Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

2 weeks 6 days ago
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Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

Book. 2019

Authors: Makarov S, Horner M, Noetscher G

Abstract
This chapter presents an overview of electric conduction in living cells when viewed as a composition of bioelectric circuits. We review the cell’s components that are known to exhibit electric conduction properties and represent them as parts of a complex circuitry. In particular, we discuss conductivity of the membrane, ion channels, actin filaments, DNA, and microtubules, each of which play important roles in the biological functioning of the cell. A new picture emerges where electrical conduction within the cell is taking place in an integrated fashion and may explain synchronization and orchestration of the cell dynamics.


PMID: 31725231

Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

2 weeks 6 days ago
Related Articles

Brain and Human Body Modeling: Computational Human Modeling at EMBC 2018

Book. 2019

Authors: Makarov S, Horner M, Noetscher G

Abstract
Our goal is to uncover the mechanism underlying tumour-treating fields’ efficacy in killing cancer cells. Modelling the effects of these 200 kHz alternating current electric fields on tumour cell sub-structures has led us to focus on the microtubules (MTs), C-termini and the motor protein kinesin, which are integral to the critical functions of MT transport of proteins during the delicate orchestration of cell division (mitosis). Leading hypotheses of the TTFields’ mechanism that we are modelling include disruption of mitosis functions (such as the ‘kinesin walk’ along MTs), C-termini state transitions and MT polymerization.


PMID: 31725240

Signaling Complexity Measured by Shannon Entropy and Its Application in Personalized Medicine.

3 weeks 6 days ago
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Signaling Complexity Measured by Shannon Entropy and Its Application in Personalized Medicine.

Front Genet. 2019;10:930

Authors: Conforte AJ, Tuszynski JA, da Silva FAB, Carels N

Abstract
Traditional approaches to cancer therapy seek common molecular targets in tumors from different patients. However, molecular profiles differ between patients, and most tumors exhibit inherent heterogeneity. Hence, imprecise targeting commonly results in side effects, reduced efficacy, and drug resistance. By contrast, personalized medicine aims to establish a molecular diagnosis specific to each patient, which is currently feasible due to the progress achieved with high-throughput technologies. In this report, we explored data from human RNA-seq and protein-protein interaction (PPI) networks using bioinformatics to investigate the relationship between tumor entropy and aggressiveness. To compare PPI subnetworks of different sizes, we calculated the Shannon entropy associated with vertex connections of differentially expressed genes comparing tumor samples with their paired control tissues. We found that the inhibition of up-regulated connectivity hubs led to a higher reduction of subnetwork entropy compared to that obtained with the inhibition of targets selected at random. Furthermore, these hubs were described to be participating in tumor processes. We also found a significant negative correlation between subnetwork entropies of tumors and the respective 5-year survival rates of the corresponding cancer types. This correlation was also observed considering patients with lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD) based on the clinical data from The Cancer Genome Atlas database (TCGA). Thus, network entropy increases in parallel with tumor aggressiveness but does not correlate with PPI subnetwork size. This correlation is consistent with previous reports and allowed us to assess the number of hubs to be inhibited for therapy to be effective, in the context of precision medicine, by reference to the 100% patient survival rate 5 years after diagnosis. Large standard deviations of subnetwork entropies and variations in target numbers per patient among tumor types characterize tumor heterogeneity.

PMID: 31695721 [PubMed]

Tubulin: Structure, Functions and Roles in Disease.

1 month 1 week ago
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Tubulin: Structure, Functions and Roles in Disease.

Cells. 2019 Oct 22;8(10):

