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A Biophysical Approach to SARS-CoV-2 Pathogenicity Received: 11/11/2021 Accepted: 16/11/2021 Published: 27/12/2021

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In order to infect the target host cell, a virus like severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), whose lytic/virulent lifestyle involves the infection, replication and lysis of the host cell, must be able to penetrate its membrane for the release of viral progeny. For this purpose, its action takes place both on a biophysical and biochemical level. Viral action begins with the alteration of physiological interactions held by the target cell with extracellular aqueous electrolytic solutions (membrane-ions interactions), followed by the disruption of the membrane structural properties. In the present paper the earliest virus-host biophysical events are addressed, in particular the electrostatic (short-range) and electrodynamic (long-range) interactions. In section one a biophysical profile of SARS-COV-2 pathogenicity is outlined. The prominent electrostatic events that characterize the earliest stages of virus-host interactions are taken into account. The host cell oxida-tive stress reaction is discussed. In section two, biological water as biphasic liquid and structured interfacial water's fourth phase are introduced by resorting to Quantum Field Theory (QFT) and Quantum Electrodynamic (QED). Structured interfacial water as a semiconductor and the proton-based self-driven liquid-flow system are also discussed. In section three it is assumed that in its approach to the target host cell SARS-CoV-2 triggers the cellular phase-matching feature (which operates as a very selective filter discriminating among perturbations and stimuli that are out of phase with the oscillatory motions allowed by the cell's inner dynamics) by emitting a stressful ultra low frequency-electromagnetic field (ULF-EMF), which generates an alert response within the cell by influencing ionic fluxes throughout cellular membrane. Therefore, it is suggested that the earliest virus-host interaction would rest on electromagnetic long-range events, before electrostatic and chemical interactions occur, which are influencing the redox potential of the target host-cell's membrane chemical species, affecting its acid-base equilibria, therefore inducing a cellular stress response (e.g. via plas-How to cite this paper: Messori, C. (2021) A Biophysical Approach to SARS-CoV-2 Pathogenicity. ma-membrane-localized redox signalling) with reactive oxygen species (ROS) and reactive nitrogen species (RNS) production. Accordingly, re-dox-responsive intracellular signaling and anti-inflammatory scavenging systems would be remotely (pre) activated by non-ionizing interference phenomena , before virus-cell come together, followed by electrostatic and chemical events that provoke a branching, cascade-like, chain of reactions. A better understanding of the earliest of biophysical events will enable a more rational approach to dealing with both the binding of the SARS-CoV-2 highly glyco-sylated Spike's S1 subunit receptor binding domain (RBD) to the host cell's angiotensin-converting enzyme 2 (ACE2) and the direct interaction with the lipid bilayer on the cell surface.
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2021, Volume 8, ****
ISSN Online: 2333-9721
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DOI:
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A Biophysical Approach to SARS-CoV-2
Pathogenicity
Claudio Messori
Department of Rehabilitation, U.S.L. Company Parma, Parma, Italy
Email: messori.claudio@gmail.com
Abstract
In order to infect the target host cell, a virus like
severe acute respiratory sy
n-
drome coronavirus
2 (SARS-CoV-2), whose lytic/virulent lifestyle involves
the infection, replication and lysis of the host cell, must be able to penetrate
its membrane for the release of viral progeny. For this purpose, its action
takes place both on a biophysical and biochemical level.
Viral action begins
wit
h the alteration of physiological interactions held by the target cell with
extracellular aqueous electrolytic solutions (membrane-
ions interactions),
followed by the disruption of the membrane structural properties. In the
present paper the earliest virus-host biophysical events are addressed, in par-
ticular the electrostatic (short-range) and electrodynamic (long-range) inte-
ractions. In section one a biophysical profile of SARS-COV-
2 pathogenicity is
outlined. The prominent electrostatic events that charac
terize the earliest
stages of virus-host interactions are taken into account. The host cell
oxid
a-
tive stress reaction
is discussed. In section two, biological water as
biphasic
liquid
and structured interfacial waters
fourth phase
are introduced by re-
sorting to Quantum Field Theory (QFT) and Quantum Electrodynamic
(QED). Structured interfacial water as a
semiconductor
and the proton-
based
self-driven liquid-flow system
are also discussed. In section three it is as-
sumed that in its approach to the target host cell SARS-CoV-
2 triggers the
cellular
phase-matching feature
(which operates as a very selective filter dis-
criminating among perturbations and stimuli that are out of phase with the
oscillatory motions allowed by the cells inner dynamics) by emitti
ng a
stressful ultra low frequency-electromagnetic field (ULF-EMF), which gene-
rates an alert response within the cell by influencing ionic fluxes throughout
cellular membrane. Therefore, it is suggested that the earliest virus-host inte-
raction would rest on electromagnetic long-
range events, before electrostatic
and chemical interactions occur, which are influencing the
redox potential
of the target host-cells membrane chemical species, affecting its acid-
base
equilibria, therefore inducing a cellular stress response (e.g. via
plas-
How to cite this paper:
Messori, C. (2021
)
A Biophysical Approach to SARS
-CoV-
2
Pathogenicity
.
Open Access Library Journal
,
8
: ****.
https://doi.org/10.4236/***.2021.*****
Received:
**** **, ***
Accepted:
**** **, ***
Published:
**** **, ***
Copyright © 20
21 by author(s) and Open
Access Library Inc
.
This work is licensed under the Creative
Commons Attribution International
License (CC BY
4.0).
http://creativecommons.org/licenses/by/4.0/
Open Access
C. Messori
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ma-membrane-localized redox signalling
) with reactive oxygen species
(ROS) and reactive nitrogen species (RNS) production. Accordingly, re-
dox-responsive intracellular signaling and anti-
inflammatory scavenging
systems would be remotely (pre) activated by non-ionizing interference phe-
nomena, before virus-cell come together, followed by electrostatic and chem-
ical events that provoke a branching, cascade-
like, chain of reactions. A better
understanding of the earliest of biophysical e
vents will enable a more rational
approach to dealing with both the binding of the SARS-CoV-2 highly glyco-
sylated Spikes S1 subunit receptor binding domain (RBD) to the host cell
s
angiotensin-converting enzyme 2
(ACE2) and the direct interaction with the
lipid bilayer on the cell surface.
Subject Areas
Infectious Diseases
Keywords
Non-Ionizing Interference Phenomena, Electromagnetotaxis, Ion
Channelling Activity, Electron-Proton Transductions and Exchange,
Redox Balance, Oxidative Stress Reactions, Structured Interfacial
Water CD/EZ; Interfacial Water Stressors
1. Introduction
Viruses have been found everywhere on Earth. Researchers estimate that viruses
outnumber bacteria by 10 to 1. They are strongly dependent on the host of one
or the other of the three primary kingdoms, namely archaea, prokaryotes and
eukaryotes, and must exploit and overcome membrane barriers, at first, to infect
cells,
i.e.
hijacking the host cell machinery to help with entry replication, pack-
aging and release of progeny to infect new cells. Often, they kill the host cell in
the process, and cause damage to the host organism.
To their purpose, viruses with a lytic/virulent lifestyle must first be able to
evade the host antiviral immune activation, as to intercept the target cell, engage
it and promote viral infection by disrupting the cellular environment and there-
fore the membrane integrity. To perform these initial steps of viral infection, vi-
ruses follow two intertwined paths, a biochemical and a biophysical one.
Nowadays, the immune system and cellular stress response is thought to be
activated by “danger signalsor perturbing agents, such as high and low tem-
perature, changes in pH, toxic metals and compounds, ionizing radiation (ther-
mal effect) and pathogens like viruses and bacteria, which are relevant to the in-
duction of inflammation and immune responses.
Biological systems are currently conceived as a set of substantially isolated
molecules, mechanical-like systems consisting of independent, incoherent mo-
lecules, subjected to disturbing agents and the driving effect of an assortment of
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external bias (
mixotaxis
1).
The production, emission and absorption of non-ionizing electromagnetic
fields by biological systems, as well as their role in biological dynamics and in
organism-organism organism-environment interactions are widely demonstrat-
ed [3]-[8], but non-ionizing radiation is still not considered relevant to the in-
duction of inflammation and immune responses.
The forces of attraction are largely electrostatic in nature and vary with dis-
tance as the interaction between dipoles is shielded by the dielectric constant of
the medium. Like other dipoles, water molecules can stack together in dipole in-
teractions with alternating positive and negative poles next to each other. It can
also engage in electrostatic interactions with charged ions and other dipoles dis-
solved in it. It is primarily the charge distribution on the surface of molecules
that determines their physical and chemical properties, such as bonding ability,
orientation, and mutual position. When the geometrical configuration of two
molecules fits in such a way that a minimum of the (electrical) Coulomb poten-
tials of the valence electrons is achieved, a chemical bonding can take place.
