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Membrane Pump Operation Synchronicity (Criticality) in Epidermal Cells: The Possibility of Quantifying the Level of Synchronization

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The authors analyze the results of atomic emission spectrometry of hair samples for Al, Cd, Fe, Cr, Cu, Li, Pb, V, and Zn in 952 healthy subjects and 952 liquidators of the Chernobyl nuclear power plant accident. Using correlation analysis (Pearson) of the obtained data, the authors have found pair correlations between metal concentration values. According to the authors, criticality or synchronization (as a particular case of the critical state of the system) can be inherent in all ATP-dependent membrane pumps (P-type) controlling metal-ligand homeostasis in epidermal cells. A quantitative criterion (synchronization index) is proposed to measure the level of criticality (synchronization) in the functioning of membrane ATPases.
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INTERNATIONAL JOURNAL OF NEGATIVE RESULTS
ISSN NO: Coming soon
Research
Membrane Pump Operation Synchronicity (Criticality) in Epidermal Cells: The Possibility of
Quantifying the Level of Synchronization
V.I.Petukhov 1,*, Е.V.Dmitriev 2, L.Kh.Baumane 3, A.V.Skalny 4, Yu.N.Lobanova 4, A.R.Grabeklis 4
1 Vladimir State University, Vladimir, Russia
2 Institute of Numerical Mathematics, Russian Academy of Sciences, Moscow, Russia
3 Latvian Institute of Organic Synthesis, Riga, Latvia
4 ANO Centre for Biotic Medicine, Moscow, Russia
Abstract
The authors analyze the results of atomic emission spectrometry of hair samples for Al, Cd, Fe, Cr, Cu,
Li, Pb, V, and Zn in 952 healthy subjects and 952 liquidators of the Chernobyl nuclear power plant accident.
Using correlation analysis (Pearson) of the obtained data, the authors have found pair correlations between
metal concentration values. According to the authors, criticality or synchronization (as a particular case of the
critical state of the system) can be inherent in all ATP-dependent membrane pumps (P-type) controlling
metal-ligand homeostasis in epidermal cells. A quantitative criterion (synchronization index) is proposed to
measure the level of criticality (synchronization) in the functioning of membrane ATPases.
DOI : COMING SOON
Corresponding author: V.I.Petukhov , Vladimir State University, Vladimir, Russia. Email: vip-val@yandex.ru
Keywords: nitric oxide, metal-ligand homeostasis, oxidative/nitrosative stress, self-organized criticality,
epidermis
Received: July 16, 2018 Accep ted: Aug 29, 2018 Published: Sep 01, 2018
Ed itor : Anoja Priyadarshani Attanayake, Senior Lecturer in Biochemistry, Department of Biochemistry,
Faculty of Medicine, University of Ruhuna, Sri Lanka.
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Introduction
For over a decade, the authors have been using
hair samples as a bio-substrate for non-invasive studies
of metal-ligand homeostasis (MLH). Our experience
allows us to make the following preliminary conclusions:
1) Quantitative assessment of the metal content in the
given substrate (hair) is not representative of the
whole body essential metal availability of (save for
extreme forms of metal deficiency or
overabundance) and, therefore, cannot serve as a
reliable diagnostic criterion for latent MLH
disturbances;
2) Having found evidence of critical (synchronous)
nature of the operation of K/Na-ATPase [1]
controlling K/Na-homeostasis in epidermis as well as
other ATPases from the P-type family that control
transmembrane traffic of Cu, Zn, Fe [2], we can
classify MLH in these cells as self-organized criticality
phenomena (SC phenomena);
3) Regulatory control of MLH in epidermal cells occurs
most likely (and mostly) by the natural law of
self-organized criticality [3] whose relevance to
cellular energy exchange seems highly probable
since a living cell is an open dynamic system;
4) Since criticality or synchronization (as a particular
case of the critical state of a system) can be
inherent in all ATP-dependent membrane pumps
(P-type) controlling the MLH of epidermis, it is of
interest to quantify the synchronization (criticality)
of membrane pump operation.