Authors: Binarová P, Tuszynski J

Abstract
Highly conserved α- and β-tubulin heterodimers assemble into dynamic microtubules and perform multiple important cellular functions such as structural support, pathway for transport and force generation in cell division. Tubulin exists in different forms of isotypes expressed by specific genes with spatially- and temporally-regulated expression levels. Some tubulin isotypes are differentially expressed in normal and neoplastic cells, providing a basis for cancer chemotherapy drug development. Moreover, specific tubulin isotypes are overexpressed and localized in the nuclei of cancer cells and/or show bioenergetic functions through the regulation of the permeability of mitochondrial ion channels. It has also become clear that tubulin isotypes are involved in multiple cellular functions without being incorporated into microtubule structures. Understanding the mutations of tubulin isotypes specifically expressed in tumors and their post-translational modifications might help to identify precise molecular targets for the design of novel anti-microtubular drugs. Knowledge of tubulin mutations present in tubulinopathies brings into focus cellular functions of tubulin in brain pathologies such as Alzheimer's disease. Uncovering signaling pathways which affect tubulin functions during antigen-mediated activation of mast cells presents a major challenge in developing new strategies for the treatment of inflammatory and allergic diseases. γ-tubulin, a conserved member of the eukaryotic tubulin superfamily specialized for microtubule nucleation is a target of cell cycle and stress signaling. Besides its microtubule nucleation role, γ-tubulin functions in nuclear and cell cycle related processes. This special issue "Tubulin: Structure, Functions and Roles in Disease" contains eight articles, five of which are original research papers and three are review papers that cover diverse areas of tubulin biology and functions under normal and pathological conditions.

PMID: 31652491 [PubMed - in process]

Docosahexaenoic Acid Inhibits PTP1B Phosphatase and the Viability of MCF-7 Breast Cancer Cells.

1 month 1 week ago
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Docosahexaenoic Acid Inhibits PTP1B Phosphatase and the Viability of MCF-7 Breast Cancer Cells.

Nutrients. 2019 Oct 23;11(11):

Authors: Kuban-Jankowska A, Gorska-Ponikowska M, Sahu KK, Kostrzewa T, Wozniak M, Tuszynski J

Abstract
BACKGROUND: Docosahexaenoic acid (DHA) is an essential polyunsaturated fatty acid compound present in deep water fishes and dietary supplements, with a wide spectrum of potential health benefits, ranging from neurological to anti-inflammatory.
METHODS: Due to the fact that DHA is considered a breast cancer risk reducer, we examined the impact of DHA on MCF-7 breast cancer cells' viability and its inhibitory properties on protein tyrosine phosphatase 1B (PTP1B), a pro-oncogenic phosphatase.
RESULTS: We found that DHA is able to lower both the enzymatic activity of PTP1B phosphatase and the viability of MCF-7 breast cancer cells. We showed that unsaturated DHA possesses a significantly higher inhibitory activity toward PTP1B in comparison to similar fatty acids. We also performed a computational analysis of DHA binding to PTP1B and discovered that it is able to bind to an allosteric binding site.
CONCLUSIONS: Utilizing both a recombinant enzyme and cellular models, we demonstrated that DHA can be considered a potential pharmacological agent for the prevention of breast cancer.

PMID: 31652764 [PubMed - in process]

Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents.

1 month 1 week ago
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Synthesis, biological evaluation and molecular docking studies of new amides of 4-bromothiocolchicine as anticancer agents.

Bioorg Med Chem. 2019 Oct 08;:115144

Authors: Klejborowska G, Urbaniak A, Preto J, Maj E, Moshari M, Wietrzyk J, Tuszynski JA, Chambers TC, Huczyński A

Abstract
Colchicine is the major alkaloid isolated from the plant Colchicum autumnale, which shows strong therapeutic effects towards different types of cancer. However, due to the toxicity of colchicine towards normal cells its application is limited. To address this issue we synthesized a series of seven triple-modified 4-bromothiocolchicine analogues with amide moieties. These novel derivatives were active in the nanomolar range against several different cancer cell lines and primary acute lymphoblastic leukemia cells, specifically compounds: 5-9 against primary ALL-5 (IC50 = 5.3-14 nM), 5, 7-9 against A549 (IC50 = 10 nM), 5, 7-9 against MCF-7 (IC50 = 11 nM), 5-9 against LoVo (IC50 = 7-12 nM), and 5, 7-9 against LoVo/DX (IC50 = 48-87 nM). These IC50 values were lower than those obtained for unmodified colchicine and common anticancer drugs such as doxorubicin and cisplatin. Further studies revealed that colchicine and selected analogues induced characteristics of apoptotic cell death but manifested their effects in different phases of the cell cycle in MCF-7 versus ALL-5 cells. Specifically, while colchicine and the studied derivatives arrested MCF-7 cells in mitosis, very little mitotically arrested ALL-5 cells were observed, suggesting effects were manifest instead in interphase. We also developed an in silico model of the mode of binding of these compounds to their primary target, β-tubulin. We conducted a correlation analysis (linear regression) between the calculated binding energies of colchicine derivatives and their anti-proliferative activity, and determined that the obtained correlation coefficients strongly depend on the type of cells used.

