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PubMed1995

A non-uniform three-dimensional perfusion model of rat tail heat transfer.

Previous models of rat tail heat transfer have assumed that the tail is uniformly perfused along its length and have introduced questionable assumptions about the heat transfer role of the major axial arteries and the venous blood shunting between the superficial and deep veins. The recent experiments of Lemons and Wu have shown that (i) perfusion of the tail tip is more than tenfold higher than that in the tail base and (ii) the perfusion of the middle region of the tail increases eightfold during heat stress compared to threefold to fourfold in the base and tip. Our anatomical studies have shown that the lateral arteries are a series of radially arcading connections from the ventral artery and probably do not serve as major axial conduit vessels. These observations indicate that current views and models for the blood flow distribution and heat transfer in the major axial arteries and veins and in the rat tail cutaneous circulation need substantial revision. Based on these new experimental findings a new three-dimensional model is developed to determine the heat transfer function of the rat tail at different local and central temperatures. The predictions of the model show good agreement with the axial surface temperature distribution in the rat tail reported by Lemons and Wu. These results, when combined with our anatomical studies, indicate that there is very little shunting of blood between the superficial lateral veins and the deep ventral vein as proposed by Raman et al. Although this model is based on the rat tail anatomy, it can be modified to treat the human limb and digit.

Animals↗
PubMed1988

Miniature implantable laser Doppler probe monitoring of free tissue transfer.

A 2.5-mm fiber-optic laser Doppler flowmetry probe has been applied in an experimental dog model as well as in 5 clinical cases to provide continuous readout of deep tissue perfusion. The rectus abdominis muscle in the dog was used for the experimental verification of the probe, which has a linear correlation with flow rate and a rapid response (6 seconds) to arterial occlusion and venous occlusion (20 seconds). Four of the 5 free tissue transfers survived with the laser Doppler instrument correctly identifying the lack of flow, both intraoperatively and postoperatively, in the failed flap. This probe greatly extends the versatility of laser Doppler flow measurement in the clinical setting and may be nearly an ideal probe for monitoring free tissue transfer, particularly muscle.

Animals↗
PubMed1998

The combined gracilis and semitendinosus free flap in the rat.

A free-flap model in rats is presented, that consists of gracilis and semitendinosus muscles pedicled on the femoral vessels, in continuation with deep femoral and saphenous vessels. This flap was transferred to the contralateral side in 40 rats and yielded a 95 percent survival rate. The weight of the flaps averaged 1.65 gm, and the mean pedicle length was 20 mm. The flap is reliable, versatile, and may be used as a muscular, musculocutaneous, or osteomusculocutaneous free flap. The gracilis and semitendinosus muscles may be innervated independently as functioning muscle units. In the musculocutaneous flap, each pedicle may be monitored separately by raising two independently vascularized skin islands. The statistical distribution of the origins of the deep femoral vessels was established in 164 groin dissections; two origins of the vessels not previously described are reported here. The volume of the transferable tissue-about three times more than described in previous studies-and the reliability of the flap make it an ideal microsurgical, experimental model.

Animals↗
PubMed2003

Development and verification of deep-water blowout models.

Modeling of deep-water releases of gas and oil involves conventional plume theory in combination with thermodynamics and mass transfer calculations. The discharges can be understood in terms of multiphase plumes, where gas bubbles and oil droplets may separate from the water phase of the plume and rise to the surface independently. The gas may dissolve in the ambient water and/or form gas hydrates--a solid state of water resembling ice. All these processes will tend to deprive the plume as such of buoyancy, and in stratified water the plume rise will soon terminate. Slick formation will be governed by the surfacing of individual oil droplets in a depth and time variable current. This situation differs from the conditions observed during oil-and-gas blowouts in shallow and moderate water depths. In such cases, the bubble plume has been observed to rise to the surface and form a strong radial flow that contributes to a rapid spreading of the surfacing oil. The theories and behaviors involved in deepwater blowout cases are reviewed and compared to those for the shallow water blowout cases.

Accidents↗
PubMed2026

Predictive design of tissue-specific mammalian enhancers that function in the mouse embryo.

