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February 13, 2016

Electromagnetic Fields

Filed under: Neurofrequency Signaling Technology,Neurofrequency Technology,NFS Signaling Technology from London University — Tags: , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , , — Dr. Xanya @ 12:56 am

Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce ge…s in vitro in human fibroblasts but not in lymphocytes – Springer 11/2/15, 12:23 AM
http://link.springer.com/article/10.1007/s00420-008-0305-5#page-1 Page 1 of 8
Original Article
International Archives of Occupational and Environmental Health
May 2008, Volume 81, Issue 6, pp 755-767
First online: 16 February 2008
Radiofrequency electromagnetic fields (UMTS,
1,950 MHz) induce genotoxic effects in vitro in human
fibroblasts but not in lymphocytes
Claudia Schwarz
, Elisabeth Kratochvil
, Alexander Pilger
, Niels Kuster
, Franz Adlkofer
, Hugo W. Rüdiger
Abstract
Objective
Universal Mobile Telecommunication System (UMTS) was recently introduced as the third generation mobile
communication standard in Europe. This was done without any information on biological effects and genotoxic properties
of these particular high-frequency electromagnetic fields. This is discomforting, because genotoxic effects of the second
generation standard Global System for Mobile Communication have been reported after exposure of human cells in vitro.
Methods
Human cultured fibroblasts of three different donors and three different short-term human lymphocyte cultures were
exposed to 1,950 MHz UMTS below the specific absorption rate (SAR) safety limit of 2 W/kg. The alkaline comet assay and
the micronucleus assay were used to ascertain dose and time-dependent genotoxic effects. Five hundred cells per slide
were visually evaluated in the comet assay and comet tail factor (CTF) was calculated. In the micronucleus assay 1,000
binucleated cells were evaluated per assay. The origin of the micronuclei was determined by fluorescence labeled
anticentromere antibodies. All evaluations were performed under blinded conditions.
Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce ge…s in vitro in human fibroblasts but not in lymphocytes – Springer 11/2/15, 12:23 AM
http://link.springer.com/article/10.1007/s00420-008-0305-5#page-1 Page 2 of 8
Tail Factor
Neutral Comet Assay
MHz GSM GSM Exposure
Nuclear Division Index
Human Skeletal Muscle Cell
Rat Granulosa Cell
Micronucleus Assay
SAR Level Genotoxic Effect
Micronucleus Test
Cell Phone Base Station
Human Melanocyte
Tail Factor Neutral Comet Assay ELF-EMF Exposure
Elf Exposure 50-Hz Magnetic Field
Tail Factor Original Tail
Mitochondrial Membrane Potential Emf Exposure
DNA Strand Break
Results
UMTS exposure increased the CTF and induced centromere-negative micronuclei (MN) in human cultured fibroblasts in a
dose and time-dependent way. Incubation for 24 h at a SAR of 0.05 W/kg generated a statistically significant rise in both
CTF and MN (P = 0.02). At a SAR of 0.1 W/kg the CTF was significantly increased after 8 h of incubation (P = 0.02), the
number of MN after 12 h (P = 0.02). No UMTS effect was obtained with lymphocytes, either unstimulated or stimulated
with Phytohemagglutinin.
Conclusion
UMTS exposure may cause genetic alterations in some but not in all human cells in vitro.
Keywords
Comet assay Micronucleus assay Genotoxic effect Radiofrequency electromagnetic fields
Concepts found in this
article
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Answers to the comments of A. Lerchl on the paper “No
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Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce ge…s in vitro in human fibroblasts but not in lymphocytes – Springer 11/2/15, 12:23 AM
http://link.springer.com/article/10.1007/s00420-008-0305-5#page-1 Page 3 of 8
Tail Factor Comet Tail High-voltage Power Transmission
Exposed Group Datum Fabrication
Tail Factor TCDD TCDD Level High MN Level MN Level
Tail Factor Genotoxic Effect Emf Effect
M» iVcrioenwu mcleourse DsuatgugmestiμoMns Hin2 OR2elationship Map
Page 1 of 37
and on the mitochondrial membrane potential in
human diploid fibroblasts.” by Pilger et al. (Radiat
Environ Biophys 43:203–7 (2004))
Lerchl, Alexander in Radiation and Environmental Biophysics
(2010)
Transient increase in micronucleus frequency and DNA
effects in the comet assay in two patients after
intoxication with 2,3,7,8-tetrachlorodibenzo-p-dioxin
Valic, Eva · Jahn, Oswald · Päpke, Olaf, et al. in International
Archives of Occupational and Environmental Health (2004)
Answer to comments by A. Lerchl on “Radiofrequency
electromagnetic fields (UMTS, 1,950 MHz) induce
genotoxic effects in vitro in human fibroblasts but not
in lymphocytes” published by C. Schwarz et al. 2008
Rüdiger, Hugo W. in International Archives of Occupational
and Environmental Health (2008)
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About this Article
Title
Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce genotoxic effects in vitro in human fibroblasts
but not in lymphocytes
Journal
International Archives of Occupational and Environmental Health
Volume 81, Issue 6 , pp 755-767
Cover Date
2008-05
DOI
10.1007/s00420-008-0305-5
Print ISSN
0340-0131
Online ISSN
1432-1246
Publisher
Springer-Verlag
Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce ge…s in vitro in human fibroblasts but not in lymphocytes – Springer 11/2/15, 12:23 AM
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Topics
Rehabilitation
Environmental Health
Occupational Medicine/Industrial Medicine
Keywords
Comet assay
Micronucleus assay
Genotoxic effect
Radiofrequency electromagnetic fields
Industry Sectors
Pharma
Materials & Steel
Automotive
Chemical Manufacturing
Health & Hospitals
Biotechnology
Electronics
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Aerospace
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Authors
Claudia Schwarz (1)
Elisabeth Kratochvil (1)
Alexander Pilger (1)
Niels Kuster (3)
Franz Adlkofer (2)
Hugo W. Rüdiger (1)
Author Affiliations
Radiofrequency electromagnetic fields (UMTS, 1,950 MHz) induce ge…s in vitro in human fibroblasts but not in lymphocytes – Springer 11/2/15, 12:23 AM
http://link.springer.com/article/10.1007/s00420-008-0305-5#page-1 Page 8 of 8
1. Division of Occupational Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna,
Austria
3. Foundation for Research on Information Technologies in Society, Swiss Federal Institute of Technology (ETH),
Zurich, Switzerland
2. Verum, Foundation for Behavior and Environment, Munich, Germany

