A Potential Connection between Activation of Transient
Receptor Potential Channels by Electromagnetic Wave
Radiation and Induction of Heat Shock Proteins in Living Cells
Etsuro
Ito, Wen-Li Hsu, Tomoko Warita, Tohru Yoshioka
Etsuro
Ito, Tomoko Warita, Kagawa School of Pharmaceutical Sciences, Tokushima
Bunri University, 1314-1 Shido, Sanuki 769-2193, Japan
Wen-Li
Hsu, Tohru Yoshioka, Graduate Institute of Medicine, School of Medicine,
Kaohsiung Medical University, 100, Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan
Correspondence to: Tohru Yoshioka, Visiting
Professor, Graduate Institute of Medicine, School of Medicine, Kaohsiung
Medical University, 100 Shih-Chuan 1st Road, Kaohsiung 80708, Taiwan.
Email: yoshitohru@gmail.com
Received: April 11,
2015
Revised: September 1, 2015
Accepted: September 3, 2015
Published online: September 22, 2015
ABSTRACT
A number of
stimuli have been shown to both induce heat shock proteins and activate
transient receptor potential channels. However, the direct and indirect
relations (i.e., causes and results) between the production of heat shock
proteins and the activation of transient receptor potential channels have not
yet been clarified. In the present review, we propose that a key phenomenon
binding these two molecular events together is the production of reactive
oxygen species by environmental electromagnetic-wave radiation. We then
hypothesize a signaling cascade from environmental electromagnetic-wave
radiation to heat shock protein production via transient receptor potential
channel opening. In addition, the roles of the intracellular Ca2+
influx through transient receptor potential channels are shown to include the
activation of mitochondria and synthesis of new proteins. These two molecular
mechanisms are thought to result in heat shock protein production and autophagy
activation in order to achieve cellular recognition of the oxidized proteins
and replace damaged proteins, respectively. It is hoped that this hypothesis
will inspire research into the various beneficial effects of environmental
electromagnetic waves on the human body.
Key words: Electromagnetic wave; Heat shock protein; Infrared
radiation; Reactive oxygen species; TRP channel
Ito E, Hsu WL,
Warita T, Yoshioka T. A Potential Connection between Activation of Transient Receptor
Potential Channels by Electromagnetic Wave Radiation and Induction of Heat
Shock Proteins in Living Cells. Journal of
Biochemistry and Molecular Biology Research 2015; 1(3): 80-86 Available from: URL:
http://www.ghrnet.org/index.php/jbmbr/article/view/1159
INTRODUCTION
A wide variety of stimuli have been shown to induce molecular
chaperones (i.e., heat shock proteins: Hsps), including temperature, ethanol,
oxygen radicals, nitric oxide, ionizing radiation, microwaves (i.e.,
electromagnetic waves: EMW), exercise, anoxia, endotoxins, and bacteria[1].
Although, at a glance, these phenomena would be expected to exert completely
different types of stimulation, they all share an ability to induce reactive
oxygen species (ROS)[2-4]. In addition, most of these stimuli can
activate transient receptor potential (TRP) channels simultaneously[5,6].
That is, the inducers of Hsps and the activators of TRP channels largely
overlap[7].
This raises
the question: between Hsp production and TRP channel activation, which is the
cause, and which is the effect? In terms of their temporal order, it is clear
that the activation of TRP channels occurs first, followed by the production of
Hsps[8], but a direct signaling pathway connecting TRP channels and
Hsps has not yet been revealed. This is because these two proteins have been
independently examined in different fields, with the studies on TRP channels
being performed mainly in biophysics and cell biology, and those on Hsps in the
area of biochemistry and the medical sciences[9-12]. However, as
described above, our studies on aging/senescence have indicated that the
stimuli inducing Hsps are often also the stimuli that activate the TRP channels[7].
In the present review, therefore, we will attempt to clarify the signaling
pathways from TRP channels to Hsps and then apply this pathway to a new hypothesis
involving environmental EMW, which is one of the stimuli mentioned above. It is
hoped that this hypothesis will inspire research into the various beneficial
effects of environmental EMW on the human body.
