Showing papers by "Andrey V. Kuznetsov published in 2019"

Investigating sensitivity coefficients characterizing the response of a model of tau protein transport in an axon to model parameters.

Abstract: Evaluating the sensitivity of biological models to various model parameters is a critical step towards advancing our understanding of biological systems. In this paper, we investigated sensitivity coefficients for a model simulating transport of tau protein along the axon. This is an important problem due to the relevance of tau transport and agglomeration to Alzheimer's disease and other tauopathies, such as some forms of parkinsonism. The sensitivity coefficients that we obtained characterize how strongly three observables (the tau concentration, average tau velocity, and the percentage of tau bound to microtubules) depend on model parameters. The fact that the observables strongly depend on a parameter characterizing tau transition from the retrograde to the anterograde kinetic states suggests the importance of motor-driven transport of tau. The observables are sensitive to kinetic constants characterizing tau concentration in the free (cytosolic) state only at small distances from the soma. Cytosolic tau can only be transported by diffusion, suggesting that diffusion-driven transport of tau only plays a role in the proximal axon. Our analysis also shows the location in the axon in which an observable has the greatest sensitivity to a certain parameter. For most parameters, this location is in the proximal axon. This could be useful for designing an experiment aimed at determining the value of this parameter. We also analyzed sensitivity of the average tau velocity, the total tau concentration, and the percentage of microtubule-bound tau to cytosolic diffusivity of tau and diffusivity of bound tau along the MT lattice. The model predicts that at small distances from the soma the effect of these two diffusion processes is comparable.

Identifying the Critical Factors Governing Translaminar Pressure Differential Through a Compartmental Model.

Abstract: Purpose The effective management of glaucoma is hindered by an incomplete understanding of its pathologic mechanism. While important, intraocular pressure (IOP) alone is inadequate in explaining glaucoma. Non-IOP-mediated risk factors such as cerebrospinal fluid (CSF) pressure have been reported to contribute to glaucomatous optic neuropathy. Due to the difficulty associated with experimental measurement of the salient variables, such as the retrobulbar CSF pressure, porosity of the subarachnoid space (SAS), and especially those concerned with the perioptic SAS, there remains a limited understanding of the CSF behavior contributing to the translaminar pressure gradient (TLPG), hypothesized to be a critical factor in the development of glaucoma. Method An integrated compartmental model describing the intracranial and orbital CSF dynamics, coupled with intraocular dynamics, is developed based on first principles of fluid mechanics. A sensitivity analysis is performed to identify anatomic characteristics that significantly affect the retrobulbar subarachnoid space (RSAS) pressure and, consequently, the TLPG. Results Of the 28 parameters considered, the RSAS pressure is most sensitive to CSF flow resistance in the optic nerve SAS and the potential lymphatic outflow from the optic nerve SAS into the orbital space. A parametric study demonstrates that a combination of resistance in the range of 1.600 × 1012 - 1.930 × 1012 Pa s/m3 (200.0 - 241.3 mm Hg min/mL) with 5% to 10% lymphatic CSF outflow yields RSAS pressures that are consistent with the limited number of studies in the literature. Conclusions The results suggest that a small percentage of lymphatic CSF outflow through the optic nerve SAS is likely. In addition, flow resistance in the orbital CSF space, hypothesized to be a function of patient-specific optic nerve SAS architecture and optic canal geometry, is a critical parameter in regulating the RSAS pressure and TLPG.

A Novel Porcine Model for the Study of Cerebrospinal Fluid Dynamics: Development and Preliminary Results.

Abstract: Idiopathic intracranial hypertension, space-flight associated neuro-ocular syndrome (SANS), and glaucoma are conditions that are among a spectrum of cerebrospinal fluid (CSF)-related ophthalmologic disease. This implies that local CSF pressures at the level of the optic nerve are involved to variable extent in these disease processes. However, CSF pressure measurements are problematic due to invasiveness and interpretation. The pressure measured by a lumbar puncture is likely not the same as the orbital CSF pressure. It is believed this is at least in part due to the flow restrictive properties of the optic canal. To investigate CSF flow within the orbit, a model for CSF dynamics was created using three medium-sized pigs. Contrast was administered through a lumbar subarachnoid space access. The contrast front was imaged with repeated computed tomographic (CT) imaging. Once contrast entered the orbit, rapid, sequential CT imaging was performed until the contrast reached the posterior globe. Head tilting was performed to highlight the role of gravitational dependence within the subarachnoid space.

Meistera caudata and Meistera sudae (Zingiberaceae: Alpinieae), two new ginger species from Bidoup-Núi Bà National Park, southern Vietnam

Abstract: Two new ginger species, Meistera caudata and Meistera sudae (Zingiberaceae: Alpinieae) from Bidoup-Nui Ba National Park in southern Vietnam, are presented here. Descriptions, notes on distribution, ecology and phenology, preliminary IUCN assessments and colour plates are provided for each newly described species. A new combination Meistera cristatissima, based on Amomum cristatissimum, is also proposed. A previously proposed IUCN preliminary assessment is amended using information from additional collections, and the new extent of known distribution of the species is discussed.