PMID: 31653441 [PubMed - as supplied by publisher]

GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets.

2 months 3 weeks ago
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GLUT1 and TUBB4 in Glioblastoma Could be Efficacious Targets.

Cancers (Basel). 2019 Sep 05;11(9):

Authors: Guda MR, Labak CM, Omar SI, Asuthkar S, Airala S, Tuszynski J, Tsung AJ, Velpula KK

Abstract
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 (PLA) and immunoprecipitation studies confirm GLUT1 interaction with TUBB4. Treatment of GSC33 and GSC28 cells with TUBB4 inhibitor, CR-42-24, reduces the expression of GLUT1 however, TUBB4 expression is unaltered upon fasentin treatment. Using human pluripotent stem cell antibody array, we demonstrate reduced levels of Oct3/4, Nanog, Sox2, Sox17, Snail and VEGFR2 (Vascular endothelial growth factor receptor 2) upon CR-42-24 treatment. Overall, our data confirm that silencing TUBB4 or GLUT1 reduce GSC tumorsphere formation, self-renewal and proliferation in vitro. These findings suggest GLUT1 and its binding partner TUBB4 as druggable targets that warrant further investigation in GBM.

PMID: 31491891 [PubMed]

Synthesis, antiproliferative activity and molecular docking studies of 4-chlorothiocolchicine analogues.

3 months ago
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Synthesis, antiproliferative activity and molecular docking studies of 4-chlorothiocolchicine analogues.

Chem Biol Drug Des. 2019 Sep 04;:

Authors: Klejborowska G, Moshari M, Maj E, Majcher U, Preto J, Wietrzyk J, Tuszynski JA, Huczyński A

Abstract
Colchicine is a therapeutic agent currently used in therapies of many diseases. It also shows antimitotic effects and its high cytotoxic activity against different cancer cell lines has been demonstrated many times. To overcome the limitations of colchicine use in anticancer therapy, we synthesized a series of novel triple-modified 4-chloro-7-carbamatethiocolchicines. All the synthesized compounds have been tested in vitro to evaluate their cytotoxicity towards A549, MCF-7, LoVo, LoVo/DX and BALB/3T3 cell lines. Additionally, their mode of binding to ß-tubulin was evaluated in silico. The majority of triple-modified colchicine derivatives exhibited significantly higher cytotoxicity than colchicine, doxorubicin and cisplatin against tested cancerous cell lines with much higher selectivity index values for four of them. This article is protected by copyright. All rights reserved.

PMID: 31483093 [PubMed - as supplied by publisher]

Probing the Basis of α-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments.

3 months ago
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Probing the Basis of α-Synuclein Aggregation by Comparing Simulations to Single-Molecule Experiments.

Biophys J. 2019 Aug 16;:

Authors: Churchill CDM, Healey MA, Preto J, Tuszynski JA, Woodside MT

Abstract
Intrinsically disordered proteins often play an important role in protein aggregation. However, it is challenging to determine the structures and interactions that drive the early stages of aggregation because they are transient and obscured in a heterogeneous mixture of disordered states. Even computational methods are limited because the lack of ordered structure makes it difficult to ensure that the relevant conformations are sampled. We address these challenges by integrating atomistic simulations with high-resolution single-molecule measurements reported previously, using the measurements to help discern which parts of the disordered ensemble of structures in the simulations are most probable while using the simulations to identify residues and interactions that are important for oligomer stability. This approach was applied to α-synuclein, an intrinsically disordered protein that aggregates in the context of Parkinson's disease. We simulated single-molecule pulling experiments on dimers, the minimal oligomer, and compared them to force spectroscopy measurements. Force-extension curves were simulated starting from a set of 66 structures with substantial structured content selected from the ensemble of dimer structures generated at zero force via Monte Carlo simulations. The pattern of contour length changes as the structures unfolded through intermediate states was compared to the results from optical trapping measurements on the same dimer to discern likely structures occurring in the measurements. Simulated pulling curves were generally consistent with experimental data but with a larger number of transient intermediates. We identified an ensemble of β-rich dimer structures consistent with the experimental data from which dimer interfaces could be deduced. These results suggest specific druggable targets in the structural motifs of α-synuclein that may help prevent the earliest steps of oligomerization.