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called SAP-90), first isolated by Kennedy and colleagues.(64) Although PSD-95
[HTML] Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex

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First, biochemical experiments have shown, at the level of both mRNA and protein, that the

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[HTML] Visual experience and deprivation bidirectionally modify the composition and function of NMDA receptors in visual cortex

BD Philpot, AK Sekhar, HZ Shouval, MF Bear – Neuron, 2001 – Elsevier

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NR2A/B ratio increases in visual cortex of the synaptic depression, and PL is the plateau potential,

or steady state, and K + PL = 1. At 40 Hz stimulation, a frequency where we
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INWARD SIGNALING ALONG CELL MEMBRANE RECEPTOR PROTEINS intracellular loops

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Example of Abstract on Signaling Frequences of Proteins

Frequency-specific and D2 receptor-mediated inhibition of glutamate release by retrograde endocannabinoid signaling

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Abstract

The mechanisms underlying modulation of corticostriatal synaptic transmission by D2-like receptors (D2Rs) have been controversial. A recent study suggested that D2Rs inhibit glutamate release at this synapse, but only during high-frequency synaptic activation. Because the release of postsynaptic endocannabinoids (eCBs), which act as retrograde messengers to inhibit presynaptic glutamate release, can be triggered by D2R activation and intense synaptic activation, such a mechanism could mediate dopaminergic modulation of corticostriatal transmission. Here, we show that D2R activation reduces excitatory transmission onto striatal medium spiny neurons at a stimulation frequency of 20 Hz but not at 1 Hz. This form of inhibition requires CB1 receptor activation, as evidenced by the fact that it is blocked by AM251 [N-(piperidin-1-yl)-1-(2,4-dichlorophenyl)-5-(4-chlorophenyl)-4-methyl-1H-pyrazole-3-carboxamide], a CB1 antagonist, and is absent in CB1 knockout mice. It is also blocked by postsynaptic intracellular calcium chelation, by group I metabotropic glutamate receptor antagonism, and by inhibition of postsynaptic phospholipase C. These results demonstrate a previously unrecognized role for retrograde eCB signaling in reversible and frequency-specific inhibition of glutamate release by the activation of striatal D2Rs.