However, charge distribution through its time variations is also responsible for
the properties of the electromagnetic (EM) radiation that molecules emit, such
as polarization, spatial distribution, and direction, and for their interaction with
impinging radiation. The interaction of radiation with matter is only possible
through redistribution of charge. Structural changes in the molecules entail
charge shifts and thus changes in the
electromagnetic field
(EMF) envelope of
the molecule, which may be the real mediator of the molecules interaction with
other molecules [9].
Biological systems have high water content containing ions. Ions in water are
not just simple charged particles as one would expect to observe in a vacuum, as
the charges attract molecules of water that may be bound to them in a variety of
configurations and with bonds of varying strength [10].
Ion-specific effects are widespread, but nowhere are more critically manifested
than at the fluid interfaces of biological structures. Action potentials, osmotic
flows, energy transduction, and the stabilization of proteins are driven by ion
concentration gradients across liquid films on hydrophobic biomaterials. Expe-
riments revealed that ions interact specifically at the prototype air-water inter-
face over separations that vastly exceed the range of direct electrostatic forces in
any dielectric medium [11]. Such long-range specific ion effects may be triggered
by electrostatic and electrodynamic forces, but they must be powered also by
other mechanisms, such as the thermal fluctuations intrinsic to fluid interfaces.
Chemical bonds (including covalent, ionic, hydrogen and van der Waals
types) have been commonly assumed to be dominating for biological organiza-
1Directed cell interaction both
in vitro
and
in vivo
has been shown to be driven by the guiding effect
of local and non-local anisotropic features in the cell environment,
i.e
. by an assortment of external
biasing cues, the so called
mixotaxis
, ranging from gradients of soluble (
chemotaxis
) to bound (
ha
p-
totaxis
) molecules, gradients of mechanical properties (
durotaxis
), electric fields (
electrotaxis
) as
well as iterative biases in the environment topology (
ratchetaxis
) [1] [2].
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tion and activity. However, these bonds represent forces acting at short distances
in the
nm
region. Biological systems maintain coherence at every dimension
scale. Long-range coherence, large distance cooperation, and the whole body
control are significant properties of biological systems. Short range interaction,
if it is there, is made possible by the long-range one which brings “near” the
components (e.g., making possible the formation of hydrogen-bonds in water).
EMFs generated in biosystems support such long-range coherence and is a
nature of Earths biological phenomenon, from viruses [12] to archaea, proka-
ryotic [13] and eukaryotic cells to pluricellular organisms [14] and human be-
ings.
Hydrogen-bonds (HBs) in cells (likely also in virions) act as piezoelectric cen-
ters of energy transduction with biophysical characteristics, and can be consi-
dered to be electromagnetic (EM) radiation emission centers. The
internal re-
gions of proteins
favor the creation of HB networks producing in the extracellu-
lar matrix and cytoskeletal system (including actin and ATP molecules)
proton
semi-conduction systems
. The HB networks act as proton conductors and are
responsible for photon-conformational interactions able to do biophysical work.
According to [15], the passage of a proton along channels of HB (
α
-helices and
β
-sheets) can alter the frequency of the EM radiation emitted by the HBs they
contain, by which protonic conformational interactions may signal the change in
the protein conformation at a distance and in real time, as well as performing the
mechanical work (such as adaptation between enzyme and substratum).
In ordered biosystems, because of the very large number of HBs in the cell,
EM emission from a complex harp orchestra takes place uniformly and in all di-
rections. In several diseases, including COVID-19, uniformity and unidirectio-
nality is lost and the system breaks in chaotic, heterogeneous models which use
more energy (ΔE) from the normal structures taxing their abilities to continue in
performance [16].
All standard chemistry is totally reliant on electrostatics and avoids all men-
tion of electrodynamics and the consequent radiation field, which is supporting
the notion of water as a primary mediator of biological effects induced via elec-
tromagnetic means into living systems. The electrodynamic structure of
interfa-
cial water Coherence Domaine
/
Exclusion Zone
(CD/EZ) (see Section 2) can be
regarded as the main agents of the self-organization of living organisms. Given
the basically electromagnetic character and piezoelectric properties of this organiza-
tion, it is not surprising that biological systems interact with endogenous/exogenous
sonic signals
(phonons) and with ultra low frequency-electromagnetic field
(ULF-EMF) in a non-ionizing way.
The role played in
structured interfacial water CD
/
EZ
by
sonic signals
(pho-
nons) and
non-ionizing EM radiation
(photons)2 emitted and absorbed by bio-
logical systems, which do not cause thermal or heating effects but do cause
2Coherent mechanical vibrations (
phonons
) of living cells are measured by atomic force microscopy
in the acoustic frequency range. Frequencies of the
mechanical vibrations and of the electromagnetic
field (
photons
) generated by a cell are equal.
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non-thermal biological effects
on electron and proton transfer reactions, en-
zymes, DNA and fluxes in the ion channels of excitable membranes, is currently
ignored or neglected.
Likely, among the biophysical modalities involved in the pathogenicity of
SARS-CoV-2 (
severe acute respiratory syndrome coronavirus
2) and in addition
to the classical electrostatic modality, other modalities based sonic signaling and
on ULF-EMF signaling [17] should be taken into account. The present work
points at introducing the possible ULF-EMF interactions.
2. SARS-CoV-2 the Virus
SARS-CoV-2 (
severe acute respiratory syndrome coronavirus
2), the causative
agent of the coronavirus disease 2019 (COVID-19) pandemic (whose immuno-
pathogenesis remains at date poorly defined), belongs to the virus order Nidovi-
rales, family Coronaviridae, genus
Betacoronavirus
(enveloped, positive-sense,
single-stranded RNA viruses that are zoonotic) and sub-genus
Sarbecovirus
,
same as SARS-COV-1 the aetiologic agent of the SARS outbreak emerged in the
Guangdong province in China in 2002, with likely origin in bats, and likely in-
volvement of another (intermediate) host animal such as the pangolin.
The most distinctive feature of Coronaviridae family is genome size: corona-
viruses have the largest genomes among all RNA viruses, including those RNA
viruses with segmented genomes. This expansive coding capacity seems to both
provide and necessitate a wealth of gene-expression strategies, most of which are
incompletely understood [18].
SARS-CoV-2 evolutionary path to humans has not been defined, and remains
controversial. Possibilities include direct spillover from a bat to humans, indirect
spillover from a bat to humans through an intermediate host (as for SARS and
MERS), and a leak from a laboratory studying bat coronaviruses, either from
bona fide
SARS-CoV-2 isolated from a natural sample or from a derivative of a
natural virus generated by serial passage in laboratory animals and/or cell cul-
ture. At present, there is no direct evidence that SARS-CoV-2 was present in any
laboratory before it was first discovered in a patient, and detailed sequence ana-
lyses have been performed to argue that it most likely spilled over naturally [19].
The closest known related coronavirus sequence, designated RaTG13 (96.2%
identical genome-wide to SARS-CoV-2), was identified by scientists from the
Wuhan Institute of Virology (WIV) in a bat fecal sample isolated from a cave in
Yunnan, China, in 2013 [20]. The complete sequence of RaTG13 was disclosed
at the same time as the sequence of SARS-CoV-2 by the same WIV research
group, which has been studying emerging infectious diseases and coronaviruses,
particularly bat coronaviruses, for about 20 years. The 3.8% nucleotide position
differences separating RaTG13 and SARS-CoV-2 are estimated to represent
decades in evolutionary distance in nature, although this gap could potentially
be breached much more rapidly by serial passage in a laboratory, for which there
is currently no direct evidence. Sequence analysis has suggested that any effort to
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derive SARS-CoV-2 by serial passage of RaTG13 or another related coronavirus
would have had to occur in vivo since there is sequence evidence of conserved
glycosylation sites in the S protein receptor binding domain indicating that it
most likely evolved under immune pressure [19].
Coronaviruses constitute a special category of viruses whose genome is hosted
into protein cells, with rod-shaped spikes projecting from their surfaces [21].
The name
coronavirus
it has been coined by June D. Almeida in 1968, who
visualized (1967) the virus by
Electron Microscopy
(EM) [22] and derived the
name from the characteristic morphology in
negative-stained electron micro-
scopy
, marked by a “fringe” of surface structures described as spikes or
club-likeprojections, that give the viral particles the appearance of having the
corona of the sun seen during an eclipse (virologists compared
the characteris-
tic
fringe
of projections
on the outside of the virus with the
solar corona
, and
not, as some have suggested, with the points on a crown [23]) (Figure 1).