PMID: 31477241 [PubMed - as supplied by publisher]

Tubulin Polarizability in Aqueous Suspensions.

3 months ago
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Tubulin Polarizability in Aqueous Suspensions.

ACS Omega. 2019 May 31;4(5):9144-9149

Authors: Guzman-Sepulveda JR, Wu R, Kalra AP, Aminpour M, Tuszynski JA, Dogariu A

Abstract
We report accurate optical measurements of tubulin polarizability in aqueous suspensions. We determined the dependence of polarizability on tubulin concentration and on the suspension's pH, providing benchmark numbers for quantifying the optical response of this protein in various artificial and cellular environments. We compare our measurement data with a few estimates found in the previous literature and also with our simplified model estimations.

PMID: 31460002 [PubMed]

Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

3 months 4 weeks ago
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Magnetic Monopole Search with the Full MoEDAL Trapping Detector in 13 TeV pp Collisions Interpreted in Photon-Fusion and Drell-Yan Production.

Phys Rev Lett. 2019 Jul 12;123(2):021802

Authors: Acharya B, Alexandre J, Baines S, Benes P, Bergmann B, Bernabéu J, Bevan A, Branzas H, Campbell M, Cecchini S, Cho YM, de Montigny M, De Roeck A, Ellis JR, El Sawy M, Fairbairn M, Felea D, Frank M, Hays J, Hirt AM, Janecek J, Kim DW, Korzenev A, Lacarrère DH, Lee SC, Leroy C, Levi G, Lionti A, Mamuzic J, Margiotta A, Mauri N, Mavromatos NE, Mermod P, Mieskolainen M, Millward L, Mitsou VA, Orava R, Ostrovskiy I, Papavassiliou J, Parker B, Patrizii L, Păvălaş GE, Pinfold JL, Popa V, Pozzato M, Pospisil S, Rajantie A, Ruiz de Austri R, Sahnoun Z, Sakellariadou M, Santra A, Sarkar S, Semenoff G, Shaa A, Sirri G, Sliwa K, Soluk R, Spurio M, Staelens M, Suk M, Tenti M, Togo V, Tuszyński JA, Vento V, Vives O, Vykydal Z, Wall A, Zgura IS, MoEDAL Collaboration

Abstract
MoEDAL is designed to identify new physics in the form of stable or pseudostable highly ionizing particles produced in high-energy Large Hadron Collider (LHC) collisions. Here we update our previous search for magnetic monopoles in Run 2 using the full trapping detector with almost four times more material and almost twice more integrated luminosity. For the first time at the LHC, the data were interpreted in terms of photon-fusion monopole direct production in addition to the Drell-Yan-like mechanism. The MoEDAL trapping detector, consisting of 794 kg of aluminum samples installed in the forward and lateral regions, was exposed to 4.0  fb^{-1} of 13 TeV proton-proton collisions at the LHCb interaction point and analyzed by searching for induced persistent currents after passage through a superconducting magnetometer. Magnetic charges equal to or above the Dirac charge are excluded in all samples. Monopole spins 0, ½, and 1 are considered and both velocity-independent and-dependent couplings are assumed. This search provides the best current laboratory constraints for monopoles with magnetic charges ranging from two to five times the Dirac charge.

PMID: 31386510 [PubMed - in process]

Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF.

4 months ago
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Targeting DNA Repair in Tumor Cells via Inhibition of ERCC1-XPF.

