Jack A Tuszynski
University of Alberta, Oncology, Faculty Member
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Research Interests: Cognitive Psychology, Cognitive Science, Computer Science, Creativity, Cognition, and 15 moreEmbodied Cognition, Consciousness, Cognitive Neuroscience, Artificial Neural Networks, Gaze, Comprehension, Brainstem, Brain Based Learning, Biological Motion, Central Nervous System, Feeling, Dynamism, Demyelinating disease, Consciousness and Creativity, and Excitation
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Research Interests: Genetics, Biology, Immunohistochemistry, Homology Modeling, Biological Sciences, and 15 moreAnalysis, Female, Animals, Cluster Analysis, Expression, Gene, Clinical Sciences, CHEMICAL SCIENCES, Cerebral, CHANGES, Gene expression profiling, Early, BMC, Medical and Health Sciences, and Genetic predisposition to disease
ABSTRACT Tubulin, the primary subunit of microtubules, is remarkable for the variety of small molecules to which it binds. Many of these are very useful or promising agents in cancer chemotherapy. One of the most useful of these is... more
ABSTRACT Tubulin, the primary subunit of microtubules, is remarkable for the variety of small molecules to which it binds. Many of these are very useful or promising agents in cancer chemotherapy. One of the most useful of these is paclitaxel. The tubulin molecule is itself an alpha/beta heterodimer, both alpha- and beta-tubulin monomers existing as multiple isotypes. Despite the success of paclitaxel as an anticancer drug, resistance often occurs in cancer cells and has been associated with variations in tubulin isotype expression, most notably with the increased expression of betaIII-tubulin. Paclitaxel is thought to reach its binding site on beta-tubulin by diffusion through nanopores in the microtubule wall. It has been suggested that a transitional step in this process may be the binding of paclitaxel to an intermediate site within a nanopore, from which it moves directly to its binding site in the microtubule interior facing the lumen. To test this hypothesis, we have computationally docked paclitaxel within a microtubule nanopore and simulated its passage to the intermediate binding site. Targeted molecular dynamics was then used to test the hypothesis that paclitaxel utilizes the H6/H7 loop as a hinge to move directly from this intermediate binding site to its final position in the luminal binding site. We observed that this motion appears to be stabilized by the formation of a hydrogen bond involving serine 275 in beta-tubulin isotypes I, IIa, IIb, IVa, IVb, V, VII, and VIII. Interestingly, this residue is replaced by alanine in the betaIII and VI isotypes. This observation raises the possibility that the observed isotype difference in paclitaxel binding may be a kinetic effect arising from the isotype difference at this residue. We are now able to suggest derivatives of paclitaxel that may reverse the isotype-specificity or lead to an alternate stabilizing hydrogen-bond interaction with tubulin, thus increasing the rate of passage to the luminal binding site and hopefully offering a therapeutic advantage in paclitaxel resistant cases.
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Optical trapping and characterization of 10 base pairs (bp) hairpin DNA as well as its interaction with tumor suppressing protein (p53), wild and mutant types, using a Double Nano-Hole (DNH) optical tweezer have been previously reported.... more
Optical trapping and characterization of 10 base pairs (bp) hairpin DNA as well as its interaction with tumor suppressing protein (p53), wild and mutant types, using a Double Nano-Hole (DNH) optical tweezer have been previously reported. This paper discusses the application of the above technique in characterizing potential tumor suppressing activators from their interactions with a p53 mutant variant and l0bp hairpin DNA while establishing a comparison with the wild protein-DNA interaction.