The present article is an attempt to obtain such
an estimate. The proposed approach is based on the
fundamental principles of the self-organized criticality
theory and the modern concept of a three-component
biosystem existing in the cell and consisting of nitric
oxide (NO), free thiols and non-heme iron [4]. Within
the framework of this system, S-nitrosothiols (RS-NO)
and dinitrosyl iron complexes with thiol-containing
ligands (DNICs) are continuously synthesized, both in
mononuclear [(RS)2Fe(NO)2] M-DNICs, and binuclear
form [(RS)2Fe2(NO)4] B-DNICs. In the self-oscillation
mode (by the Belousov-Zhabotinsky reaction), there is
constant inter-transformation of RS-NO and DNICs
whereby the most reactogenic forms of NO are formed:
nitrosonium (NO+) ions and nitroxyl (NO or HNO) which
have a longer lifetime as compared to nitrogen
monoxide. As a result, conditions are created for stable
(long-term) functioning of the short-lived NO molecule
as a universal manager [4].
Nitric oxide (NO) or, more precisely, its active
derivatives (nitrosonium and nitroxyl ions) act as ATPase
activators, due to S-nitrosylation of SH-groups of
cysteine in the protein molecules of these pumps.
Reactive oxygen species (ROS) also have the ability to
redox-modify amino acid residues to form disulfide
bonds.
Activated ATPase molecules on the cell
membrane form a system of weakly interacting
oscillators (in terms of the
self-organized criticality
theory
) which (upon reaching the threshold density)
allows for the possibility of their spontaneous self-
organization - transition to a
critical state
or
synchronization
.
The aforementioned events are evidenced by
some facts as shown below.
Material and Methods
At the Biotic Medicine Centre (Moscow), mineral
composition of hair was analysed by the atomic emission
spectrometry method in 952 healthy subjects (238 males
and 714 females aged 2 to 86) and 952 liquidators of
the consequences of the Chernobyl NPP accident
Moscow residents (213 females and 739 males aged 37
to 82).
Hair samples for spectrometric studies were
obtained upon subjectsvoluntary informed consent to
the tests. A bundle of hair 2 cm long and 0.5 cm thick
was cut off in the occipital region close to the scalp skin.
The procedure for preparing a hair sample for
spectrometric analysis was the same as in our previous
work [2].
Hair metal content was assessed by inductively
coupled plasma mass spectrometry (ICP-MS) with
NexION 300D (Perkin Elmer Inc., Shelton, CT, USA)
using Dynamic Reaction Cell technology removing the
majority of interferences with little or no loss of analyte
sensitivity and equipped with ESI SC-2 DX4 autosampler
(Elemental Scientific INC., Omaha, NE, USA).
We have analyzed the results of atomic emission
spectrometry of hair samples for Al, Cd, Fe, Cr, Cu, Li,
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Pb, V and Zn. A correlation analysis (Pearson) of the
obtained data was conducted with finding of pair
correlations between the concentration values of metals
("each with each") in 36 pairs: Al-Cd, Al-Fe, Al-Cr, Al-Cu,
Al-Li, Al-Pb, Al-V, Al-Zn, Cd-Fe, Cd-Cr, Cd-Cu, Cd-Li,
Cd-Pb, Cd-V, Cd-Zn, Fe-Cr, Fe-Cu, Fe-Li, Fe-Pb, Fe-V, Fe
-Zn, Cr-Cu, Cr-Li, Cr-Pb, Cr-V, Cr-Zn, Cu-Li, Cu-Pb, Cu-V,
Cu-Zn, Li-Pb, Li-V, Li-Zn, Pb-V, Pb-Zn, V-Zn.
The terms used herein require explanation. We
use the terms hairand epidermal cells (epidermocytes)
as synonyms since it is known that hair is derivative of
epidermis. However, the core of the human hair consists
of small, not completely keratinized epithelial cells,
which in the volume usually do not exceed 1/3 of the
hair thickness. This allows you to study the events
occurring in the MLH epidermis, practically on-line.
The trapezium method was used to measure the
area on the graph under the curve of pair correlation
coefficients (
r
). The Matlab software tool was used for
statistical data processing.
Results and Discussion
In our previous studies of MLH in a group of
Chernobyl liquidators [5, 6], we discovered that the
content of such metals as Al, Cd, Fe, Cr, PB, V were
higher, while the content of Cu and Zn were lower than
the norm (Table 1).
It was assumed that these shifts in MLH were
associated with increased production of reactive oxygen
(ROS) and nitrogen (RNS) species, i.e. oxidative/
nitrosative stress in the Chernobyl liquidators.
To verify the above assumption, we performed a
quantitative assessment of the nitric oxide level in the
epidermis (hair) by electron paramagnetic resonance
(EPR) using diethylthiocarbamate (DETC) as a trap for
NO
in vitro
. According to the EPR analysis, the NO level
in the epidermis of the Chernobyl liquidators was
significantly higher than normal [7[.