In electron micrographs, coronavirus seems similar to a distinct pair of elec-
tron-dense shells, with a small central electron-dense area or
dimple
[24] [25]
surrounded by an electron-dense
ionized plasma
,
i.e
. a corona shaped electros-
tatic discharge surrounding the spikes sharp particles “fringe” projections, which
may interfere with the target cells
plasma-membrane-localized redox signalling
[26] causing dysregulation and possibly disruption of normal cell physiology.
2.1. SARS-CoV-2 Structural Features
SARS-CoV-2 is a quasi-spherical-shaped enveloped virion positively charged
(total structural electric charge of SARS-Cov-2 is positive, depending on the
cumulative charges of its genetic material and that of the surface proteins [27]
[28]) with a single positive polarity RNA strand. Its RNA genome is similar to
that of other coronaviruses and has four genes that encode as many structural
Figure 1. Left: The virions of coronaviruses (when seen by negative stain electron mi-
croscopy). Right: The corona of the sun seen during an eclipse (resembling the virions of
coronaviruses when seen by thin section electron microscopy). Image source: Aronson, J.
K. (2020) Coronavirusesa general introduction, Centre for Evidence-Based Medicine
https://www.cebm.net/covid-19/coronaviruses-a-general-introduction/.
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transmembrane proteins, they are: the
nucleocapsid phosphoprotein
(N), which
encapsulates the RNA strand forming the helical filamentous
ribonucleoprotein
(RNP) complex, the
envelope
(E) protein, the
matrix
or
membrane
(M) protein
and the
spike protein
(S) or
peplomer
or
S-protein
, the heavily glycosylated pro-
tein that decorates the surface of coronavirus by forming characteristic spikes
sharp particles (spikes are very rarely as clear in thin-sectioned EM specimens as
they are when seen by negative stain EM), fundamental for the virus to enter the
host cell. The E, M and S proteins are embedded in the viral quasi-fluid-like,
pleomorphic, bilipid envelope, and together comprise the virus interface to the
external environment. Another envelope protein,
hemagglutinin-esterase
(HE),
serves as a receptor-destroying enzyme. HE and S are functionally intertwined,
binding of receptor by S and destruction of receptor by HE need to be carefully
balanced for efficient (pre) attachment.
The envelope E, membrane M proteins and helical nucleocapsid of enveloped
viruses are morphologic features of these pathogens that confer protection to
them outside their host cells. The helical nucleocapsid is visible in coronaviruses
in thin section EM, which can be seen in cross sections as electron-dense black
dots 6 - 12 nm in diameter on the inside of the viral particles [23]. The lack of
these dots in a subcellular structure is a good indicator that it is not coronavirus.
However, the lipid bilayer within the cell membrane of enveloped viruses con-
sists of cholesterols and phospholipids, and will only allow the virus to survive
for a limited time outside the host cell environment. Hence, to survive, also en-
veloped viruses need to be transferred directly from one host to another, as
quickly as possible.
Despite their complexity and range of function however, the structural pro-
teins occupy only about a third of the coding capacity of the genome. A much
larger section of the genome, some two-thirds, encode the
nonstructural pro-
teins
(NSP) of the virus, which are required at various stages of the virus replica-
tion cycle. SARS-CoV-2 may require an acidic environment for its entry and for
its ability to bud and infect bystander cells [29]. SARS-CoV-2 main protease 3CL
Mpro is indispensable for virus replication and do affect the host cell
protonation
state
by increasing its acidity degree (pH < pKa) [30] [31].
The most pronounced difference between SARS-CoV-1 spike proteins and
SARS-Cov-2 spike proteins is an additional (polybasic)
furin
cleavage site
cleaved by furin-like proteases, which is essential for efficient viral entry into
human lung cells, especially in cell-cell fusion to form syncytium to facilitate
viral spread from one cell to another. Different cleavage sites targeted by differ-
ent proteases are often associated with drastically different virulence and host
cell tropism in various RNA viruses. Unlike other proteases, e.g. trypsin-like
proteases, furin-like proteases are ubiquitous in human tissues. This means that
if the virus gains a furin cleavage site, cellular entry has no restrictions, resulting
in dramatic broadening of host cell tropism. In this context, the S-protein con-
tributes to host specificity, and also to tissue specificity through its differential
requirement of tissue-specific proteases. For this reason, viruses with different
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cell tropism may accumulate tissue-specific genomic signatures [32].
Another significant difference between SARS-CoV-1 and SARS-CoV-2 con-
cerns the structure of two prominent viroporins, the Orf3a and Envelope (E)
protein [33], of the three viroporins (the other one being Orf8a) encoded both
by SARS-CoV-1 and SARS-CoV-2 (while many coronaviruses encode two viro-
porins, SARS-CoV encodes three [34]).
Viroporins form multimeric complexes that act as ion channels and are im-
portant players of the viral life cycle of SARS-Cov-2 and one of the primary de-
terminants of its pathogenesis, promoting ion imbalances within cells [35]
and/or disrupting cellular pathways through protein-protein interaction [36]
[37] [38], acting as
interfacial water stressors
, implicated both in host cell apop-
tosis and proinflammatory cytokines storm.
Sarkar and colleagues in [33] found that Orf3a has several hotspots of muta-
tions which has been reported in SARS-CoV-2 with respect to SARS-CoV-1.
Mutations in SARS-CoV-2 Orf3a channel forming residues enhances the forma-
tion of a prominent the inter-subunit channel, which was not present in the
SARS-CoV-1 Orf3a. This enhanced structural feature can be correlated with
higher channelling activity in SARS-CoV-2 than in SARS-CoV-1. On the other
hand, E protein is one of the most conserved protein among the SARS-CoV
proteome. The water molecules form networks of electrostatic interactions with
the polar residues in the E protein putative wetted condition (while no water
channel formation is observed in the putative dewetted condition). This aqueous
medium mediates the non-selective translocation of cations thus affecting the
ionic homeostasis of the host cellular compartments. Ion channelling mechan-
ism of SARS-CoV-2 viroporins potentially leads to ionic imbalance and pH
change of subcellular compartments of the infected host cells causing membrane
structured interfacial water
and intracellularmisfunction. Microsomal structures
formed of the disrupted host membrane could be utilized in virion assembly and
packaging. This ionic imbalance leads to increased inflammatory response in the
host cell.
COVID-19 vaccine has been developed using various technologies by several
Pharma giants like AstraZeneca, Moderna, Pfizer, Johnson & Johnson along
with several other lead candidates in line. The mRNA (Pfizer, Moderna) and the
adenoviral vector-based vaccines (Astrazeneca, Johnson & Johnson) use epitopes
from the spike protein to generate an immunogenic response in the body and
thus creating an immunogenic memory. But since spike protein is very much
prone to mutations, these vaccines might lose their efficacies with the evolving
viral genome. Hence, the other cellular events involved in the viral pathogenesis,
which are more conserved phylogenetically, have become an important area of
research. Ion channelling activity is one such feature which encompasses viropo-
rins and their counter balancing host cellular responses which range from oppo-
site directional ion flow to downstream disruptions of the host cell signalling
pathways.
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2.2. Spike Proteins
Spike proteins (now on
S-proteins
) are trimeric class I transmembrane glyco-
proteins normally found as a homotrimer, and each monomer is composed of
two subunits, named S1 and S2. The cleavage of the S protein into S1 and S2 is
an essential step in viral entry into a host cell, and needs to occur before viral fu-
sion with the host cell membrane. The S1 subunit contains a region, the
receptor
binding domain
(RBD), that serves to bind to the target cell by adhering to the
human
angiotensin-converting enzyme
2 (ACE2), that serves as the virus recep-
tor.
ACE2 is a mammalian transmembrane zinc-containing metalloenzyme [39],
that cleaves angiotensin II (a vasoconstrictor peptide) into angiotensin (1-7) (a
vasodilatator) (thus clearing angiotensin II and lowering blood pressure), mainly
expressed in the lung, intestines, testis, arterial and venous endothelial (vascular
system, including the molecular and humoral immune defence and lymphatic
systems, acts as though it is a single organ), heart, kidney and alveolar epithelial
type II cells (an active metabolic epithelial cells with a high density of mito-
chondria).
The structure of S-protein alone or in complex with ACE2 is being intensively
studied. However, a detailed structural description of the potential interactions
of the S-protein with lipids in the mammalian plasma membrane is currently
missing [40]. This is a particularly relevant aspect since ACE2 is only the first
target of interaction for the spike proteins and subsequent or parallel interac-
tions with the surrounding membrane lipids are also pivotal for membrane fu-
sion and viral entry in the host cell.
Compared to other coronaviruses, the S-proteins from SARS-CoV-2 have a
very low dissociation constant (14.7 nM) for the binding to ACE2, which makes
SARS-CoV-2 highly infectious [40].
In [41] authors presented a strong argument that the S-protein by itself can
cause a signalling response in the vasculature with potentially widespread con-
sequences (which may lead to vascular wall thickening, mainly due to hypertro-
phy of the tunica media; enlarged smooth muscle cells may become rounded,
with swollen nuclei and cytoplasmic vacuoles).