Studies
on the molecular mechanisms of cellular damages induced by EMW have been
performed in clinical medicine and electric engineering, resulting in an
effective clinical treatment called “focal hyperthermia”[13]. Almost
all the research into focal hyperthermia has been centered on the challenge of
focusing microwaves onto an affected part of the human body to kill cancer
cells, but little attention has been paid to the question of why high
temperature treatment at 43℃ can specifically kill cancer cells
but not normal cells[14]. Nonetheless, there have been a few studies
that may suggest an answer to this question, including one showing that the
transient receptor potential vanilloid receptor 1 (TRPV1) channel opens at 43℃[15], and another showing that the
TRPV1 channel could induce cancer cell death via activation of the Ca2+
influx signal[16]. In support of this mechanism, treatment with the
TRPV1-antagonist AMG9810 promotes tumorigenesis in mouse skin[17].
In addition to
hyperthermia, it is worth paying attention to fertilization, which may also be
involved in TRP channels. The fact that successful fertilization requires the
activation of inositol trisphosphate receptors (IP3Rs) in the endoplasmic
reticula (ER) by sperm will also be explained if we assume that IP3-sensitive
TRP channels exist in the ER membrane of oocyte cells[18,19].
Thus,
the purpose of the present review is to provide examples of the involvement of
TRP channels in the plasma membrane and ER membrane in a variety of unresolved
signaling cascades. The final goal of these signaling flows is to produce a
suitable number of Hsps to slow the rate of aging and reduce age-related
diseases. Thus, we discuss the roles of TRP channels in producing Hsps in
living cells, and the possible use of carefully controlled EMW to stimulate
this process.
ACTIVATION
Of TRP CHANNELS BY EMW AS AN INITIAL STEP
Environmental EMW can produce numerous ROS in living tissues in a
wavelength-dependent manner[20]. According to the Planck-Einstein
relation for EMW energy, the following equation holds even in living tissues: E
= hν = hc/λ. Here, E is the energy of EMW; h
is Planck’s constant; ν is the frequency of EMW; c is the speed
of light; and λ is the wavelength of EMW.
This equation
demonstrates that radiation with short wavelength has high energy that can
permeate the whole human body easily. EMW ranging from UV rays to infrared (IR)
rays can reach a depth of only several mm below the skin surface, but
microwaves can reach a depth of several cm[21]. Figure 1 shows
various types of environmental EMW.
These
categories (gamma-rays to microwaves) of EMW produce ROS in different ways, as
described below.
In this
context, it is important to note that environmental EMW has three different
effects on molecules, i.e., ionization, excitation and heat response (Figure 2)[22].
Ionization is the process by which a molecule acquires a negative or positive
charge by gaining or losing electrons to form ions. In the present review, we
mainly focus on ionization resulting from the interaction with environmental
EMW, in which the inner-shell electrons are ejected. Excitation is an elevation
in energy that is often associated with an atom being raised to an excited
state. An excited state of a system, such as an atom or a molecule, is any
quantum state of the system that has a higher energy than the ground state.
After the system has absorbed energy to go to an exited state, radiation is
emitted by the system in a process called luminescence, which can take the form
of either fluorescence or phosphorescence. Near infrared (NIR) energy is
absorbed by a molecule, and the molecule changes its rotational-vibrational
movements. NIR energy excites vibrational modes in a molecule through a change
in the dipole moment (see also the description of “microwaves” below).
(1) Direct ROS production in living tissues by high-energy radiation
As shown in Figure 1, high-energy gamma-rays and X-rays, which have very
short wavelength, can permeate the human body easily, because their energy loss
is very small in living tissues[23]. When high-energy radiation
enters into tissues, it ionizes the water molecules in the tissues to form e-*
and H2O+* simultaneously. Here, * denotes the excited
state. e-* is captured by many water molecules and then changes to eaq-,
which is known as a hydrated electron. In the presence of oxygen molecules,
this eaq- forms super oxide (O2-),
while H2O+* results in a hydroxyl radical (·OH). Super
oxide (O2-) and hydroxyl radical (·OH) are members of the
ROS family (note that hydrogen peroxide (H2O2) and
singlet oxygen (1O2) are the other members of the ROS
family)[24]. Exposure to high-energy gamma-rays or X-rays does not
usually happen except during imaging or treatment in a hospital, but astronauts
are frequently exposed to intense cosmic rays, including gamma-rays and X-rays.
(2) ROS production by middle-range energy EMW (UV, visible and NIR rays)
UV rays do not have sufficient energy to ionize water molecules.