J Med Chem. 2019 Aug 01;:

Authors: Elmenoufy A, Gentile F, Jay D, Karimi-Busheri F, Yang X, Soueidan OM, Weilbeer C, Mani RS, Barakat KH, Tuszynski J, Weinfeld M, West FG

Abstract
The ERCC1-XPF heterodimer is a 5´-3´ structure-specific endonuclease, which plays an essential role in several DNA repair pathways in mammalian cells. ERCC1-XPF is primarily involved in the repair of chemically-induced helix-distorting and bulky DNA lesions, such as cyclobutane pyrimidine dimers (CPDs), and DNA interstrand crosslinks. Inhibition of ERCC1-XPF has been shown to potentiate cytotoxicity of platinum-based drugs and cyclophosphamide in cancer cells. In this study, the previously described ERCC1-XPF inhibitor 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-methylpiperazin-1-yl)methyl)phenol (F06) was used as a reference compound. Following the outcome of docking-based virtual screening (VS), we synthesized seven novel derivatives of F06 that were identified in silico as being likely to have high binding affinity for the ERCC1-XPF heterodimerization interface by interacting with the XPF double helix-hairpin-helix (HhH2) domain. Two of the new compounds, 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-cyclohexylpiperazin-1-yl)methyl)phenol (compound 3) and 4-((6-chloro-2-methoxyacridin-9-yl)amino)-2-((4-(2-(dimethylamino)ethyl) piperazin-1-yl) methyl) phenol (compound 4), were shown to be potent inhibitors of ERCC1-XPF activity in vitro. Compound 4 showed a significant inhibition of the removal of CPDs in UV-irradiated cells and the capacity to sensitize colorectal cancer cells to UV radiation and cyclophosphamide.

PMID: 31369707 [PubMed - as supplied by publisher]

Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation.

4 months 2 weeks ago
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Tubulin response to intense nanosecond-scale electric field in molecular dynamics simulation.

Sci Rep. 2019 Jul 19;9(1):10477

Authors: Marracino P, Havelka D, Průša J, Liberti M, Tuszynski J, Ayoub AT, Apollonio F, Cifra M

Abstract
Intense pulsed electric fields are known to act at the cell membrane level and are already being exploited in biomedical and biotechnological applications. However, it is not clear if electric pulses within biomedically-attainable parameters could directly influence intra-cellular components such as cytoskeletal proteins. If so, a molecular mechanism of action could be uncovered for therapeutic applications of such electric fields. To help clarify this question, we first identified that a tubulin heterodimer is a natural biological target for intense electric fields due to its exceptional electric properties and crucial roles played in cell division. Using molecular dynamics simulations, we then demonstrated that an intense - yet experimentally attainable - electric field of nanosecond duration can affect the bβ-tubulin's C-terminus conformations and also influence local electrostatic properties at the GTPase as well as the binding sites of major tubulin drugs site. Our results suggest that intense nanosecond electric pulses could be used for physical modulation of microtubule dynamics. Since a nanosecond pulsed electric field can penetrate the tissues and cellular membranes due to its broadband spectrum, our results are also potentially significant for the development of new therapeutic protocols.

PMID: 31324834 [PubMed - in process]

How signals of calcium ions initiate the beats of cilia and flagella.

5 months 2 weeks ago
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How signals of calcium ions initiate the beats of cilia and flagella.

Biosystems. 2019 Jun 13;:

Authors: Sataric MV, Nemeš T, Sekulic D, Tuszynski JA

Abstract
Cilia 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. In this paper we analyze the role of calcium (Ca2+) ions based on the experimental evidence that the flagellar asymmetry can be increased due to the entry of extracellular Ca2+ through, for example, the nimodipine-sensitive pathway located in the flagella. We propose a new scenario based on the polyelectrolyte properties of cellular microtubules (MTs) such that dynamic influx of Ca2+ ions provides the initiation and synchronization of dynein sliding along microtubules. We also point out the possible interplay between tubulin polyglutaminated C-termini and localized pulses of Ca2+ ions along microtubules.

PMID: 31202860 [PubMed - as supplied by publisher]

Molecular orbitals of delocalized dipole-bound electron clouds in neuronal domains.

5 months 2 weeks ago
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Molecular orbitals of delocalized dipole-bound electron clouds in neuronal domains.