The binding of the S1 subunit to ACE2 via the RBD suppresses ACE2, causing
a large increase in angiotensin-II (which can lead to pulmonary arterial hyper-
tension), and is fundamental to convert the S2 subunit from a
metastable
pre-fusion
state into a more
stable post-fusion state
, which triggers conforma-
tional changes that promote the fusion between the plasma membrane of the
host cell and the virus envelope.
Spikes S1 subunit is able to significantly strip away lipids from the plasma
host cell bilayer membrane, via a non-specific interaction (electrostatic manner,
ion channelling activity, protein-protein interaction, electron-proton transduc-
tions and exchange are good candidates), causing a large change in the composi-
tion of the lipid bilayer, compatible with an increase of water content, disrupting
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and potentially entering directly through the host membrane, thereby allowing
the viral RNA to be released into the host cell cytoplasm [40].
Endocytosis of Spike bound to ACE2 is one potential mechanism for viral en-
try, a mechanism that has been proposed for viral entry in some cell types [42].
Although the total structural charge of SARS-Cov-2 is positive, the structural
proteins of SARS-Cov-2 are carrying varied total electric charge related to the
amino acid content [27]. The E, M and N proteins are positive, while the surface
S-protein is negative. The latter contains 99 positively, and 111 negatively,
charged amino acids (AAs). The charged AAs in the S-protein of SARS-CoV-2
also exhibit some specific distribution. In the RBD region of the S1 unit the posi-
tive charge (cations) dominates in the protein interior (in general cations prefers
protein interior) and the negative charge (anions) prevails on the surface ex-
posed towards ACE2 receptor. The charged AAs in the S2 region preceding
heptad repeats of the S-protein, exhibit a central concentration, and the imbal-
ance of a positive charge. Both distributions of charged AAs may, in an electros-
tatic manner (eventually via compression of the membrane thickness due to
electromechanical-deformation [43]), facilitate the coronavirus infection of the
host cell.
The inhomogeneity of the electric charge distribution (dipole-like anio-
nic-cationic charge inhomogeneity) shown when considering the interface of
SARS-CoV-2 spike RBD and human ACE2, contribute to the occurrence of the
resultant mesoscopic Coulomb forces between the S-protein and the ACE2 re-
ceptor. In the stricter border area there is an excess of negative charge with some
isolated areas of positive charge, both in RBD and ACE2. The importance of the
electric charge is somewhat confirmed by the evolution trend to conserve the
total charge
q
in the central region of RBD.
The long-range electrostatic Coulomb attraction may govern an initial ap-
proaching of the SARS-CoV-2 spike RBD and human ACE2, leaving electrostat-
ic forces involved in the virus-cell approaching phase. Despite the spike and the
receptor charge in the total are negative, the local multipolar (monopolar and
dipolar) interactions may produce both attraction and repulsion of approaching
proteins (at the RBD surface cationic peptides could be more binding than anio-
nic ones, due to the prevalence of negative surface charge at the RBD). However,
the final precise binding with the receptor also requires other types of physical
interactions in the peptide-protein interface, mainly hydrogen-bonding with
polar or amphiphatic amino acids along with biophysical and biochemical
structured interfacial water stressors
(see section two).
It is thought that the membrane permeation is dependent on the membrane
fluidity, which in turn is dependent on the membrane lipid composition, cell
microenvironment and the presence of charged phospholipid head groups [44].
Modulation of the membrane fluidity may arise due to the ease of movement of
water molecules, and the dielectric constant of water, which is affected by endo-
genous and/or exogenous non-ionizing EMF [45].
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2.3. Early Stages of SARS-CoV-2 Infection in Broad Outline
The entry pathway of SARS-CoV-2 into the human host and the engagement of
target host cells can be summarized as follows (subsequent phases summarized
in Figure 2):
Virus enters the host 1) via upper respiratory tract (URT) inhalation of in-
fected respiratory droplets or aerosol, 2) via contact with infected surfaces,
such as skin-to-skin, and through touching an infected inanimate object then
mediating it through the mouth, nose or eyes, and 3) via fecal-oral route.
Virus “senses” the host environmental cues (a possible explanation is that vi-
rion ULF-EMF emission selectively tunes to ions resonance frequencies in
cells and/or cell membrane in ways that affect the target cell’s responsive
ULF-EMF, the virion detectthe emitted responsive signal and orientates
towards the signal source) and movetowards target cells (eventually by RNA
Figure 2. Mechanisms of SARS-CoV-2 entry into cells. Infection by a SARS-CoV-2 induces in the host cell perinuclear area the
formation of new membranous structures of various sizes and shapes, which likely originate from the
endoplasmic reticulum
(ER)
and as a whole are referred to as
replication organelle
. Viral structural proteins and genomic RNA synthesized at the replication
site are then translocated through an unknown mechanism to the
ER-Golgi intermediate compartment
(ERGIC), where virus
assembly and budding occur. While the N protein bound to the viral genomic RNA is packed inside the virion, the structural pro-
teins S, E and M are incorporated in the virion membrane. During biosynthesis and maturation in the infected cell, the S protein is
cleaved by furin or furin-like proprotein convertase in the Golgi apparatus into the S1 and S2 subunits, which remain associated.
In the new target cell, the S1 subunit binds the receptor and the S2 subunit anchors the S protein to the virion membrane and me-
diates membrane fusion. The E and M proteins contribute to virus assembly and budding through the interactions with other viral
proteins. Assembled viruses bud into the ERGIC lumen and reach the plasma membrane via the secretory pathway, where they are
released into the extracellular space after virus-containing vesicles fuse with the plasma membrane. FP, fusion peptide. Image
source: Mechanisms of SARS-CoV-2 entry into cells https://www.nature.com/articles/s41580-021-00418-x.
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strand machinery resting on non-ionizing EM radiation interactions, namely
electromagnetotaxis
), resorting to retroactive, non-linear, biochemical and
biophysical stimulus-response processes, which may refer to a less integrated
but no less effective form of
mixotaxis
equipped with
electromagnetotaxis
.
Airway and alveolar epithelial cells, vascular endothelial cells and alveolar
macrophages are among its first targets of viral entry.
Virus recognise (via electrochemical and
ion-cyclotron resonance
[14] inte-
ractionssee section three) the target cell ACE2 virus receptor.
The S-protein is glycosylated by the host cellular glycosylation apparatus as it
passes through the secretory pathway, before binding to the high-affinity re-
ceptor ACE2 [46] [47].
The highly glycosylated Spikes S1 subunit RBD bound to the host cell ACE2.
Direct interaction with the lipid bilayer on the cell surface occurs, lipids from
the cell membrane are stripped away, causing a large change in the composi-
tion of the lipid bilayer, disrupting and potentially entering directly through
the membrane [48].
2.4. Host Cell Oxidative Stress Reactions
Once the target host cell is engaged, SARS-CoV-2 cationic
fusion peptides
, (FP),
a short peptide segment in the S-protein, which plays a central role in the initial
penetration of the virus into the host cell membrane [49], ties up the
heparan
sulfate proteoglycans
(HSPGs) on the host membranes outer surface by charge
neutralization [50], causing sulfation of the HSPGs [51] [52], exposing localized
hydrophobic glycine-rich regions, and thus breaks up the HSPG-membrane
complex [53] [54] that connects extracellular matrix components to the intra-
cellular cytoskeleton. The resulting disconnection of the cytoskeleton from the
plasma membrane has several adverse consequences, including impaired elec-
trical conductivity of the cytoskeleton and microtubules and re-orientation of
the cytoskeleton toward the cell nucleus, which may induce membrane fusion
and accelerate viral mitosis. Once the host cell membranes barrier is disrupted,
penetration of the viral RNA into the host cell cytoplasm disrupts intracellular
water structure, leading to unfolded protein response (UPR), unfolded DNA re-
sponse, and excess
reactive oxygen species
(ROS) and
reactive nitrogen species
(RNS) production.
Viral pneumonia caused by SARS-CoV-2 induces overactivation of immune
response in the lung tissues affected by virus replication. This pathological
process is nearly always accompanied by disturbed redox balance and
oxidative
stress
(OS). OS is typical for infection of human respiratory syncytial virus, rhi-
noviruses, and many other viruses. In a large number of pathologies, inflamma-
tion is known to be closely related to OS, one process being easily induced by the
other [55].
After the virus enters the airways, its replication occurs, and the immune in-
nate response begins with the activation of macrophage and dendritic cells via
Toll-like receptors (single-pass membrane-spanning receptors usually expressed
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on sentinel cells such as macrophages and dendritic cells, that recognize struc-
turally conserved molecules derived from invading pathogens) and Nucleo-
tide-binding oligomerization domain (NOD) receptors (cytoplasmic pat-
tern-recognition receptors for detecting invading pathogens) against the pro-
duction of inflammatory cytokines and ROS/RNS.
