Ion-Based Cellular Signal Transmission, Principles of Minimum Information Loss, and Evolution by Natural Selection

The Extreme Physical Information EPI principle states that maximum information transmission or, equivalently, a minimum information loss is a fundamental property of nature. Prior work has demonstrated the universal EPI principle allows derivation of nearly all physical laws. Here, we investigate whether EPI can similarly give rise to the fundamental law of life: Evolution. Living systems require information to survive and proliferate. Heritable information in the genome encodes the structure and function of cellular macromolecules but this information remains fixed over time. In contrast, a cell must rapidly and continuously access, analyze, and respond to a wide range of continuously changing spatial and temporal information in the environment. We propose these two information dynamics are linked because the genes encode the structure of the macromolecules that form information conduits necessary for the dynamical interactions with the external environment. However, because the genome does not have the capacity to precisely locate the time and location of external signals, we propose the cell membrane is the site at which most external information is received and processed. In our model, an external signal is detected by gates on transmembrane ion channel and transmitted into the cytoplasm through ions that flow along pre-existing concentration gradients when the gate opens. The resulting cytoplasmic ion “puff” is localized in both time and space, thus producing spatial and temporal information. Small, localized signals in the cytoplasm are “processed” through alterations in the function and location of peripheral membrane proteins. Larger perturbations produce prolonged or spatially extensive changes in cytoplasmic ion concentrations that can be transmitted to other organelles via ion flows along elements of the cytoskeleton. An evolutionary constraint to the ever-increasing acquisition of environmental information is the cost of doing so. One solution to this trade-off is the evolution of information conduits that minimize signal loss during transmission. Since the structures of these conduits are encoded in the genome, evolution of macromolecular conduits that minimize signal loss is linked to and, in fact, governed by a universal principle, termed extreme physical information (EPI). Mathematical analysis of information dynamics based on the flow of ions through membrane channels and along wire-like cytoskeleton macromolecules fulfills the EPI principle. Thus, the empirically derived model of evolution by natural selection, although uniquely applicable to living systems, is theoretically grounded in a universal principle that can also be used to derive the laws of physics. Finally, if minimization of signal loss is a mechanism to overcome energy constraints, the model predicts increasing information and associated complexity are closely linked to increased efficiency of energy production or improved substrate acquisition.
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High Intensity Focused Ultrasound (HIFU) Triggers Immune Sensitization of Refractory Murine Neuroblastoma to Checkpoint Inhibitor Therapy.

Magnetic frequencies are not the only alternatives:

"Combining HIFU with αCTLA-4 and αPD-L1 significantly enhances anti-tumor response, improving survival from 0 to 62.5%.
HIFU alone causes upregulation of splenic and lymph node NK cells and circulating IL-2, IFN-Ɣ, and DAMPs, whereas immune regulators like CD4+Foxp3+, IL-10, and VEGF-A are significantly reduced.
HIFU combined with checkpoint inhibitors induced significant increases in intratumoral CD4+, CD8ɑ+, and CD8α+CD11c+ cells, CD11c+ in regional lymph nodes, and decrease in circulating IL-10 compared to untreated group.
We also report significant abscopal effect following unilateral treatment of mice with large, established bilateral tumors using HIFU and checkpoint inhibitors compared to tumors treated with HIFU or checkpoint inhibitors alone (61.1% survival, p<0.0001).
This combination treatment significantly also induces CD4+CD44+hiCD62L+low and, CD8α+CD44+hiCD62L+low population and are adoptively transferable imparting immunity, slowing subsequent de novo tumor engraftment."

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Possible traces of resonance signaling in the genome

Although theories regarding the role of sequence-specific DNA resonance in biology have abounded for over 40 years, the published evidence for it is lacking. Here, the authors reasoned that for sustained resonance signaling, the number of oscillating DNA sequences per genome should be exceptionally high and that, therefore, genomic repeats of various sizes are good candidates for serving as resonators. Moreover, it was suggested that for the two DNA sequences to resonate, they do not necessarily have to be identical. Therefore, the existence of sequences differing in the primary sequence but having similar resonating sub-structures was proposed. It was hypothesized that such sequences, named HIDERs, would be enriched in the genomes of multicellular species. Specifically, it was hypothesized that delocalized electron clouds of purine-pyrimidine sequences could serve as the basis of HIDERs. The consequent genomic analysis confirmed the enrichment of purine-pyrimidine HIDERs in a few selected genomes of mammals, an insect, and a plant, compared to randomized sequence controls. Similarly, it was suggested that hypothetical delocalized proton clouds of the hydrogen bonds of multiple stacked bases could serve as sequence-dependent hydrogen-bond-based HIDERs. Similarly, the enrichment of such HIDERs was observed. It is suggested that these enrichments are the first evidence in support of sequence-specific resonance signaling in the genome.