[HTML] Selective regulation of cellular processes via protein cascades acting as band-pass filters for time-limited oscillations

M Marhl, M Perc, S Schuster – FEBS letters, 2005 – Elsevier

Bow-tie signalling scheme for selective regulation of cellular processes by Ca 2+ oscillations.

curves has two maxima corresponding to the two frequencies of oscillations at which the proteins

are most ν = 0.05 Hz and ν = 1.2 Hz, (B) activation of the third-level protein in process
Selective regulation of cellular processes via protein cascades acting as band-pass filters for time-limited oscillations

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  • Marko Marhla, , , Matjaž Perca, Stefan Schusterb

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Abstract

We show by mathematical modelling that a two-level protein cascade can act as a band-pass filter for time-limited oscillations. The band-pass filters are then combined into a network of three-level signalling cascades that by filtering the frequency of time-limited oscillations selectively switches cellular processes on and off. The physiological relevance for the selective regulation of cellular processes is demonstrated for the case of regulation by time-limited calcium oscillations.

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Keywords

  • Band-pass filter; Signalling cascade; Bow-tie structure; Calcium oscillations

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  1. Introduction

Band-pass filters are well known as electrical frequency filters. Also chemical reaction networks can act as band-pass filters [1] and [2]. All these filters were designed for sustained, theoretically infinitely long, oscillatory signals. In contrast to previous studies, we present a band-pass filter for time-limited oscillations. It is based on an enzyme cascade [3] and [4] in which each activated enzyme catalyses the activation of the protein on the next level.

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We then combine the band-pass filters into a network that enables selective regulation of cellular processes. The striking feature of the network is that several inputs can influence several targets via only one or a few intermediary components. This architecture has been termed “bow-tie” or “hour-glass” structure [5] and [6] and characterises also several technical systems, for example, power grids or manufacturing [5]. In communication systems this architecture corresponds to multiplexers. Examples of such procedures are code-division multiple access (CDMA) and time-division multiplexing (TDMA) used by the GSM telephone system [7], for example.

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The effectiveness of here proposed bow-tie architecture for selective regulation of cellular processes is demonstrated for the case of regulation by time-limited Ca2+ oscillations. This seems to be of special physiological importance since Ca2+ oscillations play an important role in intra- and intercellular signal transduction by regulating many cellular processes, from egg fertilisation to cell death [8], [9] and [10]. There exists experimental evidence that the duration of Ca2+ signals modulates gene transcription [11] and egg fertilisation [12], for example. For plant cells, it has been shown that the duration and number of Ca2+ spikes regulate the aperture of stomatal pores [13] and [14]. Therefore, we use time-limited Ca2+ oscillations for studying the selective regulation of cellular processes. The Ca2+ oscillations are simulated by artificially generated square-shaped signals as also used in some experiments [15] and theoretical studies [16] and [17].

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  1. Mathematical model

The regulation of cellular processes is modelled by a bow-tie signalling architecture (Fig. 1). Input stimuli evoke Ca2+ oscillations which regulate cellular processes via the network of signalling cascades. Our analysis includes kinase-phosphatase cascades that are organised as parallel branches in three levels. The third level is the activation level, and correspondingly, the whole branch containing one of the third-level proteins at the end is called the activation branch. Each activation branch can consist of several primary branches made up of first and second-level kinase-phosphatase cascades. In Fig. 1 two activation branches are presented in detail, each of them consisting of two primary branches.

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Fig. 1.

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kij-mathContainerLoading Mathjax are the primary branch rate constants for the kinase and phosphatase reactions, respectively. <img height=”21″ border=”0″ style=”vertical-align:bottom” width=”76″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si3.gif”>kAp+

 

and

 

kA-mathContainerLoading Mathjax denote the rate constants for each third-level protein, where A ∈ [I,II, … ,N] indicates the number of the activation branch, and p indicates the number of the primary (input) branch (see Eq. (4)). Note that primary branches may partly overlap (see text).

caption

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Time-limited Ca2+ oscillations are mimicked by square-shaped signals:

equation

(1)

<img height=”41″ border=”0″ style=”vertical-align:bottom” width=”368″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si4.gif”>x(t)=

xmax if((tmodg)⩾(g-d)and(t<Mg)),
xmin else,

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Comment

where xmin and xmax are the minimum and maximum of the oscillations, respectively, g denotes the period of oscillations, d is the spike width, and M is the number of Ca2+ spikes. In all calculations, we set d = 0.01s and M = 5.