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The existence of an exclusion zone in which particles of a colloidal suspension in water are repelled from hydrophilic surfaces has been experimentally demonstrated in numerous studies, especially in the case of Nafion surfaces. Various... more
The existence of an exclusion zone in which particles of a colloidal suspension in water are repelled from hydrophilic surfaces has been experimentally demonstrated in numerous studies, especially in the case of Nafion surfaces. Various explanations have been proposed for the origin of this phenomenon, which is not completely understood yet. In particular, the existence of a fourth phase of water has been proposed by G. Pollack and if this theory is proven correct, its implications on our understanding of the properties of water, especially in biological systems, would be profound and could give rise to new medical therapies. Here, a simple approach based on the linearized Poisson-Boltzmann equation is developed in order to study the repulsive forces mediated by ordered water and involving the following interacting biomolecules: 1) microtubule and a tubulin dimer, 2) two tubulin dimers and 3) a tubulin sheet and a tubulin dimer. The choice of microtubules in this study is motivated ...
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Microtubules are hollow cylindrical polymers composed of the highly negatively-charged (~23e), high dipole moment (1750 D) protein a,b-tubulin. While the roles of microtubules in chromosomal segregation, macromolecular transport and cell... more
Microtubules are hollow cylindrical polymers composed of the highly negatively-charged (~23e), high dipole moment (1750 D) protein a,b-tubulin. While the roles of microtubules in chromosomal segregation, macromolecular transport and cell migration are relatively well-understood, studies on the electrical properties of microtubules have only recently gained strong interest. Here, we show that while microtubules at physiological concentrations increase solution capacitance, free tubulin has no appreciable effect. For a particular microtubule concentration, we were able to quantify these effects by determining the capacitance and resistance of a single 20 um-long microtubule to be 1.86 x 10^(-12) F and 1.07 x 10^12 Ohms respectively. Further, we observed a decrease in electrical resistance of solution, with charge transport peaking between 20-60 Hz in the presence of microtubules, consistent with recent findings that microtubules exhibit electric oscillations at such low frequencies. O...
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The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot... more
The coronavirus causing the COVID-19 pandemic, SARS-CoV-2, uses −1 programmed ribosomal frameshifting (−1 PRF) to control the relative expression of viral proteins. As modulating −1 PRF can inhibit viral replication, the RNA pseudoknot stimulating −1 PRF may be a fruitful target for therapeutics treating COVID-19. We modeled the unusual 3-stem structure of the stimulatory pseudoknot of SARS-CoV-2 computationally, using multiple blind structural prediction tools followed by μs-long molecular dynamics simulations. The results were compared for consistency with nuclease-protection assays and single-molecule force spectroscopy measurements of the SARS-CoV-1 pseudoknot, to determine the most likely conformations. We found several possible conformations for the SARS-CoV-2 pseudoknot, all having an extended stem 3 but with different packing of stems 1 and 2. Several conformations featured rarely-seen threading of a single strand through the junction formed between two helices. These struct...
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Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved... more
Glioblastoma multiforme (GBM) is the most aggressive and deadly brain tumor, portending a median 13-month survival even following gross total resection with adjuvant chemotherapy and radiotherapy. This prognosis necessitates improved therapies for the disease. A target of interest for novel chemotherapies is the Warburg Effect, which describes the tumor’s shift away from oxidative phosphorylation towards glycolysis. Here, we elucidate GLUT1 (Glucose transporter 1) and one of its associated binding partners, TUBB4 (Tubulin 4), as potentially druggable targets in GBM. Using data mining approach, we demonstrate that GLUT1 is overexpressed as a function of tumor grade in astrocytoma’s and that its overexpression is associated with poorer prognosis. Using both mass spectrometry performed on hGBM (human glioblastoma patient specimen) and in silico modeling, we show that GLUT1 interacts with TUBB4, and more accurately demonstrates GLUT1’s binding with fasentin. Proximity ligation assay (PL...
