Browsing by Author "Rezania, Vahid"
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- ItemA comparison between real and DLA simulated liver lobules using a population density analysis(2014) Wisk, Sara; Rezania, VahidA liver lobule is comprised of networks of sinusoids and hepatocytes. Here, a liver lobule was computationally constructed by using diffusion-limited aggregation (DLA) method. A population density analysis of the sinusoids and hepatocytes was performed and then compared with a real lobule image. The resulting images were compared using a histogram to interpret the ratio of hepatocytes to sinusoids.
- ItemA continuous model for microtubule dynamics with catastrophe, rescue and nucleation processes(2009) Hinow, Peter; Rezania, Vahid; Tuszynski, Jack A.Microtubules are a major component of the cytoskeleton distinguished by highly dynamic behavior both in vitro and in vivo referred to as dynamic instability. We propose a general mathematical model that accounts for the growth, catastrophe, rescue and nucleation processes in the polymerization of microtubules from tubulin dimers. Our model is an extension of various mathematical models developed earlier formulated in order to capture and unify the various aspects of tubulin polymerization. While attempting to use a minimal number of adjustable parameters, the proposed model covers a broad range of behaviors and has predictive features discussed in the paper. We have analyzed the range of resultant dynamical behavior of the microtubules by changing each of the parameter values at a time and observing the emergence of various dynamical regimes, that agree well with the previously reported experimental data. observing the emergence of various dynamical regimes, that agree well with reported experimental behavior.
- ItemA nanometric probe of the local proton concentration in microtubule-based biophysical systems(2022) Kalra, Aarat P.; Eakins, Boden B.; Vagin, Sergei I.; Wang, Hui; Patel, Sahil D.; Winter, Philip; Aminpour, Maral; Lewis, John D.; Rezania, Vahid; Shankar, Karthik; Scholes, Gregory D.; Tuszynski, Jack A.; Rieger, Bernhard; Meldrum, AlkiviathesWe show a double-functional fluorescence sensing paradigm that can retrieve nanometric pH information on biological structures. We use this method to measure the extent of protonic condensation around microtubules, which are protein polymers that play many roles crucial to cell function. While microtubules are believed to have a profound impact on the local cytoplasmic pH, this has been hard to show experimentally due to the limitations of conventional sensing techniques. We show that subtle changes in the local electrochemical surroundings cause a double-functional sensor to transform its spectrum, thus allowing a direct measurement of the protonic concentration at the microtubule surface. Microtubules concentrate protons by as much as one unit on the pH scale, indicating a charge storage role within the cell via the localized ionic condensation. These results confirm the bioelectrical significance of microtubules and reveal a sensing concept that can deliver localized biochemical information on intracellular structures.
- ItemA new method for protein characterization and classification using geometrical features for 3D face analysis: an example of tubulin structures(2021) Di Grazia, Luca; Aminpour, Maral; Vezzetti, Enrico; Rezania, Vahid; Marcolin, Federica; Tuszynski, Jack A.This article reports on the results of research aimed to translate biometric 3D face recognition concepts and algorithms into the field of protein biophysics in order to precisely and rapidly classify morphological features of protein surfaces. Both human faces and protein surfaces are free-forms and some descriptors used in differential geometry can be used to describe them applying the principles of feature extraction developed for computer vision and pattern recognition. The first part of this study focused on building the protein dataset using a simulation tool and performing feature extraction using novel geometrical descriptors. The second part tested the method on two examples, first involved a classification of tubulin isotypes and the second compared tubulin with the FtsZ protein, which is its bacterial analog. An additional test involved several unrelated proteins. Different classification methodologies have been used: a classic approach with a support vector machine (SVM) classifier and an unsupervised learning with a k-means approach. The best result was obtained with SVM and the radial basis function kernel. The results are significant and competitive with the state-of-the-art protein classification methods. This leads to a new methodological direction in protein structure analysis.
- ItemA physiologically-based flow network model for hepatic drug elimination I: regular lattice lobule model(2013) Rezania, Vahid; Marsh, Rebeccah; Coombe, Dennis; Tuszynski, Jack A.We develop a physiologically-based lattice model for the transport and metabolism of drugs in the functional unit of the liver, called the lobule. In contrast to earlier studies, we have emphasized the dominant role of convection in well-vascularized tissue with a given structure. Estimates of convective, diffusive and reaction contributions are given. We have compared drug concentration levels observed exiting the lobule with their predicted detailed distribution inside the lobule, assuming that most often the former is accessible information while the latter is not.
