preventing tissue necrosis, and in decisions of whether to perform surgery on the body compartment for prevention of Compartment Syndrome. An apparatus is used for measuring excess pressure in the body compartment having components for imparting ultrasonic waves such as a transducer, placing the transducer to impart the ultrasonic waves, capturing the reflected imparted ultrasonic waves, and converting them to electrical signals, a pulsed phase-locked loop device for assessing a body compartment configuration and producing an output signal, and means for mathematically manipulating the output signal to thereby categorize pressure build-up in the body compartment from the mathematical manipulations.

  14. Above-ground biomass of mangrove species. I. Analysis of models

    NASA Astrophysics Data System (ADS)

    Soares, Mário Luiz Gomes; Schaeffer-Novelli, Yara

    2005-10-01

    This study analyzes the above-ground biomass of Rhizophora mangle and Laguncularia racemosa located in the mangroves of Bertioga (SP) and Guaratiba (RJ), Southeast Brazil. Its purpose is to determine the best regression model to estimate the total above-ground biomass and compartment (leaves, reproductive parts, twigs, branches, trunk and prop roots) biomass, indirectly. To do this, we used structural measurements such as height, diameter at breast-height (DBH), and crown area. A combination of regression types with several compositions of independent variables generated 2.272 models that were later tested. Subsequent analysis of the models indicated that the biomass of reproductive parts, branches, and prop roots yielded great variability, probably because of environmental factors and seasonality (in the case of reproductive parts). It also indicated the superiority of multiple regression to estimate above-ground biomass as it allows researchers to consider several aspects that affect above-ground biomass, specially the influence of environmental factors. This fact has been attested to the models that estimated the biomass of crown compartments.

  15. 78 FR 19090 - Airworthiness Directives; Embraer S.A. Airplanes

    Federal Register 2010, 2011, 2012, 2013, 2014

    2013-03-29

    ...We are adopting a new airworthiness directive (AD) for certain Embraer S.A. Model ERJ 170 and ERJ 190 airplanes. This AD was prompted by a report that high rate discharge (HRD) bottle explosive cartridges of a cargo compartment fire extinguisher system were swapped between the forward and aft cargo compartments. Additional investigation also revealed the possibility of swapping between the electrical connectors of the HRD and low rate discharge (LRD) bottles, and a rotated installation of the HRD bottle. Improper assembly of the fire extinguishing bottle might cause the extinguishing agent to be discharged toward the unselected cargo compartment rather than toward the cargo compartment with fire. This AD requires an inspection of the HRD bottle for correct installation and to determine if the pressure switch is in the correct position, and re-installation if necessary; an inspection of the HRD and LRD bottle discharge heads to determine the part number, and replacement if necessary; and, for certain airplanes, an inspection to identify the HRD and LRD bottle electrical connectors, and relocation if necessary. We are issuing this AD to prevent the inability of the fire extinguishing system to suppress fire.

  16. 3D printed multi-compartment capsular devices for two-pulse oral drug delivery.

    PubMed

    Maroni, A; Melocchi, A; Parietti, F; Foppoli, A; Zema, L; Gazzaniga, A

    2017-12-28

    In the drug delivery area, versatile therapeutic systems intended to yield customized combinations of drugs, drug doses and release kinetics have drawn increasing attention, especially because of the advantages that personalized pharmaceutical treatments would offer. In this respect, a previously proposed capsular device able to control the release performance based on its design and composition, which could extemporaneously be filled, was improved to include multiple separate compartments so that differing active ingredients or formulations may be conveyed. The compartments, which may differ in thickness and composition, resulted from assembly of two hollow halves through a joint also acting as a partition. The systems were manufactured by fused deposition modeling (FDM) 3D printing, which holds special potential for product personalization, and injection molding (IM) that would enable production on a larger scale. Through combination of compartments having wall thickness of 600 or 1200μm, composed of promptly soluble, swellable/erodible or enteric soluble polymers, devices showing two-pulse release patterns, consistent with the nature of the starting materials, were obtained. Systems fabricated using the two techniques exhibited comparable performance, thus proving the prototyping ability of FDM versus IM. Copyright © 2017 Elsevier B.V. All rights reserved.

  17. Evaluation of Aztreonam Dosing Regimens in Patients With Normal and Impaired Renal Function: A Population Pharmacokinetic Modeling and Monte Carlo Simulation Analysis.