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ABSTRACTCilia and flagella are cell organelles serving basic roles in cellular motility. Ciliary movement is performed by a sweeping-like repeated bending motion, which gives rise to a self-propagating “ciliary beat”. The hallmark... more
ABSTRACTCilia and flagella are cell organelles serving basic roles in cellular motility. Ciliary movement is performed by a sweeping-like repeated bending motion, which gives rise to a self-propagating “ciliary beat”. The hallmark structure in cilia is the axoneme, a stable architecture of microtubule doublets. The motion of axoneme is powered by the axonemal dynein motor family powered by ATP hydrolysis. It is still unclear how the organized beat of cilium and flagella emerges from the combined action of hundreds of dynein molecules. It has been hypothesized that such coordination is mediated by mechanical stress due to transverse, radial or sliding deformations. The beating asymmetry is crucial for airway ciliary function and it requires tubulin glutamination a unique posttranslational modification of C-termini of constituent microtubules that is highly abundant in cilia and flagella. The exact role of tubulin glutamination in ciliary or flagellar function is still unclear. Here w...
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Toll-like receptors (TLRs) are pattern recognition transmembrane proteins that play an important role in innate immunity. In particular, TLR7 plays a role in detecting nucleic acids derived from viruses and bacteria. The huge number of... more
Toll-like receptors (TLRs) are pattern recognition transmembrane proteins that play an important role in innate immunity. In particular, TLR7 plays a role in detecting nucleic acids derived from viruses and bacteria. The huge number of pathologies in which TLR7 is involved has led to an increasing interest in developing new compounds targeting this protein. Several conjugation strategies were proposed for TLR7 agonists to increase the potency while maintaining a low toxicity. In this work, we focus the attention on two promising classes of TLR7 compounds derived from the same pharmacophore conjugated with phospholipid and polyethylene glycol (PEG). A multidisciplinary investigation has been carried out by molecular dynamics (MD), dynamic light scattering (DLS), electron paramagnetic resonance (EPR), and cytotoxicity assessment. DLS and MD indicated how only the phospholipid conjugation provides the compound abilities to self-assemble in an orderly fashion with a maximal pharmacophor...
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Microtubules (MTs) form mitotic spindles in dividing cells but have also been implicated in electrical signaling in biology, and may act as biological nanowires. Importantly, relatively weak AC electric fields with frequencies between... more
Microtubules (MTs) form mitotic spindles in dividing cells but have also been implicated in electrical signaling in biology, and may act as biological nanowires. Importantly, relatively weak AC electric fields with frequencies between 100-300 kHz and strengths in the range ~1-2.5 V/cm, called Tumor Treating Fields (TTFields), have been shown to arrest cancer cells’ mitosis and have led to an FDA approved treatment of glioblastoma multiforme. TTFields’ effect on MTs has motivated our study of their electrical properties. Here, we designed two platinum electrodes 14 μm apart and performed electrical characterization of solutions with various concentrations of MTs, tubulin dimers and ions, at a range of AC frequencies between 1 kHz and 1 MHz to uncover an optimal protocol to quantify MT electrical effects in vitro. We generated a theoretical basis for the results observed, by analyzing the response of ions as the principal charge carriers attracted to MTs and tubulin. We observed that ...
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We describe a strategy for the development of a rational approach of neoplastic disease therapy based on the demonstration that scale-free networks are susceptible to specific attacks directed against its connective hubs. This strategy... more
We describe a strategy for the development of a rational approach of neoplastic disease therapy based on the demonstration that scale-free networks are susceptible to specific attacks directed against its connective hubs. This strategy involves the (i) selection of up-regulated hubs of connectivity in the tumors interactome, (ii) drug repurposing of these hubs, (iii) RNA silencing of non-druggable hubs, (iv) in vitro hub validation, (v) tumor-on-a-chip, (vi) in vivo validation, and (vii) clinical trial. Hubs are protein targets that are assessed as targets for rational therapy of cancer in the context of personalized oncology. We confirmed the existence of a negative correlation between malignant cell aggressivity and the target number needed for specific drugs or RNA interference (RNAi) to maximize the benefit to the patient’s overall survival. Interestingly, we found that some additional proteins not generally targeted by drug treatments might justify the addition of inhibitors de...