At the same time, it was found that the absolute
majority of the accident liquidators (88%) showed a
negative and significant K-Zn correlation (in 205 persons
r
K-Zn= -0.62;
p
<0.05; in 634 persons
r
K-Zn=-0.41;
p
<0.05). In 12% of the Chernobyl liquidators (115
persons), it was not detected (
r
= -0.03) [5]. The
distribution of the groups studied with different values of
r
K-Zn was carried out according to the technique
developed by us [8].
The K-Zn correlation was absent (
r
= -0.01) in
253 healthy subjects (26,7%), feebly marked (
r
K-Zn = -
0,22;
p
<0,05) in 523 persons (55,2%) and obviously
marked (
r
K-Zn= -0.43;
p
<0.05) in 171 persons (18.1%)
only.
The analysis of metal homeostasis in epidermal
cells of healthy subjects at the extreme values of
r
K-Zn (-
0.01 and -0.43) has shown that shifts in MLH of healthy
persons with
r
K-Zn = -0.43 were similar to those of the
total group of the Chernobyl liquidators (n=954)
compared with the control group (n=947) [1]. One can
draw a conclusion, (which seems obvious although
requiring verification) about the presence of oxidative/
nitrosative stress of non-radiation nature in healthy
subjects with
r
K-Zn = -0.43 (Table 1).
Similar changes in concentration values of
metals dependent on the value of |
r
|
K
-Zn were also
found in the Chernobyl liquidators [1].
It can be assumed that the negative correlation
ratio K-Zn in the setting of oxidative/nitrosative stress
really reflects the synchronous operation of the
superfamily of membrane ATPases (which is indirectly
suggested by the spectrometry results), the revealed
sensitivity of metals to increased production of ROS/
RNS, which, alongside with the growth of |
r
|
K-
Zn, is
accompanied by notable shifts in intracellular level of
metals, lead us to the unequivocal conclusion that
normal (unfailing) operation of membrane pumps must
take place in the synchronous mode, that is, in the
self-
organized criticality
mode.
In our recent studies, we were able to detect
the signs of a critical period in MLH (due to the presence
of a power-law connection between the concentration
values) for such metals as Na, K, Ca [1], and also Fe, Cu
and Zn [2]. The fractal character of these metal
concentration distribution (not dependent on the size of
the system) can also indicate the belonging of the
homeostasis of these metals to SC phenomena.
According to the results of the correlation
analysis (coefficients
r
of linear paired correlations
without the sign), the graphs were constructed where
r
-values form a curve (Fig.1-4). The area under this
curve, calculated using the trapezium method, was used
as the quantitative criterion for synchronization
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Table 1. The content of metals in epidermal cells of the Chernobyl liquidators and healthy subjects [1]
Metals
Healthy subjects
(
n
= 947), μg/g
Chernobyl liquidators
(
n
= 954), μg/g
Healthy subjects (
n
=947), μg/g
Group I
r
K-Zn = -0.01
(
n
= 253)
Group II
r
K-Zn = -0.43
(
n
= 171)
Al 8.1<8.8<9.5 19.3<20.1<20.9* 4.3<5.2<6.2 10.8<12.3<14.2*
Cd 0.04<0.05<0.06 0.2<0.25<0.3* 0.027<0.03<0.04 0.05<0.06<0.08*
Fe 19.3<21.07<23.1 22.4<23.7<25.07** 15.0<17.8<21.5 20.0<22.5<24.9**
Cr 0.48<0.51<0.54 0.85<0.9<0.92* 0.35<0.39<0.42 0.62<0.72<0.83*
Cu 19.06<20.7<22.3 10.6<10.99<11.4* 18.6<21<23.5 14.3<16<18.2*
Li 0.03<0.04<0.05 0.05<0.06<0.062* 0.02<0.023<0.03 0.046<0.05<0.06*
Pb 1.04<1.1<1.27 1.5<1.8<2.2* 0.68<0.95<1.3 1.1<1.4<1.6**
V(female) 0.058<0.06<0.07 0.10<0.12<0.13* 0.05<0,06<0.07 0.08<0.09<0.11*
V(male) 0.08<0.09<0.1 0.11<0.116<0.12* 0.05<0.06<0.07 0.09<0.11<0.13*
Zn 181.5<185.2<189.3 162.5<165.8<169* 196.0<204.3<213.5 143.2<150.7<158.3*
Note: Since it is impossible to confirm the normal distribution hypothesis, one must abandon the standard
estimation methods and choose the bootstrap-method [11]. Mean values are shown in bold, plain script shows
confidence interval (bootstrap-method); statistical significance of differences is marked with asterisks:
*p< 0.001; **p<0.05.