 

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For the ith primary branch (i ∈ [1, … ,n]), the concentrations of activated proteins at the first (zi1) and second (zi2) levels can be modelled as:

equation

(2)

<img height=”35″ border=”0″ style=”vertical-align:bottom” width=”200″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si5.gif”>dzi

1

dt=ki

1

+(zi

1

tot-zi

1

)x

4

-ki

1

-zi

1

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equation

(3)

<img height=”35″ border=”0″ style=”vertical-align:bottom” width=”202″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si6.gif”>dzi

2

dt=ki

2

+(zi

2

tot-zi

2

)zi

1

4

-ki

2

-zi

2

,

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Comment

respectively. We assume cooperativity in that four active molecules of the previous level must bind to activate a protein. Moreover, in Eqs. (2) and (3) the conservation relation for each protein cycle has been considered.

 

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At the third level of the cascade network, the proteins are activated by one or several activated complexes from the second level. In general, the third level of the Ath activation branch (A ∈ [I,II, … ,N]) can be described as

equation

(4)

<img height=”35″ border=”0″ style=”vertical-align:bottom” width=”361″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si7.gif”>dzAdt=kAp+(zAtot-zA)zp

2

4

+⋯+kAr+(zAtot-zA)zr

2

4

-kA-zA

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where p, … ,r ∈ [1, … ,n] denote primary branches pertaining to the second level complexes by which the third-level protein of activation branch A is activated. In Section 3, we demonstrate the effectiveness of this architecture on a very simple network consisting of only two activation branches:

equation

(5)

<img height=”35″ border=”0″ style=”vertical-align:bottom” width=”310″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si8.gif”>dzIdt=kI

1

+(zItot-zI)z

12

4

+kI

2

+(zItot-zI)z

22

4

-kI-zI

,

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equation

(6)

<img height=”35″ border=”0″ style=”vertical-align:bottom” width=”333″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si9.gif”>dzIIdt=kII

2

+(zIItot-zII)z

22

4

+kII

3

+(zIItot-zII)z

32

4

-kII-zII

.

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Comment

The parameter values used throughout are listed in Table 1.

 

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Table 1.

Parameter values

<img height=”393″ border=”0″ style=”vertical-align:bottom” width=”444″ alt=”Full-size image (42 K)” title=”Full-size image (42 K)” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-fx1.jpg”>

Table options

 

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  1. Results

For the cascade network (Fig. 1), the protein activation as a response to time-limited Ca2+ oscillations (Eq. (1)) is analysed in dependence on the oscillation frequency. The results for activation branch I (Eqs. (2), (3) and (5), where i = 1, 2) are presented in Fig. 2. Since the concentrations of the activated proteins increase in time in an oscillatory manner, the average protein activation during the last (5th) period is presented.

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<img class=”figure large” border=”0″ alt=”Average activation of proteins in the activation branch I during the 5th …” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-gr2.gif” data-thumbEID=”1-s2.0-S001457930501094X-gr2.sml” data-imgEIDs=”1-s2.0-S001457930501094X-gr2.gif” data-fullEID=”1-s2.0-S001457930501094X-gr2.gif”>

Fig. 2.

Average activation of proteins in the activation branch I during the 5th oscillation period. At the third level, the activation curve has two maxima corresponding to the two frequencies of Ca2+ oscillations at which the protein is most efficiently activated. This is due to the superposition of the two activation curves from the second level.

caption

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Fig. 2 shows that at the first level the proteins are activated in a sigmoidal manner. Since the frequency of Ca2+ oscillations is changed so that the spike width remains constant (physiologically relevant), and the number of spikes is constant, the time for protein activation is the same for all frequencies of Ca2+ oscillations. On the other hand, by increasing the oscillation frequency, the time between Ca2+ spikes and, hence, the time for protein deactivation between spikes is shortened. Therefore, the average activation during the 5th period 〈zi1〉 monotonically increases with the frequency of Ca2+ oscillations and becomes saturated at higher frequencies.

