Soil mobility of synthetic and virus-based model nanopesticides.

Large doses of chemical pesticides are required to achieve effective concentrations in the rhizosphere, which results in the accumulation of harmful residues. Precision farming is needed to improve the efficacy of pesticides, but also to avoid environmental pollution, and slow-release formulations based on nanoparticles offer one solution. Here, we tested the mobility of synthetic and virus-based model nanopesticides by combining soil column experiments with computational modelling.

Quantifying proliferative and surface marker heterogeneity in colony-founding connective tissue progenitors and their progeny using time-lapse microscopy.

Connective tissue progenitors (CTPs) are defined as the heterogeneous population of tissue-resident stem and progenitor cells that are capable of proliferating and differentiating into connective tissue phenotypes. The prevalence and variation in clonal progeny of CTPs can be characterized using a colony formation assay. However, colony assays do not directly assess the characteristics of the colony-founding CTP.

Whole-body iron transport and metabolism: Mechanistic, multi-scale model to improve treatment of anemia in chronic kidney disease.

Iron plays vital roles in the human body including enzymatic processes, oxygen-transport via hemoglobin and immune response. Iron metabolism is characterized by ~95% recycling and minor replenishment through diet. Anemia of chronic kidney disease (CKD) is characterized by a lack of synthesis of erythropoietin leading to reduced red blood cell (RBC) formation and aberrant iron recycling.

Diffusion and Uptake of Tobacco Mosaic Virus as Therapeutic Carrier in Tumor Tissue: Effect of Nanoparticle Aspect Ratio.

Nanoparticle-based technologies, including platforms derived from plant viruses, hold great promise for targeting and delivering cancer therapeutics to solid tumors by overcoming dose-limiting toxicities associated with chemotherapies. A growing body of data indicates advantageous margination and penetration properties of high aspect-ratio nanoparticles, which enhance payload delivery, resulting in increased efficacy. Our lab has demonstrated that elongated rod-shaped and filamentous macromolecular nucleoprotein assemblies from plant viruses have higher tissue diffusion rates than spherical particles.

Relating tissue/organ energy expenditure to metabolic fluxes in mouse and human: experimental data integrated with mathematical modeling.

Mouse models of human diseases are used to study the metabolic and physiological processes leading to altered whole-body energy expenditure (EE), which is the sum of EE of all body organs and tissues. Isotopic techniques, arterio-venous difference of substrates, oxygen, and blood flow measurements can provide essential information to quantify tissue/organ EE and substrate oxidation. To complement and integrate experimental data, quantitative mathematical model analyses have been applied in the design of experiments and evaluation of metabolic fluxes.

Mathematical modelling of glycosaminoglycan production by stem cell aggregates incorporated with growth factor-releasing polymer microspheres.

Systems composed of high density cells incorporated with growth factor-releasing polymer microspheres have recently been shown to promote chondrogenic differentiation and cartilage formation. Within these systems, the effects of spatial and temporal patterning of growth factor release on hyaline cartilage-specific extracellular matrix production have been examined. However, at present, it is unclear which microsphere densities and growth factor delivery profiles are optimal for inducing human mesenchymal stem cell differentiation and glycosaminoglycan production.

Computational modeling and analysis of iron release from macrophages.

A major process of iron homeostasis in whole-body iron metabolism is the release of iron from the macrophages of the reticuloendothelial system. Macrophages recognize and phagocytose senescent or damaged erythrocytes. Then, they process the heme iron, which is returned to the circulation for reutilization by red blood cell precursors during erythropoiesis.

Mechanistic, mathematical model to predict the dynamics of tissue genesis in bone defects via mechanical feedback and mediation of biochemical factors.

The link between mechanics and biology in the generation and the adaptation of bone has been well studied in context of skeletal development and fracture healing. Yet, the prediction of tissue genesis within - and the spatiotemporal healing of - postnatal defects, necessitates a quantitative evaluation of mechano-biological interactions using experimental and clinical parameters. To address this current gap in knowledge, this study aims to develop a mechanistic mathematical model of tissue genesis using bone morphogenetic protein (BMP) to represent of a class of factors that may coordinate bone healing.

Modeling and experimental methods to predict oxygen distribution in bone defects following cell transplantation.