Fig.1. The coefficients |
r
| for paired correlations (Pearson) among the concentration
values of metals (Al, Cd, Fe, Cr, Cu, Li, Pb, V, Zn) in healthy subjects (n = 952). The
ordinate represents the values of |
r
|; on the abscissa - the pair number with
increasing |
r
|. The area under the curve is the synchronization index (SI = 2.17).
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Fig.2. The coefficients |
r
| pair correlations (Pearson) among the concentration values
of metals (Al, Cd, Fe, Cr, Cu, Li, Pb, V, Zn) in the Chernobyl liquidators (n = 952). The
ordinate represents the values of |
r
|; on the abscissa - the pair number with
increasing |
r
|. The area under the curve is the synchronization index (SI = 6.13).
Fig.3. The coefficients |
r
| (Pearson) among the concentration values of metals (Al,
Cd, Fe, Cr, Cu, Li, Pb, V, Zn) in healthy subjects in the group with
r
K-Zn = -0.01 (n =
76). The ordinate represents the values of |
r
|; on the abscissa - the pair number with
increasing |
r
|. The area under the curve is the synchronization index (SI = 5.18).
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Fig.4. The coefficients |
r
| (Pearson) among the concentration values of metals (Al,
Cd, Fe, Cr, Cu, Li, Pb, V, Zn) in healthy individuals in the group with
r
K-Zn = -0.43
(n = 76). The ordinate represents the values of |
r|
; on the abscissa - the pair
number with increasing |
r
|. The area under the curve is the synchronization index (SI
= 9.17).
Table 2. The content of metals and SI in epidermal cells of the Chernobyl liquidators and healthy subjects
with different level of
r
K-Zn
Metals
Median (Me) (μg/g) Median (Me) in healthy subjects
(μg/g) with different
r
K-Zn
Chernobyl liquidators
(
n
=952)
Healthy subjects
(
n
=952)
r
K-Zn= - 0,43
(
n
=76)
r
K-Zn= -0.01
(n=76)
Al ↑ 17.1 6.05 ↑ 10.3 2.58
Cd ↑ 0.16 0.01 ↑ 0.03 0.01
Fe ↑ 18.4 17,5 ↑ 18.4 9.6
Cr ↑ 0.77 0.35 ↑ 0.62 0.28
Cu ↓ 9.9 15.8 ↓ 12.1 14.2
Li ↑ 0.03 0.02 ↑ 0.05 0.01
Pb ↑ 0.81 0.51 ↑ 1.15 0.22
V ↑ 0.08 0.05 ↑ 0.08 0.03
Zn ↓ 167.9 210.5 ↓ 137.1 190.6
SI
(synchronization index)
6.13
2.17
9.17
5.18
Note: Arrows indicate changes in intracellular metal content (↑ - an increase, - a decrease).
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(criticality) - the synchronization index (SI).
As shown in the figures - in groups with n = 952
(Figure 1-2), the area under the curve of |
r
| or the
synchronization index (SI) for the Chernobyl liquidators
was almost twice that of healthy subjects (9.17
vs
5.18).
In healthy subjects with n = 76 and different
values of
r
K-Zn (Fig.3-4), the SI value in healthy
individuals with
r
K-Zn = -0.43 is also almost 2 times
higher than in the group with
r
K-Zn = -0.01. The total
sum of values of the coefficient |
r
| (without the sign)
depended on the sample size: it was larger with smaller
sample sizes. Apparently, the explanation of this fact
should be sought in the stochastic character of pair
correlations (these can be more easily detected with a
decrease in the sample size).
It is significant that the increment of SI was
independent of the sample size - it was almost the same
for groups with n = 952 (Figure 1-2) and with n = 76
(Fig.3-4): 3.96 and 3.99
resp.
At the same time, the
increase of SI among the Chernobyl liquidators in
comparison with the norm and in healthy subjects with
negative K-Zn correlation (
r
K-Zn = -0.43) was
accompanied by coincident shifts in the magnitude and
direction of the MLH: an increase in the level of Al, Cd,
Fe, Cr, Li, Pb, V, and a decrease in Cu and Zn in
epidermal cells (Table 2).