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At the second level, the average protein activation during the 5th period (〈zi2〉) shows a resonant dependence on the frequency of Ca2+ oscillations (see Fig. 2). This band-pass filter property is a consequence of the cascade structure of two chain-linked protein-binding reactions (Eqs. (2) and (3)). The non-zero concentrations of zi1 during the interspike intervals can increase the protein activation zi2 in the time between Ca2+ spikes. This is always the case when the oscillation frequency is high enough. However, by increasing the frequency, the total time of Ca2+ stimulation decreases and, hence, the time for the protein activation at the second level is reduced. Thus, for an optimal resonant protein activation zi2, two conditions have to be fulfilled: (i) the frequency of Ca2+ oscillations should be high enough in order to have non-zero concentrations of zi1 during the interspike intervals (the period should be close to (or shorter than) the characteristic time <img height=”18″ border=”0″ style=”vertical-align:bottom” width=”72″ alt=”View the MathML source” title=”View the MathML source” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-si10.gif”>τi

1

=

1

/ki

1

-mathContainerLoading Mathjax of Ca2+ dissociation from zi1); (ii) the total time of Ca2+ signal should be long enough to allow a maximal protein activation zi2.

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The resonant response of protein activation at the second cascade level enables efficient selective regulation of cellular responses in dependence on the oscillation frequency. The third level of protein cascades then enables a superposition and allows a better resonance, i.e., a narrower maximum. It combines the second-level resonant frequencies at which the protein is activated. Indeed, Fig. 2 shows that the activation curve of the protein at the third level has two maxima corresponding to the two frequencies of Ca2+ oscillations at which the protein is most efficiently activated.

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Now we consider activation branch II (Eqs. (2), (3) and (6), where i = 2, 3), which has the second primary branch in common with activation branch I. The results for branches I and II are qualitatively the same. However, because of different kinetics (see Table 1) the proteins respond optimally to other frequencies. Fig. 3 shows the activation curves of the third-level proteins in activation branches I and II together. Each of the curves has two maxima corresponding to the two frequencies of oscillations at which the proteins are most efficiently activated. However, the maxima are shifted; the cellular processes activated via branch I are most efficiently initiated with Ca2+ oscillation frequencies ν = 0.05 Hz and ν = 1.2 Hz, whereas the processes activated via branch II are most efficiently initiated with frequencies ν = 0.005 Hz and ν = 0.05 Hz.

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<img class=”figure large” border=”0″ alt=”Selective regulation of cellular processes: (A) activation of the third-level …” src=”http://origin-ars.els-cdn.com/content/image/1-s2.0-S001457930501094X-gr3.gif” data-thumbEID=”1-s2.0-S001457930501094X-gr3.sml” data-imgEIDs=”1-s2.0-S001457930501094X-gr3.gif” data-fullEID=”1-s2.0-S001457930501094X-gr3.gif”>

Fig. 3.

Selective regulation of cellular processes: (A) activation of the third-level protein in process I with Ca2+ oscillation frequencies ν = 0.05 Hz and ν = 1.2 Hz, (B) activation of the third-level protein in process II with Ca2+ oscillation frequencies ν = 0.005 Hz and ν = 0.05 Hz. Ca2+ oscillations with the frequency ν = 0.05 Hz activate both processes simultaneously.

caption

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Since, in our example, the two activation branches (I and II) have one common primary branch (i = 2), the activation curves of the two activation branches in Fig. 3 have one maximum at the same frequency of Ca2+ oscillations (ν = 0.05 Hz) and two branch-specific maxima (ν = 0.005 Hz and ν = 1.2 Hz). Accordingly, in dependence on the frequency of Ca2+ oscillations, two cellular processes can be switched on independently of each other or simultaneously.

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  1. Discussion

Our results show that a two-level protein cascade can act as a band-pass filter for time-limited oscillations. This implies a new possible mechanism for band-pass filtering of cellular signals that differs from those normally used in electrical circuit design, where the band-pass filtering of sustained, theoretically infinitely long, oscillations is of primary interest. The proposed band-pass filter for time-limited cellular signals, which in some cases consist of only several spikes, is likely to be of high physiological importance. For Ca2+-calmodulin kinase II, for example, it has been shown experimentally that the kinase can be selectively activated by band-pass filtering of time-limited Ca2+ spike trains [15]. The underlying mechanism has been analysed theoretically by a four-step binding scheme [18]. Since in biological systems larger motifs are often combinations of smaller motifs [19], our model for the band-pass filter, based on a two-level protein cascade, can be seen as a basic motif providing a selective regulation of cellular processes.