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KCa and Ca2 + Channels: The complex thought

Potassium channels belong to the largest and the most diverse super-families of ion channels. Among them, Ca2 +-activated K+ channels (KCa) comprise many members. Based on their single channel conductance they are divided into three subfamilies: big conductance (BKCa), intermediate conductance (IKCa) and small conductance (SKCa; SK1, SK2 and SK3). Ca2 + channels are divided into two main families, voltage gated/voltage dependent Ca2 + channels and non-voltage gated/voltage independent Ca2 + channels. Based on their electrophysiological and pharmacological properties and on the tissue where there are expressed, voltage gated Ca2 + channels (Cav) are divided into 5 families: T-type, L-type, N-type, P/Q-type and R-type Ca2 +. Non-voltage gated Ca2 + channels comprise the TRP (TRPC, TRPV, TRPM, TRPA, TRPP, TRPML and TRPN) and Orai (Orai1 to Orai 3) families and their partners STIM (STIM1 to STIM2). A depolarization is needed to activate voltage-gated Ca2 + channels while non-voltage gated Ca2 + channels are activated by Ca2 + depletion of the endoplasmic reticulum stores (SOCs) or by receptors (ROCs). These two Ca2 + channel families also control constitutive Ca2 + entries. For reducing the energy consumption and for the fine regulation of Ca2 +, KCa and Ca2 + channels appear associated as complexes in excitable and non-excitable cells. Interestingly, there is now evidence that KCa - Ca2 + channel complexes are also found in cancer cells and contribute to cancer-associated functions such as cell proliferation, cell migration and the capacity to develop metastases. This article is part of a Special Issue entitled: Calcium Signaling In Health and Disease.
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Voltage Gated Sodium Channels in Cancer and Their Potential Mechanisms of Action

Voltage gated sodium channels (VGSC) are implicated in cancer cell invasion and metastasis. However, the mechanism by which VGSC increase cell invasiveness and probability of metastasis is still unknown. In this review we outline lesser known functions of VGSC outside of action potential propagation, and the current understanding of the effects of VGSC in cancer. Finally, we discuss possible downstream effects of VGSC activation in cancer cells. After extensive review of the literature, the most likely role of VGSC in cancer is in the invadopodia, the leading edge of metastatic cancer cells. Sodium gradients are used to drive many biological processes in the body, and invadopodia may be similar. The function of the sodium hydrogen exchanger (NHE) and sodium calcium exchanger (NCX) are driven by sodium gradients. Voltage gated calcium channels, activated by membrane depolarization, are also capable of becoming activated in response to VGSC activity. Changes to hydrogen ion exchange or calcium handling have functional consequences for invadopodia and would explain the relationship between VGSC expression and invasiveness of cancer cells.
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Emerging medical applications based on non-ionizing electromagnetic fields from 0 Hz to 10 THz

The potential for using non-ionizing electromagnetic fields (EMF; at frequencies from 0 Hz up to the THz range) for medical purposes has been of interest since many decades. A number of established and familiar methods are in use all over the world. This review, however, provides an overview of applications that already play some clinical role or are in earlier stages of development. The covered methods include modalities used for bone healing, cancer treatment, neurological conditions, and diathermy. In addition, certain other potential clinical areas are touched upon. Most of the reviewed technologies deal with therapy, whereas just a few diagnostic approaches are mentioned. None of the discussed methods are having such a strong impact in their field of use that they would be expected to replace conventional methods. Partly this is due to a knowledge base that lacks mechanistic explanations for EMF effects at low-intensity levels, which often are used in the applications. Thus, the possible optimal use of EMF approaches is restricted. Other reasons for the limited impact include a scarcity of well-performed randomized clinical trials that convincingly show the efficacy of the methods and that standardized user protocols are mostly lacking. Presently, it seems that some EMF-based methods can have a niche role in treatment and diagnostics of certain conditions, mostly as a complement to or in combination with other, more established, methods. Further development and a stronger impact of these technologies need a better understanding of the interaction mechanisms between EMF and biological systems at lower intensity levels. The importance of the different physical parameters of the EMF exposure needs also further investigations.
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New Perspectives in the Treatment of Tumor Cells by Electromagnetic Radiation at Resonance Frequencies in Cellular Membrane Channels

Background

The use of electromagnetic fields has been considered as adjuvant therapy for the treatment of cancer given that some clinical trials have shown that the irradiation of cancer cells with electromagnetic fields can slow down the disease progression.

Aims

We hypothesize that this effect could be amplified by irradiating tumor cells with electromagnetic fields having frequencies close to the natural resonant frequencies of membrane channels in tumor cells, in order to obtain a significant change of the ion flux across tumor cell membrane channels, inducing the largest harmful alteration in their cellular function.

Methods

Neuronal-like cells were used as a cell model and exposed for 6 h to electromagnetic fields at different frequencies (0, 50 Hz, 900 MHz) at the same intensity of 2 mT.