In our opinion, these changes in MLH should be
explained by the synchronous functioning of ATPase
(P-type), which are responsible for the transmembrane
traffic of these metals [9, 10]. At the same time, the
increased production of nitric oxide in the liquidators of
the accident in the same substrate (hair), which we
previously showed by increasing the NO signal on the
EPR spectrogram [7], led to an increase in the
synchronization level (SI). Similar dynamics was
observed in the healthy group (n = 76) with different
values of
r
K-Zn (see Table 2). As already mentioned, we
do not exclude the presence of oxidative/nitrosative
stress) of non-radiation origin in healthy subjects with r K
-Zn = -0.43.
The sequence of events occurring in the
epidermis, which lead to a synchronous (critical) mode
of operation of membrane ATPases, may be as follows:
Generation of NO+ and HNO by self-oscillating
RS-NODNICs systems in a larger volume (Chernobyl
liquidators and healthy subjects with
r
K-Zn = -0.43)
induces to reach the threshold density of activated
ATPases of cell membrane. In a system of weakly
interacting oscillators, which is the ATPase system, this
inevitably leads to self-organization of the system or to a
critical (synchronous) mode of operation. One of the
criteria for the critical state of the system is the value of
the so-called branching parameter σ, equal to the
average number of the nearest neighbors to which each
of the oscillators transmits an exciting pulse. In the
critical state, σ is equal to 1 (σ=1). Along with the
critical, subcritical (σ <1) and supercritical (σ > 1)
states (or self-organization regimes) are distinguished.
In our opinion, the following questions would be
of utmost interest in further research into this problem.
Is the role of the RS-NODNICs system with respect to
membrane pumps restricted to uninterrupted production
of ATPase activators (NO+ and HNO) in the cell, and
how does the oscillatory character of the functioning of
the RS-NODNICs system affect the operation of
membrane pumps? There are no explicit answers to
these questions yet, which encourages further research
in the given field.
Conclusion
In conclusion, it should be noted that the main
points of the self-organized criticality theory, as our
experience shows, help explain some complex and
understudied processes in the MLH of epidermal cells.
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... The results of similar studies of MLH for such metals as Al, Cd, Pb, V, Li, Cr, are presented in this paper. Third, the degree of synchronization (criticality) in the functioning of membrane ATPases (P-type) can be measured using the so-called synchronization index (SI), which is equal to the area under the curve of numerical values of pair correlations (Pearson) between metals (without taking into account the sign) [11]. ...
... The values of SI noticeably differed in these categories of healthy individuals: in the subgroup with a distinct negative K-Zn bond (r = -0.43; p <0.05), the SI was 9.17; and in its absence (r =-0.01), the SI was only 5.18 [11]. ...
... Atomic emission spectrometry of hair was performed at the according to the previously proposed technique [11], and the linear correlation coefficient (Pearson) between the content of K and Zn in the hair (r K-Zn ) was found. ...
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Article
Quantitative assay of nitric oxide (NO) and iron (Fe) was carried out by the electron paramagnetic resonance (EPR) method in epidermal derivative (hair) of 45 liquidators of the Chernobyl accident, 30 employees of radiological institutions having contact with radiation, and 50 students of Vladimir State University, most of which were diagnosed with iron deficiency, namely iron deficiency anemia (4 persons) and latent iron deficiency (34 persons). Measurements were performed on a Radiopan EPR-spectrometer. It was found that the method of quantitative EPR-spectroscopy using diethyldithiocarbamate as a trap in vitro could be successfully used to measure NO-radical activity in such a biological substrate as hair. It was found that the intensity of NO-radical signal in the spectrogram depends on the Fe level (not only in the analyzed substrate, but also in the whole organism).
Electrogenic metals in epidermis: relationship with cell bioenergetics
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Petukhov V.I., Dmitriev E.V., Baumane L.Kh., Skalny A.V., and Lobanova Yu.N. (2016) Electrogenic metals in epidermis: relationship with cell bioenergetics. Insights in Biomed., 1(2): 9-14
Dinitrosyl iron complexes with thiol-containing ligands as a "working forms" of endogenous nitric oxide
  • A F Vanin
Vanin A.F. (2016) Dinitrosyl iron complexes with thiol-containing ligands as a "working forms" of endogenous nitric oxide. Nitric Oxide Biol. Chem.,