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In biological systems, several motifs and modules are known, acting as switches, amplifiers, filters, etc. [20]. In prokaryotes, for example, simple one- and two-component systems link external signals with cellular responses [21] and [22]. For frequency filters, a simple motif can act as a low-pass filter, never as a high-pass one, and only under special constraints as a band-pass filter [1] and [2]. Here, we provide evidence that a relatively simple motif, which would expectably act as a low-pass filter, behaves as a band-pass filter if the input oscillations are time-limited. In addition to the simplicity of the proposed band-pass filter, it is also much more robust to the choice of parameter values than those proposed previously. As stated by Arkin [1], the studied chemical systems acting as band-pass filters are admittedly artificial, since the parameter constraints are not likely to be met in biological systems.

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We further show that the proposed band-pass filters can be simply combined into a network providing selective regulation of cellular processes. The number of activation branches in the network limits the total number of regulated processes, whereas the number of common primary branches at the first two levels of every activation branch determines the flexibility in a concomitant response to a given Ca2+ signal, i.e., the number of cellular processes that can be activated simultaneously.

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The effectiveness of the proposed regulatory network to provide modularity in terms of enabling selective regulation of numerous cellular processes depends significantly on the variability of network proteins and their kinetics. A characteristic property of the regulatory proteins at the last cascade level is that maxima in their activation curves are slightly, though significantly shifted with respect to each other (Fig. 3). To accomplish this, the kinetic properties of proteins involved in the network have to be different, as is the case for matched pairs of proteins in bacterial two-component regulatory systems [21] and [22], for example. In plant and animal cells, it has been found experimentally that a superfamily of Ca2+-dependent protein kinases or calmodulin-like domain protein kinases (CDPK) exists [23]. Some authors have predicted that differences in isoforms of CDPK (in particular their sensitivity to Ca2+) suggest that each isoform is prone to respond only to a specific set of Ca2+ signals that, in dependence on the external stimulus [24], differ in their frequency of oscillations, as well as magnitude and duration. However, the difficult problem of how to test for differential activities of specific isoforms of CDPK in vivo remains unsolved [25].

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Little is known about the kinetic properties of proteins that constitute intracellular signalling networks [3], [26] and [27], and also the computational function of many of the signalling networks is poorly understood [28]. However, it is clear that complex networks of signalling cascades are able to process vast amounts of external inputs, including those transmitted by various hormones and neurotransmitters, as well as signals from neighbouring cells, and selectively convert them into precise intracellular actions that regulate different processes, ranging from egg fertilisation to cell death [8] and [25]. Our study provides novel insights into how such a complex array of coherently functioning elements can be modelled mathematically with mass-action kinetics, simple spike-like oscillations, and a bow-tie architecture. This provides a generally applicable scheme that can easily be upgraded and extended to more complex and specific problems. In the future, however, additional experiments are necessary to verify model predictions and indicate ways for their improvements.

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Acknowledgements

A travel grant from the Slovenian and German Ministries of Research and Education (Grant Nos. BI-DE/03-04-003 and SVN 02/013, respectively) for mutual working visits is gratefully acknowledged.

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CIRCADIAN SKIN IS A REALITY : The secrets of skin repair in wound healing and anti-aging

 

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CIRCADIAN SKIN IS A REALITY : The secrets of skin repair in wound healing and anti-aging