The exposure system was represented by two Helmholtz coils driven by a power amplifier in current mode and an arbitrary function generator.

FTIR spectroscopy was used to evaluate the results of the exposure.

Results

The results of this study showed that the Amide I vibration band increased in intensity with the increase of the frequency, leading us to assume that the displacement of the cell channels α-helices depends on the frequency of the applied electromagnetic fields.

Conclusion

This preliminary result leads us to plan future research aimed at searching for the natural frequencies of membrane channels in tumor cells using resonant electromagnetic fields in order to damage the cellular functions of tumor cells. Clinical trials are needed to confirm such a hypothesis derived from this physical study.

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Voltage-Gated Ion Channels in Cancer Cell Proliferation

Changes of the electrical charges across the surface cell membrane are absolutely necessary to maintain cellular homeostasis in physiological as well as in pathological conditions. The opening of ion channels alter the charge distribution across the surface membrane as they allow the diffusion of ions such as K + , Ca ++ , Cl − , Na +. Traditionally, voltage-gated ion channels (VGIC) are known to play fundamental roles in controlling rapid bioelectrical signaling including action potential and/or contraction. However, several investigations have revealed that these classes of proteins can also contribute significantly to cell mitotic biochemical signaling, cell cycle progression, as well as cell volume regulation. All these functions are critically important for cancer cell proliferation. Interestingly, a variety of distinct VGICs are expressed in different cancer cell types, including metastasis but not in the tissues from which these tumors were generated. Given the increasing evidence suggesting that VGIC play a major role in cancer cell biology, in this review we discuss the role of distinct VGIC in cancer cell proliferation and possible therapeutic potential of VIGC pharmacological manipulation.

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Response of neuroblastoma cells to RF currents as a function of the signal frequency

Background:

Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400–600 kHz range to tissue repair and regeneration. Previous studies by our group have shown that 48 h of intermittent exposure to a 570 kHz CRET signal at a subthermal density of 50 μA/mm2 causes significant changes in the expression and activation of cell cycle control proteins, leading to cycle arrest in human cancer cell cultures. The present study investigates the relevance of the signal frequency in the response of the human neuroblastoma cell line NB69 to subthermal electric treatment with four different signal frequency currents within the 350–650 kHz range.

Conclusions:

The understanding of the mechanisms underlying the ability of slowing down cancer cell growth through electrically-induced changes in the expression of proteins involved in the control of cell proliferation and apoptosis might afford new insights in the field of oncology.

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The variable electric field of the membrane /Questioning the HodgkinHuxley model

Hodgkin and Huxley built their theoretical model of initiation and propagation of action potential on the work of their predecessors but also that of their contemporaries.

Bernstein was the initiator of membrane theory but Hodgkin, Katz and especially Goldman sought to improve it.

The integration of the constant electric field should have allowed a better knowledge and computation of the membrane potential.

The study of the variations in the electric field that would exist through the membrane brings harsh contradictions in the hypotheses of the HH model.

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The combined treatment of 150 kHz tumor treating fields (TTFields) and cisplatin or pemetrexed inhibits mesothelioma cells in vitro and in vivo.

Background: Malignant pleural mesothelioma (MPM) is an aggressive thoracic cancer mostly linked to asbestos exposure. The standard of care (SOC) therapy for unresectable MPM is cisplatin plus pemetrexed. Treating Fields (TTFields) therapy is an effective anti-neoplastic treatment modality delivered via noninvasive application of low intensity, intermediate frequency, alternating electric fields. We explored the potential use of TTFields alone and in combination with SOC as a treatment for MPM. Methods: NCI-H2052 and MSTO-211H cells were treated at various TTFields frequencies for 72 hours using the inovitro system. The combined treatment of TTFields and cisplatin or pemetrexed was tested by applying TTFields at the optimal frequency together with various drug concentrations. Cell counts, clonogenic potential and induction of apoptosis were determined. TTFields (1.2 V/cm) were applied for 8 days to rats injected to the intrapleural cavity with IL-45 cells, and overall survival was tested. Results: TTFields optimal frequency was 150 kHz for both human cell lines. TTFields application (1.1 V/cm, 72 hours) at 150 kHz led to 45%-51% reduction in cell counts and 46-64%% additional reduction in clonogenic potential. The combined treatment of TTFields and cisplatin or pemetrexed led to a significant reduction in cell count, induction of apoptosis and reduced clonogenic potential as compared to each modality alone (p < 0.0001(. TTFields significantly prolonged the survival of rats compared to control group. Safety studies did not reveal any adverse events associated with 150 kHz TTFields application to the rat torso. Conclusions: These results demonstrate that TTFields can be an effective treatment against mesothelioma and the combination with cisplatin or pemetrexed may further enhance treatment efficacy. These results are in consistency with the recent phase 2 study (EF-23 trial) that showed improved overall survival for combined treatment as compared to historical control with no increase in systemic toxicity.
Article

Electromagnetic fields alter the motility of metastatic breast cancer cells

Interactions between cells and their environment influence key physiologic processes such as their propensity to migrate.

