1,721,010 research outputs found
A dialogue on the issue of the “quantum brain” between consciousness and unconsciousness
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Validation of a network-based strategy for the optimization of combinatorial target selection in breast cancer therapy: SiRNA knockdown of network targets in MDA-MB-231 cells as an in vitro model for inhibition of tumor development
No full textInstituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Laboratório de Modelagem de Sistemas Biológicos. Rio de Janeiro, RJ, Brasil.Instituto Nacional de Ciência e Tecnologia de Inovação em Doenças Negligenciadas. Rio de Janeiro, RJ, Brasil / Fundação Oswaldo Cruz. Centro de Desenvolvimento Tecnológico em Saúde. Laboratório de Modelagem de Sistemas Biológicos. Rio de Janeiro, RJ, Brasil.University of Alberta. Faculty of Medicine & Dentistry. Department of Oncology. Department of Physics. Edmonton, Alberta, Canada.University of Alberta. Faculty of Medicine & Dentistry. Department of Oncology. Edmonton, Alberta, Canada.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 re-organization into the inhibition of cancer progression. Previously, using systems biology approach and cancer signaling networks, we identified 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 non-invasive MCF-7 breast carcinoma cell line and the non-tumoral 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 multi-target 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 anti-metastatic 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 anti-cancer drugs
Multiscale Computational Analysis of the Effect of Taxol on Microtubule Mechanics
No full textMicrotubules (MTs) are widely recognized as targets for cancer therapies. They are directly related to unique mechanical properties, closely dependent on MT architecture and tubulin molecular features. Taxol is known to affect tubulin interactions resulting in the stabilization of the MT lattice, and thus the hierarchical organization stability, mechanics, and function. A deeper understanding of the molecular mechanisms through which taxol modulates intertubulin interactions in the MT lattice, and consequently, its stability and mechanical response is crucial to characterize how MT properties are regulated by environmental factors, such as interacting ligands. In this study, a computational analysis of the effect of taxol on the MT was performed at different scales, combining molecular dynamics simulation, dynamical network analysis, and elastic network modeling. The results show that the taxol-induced conformational differences at the M-loop region increase the stability of the lateral interactions and the amount of surface in contact between laterally coupled tubulins. Moreover, the conformational rearrangements in the taxane binding site result in a different structural communication pattern. Finally, the different conformation of the tubulin heterodimers and the stabilized lateral interactions resulted in a tendency toward higher deformation of the vibrating MT in the presence of taxol. Overall, this work provides additional insights into taxol-induced stabilization and relates the conformational changes at the tubulin level to the MT mechanics. Besides providing useful insights into taxol effect on MT mechanics, a methodological framework that could be used to characterize the effects of other MT stabilizing agents is presented
Alteration of Consciousness by Anaesthetics: A Multiscale Modulation from the Molecular to the Systems Level
Full text linkGeneral anaesthesia has been used in medical practice since the mid-nineteenth century, but its pharmacological mechanism of action is still not entirely clear. In a top-down approach, investigations probe smaller and smaller scales to shed light on how anaesthetics disrupt or alter neural activity, ultimately resulting in loss of consciousness. In the past few decades, advances in neuroscience and molecular biology allowed for investigations on the brain structure and function from the behavioural level to the systems, cellular, and molecular level. This multiscale approach implicates the molecular domain as a fundamental link between general anaesthesia and consciousness, which also sheds light on how anaesthetic agents affect the pathogenesis of postoperative behavioural changes. This review discusses the current state of knowledge about the relationship between consciousness and general anaesthesia determined using pharmacokinetics, molecular biology, and advanced medical imaging, including EEG, fMRI, PET, MEG. It is hoped that the mechanisms of action of anaesthetic gases may help solve the mystery of consciousness. Conversely, understanding the cellular and molecular mechanisms of consciousness could lead to the design and development of new anaesthetic agents and technologies to controllably turn off and on consciousness. It could also generate new concepts in neurocognitive pathophysiology disorders
Relationship between intelligence and spectral characteristics of brain biophoton emission: Correlation does not automatically imply causation
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