Enhancers control tissue-specific gene expression across animals1. Although deep learning2,3 has enabled enhancer prediction and design in mammalian cell lines and non-mammalian model organisms4-10 (reviewed in a previous publication11), it remains unclear whether such approaches can operate within the regulatory complexity of mammalian genomes and tissues in vivo. Here we present a general strategy for designing tissue-specific enhancers that function reliably in mice. We use deep learning to train compact convolutional neural networks on curated chromatin accessibility data and fine-tune them by transfer learning on validated human and mouse enhancers. Guided by these models, we design 15 synthetic enhancers for the heart, limb and central nervous system in mouse embryos, all of which are active in their intended target tissue. These results demonstrate that mammalian enhancer function can be reliably inferred from DNA sequence alone, enabling the predictive de novo design of tissue-specific synthetic enhancers from modest training sets. This work establishes a generalizable framework for programmable control of mammalian gene expression in vivo, opening new avenues in functional genomics, synthetic biology and gene therapy.

Animals↗
PubMed2005

T cells require tumor necrosis factor-alpha to provide protective immunity in mice infected with Histoplasma capsulatum.

We examined whether neutralization of tumor necrosis factor (TNF)-alpha after intranasal exposure of mice to Histoplasma capsulatum was necessary for control of primary or secondary infection. All mice given monoclonal antibody to TNF-alpha on the day of infection or on day 3 after infection died. When antibody was administered on day 5 after infection, 60% of mice with primary infection died, whereas none with secondary infection did. Antibody treatment on day 7 after infection produced a transiently higher fungal burden. Because optimal clearance required TNF-alpha after the onset of infection, we hypothesized that it may regulate T cell function. Lung CD3+ cells were the dominant population of TNF-alpha-producing cells (approximately 40%-70%). Neutralization of this cytokine decreased the number of memory T cells but not the number of activated, proliferating, or interferon-gamma-producing cells. T cells from infected, TNF-alpha-neutralized mice failed to protect T cell-deficient mice. The absence of TNF-alpha induces a defect in T cell-mediated protection.

Adoptive Transfer↗
PubMed1999

Impact of nonlinear heat transfer on temperature control in regional hyperthermia.

We describe an optimization process specially designed for regional hyperthermia of deep-seated tumors in order to achieve desired steady-state temperature distributions. A nonlinear three-dimensional heat transfer model based on temperature-dependent blood perfusion is applied to predict the temperature. Using linearly implicit methods in time and adaptive multilevel finite elements in space, we are able to integrate efficiently the instationary nonlinear heat equation with high accuracy. Optimal heating is obtained by minimizing an integral objective function which measures the distance between desired and model predicted temperatures. A sequence of minima is calculated from successively improved constant-rate perfusion models employing a damped Newton method in an inner iteration. We compare temperature distributions for two individual patients calculated on coarse and fine spatial grids and present numerical results of optimizations for a Sigma 60 Applicator of the BSD 2000 Hyperthermia System.

Algorithms↗
PubMed1979

Space-filling models of kinase clefts and conformation changes.

Space-filling models of yeast hexokinase, adenylate kinase, and phosphoglycerate kinase drawn by computer clearly portray the bilobal character of these phosphoryl transfer enzymes, and the deep cleft which is formed between the lobes. A dramatic conformational change occurs in hexokinase as glucose binds to the bottom of the cleft, which causes the two lobes of hexokinase to come together. A substrate-induced closing of the active site cleft is postulated to occur in other kinases as well. This change may provide a mechanism by which some of these enzymes reduce their inherent adenosine triphosphatase activity and could be a general requirement of the kinase reaction.

Adenylate Kinase↗
PubMed1998

Transmitter concentration at a three-dimensional synapse.