However, directed migration controlled by extrinsically applied electrical signals is poorly understood.

Using a novel microfluidic platform, we found that metastatic breast cancer cells sense and respond to the net direction of weak (∼100 µV cm−1), asymmetric, non-contact induced Electric Fields (iEFs).

iEFs inhibited EGFR (Epidermal Growth Factor Receptor) activation, prevented formation of actin-rich filopodia, and hindered the motility of EGF-treated breast cancer cells.

The directional effects of iEFs were nullified by inhibition of Akt phosphorylation.

Moreover, iEFs in combination with Akt inhibitor reduced EGF-promoted motility below the level of untreated controls.

These results represent a step towards isolating the coupling mechanism between cell motility and iEFs, provide valuable insights into how iEFs target multiple diverging cancer cell signaling mechanisms, and demonstrate that electrical signals are a fundamental regulator of cancer cell migration.

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Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy

Background: Capacitive-resistive electric transfer (CRET) is a non-invasive therapeutic strategy that applies radiofrequency electric currents within the 400-600 kHz range to tissue repair and regeneration.

Previous studies by our group have shown that 48 h of intermittent exposure to a 570 kHz CRET signal at a subthermal density of 50 μA/mm2 causes significant changes in the expression and activation of cell cycle control proteins, leading to cycle arrest in human cancer cell cultures.

The present study investigates the relevance of the signal frequency in the response of the human neuroblastoma cell line NB69 to subthermal electric treatment with four different signal frequency currents within the 350-650 kHz range.

Methods: Trypan blue assay, flow cytometry, immunofluorescence and immunoblot were used to study the effects of subthermal CRET currents on cell viability, cell cycle progression and the expression of several marker proteins involved in NB69 cell death and proliferation.

Results: The results reveal that among the frequencies tested, only a 448 kHz signal elicited both proapoptotic and antiproliferative, statistically significant responses.

The apoptotic effect would be due, at least in part, to significant changes induced by the 448 kHz signal in the expression of p53, Bax and caspase-3.

The cytostatic response was preceded by alterations in the kinetics of the cell cycle and in the expression of proteins p-ERK1/2, cyclin D1 and p27, which is consistent with a potential involvement of the EGF receptor in electrically induced changes in the ERK1/2 pathway.

This receives additional support from results indicating that the proapototic and antiproliferative responses to CRET can be transiently blocked when the electric stimulus is applied in the presence of PD98059, a chemical inhibitor of the ERK1/2 pathway.

Conclusion: The understanding of the mechanisms underlying the ability of slowing down cancer cell growth through electrically-induced changes in the expression of proteins involved in the control of cell proliferation and apoptosis might afford new insights in the field of oncology.

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Crucial functions associated with phototropism and circadian clocks

"Cryptochromes are flavoproteins whose photochemistry is important for crucial functions associated with phototropism and circadian clocks. In this report, we, for the first time, observed a magnetic response of the cryptochrome 1 (CRY1) immobilized at a gold electrode with illumination of blue light. These results present the magnetic field-enhanced photoinduced electron transfer of CRY1 to the electrode by voltammetry, exhibiting magnetic responsive rate constant and electrical current changes. A mechanism of the electron transfer, which involves photoinduced radicals in the CRY, is sensitive to the weak magnetic field; and the long-lived free radical FAD•– is responsible for the detected electrochemical Faradaic current. As a photoreceptor, the finding of a 5.7% rate constant change in electron transfer corresponding to a 50 μT magnetic field may be meaningful in regulation of magnetic field signaling and circadian clock function under an electromagnetic field."

https://www.researchgate.net/publication/324885021_Magnetoreception_of_Photoactivated_Cryptochrome_1_in_Electrochemistry_and_Electron_Transfer

Changes in chromatin accessibility and consequently in the expression of anti-inflammatory mediators and in cell differentiation.

In this study, we investigated the effects of specific low frequency electromagnetic fields sequences on U937 cells, an in vitro model of human monocyte/macrophage differentiation. U937 cells were exposed to electromagnetic stimulation by means of the SyntheXer system using two similar sequences, XR-BC31 and XR-BC31/F. Each sequence was a time series of twenty-nine wave segments. Here, we report that exposure (4 days, once a day) of U937 cells to the XR-BC31 setting, but not to the XR-BC31/F, resulted in increased expression of the histone demethylase KDM6B along with a global reduction in histone H3 lysine 27 (H3K27) tri-methylation. Furthermore, exposure to the XR-BC31 sequence induced differentiation of U937 cells towards a macrophage-like phenotype displaying a KDM6B dependent increase in expression and secretion of the anti-inflammatory interleukins (ILs), IL-10 and IL-4. Importantly, all the observed changes were highly dependent on the sequence's nature. Our results open a new way of interpretation for the effects of low frequency electromagnetic fields observed in vivo. Indeed, it is conceivable that a specific low frequency electromagnetic fields treatment may cause changes in chromatin accessibility and consequently in the expression of anti-inflammatory mediators and in cell differentiation.
https://www.researchgate.net/publication/328304138_Specific_low_frequency_electromagnetic_fields_induce_epigenetic_and_functional_changes_in_U937_cells

Morphological effects of electric fields on avian erythrocytes (nucleated red blood cells)

In this paper, morphological effects of electric fields on avian erythrocytes (nucleated red blood cells) have been studied in detail.