- ItemA physiologically-based flow network model for hepatic drug elimination II: variable lattice lobule models(2013) Rezania, Vahid; Marsh, Rebeccah; Coombe, Dennis; Tuszynski, Jack A.We extend a physiologically-based lattice model for the transport and metabolism of drugs in the liver lobule (liver functional unit) to consider structural and spatial variability. We compare predicted drug concentration levels observed exiting the lobule with their detailed distribution inside the lobule, and indicate the role that structural variation has on these results. Liver zonation and its role on drug metabolism represent another aspect of structural inhomogeneity that we consider here. Since various liver diseases can be thought to produce such structural variations, our analysis gives insight into the role of disease on liver function and performance. These conclusions are based on the dominant role of convection in well-vascularized tissue with a given structure.
- ItemA physiologically-based flow network model for hepatic drug elimination III: 2D/3D DLA lobule models(2016) Rezania, VahidRecently, we developed a physiologically-based lattice model to address the transport and metabolism of drugs in the liver lobule (liver functional unit). In this paper, we extend our idealized model to consider structural and spatial variability in two and three dimensions.
- ItemA r-mode in a magnetic rotating spherical layer: application to neutron stars(2011) Abbassi, S.; Rieutord, M.; Rezania, VahidThe impact of the combination of rotation and magnetic fields on oscillations of stellar fluids is still not well known theoretically. It mixes Alfven and inertial waves. Neutron stars are a place where both effects may be at work. We wish to decipher the solution of this problem in the context of r-modes instability in neutron stars, as it appears when these modes are coupled to gravitational radiation. We consider a rotating spherical shell filled with a viscous fluid but of infinite electrical conductivity and analyze propagation of modal perturbations when a dipolar magnetic field is bathing the fluid layer. We perform an extensive numerical analysis and find that the m = 2 r-mode oscillation is influenced by the magnetic field when the Lehnert number (ratio of Alfven speed to rotation speed) exceeds a value proportional to the one-fourth power of the Ekman number (non-dimensional measure of viscosity). This scaling is interpreted as the coincidence of the width of internal shear layers of inertial modes and the wavelength of the Alfven waves. Applied to the case of rotating magnetic neutron stars, we find that dipolar magnetic fields above 1014 G are necessary to perturb the r-modes instability.
- ItemAll wired up: an exploration of the electrical properties of microtubules and tubulin(2020) Kalra, Aarat P.; Eakins, Boden B.; Patel, Sahil D.; Ciniero, Gloria; Rezania, Vahid; Shankar, Karthik; Tuszynski, Jack A.Microtubules are hollow, cylindrical polymers of the protein α, β tubulin, that interact mechanochemically with a variety of macromolecules. Due to their mechanically robust nature, microtubules have gained attention as tracks for precisely directed transport of nanomaterials within lab-on-a-chip devices. Primarily due to the unusually negative tail-like C-termini of tubulin, recent work demonstrates that these biopolymers are also involved in a broad spectrum of intracellular electrical signaling. Microtubules and their electrostatic properties are discussed in this Review, followed by an evaluation of how these biopolymers respond mechanically to electrical stimuli, through microtubule migration, electrorotation and C-termini conformation changes. Literature focusing on how microtubules act as nanowires capable of intracellular ionic transport, charge storage, and ionic signal amplification is reviewed, illustrating how these biopolymers attenuate ionic movement in response to electrical stimuli. The Review ends with a discussion on the important questions, challenges, and future opportunities for intracellular microtubule-based electrical signaling.
- ItemBuilding a 3D virtual liver: methods for simulating blood flow and hepatic clearance on 3D structures(2016) White, Diana; Coombe, Dennis; Rezania, Vahid; Tuszynski, Jack A.In this paper, we develop a spatio-temporal modeling approach to describe blood and drug flow, as well as drug uptake and elimination, on an approximation of the liver. Extending on previously developed computational approaches, we generate an approximation of a liver, which consists of a portal and hepatic vein vasculature structure, embedded in the surrounding liver tissue. The vasculature is generated via constrained constructive optimization, and then converted to a spatial grid of a selected grid size. Estimates for surrounding upscaled lobule tissue properties are then presented appropriate to the same grid size. Simulation of fluid flow and drug metabolism (hepatic clearance) are completed using discretized forms of the relevant convective-diffusive-reactive partial differential equations for these processes. This results in a single stage, uniformly consistent method to simulate equations for blood and drug flow, as well as drug metabolism, on a 3D structure representative of a liver.