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Network-based strategies provided by systems biology are attractive tools for cancer therapy. Modulation of cancer networks by anticancer drugs may alter the response of malignant cells and/or drive network reorganization into the... more
Network-based strategies provided by systems biology are attractive tools for cancer therapy. Modulation of cancer networks by anticancer drugs may alter the response of malignant cells and/or drive network reorganization into the inhibition of cancer progression. Previously, using systems biology approach and cancer signaling networks, we identified the top 5 highly expressed and connected proteins (HSP90AB1, CSNK2B, TK1, YWHAB, and VIM) in the invasive MDA-MB-231 breast cancer cell line. Here, we have knocked down the expression of these proteins, individually or together using siRNAs. The transfected cell lines were assessed for in vitro cell growth, colony formation, migration, and invasion relative to control transfected MDA-MB-231, the noninvasive MCF-7 breast carcinoma cell line, and the nontumoral mammary epithelial cell line MCF-10A. The knockdown of the top-5 upregulated connectivity hubs successfully inhibited the in vitro proliferation, colony formation, anchorage independence, migration, and invasion in MDA-MB-231 cells, with minimal effects in the control transfected MDA-MB-231 cells or MCF-7 and MCF-10A cells. The in vitro validation of bioinformatics predictions regarding optimized multitarget selection for therapy suggests that protein expression levels together with protein-protein interaction network analysis may provide an optimized combinatorial target selection for a highly effective antimetastatic precision therapy in triple-negative breast cancer. This approach increases the ability to identify not only druggable hubs as essential targets for cancer survival, but also interactions most susceptible to synergistic drug action. The data provided in this report constitute a preliminary step toward the personalized clinical application of our strategy to optimize the therapeutic use of anticancer drugs. Citation Format: Tatiana Martins Tilli, Nicolas Carels, Jack Adam Tuszynski, Manijeh Pasdar. Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy [abstract]. In: Proceedings of the AACR International Conference held in cooperation with the Latin American Cooperative Oncology Group (LACOG) on Translational Cancer Medicine; May 4-6, 2017; São Paulo, Brazil. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(1_Suppl):Abstract nr B43.
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Research Interests: Bioinformatics, Computer Science, Human Genetics, Biology, Chemotherapy, and 13 morePersonalized Medicine, Molecular Genetics, Translational Research, Medicine, RNA-seq Analysis, Translational Medicine, Correlation, Interactome, Subnetwork Analysis, Precision Medicine, Molecular Targeted Therapy, Translational Oncology, and Adenocarcinoma
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The antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the α/β-tubulin heterodimer, GTP becomes bound to both the α and β-tubulin monomers.... more
The antitumor drug paclitaxel stabilizes microtubules and reduces their dynamicity, promoting mitotic arrest and eventually apoptosis. Upon assembly of the α/β-tubulin heterodimer, GTP becomes bound to both the α and β-tubulin monomers. During microtubule assembly, the GTP bound to β-tubulin is hydrolyzed to GDP, eventually reaching steady-state equilibrium between free tubulin dimers and those polymerized into microtubules. Tubulin-binding drugs such as paclitaxel interact with β-tubulin, resulting in the disruption of this equilibrium. In spite of several crystal structures of tubulin, there is little biochemical insight into the mechanism by which anti-tubulin drugs target microtubules and alter their normal behavior. The mechanism of drug action is further complicated, as the description of altered β-tubulin isotype expression and/or mutations in tubulin genes may lead to drug resistance as has been described in the literature. Because of the relationship between β-tubulin isoty...
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... ADVANCES IN BIOMEDICAL ENGINEERING Editor PASCAL VERDONCK Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San ... 167 5 Concluding Remarks 170 5 Monte Carlo Simulations in Nuclear Medicine Imaging 175 Steven... more
... ADVANCES IN BIOMEDICAL ENGINEERING Editor PASCAL VERDONCK Amsterdam Boston Heidelberg London New York Oxford Paris San Diego San ... 167 5 Concluding Remarks 170 5 Monte Carlo Simulations in Nuclear Medicine Imaging 175 Steven Staelens and ...