Morphological changes include rounding and cytoplasm transparency.

It has been shown that the effect is non‐thermal.

Careful imaging and image analyses have been carried out to show that the degree of this effect is frequency‐dependent, and has a higher conversion rate at higher temperatures.

Furthermore, to better understand the mechanisms behind the morphological changes, we investigated the dedifferentiation hypothesis and performed a series of tests on avian erythrocytes including fluorescence spectroscopy for hemoglobin, and tests on human umbilical cord blood, mesenchymal stem cells, and bone marrow mesenchymal stem cells including flow‐cytometry analysis for expression of certain markers and calcium staining.

https://onlinelibrary.wiley.com/doi/10.1002/bem.22195

Rotating magnetic fields within circular arrays of RNA within bacteria ...

Paper Title: Bacterial biophotons as non‐local information carriers: Species‐specific spectral characteristics of a stress response

https://www.researchgate.net/publication/328659792_Bacterial_biophotons_as_non-local_information_carriers_Species-specific_spectral_characteristics_of_a_stress_response

Could electromagnetic fields treat metastatic triple-negative breast cancer?

New research published in Communications Biology suggests that electromagnetic fields are capable of stopping the metastasis of some breast cancer cells. In the study, researchers showed that they are able to target migrating breast cancer cells using a tool called a Helmholtz coil, which was developed by scientists at Ohio State University.
https://www.labroots.com/trending/cancer/15457/electromagnetic-fields-treat-metastatic-triple-negative-breast-cancer

Slow electrons to combat cancer

Slow electons can be used to destroy cancer cells - but how exactly this happens has not been well understood. 

Now scientists have been able to demonstrate that a previously little-observed effect actually plays a pivotal role: Due to a process called interatomic Coulombic decay, an ion can pass on additional energy to surrounding atoms. 

This frees a huge number of electrons, with precisely the right amount of energy to cause optimal damage to the DNA of the cancer cells. 

https://www.sciencedaily.com/releases/2019/08/190822101429.htm

Use of systems biology in understanding the biological effectsof electromagnetic fields

This review discusses the use of systems biology in understanding the biological effects of electromagnetic fields, with particular focus on induction of genomic instability and cancer. 

We introduce basic concepts of the dynamical systems theory such as the state space and attractors and the use of these concepts in understanding the behavior of complex biological systems. 

We then discuss genomic instability in the framework of the dynamical systems theory, and describe the hypothesis that environmentally induced genomic instability corresponds to abnormal attractor states; large enough environmental perturbations can force the biological system to leave normal evolutionarily optimized attractors (corresponding to normal cell phenotypes) and migrate to less stable variant attractors. 

We discuss experimental approaches that can be coupled with theoretical systems biology such as testable predictions, derived from the theory and experimental methods, that can be used for measuring the state of the complex biological system. 

We also review potentially informative studies and make recommendations for further studies.

https://www.researchgate.net/publication/334016168_Electromagnetic_Fields_Genomic_Instability_and_Cancer_A_Systems_Biological_View

The Electrial Nature of the Body

It is well accepted that information can be conveyed to the body in the form of electromagnetic waves.  No one doubts that the eyes can detect visible light, that the ears can detect sound from pressure waves carried by the atmosphere and that the sensory information collected from both the eyes and the ears is invaluable for survival.  However, both visible light and sound are just different portions of the electromagnetic spectrum.  It is logical to conclude, and it has been proven scientifically that other portions of the electromagnetic spectrum also have beneficial biological effects.

https://www.researchgate.net/publication/327549539_The_Electrical_Nature_of_the_Body

Electromagnetic fields may hinder spread of breast cancer cells

Electromagnetic fields might help prevent some breast cancers from spreading to other parts of the body, new research has found. The study showed that low intensity electromagnetic fields hindered the mobility of specific breast cancer cells by preventing the formation of long, thin extensions at the edge of a migrating cancer cell.
https://www.sciencedaily.com/releases/2019/08/190808111440.htm

Effects of extremely low-frequency electromagnetic fields on B16F10 cancer cells

This paper presents a method to inhibit B16F10 cancer cells using extremely low-frequency electromagnetic fields (ELF-EMFs) and to evaluate cell viability using MTT (3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide) assay. 