However, UV, visible light and NIR rays can generate ROS, including hydroxyl
radicals (·OH), and singlet oxygen (1O2) by excitation,
as shown in Figure 3.
The production
of singlet oxygen (1O2) involves several complicated
processes. As shown in Figure 3, we expect that dissolved organic matter (DOM)
exists in a triplet excited state in the water of tissues. The radiation
absorption by DOM generates DOM in the singlet excited state (1DOM*),
and then 1DOM* nonradiatively passes into the triplet state (3DOM*)
via intersystem crossing. 3DOM* binds O2, resulting in
DOM and singlet oxygen (1O2)[25].
Singlet oxygen
(1O2) is a very popular topic of investigation in
dermatology research, due to its harmful effects on the cell membrane[26].
These harmful effects have been attributed, at least in part, to the
transformation of 1O2 to radicals and other ROS in
tissues[27]. It must be kept in mind that hydroxyl radicals (·OH)
are also made in the mitochondria (Mt) of liver or other tissues having high
levels of blood pigments, because visible light and NIR rays are absorbed at
high levels in these tissues[28,29].
(3) Indirect ROS production by heat (high temperature)
Hsps themselves cannot be directly induced by ROS in tissues[30].
However, heat can induce Hsps in the cells of tissues, and independently, heat
(or temperature stimulation) can also activate TRP channels, as shown in Figure
4. Here, we will take as an example the heating mechanism by microwave
radiation. Microwave ovens are often utilized to thaw frozen cells and tissues,
and thus they can be applied to the activation of TRP channels in the thawing
process. The frequency of a microwave oven is usually 2.45 GHz. This
oscillation frequency moderately changes the electric field that determines the
direction of the permanent dipoles of polarized water molecules. Thus, the
directional changes of the permanent dipoles lead water molecules to
effectively absorb the energy of microwaves and generate heat. Such directional
changes in the permanent dipoles of polarized water molecules may affect the
hydrophilic amino acids in the N- or C-terminals of
thermo-sensitive TRP channels. In the near future, it will be important to
clarify the thermo-sensitivity of TRP channels by investigating the
interactions between water molecules and a number of hydrophilic amino acids of
the long N-terminals or C-terminals.
(3) Indirect ROS production by heat (high temperature)
Hsps themselves cannot be directly induced by ROS in tissues[30].
However, heat can induce Hsps in the cells of tissues, and independently, heat
(or temperature stimulation) can also activate TRP channels, as shown in Figure
4. Here, we will take as an example the heating mechanism by microwave
radiation. Microwave ovens are often utilized to thaw frozen cells and tissues,
and thus they can be applied to the activation of TRP channels in the thawing
process. The frequency of a microwave oven is usually 2.45 GHz. This
oscillation frequency moderately changes the electric field that determines the
direction of the permanent dipoles of polarized water molecules. Thus, the
directional changes of the permanent dipoles lead water molecules to
effectively absorb the energy of microwaves and generate heat. Such directional
changes in the permanent dipoles of polarized water molecules may affect the
hydrophilic amino acids in the N- or C-terminals of
thermo-sensitive TRP channels. In the near future, it will be important to
clarify the thermo-sensitivity of TRP channels by investigating the
interactions between water molecules and a number of hydrophilic amino acids of
the long N-terminals or C-terminals.
Hsps are
expressed when the body temperature is kept at more than 41℃[7]. The most
important point to consider in the present context is whether or not “high
temperature” can produce ROS in living cells. To answer to this question, we
must consider the function of TRP channels. There are several types of
thermo-sensitive TRP channels in the skin, and when any of these channel types
open, extracellular Ca2+ and Na+ enter into the cell
abruptly, and the intracellular Ca2+ concentration is transiently
elevated[31], resulting in the activation of Ca2+-uniporters
of Mt and the production of ATP[32]. A transient increase in
intra-mitochondrial Ca2+ triggers activation of the electron
transport system of Mt, and then ROS are formed in Complex I and Complex III with
ATP in Mt, and thereby released into the cytosol[33]. This is the
proposed signaling pathway underlying the increase of Ca2+-induced
ROS in cells via Mt.