- ItemCell death and survival due to cytotoxic exposure modelled as a two-state Ising system(2020) Moghadam, Arbabi S.; Rezania, Vahid; Tuszynski, Jack A.Cancer chemotherapy agents are assessed for their therapeutic utility primarily by their ability to cause apoptosis of cancer cells and their potency is given by an IC50 value. Chemotherapy uses both target-specific and systemic-action drugs and drug combinations to treat cancer. It is important to judiciously choose a drug type, its dosage and schedule for optimized drug selection and administration. Consequently, the precise mathematical formulation of cancer cells' response to chemotherapy may assist in the selection process. In this paper, we propose a mathematical description of the cancer cell response to chemotherapeutic agent exposure based on a time-tested physical model of two-state multiple-component systems near criticality. We describe the Ising model methodology and apply it to a diverse panel of cytotoxic drugs administered against numerous cancer cell lines in a dose–response manner. The analysed dataset was generated by the Netherlands Translational Research Center B.V. (Oncolines). This approach allows for an accurate and consistent analysis of cytotoxic agents' effects on cancer cell lines and reveals the presence or absence of the bystander effect through the interaction constant. By calculating the susceptibility function, we see the value of IC50 coinciding with the peak of this measure of the system's sensitivity to external perturbations.
- ItemFrom a quantum mechanical description of the assembly processes in microtubules to their semiclassical nonlinear dynamics(2007) Rezania, Vahid; Tuszynski, Jack A.In this paper a quantum mechanical description of the assembly/disassembly process for microtubules is proposed. We introduce creation and annihilation operators that raise or lower the microtubule length by a tubulin layer. Following that, the Hamiltonian and corresponding equations of motion are derived that describe the dynamics of microtubules. These Heisenberg-type equations are then transformed to semi-classical equations using the method of coherent structures. The latter equations are very similar to the phenomenological equations that describe dynamic instability of microtubules in a tubulin solution.
- ItemInvestigation of the electrical properties of microtubule ensembles under cell-like conditions(2020) Aarat, Kalra P.; Patel, Sahil D.; Bhuiyan, Asadullah; Preto, Jordane; Scheuer, Kyle G.; Mohammed, Usman; Lewis, John D.; Rezania, Vahid; Shankar, Karthik; Tuszynski, Jack A.Microtubules (MTs) are cylindrical polymers composed of the heterodimers of protein α, β- tubulin that play a variety of well-recognised intracellular roles, such as maintaining the shape and rigidity of the cell, aiding in positioning and stabilisation of the mitotic spindle for allowing chromosomal segregation, acting as ‘rails’ for macromolecular transport and forming cilia and flagella for cell movement. Since the tubulin dimer possesses a high negative electric charge of ~23e and a large intrinsic high dipole moment of approximately 1750 D [1,2], MTs have been implicated in electrically-mediated biological roles [3,4,5,6]. They have been modelled as nanowires capable of enhancing ionic transport [7,8], and simulated to receive and attenuate electrical oscillations [4,9,10,11]. In solution, MTs have been shown to align with applied electric fields [2,12,13,14,15,16]. Recently, MTs have also been modelled as the primary cellular targets for low-intensity (1–2 V), intermediate-frequency (100–300 kHz) electric fields termed TTFields (tumour-treating electric fields) that inhibit cancer cell proliferation, in particular glioma [17,18,19]. Indeed, MTs have been reported to decrease buffer solution resistance [12,13], leading to a conductance peak at frequencies close to the TTField regime . While these studies show that MTs are highly sensitive to external electric fields, answers to the questions ‘How do MTs effect a solution’s capacitance?’ and ‘What is the capacitance of a single MT?’ are still elusive and crucial to the determination of the dielectric properties of living cells. The tubulin concentration in mammalian cells varies in the micromolar range (~10–25 μM) [21,22]. In vitro, polymerizing tubulin at such high concentrations can lead to the formation of entangled networks, confounding quantification of the individual MT response to electric fields. Electro-rotation, di-electrophoresis and impedance spectroscopy are thus performed using low concentrations of tubulin, in the nanomolar regime, to enable robust observation of individual MTs.