The study examined the effect of a natural EMF resonance frequency (7.83 Hz) and a power line frequency (60 Hz) on B16F10 cancer cells for 24 and 48 h. 

The B16F10 cancer cells were also exposed to sweep frequencies in several sweep intervals to quantitatively analyze the viability of cancer cells. 

The results yielded a 17% inhibition rate under 7.83 Hz compared with that of the control group. 

Moreover, sweep frequencies in narrow intervals (7.83 ± 0.1 Hz for the step 0.05 Hz) caused an inhibition rate of 26.4%, and inhibitory effects decreased as frequency sweep intervals increased. 

These results indicate that a Schumann resonance frequency of 7.83 Hz can inhibit the growth of cancer cells and that using a specific frequency type can lead to more effective growth inhibition.

https://www.researchgate.net/publication/331905143_Effects_of_extremely_low-frequency_electromagnetic_fields_on_B16F10_cancer_cells

Evidences of plasma membrane-mediated ROS generation upon ELF exposure in neuroblastoma cells supported by a computational multiscale approach

Background

Molecular mechanisms of interaction between cells and extremely low frequency magnetic fields (ELF-MFs) still represent a matter of scientific debate. In this paper, to identify the possible primary source of oxidative stress induced by ELF-MF in SH-SY5Y human neuroblastoma cells, we estimated the induced electric field and current density at the cell level.

Methods

We followed a computational multiscale approach, estimating the local electric field and current density from the whole sample down to the single cell level. The procedure takes into account morphological modeling of SH-SY5Y cells, arranged in different topologies. Experimental validation has been carried out: neuroblastoma cells have been treated with Diphenyleneiodonium (DPI) -an inhibitor of the plasma membrane enzyme NADPH oxidase (Nox)- administered 24 h before exposure to 50 Hz (1 mT) MF.

Results

Macroscopic and microscopic dosimetric evaluations suggest that increased current densities are induced at the plasma membrane/extra-cellular medium interface; identifying the plasma membrane as the main site of the ELF-neuroblastoma cell interaction. The in vitro results provide an experimental proof that plasma membrane Nox exerts a key role in the redox imbalance elicited by ELF, as DPI treatment reverts the generation of reactive oxygen species induced by ELF exposure.

https://www.sciencedirect.com/science/article/pii/S0005273619301373?via%3Dihub

On the magnetosensitivity of lipid peroxidation: two- versus three-radical dynamics

We present a theoretical analysis of the putative magneto sensitivity of lipid peroxidation. We focus on the widely accepted radical pair mechanism (RPM) and a recently suggested idea based on spin dynamics induced in three-radical systems by the mutual electron–electron dipolar coupling (D3M).

Most chemical reactions are insensitive to the weak magnetic fields that pervade our everyday surroundings.  An exception to this rule is the recombination of radical pairs, which depends on the overall electron spin of the reactants.  As a consequence of weak magnetic interactions modulating the overall spin of the radicals, the associated recombination yields are, at least in principle, susceptible to the strength and direction of external magnetic fields.

https://www.researchgate.net/publication/333848825_On_the_magnetosensitivity_of_lipid_peroxidation_two-_versus_three-radical_dynamics

The future of quantum biology

 How does DNA, with stacked nucleotides separated by about 0.3 nm, deal with UV photons?

How does an enzyme catalyze an essential biochemical reaction?

How does our brain with neurons organized on a sub-nanometer scale deal with such an amazing amount of information?

How do DNA replication and expression work?

All these bio-logical functions should, of course, be considered in the context of evolutionary fitness.

The differences between a classical approximation and a quantum-mechanical model are generally thought to be negligible in these cases, even though at the basis every process is entirely governed by the laws of quantum mechanics.

https://www.researchgate.net/publication/328934332_The_future_of_quantum_biology

Experimental Demonstration That Aharanov-Bohm Phase Shift Voltages In Optical Coupler Circuits of Tuned Patterned Magnetic Fields Is Critical for Inhibition of Malignant Cell Growth

The physical processes by which specific point duration magnetic fields affect aberrant expressions of living matter may involve  non-classical  mechanisms.    The  Aharanov-Bohm  voltage  for  a  quantum  of  energy  that  is  convergent  with  the quotient of the proton’s magnetic moment to its charge multiplied by the viscosity of water at homeostatic  temperatures applied  across  the  distance  of  O-H  bonds  in  conjunction  with  its  phase  modulation  is  about  ±4.3  V.  Application  of frequency  shifting,  temporally-patterned  magnetic  fields  produced  by  3  ms  point  durations  at  average  intensities  of  ~28mG (that are equivalent to Nernst thresholds for plasma membranes) generated through optocoupler light emitting diodes produced  the  strongest  inhibition  of  malignant  cells  growth  when  the  pre-coupler  value  for  the  circuit  maintenance  was ±4.3 V compared to increments of voltage below or above this value. Spatial expansion of the effective zone for growth diminishment  also  occurred  with  this  pre-voltage  level.  These  results  indicate  that  phase  modulation  of  the  electrons mediating cellular molecular pathways may be central to the etiology and potential treatment of malignant cells but not for normal  cells’dynamics.  Consideration  of  quantum  effects  rather  than  classical  electromagnetic  theory  may  be  a  more effective strategy for impeding the physical bases for the molecular pathways that define malignant cells.