Much of the cytosolic water is created as a byproduct of mitochondrial respi-
ration and electron chain transport. This metabolism makes heat (
biophotons
emission and
phonons
transfer) and the density of electrons flowing along the
inner mitochondrial membrane correspond the electronegative charge (which
makes proteins hydrophilic). Mitochondria transport protons into the inter-
membrane space, and their diffusion into cytosol leads to generation of a strong
static electric field and water ordering.
When mitochondrial function slows, the infrared light and electronegative
outputs of the cell drop and so does the volume of
structured interfacial water
(CD/EZ) [56].
In presence of dysfunctional mitochondria, the surrounding structured inter-
facial waters layer reorganize with a reversed orientation of the electric field,
which enables transport of electrons released into cytosol. As biological water
occupies 70% of the cell volume, it is capable of releasing a huge amount of elec-
trons into the cytosol. Free electrons increase conductivity which causes damp-
ing of cellular electromagnetic field (EMF). The mechanism of damping elec-
tromagnetic oscillations generated by microtubules [57] may explain the dis-
turbed organization in cells with dysfunctional mitochondria [58] [59].
When O2 is absent during periods of irregular cell hypoxia in mitochondrial
energy synthesis, the generation of excess electrons can develop free radicals
(mitochondria are major sources of free radicals) or excess protons can produce
acid, the latter case being enhanced if ROS hydrogen peroxide (H2O2) produce
ROS hydroxyl radical (OH) when exposed to transition metal cations such as
divalent ferrous iron or Fe2+ common to the heme molecule3. Free radicals
formed by limited O2 can damage lipids and proteins and greatly increase mole-
cular sizes in growing vicious cycles to reduce oxygen availability even more for
mitochondria during energy synthesis. Further, at adequate free-radical concen-
trations a reactive crosslinking unsaturated aldehyde lipid breakdown product
can significantly support free-radical polymerization of lipid oils into rubbery
gel-like solids and eventually even produce a crystalline lipid peroxidation with
the double bond of O2 [60].
The consequent spread of inflammatory cytokines and ROS/RNS to the blood
has two consequences: 1) erythrocytes are damaged by ROS and other inflam-
matory mechanisms leading to denaturation of hemoglobin and iron metabol-
ism dysregulation (
ferroptosis
) with release of toxic free iron ion [61]; and 2) ac-
3
Heme proteins are important biological molecules that catalyze radical reactions, and thus they can
induce proton spin coupling dependent local field effects on the involved intermediate free radical
substrates. Heme proteins are the antioxidant enzymes catalases and peroxidases, the oxygen trans-
porters hemoglobin and myoglobin, and all mitochondrial respiratory chain (and photosynthetic
electron chain) cytochromes.
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tivated macrophages and neutrophils produce respiratory bursts generating su-
peroxide radicals and H2O2 leading to OS. OS plus free iron ions converts so-
luble plasma fibrinogen into abnormal fibrin clots in the form of dense matted
deposits (DMD, resistant to the enzymatic degradation; blood clots), leading to
disseminated intravascular coagulation (microthrombosis in the vascular system
and the pulmonary microcirculation), cell hypoxia and endothelial dysfunction
(both microvascular and endothelial dysfunction share a common initial patho-
physiology).
The cytokines storm occurs through damped or impairment
chemokine
regu-
lation. The severity of COVID-19 can be stratified based on plasma/serum che-
mokine levels. Chemokines are a large family of small secreted cytokines that
coordinate leukocyte trafficking and activation, thereby regulating diverse phy-
siological processes, including development, inflammation, immune responses
and wound healing.
After this scenario is established, the cytokines storm induces OS via macro-
phage and neutrophil respiratory burst activity, and OS induces the cytokines
storm. This cycle provokes serious tissue damage independent of the virus. Low
hemoglobin-carrier, high lung proteinaceous exudate leads to pulmonary hy-
poxia, cytopathic hypoxia and endothelium damage, and disseminated coagula-
tion results in multiple organ collapse.
Several signs and changes in clinical and laboratory examinations presented
by patients with severe COVID-19 have been described. The changes observed
include decreased total lymphocytes, prolonged prothrombin time, elevated lac-
tate dehydrogenase, cellular immune deficiency, coagulation activation, myocar-
dial, hepatic, and renal injury and endotheliitis in the lung, heart and small bowel.
Although the mechanisms involved in these changes are still under research,
OS by ROS is related to all the main changes observed and could be the con-
necting point that unites all these events [62].
Overall, a model has emerged in which SARS-CoV primarily infects lung epi-
thelial cells to undergo replication, followed by infection in macrophages, with
induction of chemokine expression in both cell types. Next, chemokines mediate
recruitment of additional macrophages, neutrophils and T cells. Upon activa-
tion, these leukocytes contribute to an exuberant immune response which may
involve further production of chemokines, potentially contributing to immuno-
pathological damage in the lung and development of acute respiratory distress
syndrome (ARDS) [63].
3. Discussion
Oxidative stress is defined as an imbalance between toxic ROS and
antioxidants
in favor of oxidants, leading to a disruption of redox signaling and/or irreversi-
ble oxidative damage to lipids, deoxyribonucleic acid (DNA) or proteins. Oxida-
tive damages are involved in the development of different pathologies including
cancer, cardiovascular, neurodegenerative and lung diseases.
Most organisms rely on the role of oxygen as a terminal electron acceptor for
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efficient energy production in the form of ATP. Increased intracellular levels of
oxygen, however, are potentially toxic. This toxicity is mainly due to partially
reduced forms of O2, since the O2 molecule
per se
has low reactivity. The mole-
cules and radicals formed by the incomplete reduction of oxygen are termed
ROS and RNS. ROS/RNS commonly formed in vivo include the superoxide radical
anion (
), hydrogen peroxide (H2O2), and the hydroxyl radical (OH) [64] [26].
ROS/RNS free radicals play important roles in regulation of cell survival. In
general, moderate levels of ROS/RNS may function as signals to promote cell
proliferation and survival, whereas severe increase of ROS/RNS can induce cell
impairment and death. Under physiologic conditions, the balance between gen-
eration and elimination of ROS/RNS (which is known to rest on the
free radical
pair mechanism
[63]) maintains the proper function of redox-sensitive signaling
proteins. Normally, the redox balance ensures that the cells respond properly to
endogenous and exogenous stimuli. However, when the redox balance is dis-
turbed, OS can result in damage to proteins, lipids, nucleic acids, and contribute
to disease development.
3.1. Structured Interfacial Water: Coherence Domaine and
Exclusion Zone
In biological systems, liquid water interacts not only with small solutes but also
with many larger, extended hydrophilic and hydrophobic surfaces, such as those
of proteins, nucleic acids, various organelles, and cell membranes [65]. Results of
inelastic incoherent neutron scattering studies of several cell and tissue types
suggest that ca. 20% - 30% of the total (intracellular plus extracellular) water in
these systems is
interfacial water
,
i.e
. water located within 1 - 4 nm of these sur-
faces (thus,
biological water
can be considered as
interfacial water
because there
is almost no point in an organism that is not far more than a fraction of a micron
from a surface), with
bulk water
comprising the remaining 70% - 80% [66] [67].
Water at an interface, as with the atmosphere, has a
surface tension
due to the
polar interactions of water with other water molecules at the interface surface.
This clustering imparts a
crystalline like
property to the water. In the bodies of
living organisms, the clusters form
hydration layers
around biological molecules.
It is known from electronics that different patterns which contain
in-formation
4
result within a cluster depending upon its structure. Thus, depending on its
structure, each molecule has an oscillatory pattern (resonance frequency) that
can be determined by spectroscopy. It is known, through spectrographic analy-
sis, that water and other dipole molecules are able to be entrained to exogenous
4It must be stressed out that the physical concept of “
information
it has absolutely nothing to do
with that of
data transmission
, and even less with that of
transmission of messages containing a
(
semantic
)
meaning
. The former (physical concept) consider
information
as a measure of coh
e-
rence or structural
complexity
of surrounding system related to various entropic processes in
physical world, that is the measure of in-formation amount, related to a certain obje
ct, may be a
complexity of its internal structure (
negentropy
), while the latter (IT concept) consider
amount of
information
as frequency characteristic of code letters-
signals, that is improving of messages coding
and decoding methods and solving of other questions related to optimization of technical commu-
nication systems operation.
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oscillatory patterns by rearranging their cluster patterns. The cluster rearrange-
ments then resonate with the entraining frequency.