- ItemLiver bioreactor design issues of fluid flow and zonation, fibrosis, and mechanics: a computational perspective(2020) Rezania, Vahid; Coombe, Dennis; Tuszynski, Jack A.Tissue engineering, with the goal of repairing or replacing damaged tissue and organs, has continued to make dramatic science-based advances since its origins in the late 1980’s and early 1990’s. Such advances are always multi-disciplinary in nature, from basic biology and chemistry through physics and mathematics to various engineering and computer fields. This review will focus its attention on two topics critical for tissue engineering liver development: (a) fluid flow, zonation, and drug screening, and (b) biomechanics, tissue stiffness, and fibrosis, all within the context of 3D structures. First, a general overview of various bioreactor designs developed to investigate fluid transport and tissue biomechanics is given. This includes a mention of computational fluid dynamic methods used to optimize and validate these designs. Thereafter, the perspective provided by computer simulations of flow, reactive transport, and biomechanics responses at the scale of the liver lobule and liver tissue is outlined, in addition to how bioreactor-measured properties can be utilized in these models. Here, the fundamental issues of tortuosity and upscaling are highlighted, as well as the role of disease and fibrosis in these issues. Some idealized simulations of the effects of fibrosis on lobule drug transport and mechanics responses are provided to further illustrate these concepts. This review concludes with an outline of some practical applications of tissue engineering advances and how efficient computational upscaling techniques, such as dual continuum modeling, might be used to quantify the transition of bioreactor results to the full liver scale.
- ItemMicrotubule assembly of isotypically purified tubulin and its mixtures(2008) Rezania, Vahid; Azarenko, Olga; Jordan, Mary Ann; Bolterauer, Hannes; Huzil, J. Torin; Tuszynski, Jack A.; Luduena, Richard F.Numerous isotypes of the structural protein tubulin have now been characterized in various organisms and their expression offers a plausible explanation for observed differences affecting microtubule function in vivo. While this is an attractive hypothesis, there are only a handful of studies demonstrating a direct influence of tubulin isotype composition on the dynamic properties of microtubules. Here, we present the results of experimental assays on the assembly of microtubules from bovine brain tubulin using purified isotypes at various controlled relative concentrations. A novel data analysis is developed using recursive maps which are shown to be related to the master equation formalism. We have found striking similarities between the three isotypes of bovine tubulin studied in regard to their dynamic instability properties, except for subtle differences in their catastrophe frequencies. When mixtures of tubulin isotypes are analyzed, their nonlinear concentration dependence is modeled and interpreted in terms of lower affinities of tubulin dimers belonging to the same isotype than those that represent different isotypes indicating hitherto unsuspected influences of tubulin dimers on each other within a microtubule. Finally, we investigate the fluctuations in microtubule assembly and disassembly rates and conclude that the inherent rate variability may signify differences in the guanosine-59-triphosphate composition of the growing and shortening microtubule tips. It is the main objective of this article to develop a quantitative model of tubulin polymerization for individual isotypes and their mixtures. The possible biological significance of the observed differences is addressed.
- ItemModel of ionic currents through microtubule nanopores and the lumen(2010) Freedman, Holly; Rezania, Vahid; Priel, Avner; Carpenter, Eric; Noskov, Sergei Y.; Tuszynski, Jack A.It has been suggested that microtubules and other cytoskeletal filaments may act as electrical transmission lines. An electrical circuit model of the microtubule is constructed incorporating features of its cylindrical structure with nanopores in its walls. This model is used to study how ionic conductance along the lumen is affected by flux through the nanopores when an external potential is applied across its two ends. Based on the results of Brownian dynamics simulations, the nanopores were found to have asymmetric inner and outer conductances, manifested as nonlinear IV curves. Our simulations indicate that a combination of this asymmetry and an internal voltage source arising from the motion of the C-terminal tails causes a net current to be pumped across the microtubule wall and propagate down the microtubule through the lumen. This effect is demonstrated to enhance and add directly to the longitudinal current through the lumen resulting from an external voltage source, and could be significant in amplifying low-intensity endogenous currents within the cellular environment or as a nano-bioelectronic device.