We have developed a mathematical model that allows simulation of oxygen distribution in a bone defect as a tool to explore the likely effects of local changes in cell concentration, defect size or geometry, local oxygen delivery with oxygen-generating biomaterials (OGBs), and changes in the rate of oxygen consumption by cells within a defect. Experimental data for the oxygen release rate from an OGB and the oxygen consumption rate of a transplanted cell population are incorporated into the model. With these data, model simulations allow prediction of spatiotemporal oxygen concentration within a given defect and the sensitivity of oxygen tension to changes in critical variables.

Distinguishing the effects of convective and diffusive O₂ delivery on VO₂ on-kinetics in skeletal muscle contracting at moderate intensity.

With current techniques, experimental measurements alone cannot characterize the effects of oxygen blood-tissue diffusion on muscle oxygen uptake (Vo₂) kinetics in contracting skeletal muscle. To complement experimental studies, a computational model is used to quantitatively distinguish the contributions of convective oxygen delivery, diffusion into cells, and oxygen utilization to Vo₂ kinetics. The model is validated using previously published experimental Vo₂ kinetics in response to slowed blood flow (Q) on-kinetics in canine muscle (τQ = 20 s, 46 s, and 64 s) [Goodwin ML, Hernández A, Lai N, Cabrera ME, Gladden LB.

Model analysis of the relationship between intracellular PO2 and energy demand in skeletal muscle.

On the basis of experimental studies, the intracellular O(2) (iPo(2))-work rate (WR) relationship in skeletal muscle is not unique. One study found that iPo(2) reached a plateau at 60% of maximal WR, while another found that iPo(2) decreased linearly at higher WR, inferring capillary permeability-surface area (PS) and blood-tissue O(2) gradient, respectively, as alternative dominant factors for determining O(2) diffusion changes during exercise. This relationship is affected by several factors, including O(2) delivery and oxidative and glycolytic capacities of the muscle.

Computational Model of Cellular Metabolic Dynamics in Skeletal Muscle Fibers during Moderate Intensity Exercise.

Human skeletal muscles have different fiber types with distinct metabolic functions and physiological properties. The quantitative metabolic responses of muscle fibers to exercise provide essential information for understanding and modifying the regulatory mechanisms of skeletal muscle. Since in vivo data from skeletal muscle during exercise is limited, a computational, physiologically based model has been developed to quantify the dynamic metabolic responses of many key chemical species.

Coding region polyadenylation generates a truncated tRNA synthetase that counters translation repression.

Posttranscriptional regulatory mechanisms superimpose "fine-tuning" control upon "on-off" switches characteristic of gene transcription. We have exploited computational modeling with experimental validation to resolve an anomalous relationship between mRNA expression and protein synthesis. The GAIT (gamma-interferon-activated inhibitor of translation) complex repressed VEGF-A synthesis to a low, constant rate independent of VEGF-A mRNA expression levels.

Experimental studies and modeling of drug release from a tunable affinity-based drug delivery platform.

An affinity-based drug delivery platform for controlling drug release is analyzed by a combination of experimental studies and mathematical modeling. This platform has the ability to form selective interactions between a therapeutic agent and host matrix that yields advantages over systems that employ nonselective methods. The incorporation of molecular interactions in drug delivery can increase the therapeutic lifetime of drug delivery implants and limit the need for multiple implants in treatment of chronic illnesses.

Regulation of Adipose Tissue Metabolism in Humans: Analysis of Responses to the Hyperinsulinemic-Euglycemic Clamp Experiment.

The suppression of lipolysis is one of the key metabolic responses of the adipose tissue during hyperinsulinemia. The failure to respond and resulting increase in plasma fatty acids could contribute to the development of insulin resistance and perturbations in the fuel homeostasis in the whole body. In this study, a mechanistic, computational model of adipose tissue metabolism has been enhanced to simulate the physiological responses during hyperinsulinemic-euglycemic clamp experiment in humans.

Hemoglobin and myoglobin contributions to skeletal muscle oxygenation in response to exercise.

The quantitative contributions of hemoglobin and myoglobin oxygenation in skeletal muscle depend on physiological factors, especially muscle blood flow (Q( m )) and capillary permeability-surface area (PS). Near-infrared spectroscopy (NIRS) can be used to quantify total heme oxidation, but it is unable to distinguish between hemoglobin and myoglobin. Therefore, a mechanistic computational model has been developed to distinguish the contributions of oxygenated hemoglobin and myoglobin to the total NIRS signal.

Regulation of cytosolic and mitochondrial oxidation via malate-aspartate shuttle: an observation using dynamic ¹³C NMR spectroscopy.