Biosystems. 2019 Jun 10;:103982

Authors: Poznanski RR, Cacha LA, Latif AZA, Salleh SH, Ali J, Yupapin PP, Tuszynski JA, Ariff TM

Abstract
We have further developed the two-brains hypothesis as a form of biological complementarity (or complementary relationship) of endogenously induced weak magnetic fields in the electromagnetic brain. Here, locally induced magnetic field between electron magnetic dipole moments of delocalized electron clouds in neuronal domains are complementary to the exogenous electromagnetic waves created by the oscillating molecular dipole in the electro-ionic brain. In this paper, we mathematically model the integral operation of the electromagnetic grid, especially in regard to the functional role of atomic orbitals of dipole-bound delocalized electrons. A quantum molecular dynamic approach under quantum equilibrium conditions is taken to illustrate phase differences between quasi-free electrons tethered to an oscillating molecular core. We use a simplified version of the many-body problem to analytically solve the macro-quantum wave equation (equivalent to the Kohn-Sham equation) in order to compute the molecular orbital approximated as the mechanical angular momentum due to non-adiabatic motion of the molecular core. We address how the effects of the enveloping fields of dipole-bound delocalized electrons as 'guidance waves' affect delocalized macro-quantum wave functions in generating nonlocal phase correlations. The intrinsic magnetic properties of the origins of the endogenous electromagnetic field are considered a nested hierarchy of electromagnetic fields of brain activity that includes electromagnetic patterns in three-dimensional space. The coupling between the two-brains may involve an 'anticipatory affect' underlying the conceptualization of anticipation as potentiality arising from the macro-quantum potential energy or electrostatic effects of residual charges in the quantum and classical subsystems of the two-brains that occurs through partitioning of the potential energy of the combined quantum molecular dynamic system.

PMID: 31195028 [PubMed - as supplied by publisher]

The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils.

6 months 2 weeks ago
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The Role of Structural Polymorphism in Driving the Mechanical Performance of the Alzheimer's Beta Amyloid Fibrils.

Front Bioeng Biotechnol. 2019;7:83

Authors: Grasso G, Rebella M, Morbiducci U, Tuszynski JA, Danani A, Deriu MA

Abstract
Alzheimer's Disease (AD) is related with the abnormal aggregation of amyloid β-peptides Aβ1-40 and Aβ1-42, the latter having a polymorphic character which gives rise to U- or S-shaped fibrils. Elucidating the role played by the nanoscale-material architecture on the amyloid fibril stability is a crucial breakthrough to better understand the pathological nature of amyloid structures and to support the rational design of bio-inspired materials. The computational study here presented highlights the superior mechanical behavior of the S-architecture, characterized by a Young's modulus markedly higher than the U-shaped architecture. The S-architecture showed a higher mechanical resistance to the enforced deformation along the fibril axis, consequence of a better interchain hydrogen bonds' distribution. In conclusion, this study, focusing the attention on the pivotal multiscale relationship between molecular phenomena and material properties, suggests the S-shaped Aβ1-42 species as a target of election in computational screen/design/optimization of effective aggregation modulators.

PMID: 31106199 [PubMed]

Theorizing how the brain encodes consciousness based on negentropic entanglement.

6 months 2 weeks ago
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Theorizing how the brain encodes consciousness based on negentropic entanglement.

J Integr Neurosci. 2019 Mar 30;18(1):1-10

Authors: Poznanski RR, Cacha LA, Latif AZA, Salleh SH, Ali J, Yupapin P, Tuszynski JA, Tengku MA