- ItemModeling microtubule counterion distributions and conductivity using the Poisson-Boltzmann equation(2021) Eakins, Boden B.; Patel, Sahil D.; Kalra, Aarat P.; Rezania, Vahid; Shankar, KarthikMicrotubules are highly negatively charged proteins which have been shown to behave as bio-nanowires capable of conducting ionic currents. The electrical characteristics of microtubules are highly complicated and have been the subject of previous work; however, the impact of the ionic concentration of the buffer solution on microtubule electrical properties has often been overlooked. In this work we use the non-linear Poisson Boltzmann equation, modified to account for a variable permittivity and a Stern Layer, to calculate counterion concentration profiles as a function of the ionic concentration of the buffer. We find that for low-concentration buffers ([KCl] from 10 μM to 10 mM) the counterion concentration is largely independent of the buffer's ionic concentration, but for physiological-concentration buffers ([KCl] from 100 to 500 mM) the counterion concentration varies dramatically with changes in the buffer's ionic concentration. We then calculate the conductivity of microtubule-counterion complexes, which are found to be more conductive than the buffer when the buffer's ionic concentrations is less than ≈100 mM and less conductive otherwise. These results demonstrate the importance of accounting for the ionic concentration of the buffer when analyzing microtubule electrical properties both under laboratory and physiological conditions. We conclude by calculating the basic electrical parameters of microtubules over a range of ionic buffer concentrations applicable to nanodevice and medical applications.
- ItemModeling the effects of drug binding on the dynamic instability of microtubules(2011) Hinow, Peter; Rezania, Vahid; Lopus, Manu; Jordan, Mary Ann; Tuszynski, Jack A.We propose a stochastic model that accounts for the growth, catastrophe and rescue processes of steady state microtubules assembled from MAP-free tubulin in the possible presence of a microtubule associated drug. As an example for the latter, we both experimentally and theoretically study the perturbation of microtubule dynamic instability by S-methyl-D-DM1, a synthetic derivative of the microtubule-targeted agent maytansine and a potential anticancer agent. Our model predicts that among drugs that act locally at the microtubule tip, primary inhibition of the loss of GDP tubulin results in stronger damping of microtubule dynamics than inhibition of GTP tubulin addition. On the other hand, drugs whose action occurs in the interior of the microtubule need to be present in much higher concentrations to have visible effects.
- ItemMultifractality nature of microtubule dynamic instability process(2021) Rezania, Vahid; Sudirga, Ferry C.; Tuszynski, Jack A.The irregularity of growing and shortening patterns observed experimentally in microtubules and their ensembles reflects a dynamical system that fluctuates stochastically between assembly and disassembly phases. The observed time series of microtubule lengths have been extensively analyzed to shed light on structural and dynamical properties of microtubules. Here, for the first time, Multifractal Detrended Fluctuation analysis (MFDFA) has been employed to investigate the multifractal and topological properties of both experimental and simulated microtubule time series. We find that the time dependence of microtubule length possesses true multifractal characteristics and cannot be described by mono-fractal distributions. Based on the multifractal spectrum profile, a set of multifractal indices have been calculated that can be related to the level of dynamical processes in microtubules. We also show that the resulting multifractal spectra for the simulated data might not be comparable with experimental data.
- ItemNotes for slides: Quantum computation and search algorithms(2020) Eliasson, Leif; Rezania, VahidQuantum computation is the study of the information processing tasks which may be accomplished using quantum mechanical systems. At the heart of inquiries to ascertain the potential of quantum computation is the question of whether it is possible for a quantum computer to efficiently solve computational problems which have no efficient solution on a classical computer. Pioneering work done by David Deutsch, Peter Shor, Lov Grover and others in the 1980s and 1990s established a great deal of the essential theoretical framework and results which provided answers to this question which has justified continued research and interest in quantum computing ever since. Today we will provide a brief historical and functional overview of the development of quantum computing and its applications during this time, and contrast it with classical computing, and in particular, we will examine Grover’s algorithm as an illustrative example of the potential benefits of quantum search algorithms.