If the above
scenario is accurate, then IR rays would be a strong candidate for
intracellular Ca2+ production, because IR can carry heat into
biological tissues[34]. The basic laws of IR radiation were
established in the field of thermodynamics (physics) in the beginning of the 20th
century (e.g., in 1911, Wilhelm Wien was awarded the Nobel Prize in Physics
"for his discoveries regarding the laws governing the radiation of heat”).
In the 1970s, IR was established as an effective heat conductor for thawing
frozen materials, but at present it is more often used for food processing
operations such as drying, hydration, enzyme inactivation and pathogen
inactivation[35], and quite recently, in the medical sciences to
treat hyperthermia[36]. In addition, the development of diode lasers
for the study of hyperthermia and thermo-sensitive TRP channels has also
progressed[37,38], and this should also encourage further research
into TRP channels.
(4) Uncertain effects of radiofrequency on living cells
Mobile phones are now distributed across the planet. In association with
this ubiquitous distribution, a toxic effect of EMW in the radiofrequency (RF)
region has been proposed[39]. It was initially conjectured that this
toxic effect may arise due to DNA damage caused by RF-induced disturbance of
the proton current on DNA[40,41]. In this model, the double-strand structure
of DNA would act as a semiconductor with free protons. The wavelength of RF-EMW
is much longer than that of IR, and the frequency exceeds the order of
gigahertz, which is enough to vigorously oscillate protons on the DNA surface[42].
However, DNA damages were shown to occur selectively at the G:C pair in the DNA
double-strand[43], which suggested another possibility. Namely, the
DNA damage by RF radiation could be a form of ROS-induced chemical damage[2,44-47].
If ROS are produced directly by RF-EMW, the molecular mechanism of ROS
production would be quite different from that by heat or radicals, because the
energy of RF is far too low to produce heat in living tissues[4].
ROLES OF
TRANSIENT Ca2+ ELEVATION IN
NORMAL CELLS
Once TRP channels open, the level of cytosolic calcium is elevated
transiently and triggers various Ca2+ signaling pathways. In regard
to ROS signaling, the most interesting aspect of these Ca2+
signaling pathways is their mutual interaction with Mt responses and ROS
production. Indeed, this interaction is closely related to the aging process[48].
Intracellular Ca2+ elevation triggers the function of mitochondrial
Ca2+-uniporters, and Ca2+ increase in Mt activates the
tricarboxylic acid (TCA) cycle and produces ATP, which is followed by
activation of the electron transport system[49]. Complex 1 is known
to play a major role in ROS production in the electron transport system, and
the molecular mechanism of ROS production in the activated state of the
respiratory chain has been established[50]. Another significant ROS
production apparatus is Complex III, and although it is not known how Ca2+
is involved in ROS production in Complex III, it is clear that both these
processes are involved in the Ca2+-activated TCA cycle[51].
Given the
above facts, the important point would be determining how cytosolic Ca2+
triggers the TCA cycle. In the 1990s, a process called RaM (rapid uptake mode)
was discovered and shown to drive the rapid Ca2+ uptake into
mitochondria from the cytosol[52]. A rapid and transient increase of
Ca2+ is more efficient for the production of ATP in Mt than a slower
or longer-term uptake. Although several types of experiments were previously
performed using Mt isolated from cells, recent advances in Ca2+
indicators have allowed us to measure intra-mitochondrial and cytosolic calcium
dynamics simultaneously in living cells[53,54]. In particular, a
gene-encoded fluorescent Ca2+ indicator, Pericam, was established as
a powerful Ca2+-sensitive dye to measure Ca2+
concentration change in the organelles of living cells[55]. The rate
of Ca2+ uptake via the uniporter/RaM was estimated to be two orders
of magnitude higher than that of Ca2+ uptake under the same
conditions but via the uniporter alone[56]. Consequently, Ca2+
uptake via RaM may be more effective in activating Ca2+-sensitive
processes in the matrix than Ca2+ uptake via the Ca2+-uniporter.
The next
question we have to consider is whether TRP canonical (TRPC) channels evoke a
transient increase in Ca2+ intracellularly. A fraction of TRPC3
channels are localized to Mt. A significant fraction of Mt Ca2+
uptake that relies on extramitochondrial Ca2+ concentration is
TRPC3-dependent, and the up- and down-regulation of TRPC3 expression in the
cell influences the Mt membrane potential[57]. If TRPC channels are
activated by long-lasting ROS produced by Mt, the role of TRPC channels would
be changed. The accumulated data suggest that TRPC channels are activated by
ROS[58,59]. In these cases, Ca2+-uniporters are involved
in this process, because the Ca2+-uniporter activity is regulated by
mitochondrial membrane potential.