Interfacial water assumes a
glassy
appearance,
i.e
.
semi-crystalline
, and has
been studied by several researchers [68], suggesting the possibility that it is of a
different phase
(Pollacks
four phase
[69]) from that of common water in the
liquid state [70] [71].
All biological envelopes, from cell membrane to epithelial tissue, contain this
aqueous phase in a
liquid-crystalline state
or are perfused by it. It is water in a
particular
phase of quantum organization
that close to charged hydrophilic sur-
faces is confined in
Coherence Domains
(CDs) of about 100 nm in diameter at
ambient conditions [72]) and in layers of
Exclusion Zone
[73] [74] (which may
be regarded as long-range ensembles of CDs), and gives it a high capacity to:
retain electronic charges, in the form of vortical excitations of quasi-free
electrons, storable as energy reserve;
induce an electronic and protonic long-range and long life excitation of the
different molecular species available, enabling their selective activation and
mutual attraction;
convert mechanical vibrations (
phonons
) in quanta of electromagnetic ener-
gy (
photons
) and
viceversa
(piezoelectric effect).
EZ interfacial water shows specific properties which may be summarized as
follows [73] [75]:
EZ interfacial water is considerably more viscous than bulk water (about
10-fold) [76].
EZ interfacial water has a negative electric potential (up to 200 mV) with re-
spect to the neighboring normal bulk water; thus the pair EZ interfacial wa-
ter-bulk water is a
redox pile
. This property of EZ interfacial water could ac-
count for the source of electron excitations.
Protons concentrate at the boundary between EZ interfacial water and bulk
water.
EZ interfacial water exhibits a peak of light absorption at 270 nm; it emits
fluorescence when excited by light having this wavelength.
The illumination of EZ interfacial water by light (especially IR radiation) in-
creases the depth of the layer.
EZ interfacial water cannot host solutes.
The above list of properties appears quite mysterious in the frame of conven-
tional ideas about liquid water (
monophasic liquid
), while is well explained in
the frame of QED (
biphasic liquid
)5.
5Neither classical nor standard quantum theory predicts
quantum coherence for water
, largely be-
cause they ignore quantum fluctuations and the interaction between matter and the
vacuum ele
c-
tromagnetic field
(VEMF), which are taken into account in
Quantum Field Theory
(QFT). The co
n-
ventional
ab initio
approaches to water, based just on
Quantum Mechanics
(QM), describe it as a
monophasic liquid
. On the contrary, the conceptual frame of QFT admits infinitely many
ground
states (vacua), each one corresponding to a particular function describing the expectation value of
the involved field. Quantum coherence for water appears quite mysterious in the frame of conven-
tional ideas about liquid water (
monophasic liquid
), w
hile is well explained in the frame of quantum
electrodynamic QED (
biphasic liquid
) [77].
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The Coherence Domaine is a resonating cavity produced by a self-trapped
EMF (a self-produced cavity resonator for the EMF), whose size is just the wa-
velength
λ
of the trapped EMF, that ends up trapping the field because the pho-
ton acquires an imaginary mass, so the frequency of the CD EMF becomes much
smaller than the frequency of the free field with the same wavelength.
Within the CD water molecules oscillate between the ground state and an ex-
cited state close to the ionizing potential of water and, therefore, contain close to
a million almost-free electrons. That means CD is most likely negatively charged
at the periphery close to or at the surface of its domain (at the same time, posi-
tively-charged protons are present just outside the CD).
According to [65]
structured interfacial water
, namely
biological water
, pro-
motes life-enabling biological processes by:
promoting electrical conductivity at biological interfaces, thereby facilitating
metabolism and voltage differences maintained by intracellular organelles;
absorbing, storing, and emitting electromagnetic energy, enabling storage
and transmission of energy and in-formation;
overcoming the kT or
thermal diffusion
problem and solving the intracel-
lular crowding and molecular self-assembly problems by way of chirality
(handedness of molecules) and magnetization.
Therefore, pure bulk liquid water consists of two interspersed phases,
cohe-
rent
and
incoherent
, having widely different dielectric constants (that of the co-
herent phase is 160, due to the high polarizability of the coherently aligned water
molecules that are oscillating in concert; while the dielectric constant of the in-
coherent state is about 15) and appears to behave as an
active medium
able to
perform through
ultra low frequency-electromagnetic fields
(ULF-EMF).
In the
coherent phase
, the water molecules oscillate between two electronic
configurations (that of the CD and that of its
matrice
) in phase with a
resonating
EMF
. The EMF that are trapped within the CD of water and within its
coherent
matrice
[77], produce
electromagnetic potentials
(EP) that regulate the
phase
Ф
of the entire system, which in turn gives rise to selective attractions between the
molecules of the solute.
Contrary to the objects described by Classical Physics, a coherent quantum
system is not defined in isolation, but gets defined by the array of its relation-
ships. The phase Ф is connected with the EM potential in a mutual relationship
so that we could be able to change the phase Ф of a biological organism by ap-
plying an EM potential [78] [79] [80].
We could interpret the biological effectiveness of very- and ultra-weak EM
and magnetic fields just by assuming that the agent at work in the interaction is
not the field but the potential and the mechanism of interaction is the
phase-sharing
6.
6
Exogenous and endogenous electromagnetic signals can be selectively damped by tissues and cells,
according to their being or not in phase with the possible oscillatory motion of the system’s compo-
nents. This specific
phase-matching
feature operates as a very selective mechanism, a sort of filter
discriminating among perturbations and stimuli acting on the system, thus protecting it against any
noisy perturbative background or even strong actions, which, however, are
out of phase
with the o
s-
cillatory motions allowed by the system’s inner dynamics [81].
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That is, biological organisms, being coherent, can interact with environment
in two basically different ways:
through the conventional exchanges of energy which amount to the applica-
tion of mutual forces. This mechanism of interaction obeys the causality
principle, since energy cannot travel faster than light (
c
);
through the sharing of the phase Ф with other coherence based systems (bio-
logical organisms) and with the environment itself, which leads to relation-
ship systems based on resonance (phase-matching means oscillatory reson-
ance). The phase Ф velocity is not bounded above and can be larger than
light speed
c
.
3.2. Coherent Water and Biological Structures Are
Semiconductors
Because coherent water is excited water with a plasma of almost free electrons, it
can easily transfer electrons to molecules on its surface. Non-coherent water is
an almost perfect insulator and chemically an oxidant, coherent water is a
semi-
conductor
and chemically a reducer; the interface
coherent water
/
non-coherent
water
is therefore a
redox pile
[74] and a difference of electric potential can be
found across it (estimated to be included in the interval between 50 and 100 mV)
[82].
Various biological structures, e.g. keratin, collagen, alpha and beta sheaths of
proteins, genes and so forth are
semiconductors
and possess the ability to acti-
vate charges without participation of ions [83].
They have been conceived to be
piezoelectric
(the ability to generate an elec-
tric charge in response to applied mechanical stress) and
pyroelectric
(the ability
to generate an electrical potential in response to applied thermal stress), which
means they possess the capacity for
thermal
and
mechanical polarization
.
Whereas, these structures may form an uninterrupted reticulum that may act
as
quasi-crystalline piezoelectric-pyroelectric networks
, capable of converting
electromagnetic oscillations to mechanical or thermal stress, or vice-versa.
Hence, basic organic compounds and the whole organism are subjected to
elec-
trostriction
, i.e. the mechanical deformation of a dielectric (insulator) in the
presence of an electric field, and become quantum generators of
phonons
or
acoustic waves (a phonon being a quantized mode of vibration). The transition
from the induced state to the basic state has got thus two possibilities: the gener-
ation of
photon
or the generation of
phonon
. Thus, photon-phonon transduc-
tions arguably must exist in all material bodies, especially because all ordinary
matter is nothing else than condensed electromagnetic field.
Interfacial water EZ layer is an electron-donor, namely a reducer, whereas
normal water is a mild oxidant, consequently the interface EZ-water/bulk water
is a
redox pile
, where the redox potential could have a jump of a fraction of a
Volt. Hence, life could be defined as the dynamics occurring between two levels
of the electron clouds of water molecules: an excited state and a ground state. It
is just this electrondynamics at the origin of the singular redox properties found
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in the water in living matter [84].
In this conceptual frame life can be linked to a little electric current going
round and round. It is apparent that here electromagnetic fields find a place
within the biological dynamics. Electromagnetic fields are just able to couple
with the current of electron excitation producing important consequences on the
biochemistry which is just governed by this electron excitation.
At micro- and mesoscopic level life is a result of all the chemical, electrical,
magnetic, optical and acoustic events occurring in the living organism, in the
system of organic-like semiconductors, piezo- and pyroelectrics. Therefore, life
takes place not in a chemical or electronic system, but to some extent among
these two processes, where photon-phonon and electron-proton transductions
and exchange play a central role.