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We investigate the messenger role of calcium ions implicated in the regulation of wave-like bending dynamics of flagella. The emphasis is on microtubules of flagellar axoneme serving as nonlinear transmission lines for bell-shaped spikes... more
We investigate the messenger role of calcium ions implicated in the regulation of wave-like bending dynamics of flagella. The emphasis is on microtubules of flagellar axoneme serving as nonlinear transmission lines for bell-shaped spikes of calcium ions. The calcium sensitive proteins, such as calmodulin, exhibit activation dependence on the spike train frequency and amplitude. Here, we analyze a Ca2+ decoding module IDA-I1 whose activity is controlled by Ca2+ activated kinase. We find that trains of Ca2+ spikes are advantageous compared to a constant rise in Ca2+ concentration as being more efficient and much less prone to noisy fluctuations.
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ABSTRACT In this paper we try to elucidate the physical significance of the analytical solutions in the Peyrard-Bishop-Dauxois (extended Peyrard-Bishop) model of DNA dynamics. We discuss the impact of some parameters of the model,... more
ABSTRACT In this paper we try to elucidate the physical significance of the analytical solutions in the Peyrard-Bishop-Dauxois (extended Peyrard-Bishop) model of DNA dynamics. We discuss the impact of some parameters of the model, especially the harmonic constant of the helicoidal springs. We study both the case of DNA dynamics when viscosity is ignored and when it is taken into consideration.
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Given its critical role in cell mitosis, the tubulin γ chain represents a viable chemotherapeutic target to solve the specificity issues associated with targeting α and β tubulin. Since γ tubulin is overexpressed in glioblastoma... more
Given its critical role in cell mitosis, the tubulin γ chain represents a viable chemotherapeutic target to solve the specificity issues associated with targeting α and β tubulin. Since γ tubulin is overexpressed in glioblastoma multiforme (GBM) and some breast lesions, the glaziovianin A derivative gatastatin, presented as a γ-tubulin-specific inhibitor, could yield a successful therapeutic strategy. The present work aims to identify the binding sites and modes of gatastatin and its derivatives through molecular-docking simulations. Computational binding free energy predictions were compared to experimental microscale thermophoresis assay results. The computational simulations did not reveal a strong preference toward γ tubulin, suggesting that further derivatization may be needed to increase its specificity.
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We describe non-equilibrium ϕ4 theory in a hierarchical manner to develop a method for manipulating coherent fields as a toy model of introducing control into Quantum Field Theory (QFT) of the brain, which is called Quantum Brain Dynamics... more
We describe non-equilibrium ϕ4 theory in a hierarchical manner to develop a method for manipulating coherent fields as a toy model of introducing control into Quantum Field Theory (QFT) of the brain, which is called Quantum Brain Dynamics (QBD). We begin with the Lagrangian density of ϕ4 model, where we adopt 2-Particle-Irreducible (2PI) effective action, and derive the Klein–Gordon equation of coherent fields with a damping term as an input–output equation proposed in areas of morphological computation or reservoir computing. Our analysis is extended to QFT in a hierarchy representing multiple layers covering cortex in a brain. We find that the desired target function is achieved via time-evolution in the Klein–Gordon equations in a hierarchy of numerical simulations when a signal in both the input and output prevails over noise in the intermediate layers. Our approach will be applied to control coherent fields in the systems (in a hierarchy) described in the QFT framework, with po...