https://www.researchgate.net/publication/328720507_Experimental_Demonstration_That_Aharanov-Bohm_Phase_Shift_Voltages_In_Optical_Coupler_Circuits_of_Tuned_Patterned_Magnetic_Fields_Is_Critical_for_Inhibition_of_Malignant_Cell_Growth

Tumour-treating fields (TTFields): Investigations on the mechanism of action by electromagnetic exposure of cells in telophase/cytokinesis

Tumour-treating fields (TTFields) use alternating electric fields which interfere with dividing cells, thereby reducing tumour growth. Previous reports suggest that electrical forces on cell structure proteins interfered with the chromosome separation during mitosis and induced apoptosis. In the present report we evaluate electromagnetic exposure of cells in telophase/cytokinesis in order to further analyse the mechanism of action on cells. We performed numerical electromagnetic simulations to analyse the field distribution in a cell during different mitotic phases. Based thereon, we developed an electric lumped element model of the mitotic cell. Both the electromagnetic simulation and the lumped element model predict a local increase of the specific absorption rate (SAR) as a measure of the electromagnetically induced power absorption density at the mitotic furrow which may help to explain the anti-proliferative effect. In accordance with other reports, cell culture experiments confirmed that TTFields reduce the proliferation of different glioma cell lines in a field strength- and frequency-dependent manner. Furthermore, we found an additional dependence on the commutation time of the electrical fields. The report gives new insights into TTFields’ anti-proliferative effect on tumours, which could help to improve future TTFields application systems.
https://www.researchgate.net/publication/333088748_Tumour-treating_fields_TTFields_Investigations_on_the_mechanism_of_action_by_electromagnetic_exposure_of_cells_in_telophasecytokinesis

Life on Magnets: Stem Cell Networking on Micro-Magnet Arrays

Interactions between a micro-magnet array and living cells may guide the establishment of cell networks due to the cellular response to a magnetic field. 

To manipulate mesenchymal stem cells free of magnetic nanoparticles by a high magnetic field gradient, we used high quality micro-patterned NdFeB films around which the stray field's value and direction drastically change across the cell body. 

Such micro-magnet arrays coated with parylene produce high magnetic field gradients that affect the cells in two main ways: i) causing cell migration and adherence to a covered magnetic surface and ii) elongating the cells in the directions parallel to the edges of the micro-magnet. 

To explain these effects, three putative mechanisms that incorporate both physical and biological factors influencing the cells are suggested. 

It is shown that the static high magnetic field gradient generated by the micro-magnet arrays are capable of assisting cell migration to those areas with the strongest magnetic field gradient, thereby allowing the build up of tunable interconnected stem cell networks, which is an elegant route for tissue engineering and regenerative medicine.

https://www.researchgate.net/publication/255737633_Life_on_Magnets_Stem_Cell_Networking_on_Micro-Magnet_Arrays

The subtle effects of low-frequency magnetic fields on oxidative metabolism, ROS signaling, and cellular growth

The effects of weak magnetic fields on the biological production of reactive oxygen species (ROS) from intracellular superoxide (O2•-) and extracellular hydrogen peroxide (H2O2) were investigated in vitro with rat pulmonary arterial smooth muscle cells (rPASMC). 

A decrease in O2•- and an increase in H2O2 concentrations were observed in the presence of a 7 MHz radio frequency (RF) at 10 μTRMS and static 45 μT magnetic fields. 

We propose that O2•- and H2O2 production in some metabolic processes occur through singlet-triplet modulation of semiquinone flavin (FADH•) enzymes and O2•- spin-correlated radical pairs. 

Spin-radical pair products are modulated by the 7 MHz RF magnetic fields that presumably decouple flavin hyperfine interactions during spin coherence. 

RF flavin hyperfine decoupling results in an increase of H2O2 singlet state products, which creates cellular oxidative stress and acts as a secondary messenger that affects cellular proliferation. 

This study demonstrates the interplay between O2•- and H2O2 production when influenced by RF magnetic fields and underscores the subtle effects of low-frequency magnetic fields on oxidative metabolism, ROS signaling, and cellular growth.

https://www.researchgate.net/publication/261220958_Spin_Biochemistry_Modulates_Reactive_Oxygen_Species_ROS_Production_by_Radio_Frequency_Magnetic_Fields

The effect of pulsed electromagnetic field exposure on osteoinduction of human mesenchymal stem cells cultured on nano-TiO2 surfaces.