3.3. The Self-Driven Liquid-Flow System
Proton currents and concentration gradients are ubiquitous in all biological sys-
tems and play essential roles in a number of physiological processes [85]. The
most striking example is oxidative phosphorylation in mitochondria in which
proton gradients serve as a means to translate the energy from oxidation of glu-
cose during the Krebs cycle into ATP, the biological energy currency [86] [87].
Thanks to the
hydrogen-bonded chain mechanism
[88] [89], called the
Grot-
thuss mechanism
, protons tunnel from one water molecule to the next via hy-
drogen-bonding [90].
Surprisingly, excess protons can create their own pathways,
water-wires
, be-
fore protons can migrate along [91].
Water electricity is special in that it also involves the movement of positive
charges associated with
protons
. According to quantum electrodynamic (QED)
not only do electrons of the hydrogen-bonds fail to conform to the classical elec-
trostatic model, the protons also are quantum mechanical. Changes in the
redox
potential
(oxidation state or electronic configuration) or
proton transfer equili-
bria
of a chemical species can influence each other, thereby these two chemical
reactions often occur in association. This fundamental concept of chemistry is
best exemplified by the Nernst Equation which relates the variation of the
aqueous oxidation/reduction potential of chemical reactions with the pH when
protons are involved.
It is known that cells can exist and perform particular functions in complex
environments within a particular range of temperature and pH conditions [92].
The pH level is different for different parts of the body. Thus, for example, in
order to decompose food to basic components, the stomach maintains an acidic
environment. The cells, covering inner walls of stomach, must be resistant to
these extreme conditions and the proteins and receptor-ligand complexes within
should be able to perform their functions. Another example is immunocompe-
tent cells, such as monocytes and neutrophils. While being activated, they pro-
duce reactive oxygen species (ROS) that acidify the environment. Thus, the
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change in pH is used as a powerful weapon against pathogen organisms (an aci-
dified environment which instead favors SARS-CoV-2 pathogenicity). In addi-
tion, these cells perform phagocytosis, at which monocytes and neutrophils cap-
ture the pathogens inside phagosomes inside cells. Furthermore, the pH value is
not constant throughout the cell, compartments of the cells can have widely dif-
fering pH.
In a more general sense, the thermodynamic correlation between
electron
and
proton transfer
establishes that the
redox potential
of a chemical species can af-
fect its acid-base equilibria, that is, its pKa (
protonation state
) [93]. As pointed
out earlier, SARS-CoV-2 main protease 3CL Mpro is indispensable for virus rep-
lication and do affect the host cell
protonation state
by increasing its acidity de-
gree.
This concept constitutes the thermodynamic basis of
proton-coupled electron
transfer
(PCET) reactions [94] [95], also called
Concerted proton electron trans-
fer
(CPET), in which proton and electron movement are intercorrelated and
were
proton transfer
7:
Is involved in regulating enzyme reactions within the cell, where metabolic
reactions are predominantly of a redox nature.
Proton currents may well flow throughout the extracellular matrix, and
linked into the interior of every single cell through proton channels.
Proton currents could flow from the most local level within the cell to the
most global level of the entire organism.
Protons (reducing power) give a boost of energy where it is needed.
Protons can flow directly along the membrane within the interfacial water
layer, from proton pump to ATP synthase, both of which are embedded in
the membranes.
Proton currents and concentration gradients play essential role also for it can
mimic a
motive-like pump
that turns any biological liquid flow collagen-related
system in a
self-driven liquid-flow system
(S-DLF-S). That is a
light-driven-flow
[96].
Collagen
is the most abundant protein in the organism, and is known to form
liquid crystalline mesophases
(liquid crystals are states or phases of matter in
between solid crystals and liquids, hence the term,
mesophases
). It is the main
protein in the extracellular matrix and connective tissues (
connective-collagen
membrane system happens to be composed almost entirely of hydrophilic ma-
terial, which are defined by the density of electrons on their surfaces, and the
protons formed when (a) ultraviolet to infrared light energy, (b) water, and (c)
hollow hydrophilic surfaces come together in space and time and may thus ac-
count for the liquid crystallinity of living organisms as a whole, facilitating
short
and long range collective coherent correlation
throughout the body [70]).
7
Electron transfer (ET) and proton transfer (PT) denote the electron/proton flow process with an
electrolyte, which is ionically conducting and which can function as an electron/proton sink or
source via a redox process. The electrolyte also provides charges, which screen the change in electr
i-
cal potential due to the electron/proton flow and makes a charge balance possible.
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Cells and complex molecules suspended in the blood avoid agglomeration
through a negative charge field maintained in the immediate surrounding space.
The rate at which a charged particle suspended in a medium will travel in an ap-
plied electric field is an important measure of colloidal stability in the medium,
and is associated in physics with the electrical potential drop from the particle
surface across the bound fluid, to the interface where the liquid begins to flow
under the shear stress, namely
Zeta Potential
(ZP), a measure of the net charge
density of a particle (also a measure of surface charges of virus particles which
characterize the viral electrostatic properties),
i.e
. the potential at the surface
boundary between the stationary fluid and the liquid that is moving with the
particle. A high negative value for ZP (if a nanoparticle in a dispersed system
moves with electrophoresis to a positive electrode, its charge is negative and vice
versa) is essential for maintaining blood as a colloidal suspension.
Blood vessels are made of
hydrophilic proteins
, which structure the water in
blood and form the EZ gel-like state observed at nanoscale in the interaction
between water and hydrophilic surface. The negative ions (also in the form of
vortical excitations of quasi-free electrons) propel the protons through the mid-
dle and drive perfusion. Once the blood plasma is electrically structured, the
negative electrical value for ZPof red blood vessels builds and prevents them
from clustering8. A systemic lowering of serum ZP mediated by exogenous ca-
tionic surfactant administration, together with lowered bioavailability of certain
endogenous sterol sulfates, sulfated glycolipids, and sulfated glycosaminogly-
cans, which are essential in maintaining biological equipose, energy metabolism,
membrane function, and thermodynamic stability in living organisms, leads to
subsequent inflammation, serum sickness, thrombohemorrhagic phenomena,
colloidal instability, and ultimately even death.
According to [98] [99], the highly ordered collagen water chains (linked to
Pollacks
fourth phase
of water), are reminiscent of those seen in carbon nano-
tubes (<5 nm diameter).
Under certain conditions, Pollacks team have been able to visualize EZ water
inside tunneled gels and hydrophilic tubes made of Nafion immersed in an
aqueous microsphere suspension. Videos show a steady flow of microspheres
and water along that interior channel, the so-called
self-driven
flow (see also
[100]).
Light drives that flow; increasing light speeds it by up to five times. Hence, the
light driven-flow phenomenon is general; and, it is driven by light. They found
that the flow resulted from the protons generated as consequence of EZ growth.
Those protons lie in the tunnels central core. Repulsion among protons creates
a pressure, which pushes the protons out of one end of the tube or the other.
8
In an ideal system like blood, we want all particulates to have a like electrical charge. If the particles
have no electrical charge, the various particles will clump together and form
sludge. Therefore, the
higher the Zeta Potential, or negative electrical charge, the better the dispersion of particles in sus-
pension. The high Zeta Potential on particles entering the bloodstream may help to increase the di
s-
persion or discreteness of bloo
d cells by helping to enhance the electrical charge on blood colloids
which include blood cells [97].
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Once that flow begins, additional water gets drawn in from the opposite end of
the tube, perpetuating the process.
Pollacks hydroelectric EZ reveal, at least
in vitro
[96], that IR/UV energy
from light outside the organism, and possibly also from biophotons derived
from internal exothermic metabolic reactions, may transform simple hydrophilic
tubes and vessels, including arteries, veins and capillaries, lymphatic ducts, renal
tubules, sweat glands, ureters, tear ducts, Eustachian tubes, respiratory alveolar
ducts, bile ducts, cerebrospinal fluid-flow system, axons, etc., into the equivalent
of mechanical pumps but without a motor,
i.e
. into S-DLF-S. That is, all of these
tubes and vessels, as well as any other collagen-related liquid-flow system, need
pumps to actively move the associated fluids within.
The pumping action exerted, e.g. by the cardiac activity on blood and on
CSF-FS circulation, as well as the pumping action exerted by the contractile ac-
tivity of the striated and smooth muscles, behave as pumps and actively move
the body fluids, but their efficiency would be drastically reduced without the ac-
tive contribution of the S-DLF-S (Figure 3) engaged by proton currents and
concentration gradients. S-DLF-Sengaged in blood circulation within the blood
vessels is an example: red blood cells flow in the core of vessels and are excluded
from the periphery. This feature is long known, and is generally attributed to
hydrodynamic effects; but the evidence above implies that it might arise instead
from the EZ proton currents and concentration gradients [99].