FUNCTION
OF DELAYED PRODUCTION OF ROS BY MITOCHONDRIA
Here, we consider the production of ROS in Mt. Although the molecular
process of this production has already been established[60], we
should note the following fact. When living cells are exposed to UV radiation,
ROS production is long-lasting, generally continuing for more than 24 h, even
though the lifespan of ROS is estimated to be less than several msec[61].
This long-lasting ROS elevation by UV radiation can be explained if ATP
production is continued for a long time after the TCA cycle is triggered by
rapid Ca2+ entry into Mt. Alternatively, long-lasting intracellular
Ca2+ elevation may occur, once a transient Ca2+ activates
a continuous Ca2+ elevation in Mt using Ca2+-uniporters.
At present,
the latter is more likely, because a long-lasting intracellular Ca2+
elevation always requires ATP for activating Ca-ATPase in the plasma membrane
as well as in the ER membrane. This mechanism is referred to as the
sarco(endo)plasmic reticulum calcium ATPase system (SERCA)[62]. The
protein oxidization and lipid peroxidation may support the fact that living
cells are destroyed in the presence of long-lasting Ca2+ elevation[63].
However, to confirm this hypothesis, further experiments should be performed.
In fact, it is not especially important how intracellular ROS/Ca2+
are elevated; the cells can survive if Hsps are produced in proportion to the
number of systems for reducing ROS in living cells. That is, the function of
chaperones is the most desirable for the viability of cells in this context.
When a protein is oxidized, two cysteine residues form a single S-S bond, which
distorts the tertiary structure of the protein[64]. The subsequent
reduction of oxidized proteins cannot recover their structure, and therefore
the chaperoning function by Hsps is required. A large number of chaperoning
functions of Hsps have been proposed[65], but almost all are still
at the hypothesis stage. In the following sections, we will propose a new
hypothesis for the function of Hsps.
INDUCTION
OF Hsps BY Ca2+ AND ROS
RELEASED FROM MITOCHONDRIA
With respect to the relation between Hsps and ROS, Hsps are produced
directly by ROS, and are produced indirectly in response to recognition of the
oxidized state of cysteine residues—i.e., the recognition of S-S bonds—in
proteins by Hsps themselves[66,67]. On the other hand, Ca2+
activates protein synthetic signals[68]. Therefore, it is reasonable
to assume that ROS induce intracellular Ca2+ signaling via the
activation of TRP channels, as described in the previous sections, resulting in
the production of Hsps. Jorquera et al. reported that membrane
depolarization can induce Ca2+-dependent up-regulation of Hsp70 and
HO-1/Hsp32, called Hmox-1, in skeletal muscle cells[69]. This was
quite an important discovery, because all living cells have voltage-dependent
Ca2+ channels and K+ channels. That is, not only muscle
cells but also non-excitable cells can show a transient Ca2+
increase by electrical stimulation or by high K+ treatment. Thus,
all cells have the potential to up-regulate Hsps in a Ca2+-dependent
manner.
What is the
role of Mt in this case? As pointed out by Barret et al, Mt-derived
oxidative stress induces Hsp responses[70], a finding which lends
further support to our hypothesis. Taken together, the results suggest that all
processes of ROS-induced Hsp formation are described time-sequentially from EMW
exposure to Hsp production in the blood, as shown in Figure 5.
When cells in
living tissues are exposed to EMW for a short time, and especially to teraheltz
radiation, ROS are transiently produced both inside and outside of cells[71].
The externally produced ROS transiently open the TRP channels of the cells,
allowing external Ca2+ to enter[6]. On the other hand,
internally produced ROS form S-S bonds in functional proteins, which are easily
recognized by Hsps. The transiently increased Ca2+ in the cytosol
triggers the function of Ca2+-uniporters of Mt, and
intra-mitochondrial Ca2+ increases to produce ATP. Simultaneously,
Complexes I and III in Mt induce the delayed production of ROS, which will also
form additional S-S bonds in the functional proteins[48]. In
proportion to the increase in the number of S-S bonds, the up-regulated Hsps
recognize the oxidized proteins and proceed to repair them or break them down.