Abstract
The physicality of subjectivity is explained through a theoretical conceptualization of guidance waves informing meaning in negentropically entangled non-electrolytic brain regions. Subjectivity manifests its influence at the microscopic scale of matter originating from de Broglie 'hidden' thermodynamics as action of guidance waves. The preconscious experienceability of subjectivity is associated with a nested hierarchy of microprocesses, which are actualized as a continuum of patterns of discrete atomic microfeels (or "qualia"). The mechanism is suggested to be through negentropic entanglement of hierarchical thermodynamic transfer of information as thermo-qubits originating from nonpolarized regions of actin-binding proteinaceous structures of nonsynaptic spines. The resultant continuous stream of intrinsic information entails a negentropic action (or experiential flow of thermo-quantum internal energy that results in a negentropic force) which is encoded through the non-zero real component of the mean approximation of the negentropic force as a 'consciousness code'. Consciousness consisting of two major subprocesses: (1) preconscious experienceability and (2) conscious experience. Both are encapsulated by nonreductive physicalism and panexperiential materialism. The subprocess (1) governing "subjectivity" carries many microprocesses leading to the actualization of discrete atomic microfeels by the 'consciousness code'. These atomic microfeels constitute internal energy that results in the transfer intrinsic information in terms of thermo-qubits. These thermo-qubits are realized as thermal entropy and sensed by subprocess (2) governing "self-awareness" in conscious experience.

PMID: 31091842 [PubMed - in process]

An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.

6 months 4 weeks ago
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An Overview of Molecular Modeling for Drug Discovery with Specific Illustrative Examples of Applications.

Molecules. 2019 Apr 30;24(9):

Authors: Aminpour M, Montemagno C, Tuszynski JA

Abstract
In this paper we review the current status of high-performance computing applications in the general area of drug discovery. We provide an introduction to the methodologies applied at atomic and molecular scales, followed by three specific examples of implementation of these tools. The first example describes in silico modeling of the adsorption of small molecules to organic and inorganic surfaces, which may be applied to drug delivery issues. The second example involves DNA translocation through nanopores with major significance to DNA sequencing efforts. The final example offers an overview of computer-aided drug design, with some illustrative examples of its usefulness.

PMID: 31052253 [PubMed - indexed for MEDLINE]

The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.

10 months 2 weeks ago
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The molecular mechanism of action of methylene quinuclidinone and its effects on the structure of p53 mutants.

Oncotarget. 2018 Dec 14;9(98):37137-37156

Authors: Omar SI, Tuszynski J

Abstract
One of the most important tumor suppressor proteins in eukaryotic cells is the transcription factor called p53. The importance of this protein in cells comes from the fact that it regulates a wide variety of cellular processes including the cell cycle, metabolism, DNA repair, senescence and apoptosis. In cancer cells, p53 is a major target as the most mutated protein, which has led to the search for potential activators of the mutant protein. Currently, the only mutated-p53 activator in clinical trials is a small molecule called APR-246. There is evidence that the active metabolite of APR-246 binds covalently to mutant p53 and restores its wild-type (wt) activity. In this work, we created atomistic in silico models of the wt, mutant and drugged mutant p53 proteins each in complex with DNA. Using molecular dynamics simulations we generated equilibrated models of the complexes. Detailed analysis revealed that the binding of the APR-246 active metabolite to the mutant proteins alters their interaction with DNA. In particular, the binding of the molecule at loop L1 of the protein allows the loop to anchor the protein to DNA similarly to wt p53. Several important p53-DNA interactions lost due to mutation were also restored in the drugged mutants. These findings, not only provide a possible mechanism of action of this drug, but also criteria to use in virtual screening campaigns for other p53 activators.

PMID: 30647850 [PubMed]

EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.

11 months 1 week ago
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EDEn-Electroceutical Design Environment: Ion Channel Tissue Expression Database with Small Molecule Modulators.

iScience. 2018 Dec 11;11:42-56

Authors: Churchill CDM, Winter P, Tuszynski JA, Levin M

Abstract
The emerging field of bioelectricity has revealed numerous new roles for ion channels beyond the nervous system, which can be exploited for applications in regenerative medicine. Developing such biomedical interventions for birth defects, cancer, traumatic injury, and bioengineering first requires knowledge of ion channel targets expressed in tissues of interest. This information can then be used to select combinations of small molecule inhibitors and/or activators that manipulate the bioelectric state. Here, we provide an overview of electroceutical design environment (EDEn), the first bioinformatic platform that facilitates the design of such therapeutic strategies. This database includes information on ion channels and ion pumps, linked to known chemical modulators and their properties. The database also provides information about the expression levels of the ion channels in over 100 tissue types. The graphical interface allows the user to readily identify chemical entities that can alter the electrical properties of target cells and tissues.

PMID: 30590250 [PubMed - as supplied by publisher]