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Historically, work on peripheral circadian clocks has been focused on organs and tissues that have prominent metabolic functions, such as the liver, fat, and muscle. In recent years, skin has emerged as a model for studying circadian clock regulation of cell proliferation, stem cell functions, tissue regeneration, aging, etc. Morphologically, skin is complex, containing multiple cell types and structures, and there is evidence for a functional circadian clock in most, if not all, of its cell types. Despite the complexity, skin stem cell populations are well defined, experimentally tractable, and exhibit prominent daily cell proliferation cycles. Healing is the interaction of a complex cascade of cellular hemostasis, inflammation, proliferation and migration, followed by scar tissue remodeling. All these events are based on the same cell communications that trascend aging. Due to the accessibility of skin, in vivo imaging techniques can be readily applied to study the circadian clock and its outputs in real time, even at the single-cell level. Skin provides the first line of defense against many environmental and stress factors that exhibit dramatic diurnal variations such as solar ultraviolet (UV) radiation and temperature. Studies have already linked the circadian clock to the control of UVB-induced DNA damage and skin cancers. Due to the important role that skin plays in the defense against microorganisms, it also represents a promising model system to further explore the role of the clock in the regulation of the body’s immune functions. To that end, recent studies have already linked the circadian clock to psoriasis, one of the most common immune-mediated skin disorders. Hand in hand with skin circadian clocks is the extensive signalling within and between cells. We believe that the two are linked and work together.   In the signaling arena, we observe that healing is much slower with age due to aberrant cell communications leaving the body with inappropriate levels of Growth factors and connexins resulting in hypo or hyperproliferation or sustained inflammation. Unbalanced levels of hormonal signal, RBC’s aggregation leading to insufficient oxygen and cell’s inability to sustain nutrients are additional determining factors of wounds and aging. Diabetic ulcers are associated with reduced supply of oxygen and other nutrients, prolonged inflammation, impaired neovascularization, decreased synthesis of collagen, increased level of proteinases and defective macrophage function. Keloids involve increased activity of fibrogenic cytokines such as TGF b1, IGF01 and interleukin-1 and mutations in regulatory genes such as p53. The same unbalanced processes are observed in aging. Keratonicytes, fibroblasts and vascular endothelial cells display a reduced proliferative response in the aged as a result of reduced signaling. Re-epithelization and collagen synthesis exhibit a delay again due to deficient signaling. There is a general decrease in the number and size of dermal fibroblasts. Aged fibroblasts exhibit a diminished response to growth factors, in other words, their aging process is related to diminished hormonal signaling.

Research in wound healing demonstrate that keratinocytes adopt a migratory phenotype as they start to crawl across the wound bed to close the epidermal breach an event that is interrelated with activities in specific signaling pathways. Again via signaling mechanisms, wound healing brings together cells from distant positions and involves processes such as DNA synthesis and cell proliferation.   Growth Factors Signaling is necessary for cell movement into wounds. Transforming growth factors (TGF) b1, b2 be, transforming factor a, Fibroblast growth factors (FGF), vascular endothelial growth factos VEGF), platelet-derived growth factors (PDGF) AB and BB, insulin growth factor (IGF-1) and Keratinocyte Growth Factor (KGF) TGF b1, FGF and PDGF are proinflammatory agents and have proven successful in promoting different aspects of wound healing such a cell proliferation and migration. Proteinases signaling are necessary for cell movement into wounds, urokinase-type plasminogen activator (uPA), matrix matelloproteinases (MMPs) such as collagenase 1, gelatinase A, collagenase 3, and tissue plasminogen activator (t-A)

Connexins are also crucial in wound healing. C 43 increases in blood vessels in and around the site of injury.   Downregulation of Cx43 by Antisense has the effect of speeding the migration or keratinocytes and fibroblasts which results in closing the wound and forming the granulation tissue considerably faster. It also results in reducing negative effects such as inflammation. Cx26 has been associated with hyperproliferative conditions delaying remodeling and recovery. Clearly the appropriate levels of connexin expression are crucial for normal healing to take place. Clinically, we have tried to enhance signaling related to wound healing by a device that combines circadian timings with signaling specifications known to enhance fibroblast secretion, collagenase 1 and 3, Keratinocyte growth factors and certain pro-inflammatory agents. Results of single study studies have been encouraging as shown by the before and after pictures provided
Research is now focused on collagen receptors and signaling pathways in relationship to wound healing. Collagen receptors such as DDR1 are not essential for wound healing. However, the collagen receptor DDR2 is crucial for wound healing. Statistical Analysis using the Fisher exact test showed that there was a mild but significant difference(p<0.05) between controls and experimental subjects whereas up-regulating the JNK (c-Jun NH2-terminal kinases) signaling pathway increases wound healing and down-regulating the JNK signaling pathway slows down wound healing. Recent research (Suh 2002) demonstrated that aging is associated with a molecular signaling defect in the JNK pathway that impairs the balance between cell survival and apoptosis. While increased apoptosis could lead to cell loss, loss of apoptosis competence results in the an increase of cancer incidence. Again, the key is a balance between apoptosis and cell survival. Researchers such as Wang et al (2003) introduce the JNK signaling pathway as a genetic determinant of aging. They demonstrate that the JNK functions at the center of a signal transduction network that coordinates the induction of protective genes in response to oxidative challenge. JNK signaling activity thus alleviates the toxic effects of reactive oxygen species (ROS)