Transmitter concentration at a three-dimensional synapse. J. Neurophysiol. 80: 3163-3172, 1998. At intensities from starlight to 1000-fold brighter, the mammalian rod synapse transmits a binary signal, the capture of 0 or 1 photon. Zero is signified by tonic exocytosis, and 1 is signified by a brief pause. The synapse is three dimensional: vesicles discharge at the apex of a deep cleft created by the invagination of four postsynaptic processes. Two horizontal cell spines bearing alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reach near to the release sites (16 nm), and two bipolar dendrites bearing mGluR6 receptors end far from the release sites (up to 640 nm). We considered two hypotheses for signal transfer: transmitter quanta might be integrated in the cleft and sensed as a steady concentration (high for 0 and low for 1); or quanta might be sensed at the postsynaptic membrane as discrete postsynaptic potentials (PSPs) and integrated within the dendrite. We calculate from a passive diffusion model that the invagination empties rapidly (tau approximately 1.7 ms). Further calculations suggest that a glutamate concentration high enough to hold a bipolar cell in darkness at one end of its response range would require approximately 4,000 vesicles/s. On the other hand, the glutamate pulse from a single vesicle would reach both nearby AMPA receptors (low affinity) and distant mGluR6 receptors (high affinity) at spatiotemporal concentrations matched to their apparent binding affinities. Thus one vesicle could evoke a discrete PSP in all four postsynaptic processes. We calculate from a stochastic model that PSPs could transfer the binary signal at approximately 100 vesicles/s. Thus dendritic integration of unitary PSPs is both plausible and 40-fold more efficient than the alternative mechanism. The rod's deep invagination, rather than serving to pool transmitter, may serve to prevent "spillover" of transmitter to neighboring rods. Spillover, by pooling the noise from neighboring rods, would impair transmission of their binary signals.

Algorithms↗
PubMed2006

Deep-breath frequency in bronchoconstricted monkeys (Macaca fascicularis).

Deep-breath frequency has been shown to increase in spontaneously obstructed asthmatic subjects. Furthermore, deep breaths are known to be regulated by lung rapidly adapting receptors, yet the mechanism by which these receptors are stimulated is unclear. This study tested the hypothesis that deep-breath frequency increases during experimentally induced bronchoconstriction, and the magnitude of the increased deep-breath frequency is dependent on the method by which bronchoconstriction is induced. Nine cynomolgus monkeys (Macaca fascicularis) were challenged with methacholine (MCh), Ascaris suum (AS), histamine, or an external mechanical resistance. Baseline (BL) and challenge deep-breath frequency were calculated from the number of deep breaths per trial period. Airway resistance (Raw) and tissue compliance (Cti), as well as tidal volume, respiratory rate, and minute ventilation, were analyzed for BL and challenged conditions. Transfer impedance measurements were fit with the DuBois model to determine the respiratory parameters (Raw and Cti). The flow at the airway opening was measured and analyzed on a breath-by-breath basis to obtain the ventilatory parameters (tidal volume, respiratory rate, and minute ventilation). Deep-breath frequency resulting from AS and histamine challenges [0.370 (SD 0.186) and 0.467 breaths/min (SD 0.216), respectively] was significantly increased compared with BL, MCh, or external resistance challenges [0.61 (SD 0.046), 0.156 (SD 0.173), and 0.117 breaths/min (SD 0.082), respectively]. MCh and external resistance challenges resulted in insignificant changes in deep-breath frequency compared with BL. All four modalities produced similar levels of bronchoconstriction, as assessed through changes in Raw and Cti, and had similar effects on the ventilatory parameters except that non-deep-breath tidal volume was decreased in AS and histamine. We propose that increased deep-breath frequency during AS and histamine challenge is the result of increased vascular permeability, which acts to increase rapidly adapting receptor activity.

Airway Resistance↗
PubMed1994

Pharmacokinetic modeling of 2,4-dichlorophenoxyacetic acid (2,4-D) in rat and in rabbit brain following single dose administration.

A physiologically based pharmacokinetic (PBPK) model has been developed to describe the kinetics of organic anions in the central nervous system using 2,4-dichlorophenoxyacetic acid (2,4-D) as a model compound. The model consists of brain, body, venous, and arterial compartments. The brain compartment is subdivided into brain plasma, brain tissue and cerebrospinal fluid (CSF). Brain uptake is membrane-limited via a blood-brain barrier with saturable clearance from the CSF into the venous blood by the choroid plexus. The body has both a central and a deep compartment with saturable renal clearance from the central compartment. The model was used to examine venous plasma time course curves with experimental data from rats given 2,4-D by i.v. (5 or 90 mg/kg) or by oral ingestion (10, 50, or 150 mg/kg). The model was then extended to examine studies in which rabbit plasma, brain, and CSF concentrations were measured at 2 h after i.p. injection (40 mg/kg). In the rat, elimination was saturable (Vmax2 = 3.45 mg/h; Km2 = 86 mg/l) and the deep-compartment transfer coefficients were K12 (0.013 l/h) and K21 (0.048 l/h) between body and deep tissue compartment. Both oral and i.v. data were well described with these values. Limited single time point brain data from rabbits were analyzed with a lumped brain model assuming the generic model for 2,4-D in rat applies to the rabbit. The model simulations were in good agreement with rabbit plasma, brain, and CSF concentrations at 2 h after i.p. injection.