    PubMed

    Xu, Hongmei; Zhou, Wangda; Zhou, Diansong; Li, Jianguo; Al-Huniti, Nidal

    2017-03-01

    Aztreonam is a monocyclic β-lactam antibiotic often used to treat infections caused by Enterobacteriaceae or Pseudomonas aeruginosa. Despite the long history of clinical use, population pharmacokinetic modeling of aztreonam in renally impaired patients is not yet available. The aims of this study were to assess the impact of renal impairment on aztreonam exposure and to evaluate dosing regimens for patients with renal impairment. A population model describing aztreonam pharmacokinetics following intravenous administration was developed using plasma concentrations from 42 healthy volunteers and renally impaired patients from 2 clinical studies. The final pharmacokinetic model was used to predict aztreonam plasma concentrations and evaluate the probability of pharmacodynamic target attainment (PTA) in patients with different levels of renal function. A 2-compartment model with first-order elimination adequately described aztreonam pharmacokinetics. The population mean estimates of aztreonam clearance, intercompartmental clearance, volume of distribution of the central compartment, and volume of distribution of the peripheral compartment were 4.93 L/h, 9.26 L/h, 7.43 L, and 6.44 L, respectively. Creatinine clearance and body weight were the most significant variables to explain patient variability in aztreonam clearance and volume of distribution, respectively. Simulations using the final pharmacokinetic model resulted in a clinical susceptibility break point of 4 and 8 mg/L, respectively, based on the clinical use of 1- and 2-g loading doses with the same or reduced maintenance dose every 8 hours for various renal deficiency patients. The population pharmacokinetic modeling and PTA estimation support adequate PTAs (>90% PTA) from the aztreonam label for dose adjustment of aztreonam in patients with moderate and severe renal impairment. © 2016, The American College of Clinical Pharmacology.

  18. Stable carbon isotope signals in particulate organic and inorganic carbon of coccolithophores - A numerical model study for Emiliania huxleyi.

    PubMed

    Holtz, Lena-Maria; Wolf-Gladrow, Dieter; Thoms, Silke

    2017-05-07

    A recent numerical cell model, which explains observed light and carbonate system effects on particulate organic and inorganic carbon (POC and PIC) production rates under the assumption of internal pH homeostasis, is extended for stable carbon isotopes ( 12 C, 13 C). Aim of the present study is to mechanistically understand the stable carbon isotopic fractionation signal (ε) in POC and PIC and furthermore the vital effect(s) included in measured ε PIC values. The virtual cell is divided into four compartments, for each of which the 12 C as well as the 13 C carbonate system kinetics are implemented. The compartments are connected to each other via trans-membrane fluxes. In contrast to existing carbon fractionation models, the presented model calculates the disequilibrium state for both carbonate systems and for each compartment. It furthermore calculates POC and PIC production rates as well as ε POC and ε PIC as a function of given light conditions and the compositions of the external carbonate system. Measured POC and PIC production rates as well as ε PIC values are reproduced well by the model (comparison with literature data). The observed light effect on ε POC (increase of ε POC with increasing light intensities), however, is not reproduced by the basic model set-up, which is solely based on RubisCO fractionation. When extending the latter set-up by assuming that biological fractionation includes further carbon fractionation steps besides the one of RubisCO, the observed light effect on ε POC is also reproduced. By means of the extended model version, four different vital effects that superimpose each other in a real cell can be detected. Finally, we discuss potential limitations of the ε PIC proxy. Copyright © 2017 Elsevier Ltd. All rights reserved.

  19. Towards deep learning with segregated dendrites

    PubMed Central

    Guerguiev, Jordan; Lillicrap, Timothy P

    2017-01-01

    Deep learning has led to significant advances in artificial intelligence, in part, by adopting strategies motivated by neurophysiology. However, it is unclear whether deep learning could occur in the real brain. Here, we show that a deep learning algorithm that utilizes multi-compartment neurons might help us to understand how the neocortex optimizes cost functions. Like neocortical pyramidal neurons, neurons in our model receive sensory information and higher-order feedback in electrotonically segregated compartments. Thanks to this segregation, neurons in different layers of the network can coordinate synaptic weight updates. As a result, the network learns to categorize images better than a single layer network. Furthermore, we show that our algorithm takes advantage of multilayer architectures to identify useful higher-order representations—the hallmark of deep learning. This work demonstrates that deep learning can be achieved using segregated dendritic compartments, which may help to explain the morphology of neocortical pyramidal neurons. PMID:29205151

  20. Towards deep learning with segregated dendrites.

    PubMed

    Guerguiev, Jordan; Lillicrap, Timothy P; Richards, Blake A

    2017-12-05

    Deep learning has led to significant advances in artificial intelligence, in part, by adopting strategies motivated by neurophysiology. However, it is unclear whether deep learning could occur in the real brain. Here, we show that a deep learning algorithm that utilizes multi-compartment neurons might help us to understand how the neocortex optimizes cost functions. Like neocortical pyramidal neurons, neurons in our model receive sensory information and higher-order feedback in electrotonically segregated compartments. Thanks to this segregation, neurons in different layers of the network can coordinate synaptic weight updates. As a result, the network learns to categorize images better than a single layer network. Furthermore, we show that our algorithm takes advantage of multilayer architectures to identify useful higher-order representations-the hallmark of deep learning. This work demonstrates that deep learning can be achieved using segregated dendritic compartments, which may help to explain the morphology of neocortical pyramidal neurons.

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