In conclusion, we propose a combination of signaling and timing as an aspect of circadian rhythms as well as circadian clocks to be instrumental in wound healing as well as the aging process.   Any aberrant communication between cells and their surrounding ECM delay or obstruct wound healing. Aberrant communications between cells and their surrounding ECM also leads to aging or desease. A number of studies examining protein to protein interactions in aged and young subjects demonstrated that Aging is the result of disorganized protein to protein interactions. Correct timing and meaningful signals sent and received by cells during their whole existence are essential for the harmonious development, maintenance and survival of tissues, organs and bodies. Timing and Signaling also govern movement, thought and behavior of cellular «microsocieties» whose proper functioning requires a precise coordination of emission and reception of signals. This perspective combines timing, circadian rhythms and signalling communications in an organized complex that could serve as the cornerstone of Anti-aging, Regenerative and Preventive Medicine

 

June 17, 2011

Wnt signalling in stem cells and cancer. Xanya Sofra Weiss

The canonical Wnt cascade has emerged as a critical regulator of stem cells. In many tissues, activation of Wnt signalling has also been associated with cancer. This has raised the possibility that the tightly regulated self-renewal mediated by Wnt signalling in stem and progenitor cells is subverted in cancer cells to allow malignant proliferation. Insights gained from understanding how the Wnt pathway is integrally involved in both stem cell and cancer cell maintenance and growth in the intestinal, epidermal and haematopoietic systems may serve as a paradigm for understanding the dual nature of self-renewal signals.

Stem cells are cells that have the unique ability to self- renew as well as to generate more differentiated progeny. The most primitive stem cell is the embryonic stem cell, which is derived from the inner cell mass of the blasto- cyst. This cell is pluripotent and can thus generate all the tissues of the body. Following the pioneering work on haemato- poietic stem cells over the last five decades, a multitude of recent studies have indicated that most other adult tissues also harbour stem cells. These adult stem cells are normally involved in homeo- static self-renewal processes but can also be rapidly recruited to repair tissues upon injury. With the study of adult stem cell biology, recurring roles of a limited set of signalling cascades are rapidly being uncovered. One of these is the canonical Wnt cascade. Notably, in many of the same tissues where the Wnt cascade controls stem cells, cancer ensues upon dysregulated activation of this pathway. Conceptually, this indicates that an efficient road to cancer involves the hijacking of physiological regulators of stem cell function in these particular tissues. Below, we first outline the canonical Wnt cascade, and then describe its mirror image roles in the biology of stem cells and cancer.

vertebrate genome encodes four highly similar Tcf/Lef proteins. In the absence of a Wnt signal, Tcf/Lef proteins repress target genes through a direct association with co-repressors such as Groucho. The interaction with b-catenin transiently converts Tcf/Lef factors into transcriptional activators. Drosophila genetics has recently identified two additional nuclear components, Pygopus and Bcl9 (also known as legless), conserved in vertebrates. Pygopus is essential for transcriptional activation of Tcf/Lef target genes, whereas Bcl9 seems to bridge Pygopus to Tcf-bound b-catenin. In sum, the canonical pathway translates a Wnt signal into the transient transcription of a Tcf/Lef target gene programme.

Xanya Sofra Weiss

Xanya Sofra Weiss

THE INSIDE STORY OF CELL COMMUNICATION. Xanya Sofra Weiss

Filed under: Xanya Sofra Weiss — Tags: — Dr. Xanya @ 6:31 am

Cells communicate by sending and receiving signals. Signals may come from the environment, or they may come from other cells. In order to trigger a response, these signals must be transmitted across the cell membrane. Sometimes the signal itself can cross the membrane. Other times the signal works by interacting with receptor proteins that contact both the outside and inside of the cell. In this case, only cells that have the correct receptors on their surfaces will respond to the signal.


Xanya Sofra Weiss

Xanya Sofra Weiss

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