2,4-Dichlorophenoxyacetic Acid↗
PubMed2005

Motion of discrete solitons assisted by nonlinearity management.

We demonstrate that time-periodic modulation of the nonlinearity coefficient in the discrete nonlinear Schrödinger equation strongly facilitates creation of traveling solitons in the lattice. We predict this possibility in a semi-qualitative form analytically, and test it in direct numerical simulations. Systematic computations reveal several generic dynamical regimes, depending on the amplitude and frequency of the time modulation, and on the initial thrust which sets the soliton in motion. These regimes include irregular motion of the soliton, regular motion of a decaying one, and regular motion of a stable soliton. The motion may occur in both the straight and reverse directions, relative to the initial thrust. In the case of stable motion, extremely long simulations in a lattice with periodic boundary conditions demonstrate that the soliton keeps moving indefinitely long without any visible loss. Velocities of moving stable solitons are in good agreement with the analytical prediction, which is based on requiring a resonance between the ac drive and motion of the soliton through the periodic lattice. The generic dynamical regimes are mapped in the model's parameter space. Collisions between moving stable solitons are briefly investigated too, with a conclusion that two different outcomes are possible: elastic bounce, or bounce with mass transfer from one soliton to the other. The model can be realized experimentally in a Bose-Einstein condensate trapped in a deep optical lattice.

Journal Article↗
PubMed1985

Influence of hypothermia and circulatory arrest on cerebral temperature distributions.

A finite element model of the bioheat transfer equation has been developed to simulate the temperature distribution in the head of a subhuman primate. Simulations were made of the induction of deep hypothermia and of subsequent hypothermic circulatory arrest (HCA). Simulations of the circulatory arrest phase were performed with different values of surface heat transfer coefficient and tissue metabolic heat generation. Numerical results were compared with experimental data for the same procedure. The simulations indicate the brain cools rapidly to a near isothermal condition in response to an infusion of cold arterial blood. However, extracerebral structures cool much more slowly. The bulk of heat gain by the brain during HCA is due to heat transfer from these warmer extra-cerebral tissues. These results suggest extended cooling by cardiopulmonary bypass (CPB) combined with surface cooling pads should reduce or even prevent the rise of brain temperatures during HCA.

Animals↗
PubMed2000

Effect of diffusive and convective substrate transport on biofilm structure formation: a two-dimensional modeling study.

A two-dimensional model for quantitative evaluation of the effect of convective and diffusive substrate transport on biofilm heterogeneity was developed. The model includes flow computation around the irregular biofilm surface, substrate mass transfer by convection and diffusion, biomass growth, and biomass spreading. It was found that in the absence of detachment, biofilm heterogeneity is mainly determined by internal mass transfer rate of substrates and by the initial percentage of carrier-surface colonization. Model predictions show that biofilm structures with highly irregular surface develop in the mass transfer-limited regime. As the nutrient availability increases, there is a gradual shift toward compact and smooth biofilms. A smaller fraction of colonized carrier surface leads to a patchy biofilm. Biofilm surface irregularity and deep vertical channels are, in this case, caused by the inability of the colonies to spread over the whole substratum surface. The maximum substrate flux to the biofilm was greatly influenced by both internal and external mass transfer rates, but not affected by the inoculation density. In general, results of the present model were similar to those obtained by a simple diffusion-reaction-growth model.

Algorithms↗
PubMed2025

DeepWheat: predicting the effects of genomic variants on gene expression and regulatory activities across tissues and varieties in wheat using deep learning.