Human bone marrow-derived mesenchymal stem cells (hBM-MSCs) are considered a great promise in the repair and regeneration of bone. Considerable efforts have been oriented towards uncovering the best strategy to promote stem cells osteogenic differentiation. In previous studies, hBM-MSCs exposed to physical stimuli such as pulsed electromagnetic fields (PEMFs) or directly seeded on nanostructured titanium surfaces (TiO2) were shown to improve their differentiation to osteoblasts in osteogenic condition. In the present study, the effect of a daily PEMF-exposure on osteogenic differentiation of hBM-MSCs seeded onto nanostructured TiO2 (with clusters under 100 nm of dimension) was investigated. TiO2-seeded cells were exposed to PEMF (magnetic field intensity: 2 mT; intensity of induced electric field: 5 mV; frequency: 75 Hz) and examined in terms of cell physiology modifications and osteogenic differentiation. Results showed that PEMF exposure affected TiO2-seeded cells osteogenesis by interfering with selective calcium-related osteogenic pathways, and greatly enhanced hBM-MSCs osteogenic features such as the expression of early/late osteogenic genes and protein production (e.g., ALP, COL-I, osteocalcin and osteopontin) and ALP activity. Finally, PEMF-treated cells resulted to secrete into conditioned media higher amounts of BMP-2, DCN and COL-I than untreated cell cultures. These findings confirm once more the osteoinductive potential of PEMF, suggesting that its combination with TiO2 nanostructured surface might be a great option in bone tissue engineering applications.
https://www.ncbi.nlm.nih.gov/pubmed/29902240

Determinants of bioelectrical phase angle in disease

Phase angle (PhA), a parameter of bioelectrical impedance analysis, is a well-known predictor of morbidity and mortality in various diseases. The causes of decreased PhA are, however, not yet completely understood. We therefore investigated determinants of PhA in 777 hospitalised patients in a retrospective analysis. PhA was assessed by bioelectrical impedance analysis at 50 KHz. Subjective global assessment (SGA) was used to evaluate nutritional status. Age, sex, BMI as well as nutritional status (SGA), benign or malignant disease and C-reactive protein (CRP) were investigated as potential determinants of PhA and standardised PhA (SPhA) = (observed PhA - mean PhA of reference values)/standard deviation of reference values in a general linear model regression analysis. Next to age (estimated effect size, 46·6%; P<0·0001), malnutrition (39·1%; P<0·0001) emerged as a major PhA determinant in our study population. Moreover, sex (6·4%; P<0·0001), CRP (4·4%; P<0·0001) and BMI (3·5%; P < 0·0001) exhibited a significant influence on PhA, whereas malignant disease showed no significant effect in this model. The only significant determinants of SPhA were malnutrition (85·4%; P<0·0001) and inflammation (9·6 %; P<0·0001). In conclusion, next to the established predictors, malnutrition and inflammation have a strong impact on PhA in sick individuals, which partly explains its prognostic power. When investigating the SPhA, only malnutrition and inflammation were found to be significant predictors, as a result of which the SPhA is considered a more suitable indicator of nutritional and health status.
https://www.researchgate.net/publication/221810319_Determinants_of_bioelectrical_phase_angle_in_disease

Electroencephalographic field influence on calcium momentum waves

Macroscopic electroencephalographic (EEG) fields can be an explicit top-down neocortical mechanism that directly drives bottom-up processes that describe memory, attention, and other neuronal processes. The top-down mechanism considered are macrocolumnar EEG firings in neocortex, as described by a statistical mechanics of neocortical interactions (SMNI), developed as a magnetic vector potential A. The bottom-up process considered are Ca(2+) waves prominent in synaptic and extracellular processes that are considered to greatly influence neuronal firings. Here, the complimentary effects are considered, i.e., the influence of A on Ca(2+) momentum, p. The canonical momentum of a charged particle in an electromagnetic field, Π=p+qA (SI units), is calculated, where the charge of Ca(2+) is q=-2e, e is the magnitude of the charge of an electron. Calculations demonstrate that macroscopic EEG A can be quite influential on the momentum p of Ca(2+) ions, in both classical and quantum mechanics. Molecular scales of Ca(2+) wave dynamics are coupled with A fields developed at macroscopic regional scales measured by coherent neuronal firing activity measured by scalp EEG. The project has three main aspects: fitting A models to EEG data as reported here, building tripartite models to develop A models, and studying long coherence times of Ca(2+) waves in the presence of A due to coherent neuronal firings measured by scalp EEG. The SMNI model supports a mechanism wherein the p+qA interaction at tripartite synapses, via a dynamic centering mechanism (DCM) to control background synaptic activity, acts to maintain short-term memory (STM) during states of selective attention.
https://www.researchgate.net/publication/258635626_Electroencephalographic_field_influence_on_calcium_momentum_waves