Figure 3. Self-driven flow was observed in Nafion and other hydrophilic tubes immersed
in water. The intratubular flow was generated when water came in contact with the tube’s
hydrophilic surfaces. Flow characteristics were studied in tubes of varying size, exposed to
light of different intensities and wavelengths. The results lead to the hypothesis that the
flow is driven by a high concentration of protons accumulating inside the tube, creating
an axial proton gradient between the inside and outside of the tube. It is also demon-
strated a faster flow under incident light, particularly at UV wavelengths, implying that
proton generation may be driven by light. Credit [96]. Image source:
https://pubs.acs.org/doi/abs/10.1021/la4001945?journalCode=langd5.
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Thus, if we exclude the mechanical action exerted by the smooth and striated
muscles, the main motor force of any biological liquid-flow system is generated
across biological membranes and connective-collagen membrane system, that is
under EZ/CD electrodynamics laws, by
proton currents and concentration gra-
dients
.
3.4. Viral ULF-EMF as Host Cell Stressor
Electromagnetic signals are endogenously generated at different levels of the bi-
ological organization and, likely, play an active role in synchronizing internal
cell function or local/systemic adaptive response [101]. Consequently, each
adaptive response can be described by its specific electromagnetic pattern and,
therefore, correlates with a unique and specific electromagnetic signature.
According to QED, biological water can be viewed as an unstable balance be-
tween coherent and incoherent components, that is structured and bulk water.
The molecules of water, the ions and the biomolecules of the coherent compo-
nent form extended mesoscopic regions, called Coherence Domains (CDs) and
Exlusion Zones (EZs), where they synchronously oscillate with the same phase,
i.e
. they oscillate in unison between two selected levels of their spectra in tune
with a self-produced coherent EMF having a well defined frequency, dynamical-
ly trapped within the CD/EZ. Extended coherent mesoscopic regions are sur-
rounded by the incoherent component where molecules oscillate with casual
phases relative to one another.
It is possible to induce by an externally applied field (either hydrodynamical
or electromagnetic) or also by a chemical stimulation, coherent excitations of
CD/EZ that give rise to electric currents circulating without friction within the
CD/EZ: as a consequence magnetic fields are produced. A resonating magnetic
field thus is able to extract the ions from the orbit and push them in the flowing
current [102].
Accordingly, if an exogenous source of non-ionizing very weak low frequency
electro-magnetic field, e.g. that of a virus or bacteria [103], enter an organism
and interact with target cells by matching the ion cyclotron frequency resonance
of a particular charged molecule, an intrinsic weak magnetic field is generated by
ion currents in the cell. One of the main hypotheses currently available to ex-
plain this interaction is the parametric resonance Lednevs original model effect.
The Ion Parametric Resonance (IPR) theory, first proposed by Lednev (1991)
and then by Blanchard and Blackman (1994) [104], is one of the most discussed
models of low frequency electromagnetic field (LF-EMF) interaction with bio-
logical systems. The assumptions of this theory are based on the Ion Cyclotron
Resonance theory (ICR), first described by the American physicist Abraham Li-
boff (1984), speculating that the physiological activity of certain important ions
can be altered when the frequency of applied time-varying magnetic field is
equal to the frequency of ion motion in a static magnetic field. Ions in IPR mod-
el are represented by a harmonic oscillator, bound to a specific location at the
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surface of the cell membrane, and application of combined magnetic field should
alter its oscillations.
SARS-CoV-2, as any other virus, does emit and absorb ULF-EMF [17]. Given
the extremely reduced nature of viral proteomes, ULF-EMF activity can rely on
hydrogen-bonds (HBs), as piezoelectric centers of energy transduction and EM
radiation emission centers, and on the single- or double-stranded nucleic acid
machinery [105] [106], surrounded by a protein coat, which is everything a virus
is made of.
It can be assumed that in its approach to the target host cell SARS-CoV-2
emits a stressful ULF-EMF [104] that may influence ionic fluxes throughout cel-
lular membrane, before electrostatic interactions occur [107], activating the cel-
lular
phase-matching
feature (see footnote 6), generating (also via plas-
ma-membrane-localized redox signalling) an alert response in the cell mem-
brane interfacial water phase (CD/EZ) which activate redox-responsive intracel-
lular signaling and anti-inflammatory scavenging systems.
However, membrane ionic fluxes may be influenced by ULF-EMF in two
non-mutually canceling ways, one based on QED and the other on QM.
Circular orbits of ions dissolved in water are localized on the surface of
CD/EZ. The frequency of ionic orbits, called
cyclotron orbits
[108] [109], are
proportional to a static EMF resulting from the vector addition of all EMFs
present in the environment [110].
If an oscillating EMF with a frequency similar to the cyclotron overlaps the
static EMF, ionic orbits are altered and ions change their position as to the sur-
face of the interfacial water coherence domains. If domains are not next to the
cell membrane, ions stop in the
non-coherent
water region and they are replaced
by other ions. If domains are next to the cell membrane, ions go across it, thanks
to the potential difference between the two side of the cell membrane. That is.
Despite many physiologic oscillating EMFs exist into the human body providing
the preservation of the structured interfacial water, if an exogenous EMF with a
frequency matching the cyclotron frequency of a ionic species is present in the
environment, that ionic species will be influenced by it and non-physiologic io-
nic fluxes through the cell membrane can occur causing membrane imbalance
[111] [112] [113].
Another possible mechanism, based on Quantum Mechanics, which can be
intertwined with the previous one, is the dissociation of ion-protein complexes
due to weak oscillating EMFs in the presence of a static electromagnetic field. In
this case there is an imbalance between intra and extra-cellular ionic concentra-
tion which originates metabolic disorders and high stress levels [114].
Therefore, long-range ULF-EMF interference events would precede the earli-
est steps in infection and infectivity by activating redox-responsive intracellular
signaling and anti-inflammatory scavenging systems. Viral ULF-EMF would act
as
host cell stressor
[103] [115], predisposing the target cells to infection and fa-
cilitating infectivity [116], by affecting membranal protein distribution, pro-
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moting ROS/RNS production, causing
exogenous interfacial water stress
(EIWS)
[65] [117], disrupting structured interfacial water phase (CD/EZ) in favour of
bulk water, stabilizing free radicals in such a way as to permit their dispersion
rather than their return to the ground state, leading to localized water hydro-
phobicity, unwetting, increased water tension and membrane softening”.
4. Conclusions
Viruses act as parasites; they infect and either replicate within the host cell or
integrate within the host genome. There are many direct and indirect causes of
viral pathogenesis, but given the sheer numbers of viruses within a holobiont
(the functional association between a host, prokaryotic, eukaryotic, and viral
entities within a particular environment is the holobiont), and the limited pa-
thogenesis that actually occurs, it seems more likely that viral pathogenesis is not
as common as viral commensalism and mutualism [118]. A virus can be com-
mensal, the virus benefits while host fitness is unaffected. A virus can be mutua-
listic, in which both organisms benefit and fitness increases. Such viral associa-
tions may provide advantages that promote evolution and biodiversity. One vi-
rulent virus among a sea of non-virulent viruses does not equate to pathogenesis.
Unless transmission and recovery rates are high, pathogenicity may be an evolu-
tionarily poor strategy for viral survival. More likely, pathogenesis is the excep-
tion and not the rule, with more instances being discovered of viruses having
cooperative roles with the host [119].
SARS-CoV-2 belongs to viruses whose lytic/virulent lifestyle involves the in-
fection, replication, and lysis of the cell, leading to the death of the cell and re-
lease of viral progeny. The earliest phase of its lytic/virulent lifestyle involves
sensing and moving towards target cells, likely resorting to retroactive,
non-linear, biochemical and biophysical stimulus-response processes (mixotax-
is) equipped with
electromagnetotaxis
. In its approach to the target cell, specific
ion effects may be triggered by electrostatic and electrodynamic forces. The lat-
ter likely consist of the emission of a long-range ULF-EMF which influences
target ionic fluxes throughout cellular membrane generating an alert response
within the cell, before electrostatic interactions occur. Therefore, it is suggested
that the earliest virus-host interaction would rest on long-range electromagnetic
events influencing the redox potential of the target host-cells membrane chemi-
cal species, that is, affecting its acid-base equilibria, hence inducing a cellular
stress response (plasma-membrane-localized redox signalling) with reactive
oxygen species (ROS) and reactive nitrogen species (RNS) production. Accor-
dingly, redox-responsive intracellular signaling and anti-inflammatory scaveng-
ing systems would be remotely (pre) activated by non-ionizing interference
phenomena, before virus-cell come together, followed by electrostatic and
chemical events that provoke a branching, cascade-like, chain of reactions.
Conflicts of Interest
The author declares that this work was conducted in the absence of any com-
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mercial or financial relationships that could be construed as a potential conflict
of interest.
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