Spatiotemporal gene expression shapes key agronomic traits, yet tissue-specific prediction remains challenging in complex crops. We present DeepWheat, a broadly applicable deep learning framework comprising DeepEXP and DeepEPI, for accurate, tissue-specific gene expression prediction. DeepEXP integrates sequence and epigenomic features to predict gene expression (PCC 0.82-0.88), while DeepEPI predicts epigenomic maps from DNA sequence to support model transfer across varieties. Validations in five wheat cultivars confirm robustness and accuracy. DeepWheat also identifies regulatory variants with strong expression effects, enabling targeted cis-regulatory elements editing and offering a powerful tool for crop functional genomics and breeding.

Triticum↗
PubMed2006

Predicting the transfer of 137Cs to rice plants by a dynamic compartment model with a consideration of the soil properties.

This paper describes the predictions of the transfer of 137Cs to rice plants following soil deposition during a non-growth season of rice by a dynamic compartment model considering the soil properties, and their comparison with experimental results. Major processes considered in the model were percolation, soil mixing by plowing, plant uptake, leaching to deep soil, fixation to clay mineral, and time-dependent growth of a plant. To consider the effects of the soil properties (pH, clay mineral, organic matter content, and exchangeable K) on plant uptake and the leaching rates of 137Cs in a root zone soil, the Absalom model was used for the present model. The 137Cs aggregated transfer factors (TFa, m2kg-1 dry plant) of rice plants for two consecutive cultivation years were obtained as a result of simulated 137Cs soil deposition experiments with 17 paddy soils of different properties, all of which were performed before transplanting of the rice. Observed 137Cs TFa values of the rice plants did not show an evident trend for the pH and clay content of the soil properties, while they increased with an increasing organic matter content and a decreasing exchangeable K concentration. Predicted 137Cs TFa values of the rice plants were found to be comparable with those observed.

Ammonia↗
PubMed2004

Staging deep venous thrombosis using ultrasound elasticity imaging: animal model.

Deep venous thrombi undergo progressive hardening with age. However, the evolution rate remains poorly characterized by both invasive and noninvasive techniques. In a previous study (Emelianov et al. 2002), we demonstrated the potential of ultrasound elasticity imaging to noninvasively detect and age thrombus using a rat-based model. Knowing that thrombi harden over time is useful, but the value of the technique relies on whether the age of a thrombus can be predicted from strain estimates, and how accurate these predictions are. The objective of the present study is to answer these two questions. In the previous study, thrombus elasticity changes were monitored only on day 3, 6 and 9 after surgically induced formation of thrombosis in rat inferior vena cavas. In this study, ultrasound elasticity imaging was performed on two independent groups of rats (16 in total) starting from day 3 through day 10 with more temporal samples through the thrombus maturation process. For each rat, thrombus hardness was quantified at each scan interval by measures of normalized strains and reconstructed relative Young's moduli. In both groups, strain magnitudes exhibit progressive decrease as clots age. The relationship between the normalized strain and the clot age was developed from the first group and evaluated by the second group. Statistical analysis showed that the age estimation accuracy is within 0.8 day. If further research can successfully transfer the animal clot-hardening model to human patients, we believe that elasticity imaging will become a key component of venous compression ultrasound for effective diagnosis and treatment of deep venous thrombosis.

Animals↗
PubMed1990

The influence of model parameter values on the prediction of skin surface temperature: I. Resting and surface insulation.

A model is presented of heat transfer and temperature distributions in the skin and superficial tissues. It is based on a finite difference numerical solution of the one-dimensional multilayer coupled bioheat equation. In this paper, the model is used to investigate the influence of the values of parameters chosen to represent the physiological and heat transfer processes on the temperature of the skin under resting conditions and after insulation of the skin surface. Equilibrium resting temperatures were strongly influenced by deep body temperature especially at lower heat transfer coefficients on the skin surface, but slightly affected by the values chosen for skin blood flow and metabolic heat generation; both the heat transfer coefficients and environmental temperature strongly influenced the surface temperature. After surface insulation the temperature elevation was strongly influenced by the thermal conductivities of tissues, skin blood flow and deep boundary temperature; metabolic heat generation was only significantly at unphysiologically high values.

Humans↗