The malate-aspartate (M-A) shuttle provides an important mechanism of metabolic communication between the cytosol and the mitochondria. In this study, dynamic (13)C NMR spectroscopy was combined with a multi-domain model of cardiac metabolism for direct quantification of metabolic fluxes through the tricarboxylic acid (TCA) cycle (VTCA) and the M-A shuttle (VM-A) in intact heart. The sensitivity of this approach to altered M-A shuttle activity was examined at different cytosolic redox states.

Modeling of laser coagulation of tissue with MRI temperature monitoring.

Light energy from a laser source that is delivered into body tissue via a fiber-optic probe with minimal invasiveness has been used to ablate solid tumors. This thermal coagulation process can be guided and monitored accurately by continuous magnetic resonance imaging (MRI) since the laser energy delivery system does not interfere with MRI. This report deals with mathematical modeling and analysis of laser coagulation of tissue.

Computational model of cellular metabolic dynamics: effect of insulin on glucose disposal in human skeletal muscle.

Identifying the mechanisms by which insulin regulates glucose metabolism in skeletal muscle is critical to understanding the etiology of insulin resistance and type 2 diabetes. Our knowledge of these mechanisms is limited by the difficulty of obtaining in vivo intracellular data. To quantitatively distinguish significant transport and metabolic mechanisms from limited experimental data, we developed a physiologically based, multiscale mathematical model of cellular metabolic dynamics in skeletal muscle.

Multiscale modeling of respiration.

In human studies investigating factors that control cellular respiration in working skeletal muscle, pulmonary VO dynamics (VO) measured at the mouth by indirect calorimetry is typically used to represent muscle O consumption (UO). Furthermore, measurement of muscle oxygenation using near-infrared spectroscopy has provided information on the dynamic balance between oxygen delivery and oxygen consumption at the microvascular level. To relate these measurements and gain quantitative understanding of the regulation of VO at the cellular, tissue and whole-body level, a multiscale computational model of oxygen transport and metabolism during exercise was developed.

Modeling oxygenation in venous blood and skeletal muscle in response to exercise using near-infrared spectroscopy.

Noninvasive, continuous measurements in vivo are commonly used to make inferences about mechanisms controlling internal and external respiration during exercise. In particular, the dynamic response of muscle oxygenation (Sm(O(2))) measured by near-infrared spectroscopy (NIRS) is assumed to be correlated to that of venous oxygen saturation (Sv(O(2))) measured invasively. However, there are situations where the dynamics of Sm(O(2)) and Sv(O(2)) do not follow the same pattern.

Non-invasive estimation of metabolic flux and blood flow in working muscle: effect of blood-tissue distribution.

Muscle oxygenation measurements by near infrared spectroscopy (NIRS) are frequently obtained in humans to make inferences about mechanisms of metabolic control of respiration in working skeletal muscle. However, these measurements have technical limitations that can mislead the evaluation of tissue processes. In particular, NIRS measurements of working muscle represent oxygenation of a mix of fibers with heterogeneous activation, perfusion and architecture.

Mathematical modeling of thermal ablation in tissue surrounding a large vessel.

Thermal ablation of a solid tumor in a tissue with radio-frequency (rf) energy can be accomplished by using a probe inserted into the tissue under the guidance of magnetic resonance imaging. The extent of the ablation can be significantly reduced by heat loss from capillary perfusion and by blood flow in a large vessel in the tissue. A mathematical model is presented of the thermal processes that occur during rf ablation of a tissue near a large blood vessel, which should not be damaged.

Permeability change of arterial endothelium is an age-dependent function of lesion size in apolipoprotein E-null mice.

The remodeling process of the arterial wall in atherosclerosis involves intimal thickening, which can be related to the barrier functions of the endothelial cell layer (ECL) and internal elastic lamina (IEL) using horseradish peroxidase (HRP) as a tracer. To evaluate the ECL and IEL permeabilities (PECL and PIEL, respectively) and intimal transport parameters, e.g.

Role of NADH/NAD+ transport activity and glycogen store on skeletal muscle energy metabolism during exercise: in silico studies.

Skeletal muscle can maintain ATP concentration constant during the transition from rest to exercise, whereas metabolic reaction rates may increase substantially. Among the key regulatory factors of skeletal muscle energy metabolism during exercise, the dynamics of cytosolic and mitochondrial NADH and NAD+ have not been characterized. To quantify these regulatory factors, we have developed a physiologically based computational model of skeletal muscle energy metabolism.