The residual Ca2+ in living cells is pumped out by Ca-ATPase in the
cell membrane.
A NOVEL
HYPOTHESIS ON THE ROLES OF Hsps IN LIVING CELLS
Hsps are found not only within cells but also outside cells in the
blood[72-75], which raises the question of the roles of the external
Hsps. Previously, it was thought that Hsps could distinguish between oxidized
and normal proteins, and then repair the damaged proteins with the aid of Ca2+[76].
Because oxidized proteins have more S-S bonds than normal proteins, they also
have more distorted structures and different distribution of negative charges
compared to their normal counterparts[77]. Thus, Hsps can
distinguish oxidized proteins from normal ones with the aid of attached ATP[78].
In other words, Hsps have the ability to recognize all “native” proteins from
others that enter the body from the outside[79].
Because
protein repair is more difficult than mere protein recognition, the “autophagy”
system in cells selectively destroys the damaged proteins among huge numbers of
normal proteins[80]. Hsps acting as repairmen must first loosen the
folded parts of the protein and then return the thread of amino acids to the
original tertiary structure. However, given the ability of Hsps to perform such
repair, we must ask why living cells have an autophagy system for removing
damaged proteins. In answer to this question, we now assume that Hsps play a
role only in recognition, and that the autophagy system in cells removes
damaged proteins and sends orders to the nucleus to synthesize new and flawless
proteins to take their place in the original positions. This “self and
non-self” recognition function of Hsps is perhaps the most valuable
characteristic of the immune system[79]. Recently, the roles of Hsps
in the immune system have been demonstrated in the context of various diseases,
such as chronic inflammatory diseases, autoimmune disorders, and cancer[81].
Our new model for the roles of Hsps in cells is shown in Figure 6.
According to
Kalmar and Greensmith (2009), both Hsp32 and Hsp70 act as redox sensors in
eukaryotic cells by detecting intramolecular S-S bond formation[65].
On the other hand, in the case of the repair of damaged proteins, Hsp90, Hsp70,
Hop (p60), Hip (p48) and p23 must act together on the surface of oxidized
proteins[65]. Here, Hop, Hip and p23 are the cochaperones for the
Hsp90 dynamic heterocomplex[82]. Therefore, it is thought to be
easier for Hsps to recognize oxidized proteins than to repair them.
SUGGESTED
PATHWAYS FROM EMW STIMULATION TO HSP PRODUCTION
Finally, we propose the most probable pathways from EMW stimulation to
Hsp production as follows.
(A) When
animal (or human) bodies are exposed to EMW, ROS including free radicals are
produced in the body in a wavelength-dependent manner: high-energy EMW (cosmic
ray, gamma-ray and X-ray) initially produces hydrated electrons, and then free
radicals and other ROS. Intermediate-energy EMW (UV ray, visible light and NIR
ray) first generates a singlet oxygen in the body, and then the singlet oxygen
is changed to a free radical. The lowest-energy microwave and radiofrequency
waves generate heat in the body, which induces ROS production in the cellular
Mt.
(B) Both heat
and the generated ROS can transiently activate various types of TRP channels
and increase the Ca2+ levels in cells.
(C) The
increased Ca2+ plays a dual role. First, it activates the TCA cycle
in Mt and generates ROS production with ATP. Second, the residual Ca2+
is used as a signal molecule to synthesize new proteins to replace oxidized
(damaged) proteins.
(D) The
increased Ca2+ triggers switches to increase the production of Hsps
and protect against cellular damages.
In the near future, it might be possible to control the production of
Hsps in cells/tissues by carefully exposing them to limited amounts of EMW. For
this purpose, the Raman spectrometer could help to detect the oxidized proteins
(S-S bonds) in cells of the whole body in real time.
CONFLICT OF INTERESTS
The Authors have no conflicts of interest to declare.
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Peer reviewers: Olga
A. Gorobchenko, Department of Molecular and Medical Biophysics, Radio Physics
School, V.N. Karazin Kharkiv National University, 4 Svobody Sq., Kharkiv,
61022, Ukraine; Daniel Fologea, Department of Physics, Boise State University,
1910 University Dr. Boise, ID83725-1570, USA; Vittorio Gentile, Department of
Biochemistry, Biophysics and General Pathology, Second University of Naples,
via Costantinopoli 16, 80138 Napoli, Italy.
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