The Onset of Convection in an Anisotropic Heterogeneous Porous Medium: A New Hydrodynamic Boundary Condition

Abstract: The Horton–Rogers–Lapwood problem with strong heterogeneity and anisotropy is examined for a simple case, namely where the heterogeneity is provided by two layers, each of which is homogeneous and isotropic in a horizontal plane. We derived a new hydrodynamic boundary condition at the interface between two different porous media and then formulated and numerically solved the eigenvalue problem to determine the critical values of the wavenumber and Rayleigh number. We found that our approach works and gives the correct result for the homogeneous situation independent of the position of the interface. We also showed that for weak heterogeneity, by using modified anisotropy parameters weighted with the two layer depths, results obtained in Kvernvold and Tyvand (J Fluid Mech 90:609–624, 1979) for a single-layer problem can be used to approximate the critical Rayleigh number for the double-layer problem. We found that the agreement with the two-layer solution is best if a harmonic mean is used to define the mean permeability ratio and an arithmetic mean is utilized to define the mean conductivity ratio.

A numerical study of sensitivity coefficients for a model of amyloid precursor protein and tau protein transport and agglomeration in neurons at the onset of Alzheimer's disease.

Abstract: Modeling of intracellular processes occurring during the development of Alzheimer's disease (AD) can be instrumental in understanding the disease and can potentially contribute to finding treatments for the disease. The model of intracellular processes in AD, which we previously developed, contains a large number of parameters. To distinguish between more important and less important parameters we performed a local sensitivity analysis of this model around the values of parameters that give the best fit with published experimental results. We show that the effect of model parameters on the total concentration of amyloid precursor protein (APP) and tau protein in the axon, respectively, is reciprocal to the effect of the same parameters on the average velocities of the same proteins during their transport in the axon. The results of our analysis also suggest that in the beginning of AD the aggregation of amyloid-s and misfolded tau protein have little effect on transport of APP and tau in the axon, which suggests that early effects of AD may be reversible.

Modeling transport and mean age of dense core vesicles in large axonal arbors

Abstract: A model simulating transport of dense core vesicles (DCVs) in type II axonal terminals of Drosophila motoneurons has been developed. The morphology of type II terminals is characterized by the large number of en passant boutons. The lack of both scaled up DCV transport and scaled down DCV capture in boutons results in a less efficient supply of DCVs to distal boutons. Furthermore, the large number of boutons that DCVs pass as they move anterogradely, until they reach the most distal bouton, may lead to the capture of a majority of DCVs before they turn around in the most distal bouton to move in the retrograde direction. This may lead to a reduced retrograde flux of DCVs and a lack of DCV circulation in type II terminals. The developed model simulates DCV concentrations in boutons, DCV fluxes between the boutons, age density distributions of DCVs, and the mean age of DCVs in various boutons. Unlike published experimental observations, our model predicts DCV circulation in type II terminals after these terminals are filled to saturation. This disagreement is likely because experimentally observed terminals were not at steady-state, but rather were accumulating DCVs for later release. Our estimates show that the number of DCVs in the transiting state is much smaller than that in the resident state. DCVs traveling in the axon, rather than DCVs transiting in the terminal, may provide a reserve of DCVs for replenishing boutons after a release. The techniques for modeling transport of DCVs developed in our paper can be used to model the transport of other organelles in axons.

Modelling transport and mean age of dense core vesicles in large axonal arbours

Abstract: A model simulating the transport of dense core vesicles (DCVs) in type II axonal terminals of Drosophila motoneurons has been developed. The morphology of type II terminals is characterized by the ...

Effect of Microscopic Vortices Caused by Flow Interaction With Solid Obstacles on Heat Transfer in Turbulent Porous Media Flows

Abstract: Turbulent flow in a homogeneous porous medium was investigated through the use of numerical methods by employing the Reynolds Averaged Navier-Stokes (RANS) modeling technique. The focus of our research was to study how microscopic vortices in porous media flow influence the heat transfer from the solid obstacles comprising the porous medium to the fluid. A Representative Elementary Volume (REV) with 4 × 4 cylindrical obstacles and periodic boundary conditions was used to represent the infinite porous medium structure. Our hypothesis is that the rate of heat transfer between the obstacle surface and the fluid (qavg) is strongly influenced by the size of the contact area between the vortices and the solid obstacles in the porous medium (Avc). This is because vortices are regions with low velocity that form an insulating layer on the surface of the obstacles. Factors such as the porosity (φ), Pore Scale Reynolds number (Rep), and obstacle shape of the porous medium were investigated. All three of these factors have different influences on the contact area Avc, and, by extension, the overall heat transfer rate qavg. Under the same Pore Scale Reynolds number (Rep), our results suggest that a higher overall heat transfer rate is exhibited for smaller contact areas between the vortices and the obstacle surface. Although the size of the contact area, Avc, is affected by Rep, the direct influence of Rep on the overall heat transfer rate qavg is much stronger, and exceeds the effect of Avc on qavg. The Pore Scale Reynolds number, Rep, and the mean Nusselt number, Num, have a seemingly logarithmic relationship.

Marangoni convection of a viscous fluid over a vibrating plate

Abstract: This research presents a new insight into Marangoni convection through investigating, both numerically and analytically, the surface tension driven instability activated by a coupled effect of a vi...