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Omicron is the dominant strain of COVID-19 in the United States and worldwide. Although this variant is highly transmissible and may evade natural immunity, vaccines, and therapeutic antibodies, preclinical results in animal models and... more
Omicron is the dominant strain of COVID-19 in the United States and worldwide. Although this variant is highly transmissible and may evade natural immunity, vaccines, and therapeutic antibodies, preclinical results in animal models and clinical data in humans suggest omicron causes a less severe form of infection. The molecular basis for the attenuation of virulence when compared to previous variants is currently not well understood. Using protein–ligand docking simulations to evaluate and compare the capacity of SARS-CoV-2 spike-1 proteins with the different COVID-19 variants to bind to the human α7nAChr (i.e., the core receptor under the control of the vagus nerve regulating the parasympathetic nervous system and the cholinergic anti-inflammatory pathway), we found that 10 out of the 14 mutated residues on the RBD of the B.1.1.529 (Omicron) spike, compared to between 0 and 2 in all previous variants, were present at the interaction interface of the α7nAChr. We also demonstrated, t...
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<p>Two pairs of cell lines were used to determine expression of βIII tubulin isotype and P-gp efflux pump. Parental cell lines MES-SA (uterine sarcoma) and K-562 (chronic myelogenous leukemia) are P-gp negative, whereas daughter... more
<p>Two pairs of cell lines were used to determine expression of βIII tubulin isotype and P-gp efflux pump. Parental cell lines MES-SA (uterine sarcoma) and K-562 (chronic myelogenous leukemia) are P-gp negative, whereas daughter cell lines MES-SA/Dx5 and K-562/R7 express P-gp, and have been characterized in the literature as multidrug-resistant lines [<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129168#pone.0129168.ref028" target="_blank">28</a>,<a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0129168#pone.0129168.ref030" target="_blank">30</a>]. Experiments were carried out under normal media conditions (−) and after 24 h paclitaxel exposure with concentration at one-half IC<sub>50</sub> (+). The image is representative of the results from n = 3 independent experiments. Actin protein was used as a loading control.</p
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<p>Energetic contributions of important domains across lateral interface in (A) <i>α</i> and (B) <i>β</i> subunits and across longitudinal inter-dimer interface in (C) <i>α</i> and (D)... more
<p>Energetic contributions of important domains across lateral interface in (A) <i>α</i> and (B) <i>β</i> subunits and across longitudinal inter-dimer interface in (C) <i>α</i> and (D) <i>β</i> subunits. Data are shown for GDP- and GTP-Model as well as the difference between them (GTP-GDP). On the <i>x</i>-axis of (A) and (B), domains H4 helix and before occur at lateral interface of the ligand while domains after that occur at receptor lateral interface. In (C), all domains belong to receptor while all the domains in (D) belong to ligand. See ligand and receptor definitions in <a href="http://www.ploscompbiol.org/article/info:doi/10.1371/journal.pcbi.1004313#pcbi.1004313.g003" target="_blank">Fig 3</a>.</p
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We report the results of experimental investigations involving photobiomodulation (PBM) of living cells, tubulin, and microtubules in buffer solutions exposed to near-infrared (NIR) light emitted from an 810 nm LED with a power density of... more
We report the results of experimental investigations involving photobiomodulation (PBM) of living cells, tubulin, and microtubules in buffer solutions exposed to near-infrared (NIR) light emitted from an 810 nm LED with a power density of 25 mW/cm2 pulsed at a frequency of 10 Hz. In the first group of experiments, we measured changes in the alternating current (AC) ionic conductivity in the 50–100 kHz range of HeLa and U251 cancer cell lines as living cells exposed to PBM for 60 min, and an increased resistance compared to the control cells was observed. In the second group of experiments, we investigated the stability and polymerization of microtubules under exposure to PBM. The protein buffer solution used was a mixture of Britton-Robinson buffer (BRB aka PEM) and microtubule cushion buffer. Exposure of Taxol-stabilized microtubules (~2 μM tubulin) to the LED for 120 min resulted in gradual disassembly of microtubules observed in fluorescence microscopy images. These results were ...