![Theoretical mechanism of LED red light photobiomodulation. 1 Light has optimal tissue penetration when its wavelength is within the “optical window,” (600–1070 nm). Red light (620–750 nm) takes advantage of this penetration window [15]. 2 LED-RL stimulates the photo-acceptor copper complex in cytochrome C oxidase, stimulating the photodissociation of nitric oxide (NO), leading to upregulation of the electron transport chain [15, 16]. 3 This stimulation of the electron transport leads to the following intramitochondrial changes: increased generation of ATP and reactive oxygen species (ROS), increased intramitochondrial calcium concentration, and an increase in the mitochondrial membrane potential [16]. 4 TGF-Betas are secreted associated with latency-associated peptide (LAP). These associated latency peptides determine the activity TGF-Beta subtypes [17]. Reactive oxygen species have been shown to trigger a conformational change in LAP, thus freeing TGF-Beta 1 from its latency peptide [17–20]. It has been suggested that activation of TGF-Beta 3 may function by a similar ROS-induced release of LAP [20]. 5 TGF-B1, upon being released from its latency complex, binds to the TGF-Beta receptor II (TGF-BRII) stimulating activation [21]. TGF-B3 inhibits activation of the TGF-BRII and antagonizes TGF-B1 signaling [21]. 6 TGF-BRII then forms a heteromeric complex with TGF-BRI, causing the phosphorylation of specific serine residues [21, 22]. 7 When activated, the intracytoplasmic domain of the TGF-Beta receptor complex phosphorylates SMAD proteins. Once phosphorylated, pSMAD2/3 has the ability to migrate to the nucleus and associates with DNA-binding partners to cause changes in target gene expression [22]. SMAD7 activation functions as a negative feedback loop, inhibiting TGF-B1 signaling [23]. 8 SMAD signaling alters COL1A1 gene expression leading to changes in extracellular collagen deposition and changes in fibroblast proliferation [24]. In addition, SMAD signaling contributes to the collagen deposition and pathogenesis of skin fibrosis [25]. These pathways, and related pathways such as Akt, are believed to contribute to skin fibrosis through modulation of fibroblast proliferation and migration speed [26]. 9 TGF-B1 has been shown to increase cell proliferation at low levels; however, high levels of TGF-B1 inhibits dermal fibroblast proliferation, supporting the idea that modulation of levels of TGF-B1 may contribute to LED-RL’s modulation of proliferation [27]. In addition, the release of TGF-B1 or TGF-B3 from their LAP has been suggested as a possible mechanism behind the photobiomodulation of LED-RL [20]. Figure legend: ψm, mitochondrial membrane potential; [Ca]m, intramitochondrial calcium concentration; ATP, adenosine triphosphate; ROS, reactive oxygen species; LAP/LTBP, latency-associate peptide/latent transforming growth factor beta binding protein; TGF-B1, transforming growth factor beta-1; TGF-B3, transforming growth factor beta-3; BR2, transforming growth factor receptor II; BR1, transforming growth factor receptor I; miRNA, microRNA](https://www.researchgate.net/publication/301343375/figure/fig3/AS:963429703639047@1606710949087/Theoretical-mechanism-of-LED-red-light-photobiomodulation-1-Light-has-optimal-tissue_Q320.jpg)
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LASER THERAPY (J JAGDEO, SECTION EDITOR)
Visible Red Light Emitting Diode Photobiomodulation for Skin
Fibrosis: Key Molecular Pathways
Andrew Mamalis
1,2
&Daniel Siegel
3
&Jared Jagdeo
1,2,3
Published online: 16 April 2016
#The Author(s) 2016. This article is published with open access at Springerlink.com
Abstract Skin fibrosis, also known as skin scarring, is an
important global health problem that affects an estimated
100 million persons per year worldwide. Current therapies
are associated with significant side effects and even with com-
bination therapy, progression, and recurrence is common. Our
goal is to review the available published data available on
light-emitting diode-generated (LED) red light phototherapy
for treatment of skin fibrosis. A search of the published liter-
ature from 1 January 2000 to present on the effects of visible
red light on skin fibrosis, and related pathways was performed
in January 2016. A search of PubMed and EMBASE was
completed using specific keywords and MeSH terms.
BFibrosis^OR Bskin fibrosis^OR Bcollagen^was combined
with (Blight emitting diode,^BLED,^Blaser,^or Bred light^).
The articles that were original research studies investigating
the use of visible red light to treat skin fibrosis or related
pathways were selected for inclusion. Our systematic search
returned a total of 1376 articles. Duplicate articles were re-
moved resulting in 1189 unique articles, and 133 non-English
articles were excluded. From these articles, we identified six
articles related to LED effects on skin fibrosis and dermal
fibroblasts. We augmented our discussion with additional
in vitro data on related pathways. LED phototherapy is an
emerging therapeutic modality for treatment of skin fibrosis.
There is a growing body of evidence demonstrating that vis-
ible LED light, especially in the red spectrum, is capable of
modulating key cellular characteristic associated with skin
fibrosis. We anticipate that as the understanding of LED-
RL’s biochemical mechanisms and clinical effects continue
to advance, additional therapeutic targets in related pathways
may emerge. We believe that the use of LED-RL, in combi-
nation with existing and new therapies, has the potential to
alter the current treatment paradigm of skin fibrosis. There is a
current lack of clinical trials investigating the efficacy of LED-
RL to treat skin fibrosis. Randomized clinical trials are needed
to demonstrate visible red light’s clinical efficacy on different
types of skin fibrosis.
Keywords Skin fibrosis .LED .Visible lig ht .Red light .
Fibroblast .Low level light therapy .Photobiomodulation .
Reactive oxygen species .Collagen
Introduction
Skin fibrosis, also known as skin scarring, is a significant
international health problem with an estimated incidence of
greater than 100 million persons affected per annum world-
wide [1,2]. Skin fibrosis is the key clinical characteristic of
several diseases including systemic sclerosis, morphea, ke-
loids, hypertrophic scars, chronic graft versus host disease,
and gadolinium-induced nephrogenic systemic fibrosis. Skin
fibrosis often results from chronic tissue injury, infection, in-
flammation, or immune response leading to fibroblast activa-
tion. The hallmarks of skin fibrosis are increased fibroblast
proliferation, increased collagen production, increased extra-
cellular matrix (ECM) deposition, and upregulation of pro-
fibrotic signaling pathways (Fig. 1). Despite the morbidity
This article is part of the Topical Collection on Laser Therapy
*Jared Jagdeo
jrjagdeo@gmail.com
1
Department of Dermatology, University of California at Davis,
Sacramento, CA, USA
2
Dermatology Service, Sacramento VA Medical Center, Mather, CA,
USA
3
Department of Dermatology, SUNY Downstate, Brooklyn, NY, USA
Curr Derm Rep (2016) 5:121–128
DOI 10.1007/s13671-016-0141-x
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
122 Curr Derm Rep (2016) 5:121–128
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
and socioeconomic burdens associated with skin fibrosis,
there are limited effective therapeutic options for skin fibrosis.
Current therapies are associated with significant side effects
and even with combination therapy, progression, and recur-
rence often occurs [3,4].
Ultraviolet (UV) phototherapy is a non-invasive modality
that has been used to treat several diseases associated with
skin fibrosis including morphea, systemic sclerosis, chronic
graft versus host disease, and nephrogenic systemic fibrosis
[5–7]. However, UV phototherapy causes thymidine dimer
DNA damage that is associated with an increased incidence
of skin cancers and premature photoaging [8–10]. In addition
to these safety concerns, UV phototherapy units are often
prohibitively expensive for home use and require fluorescent
or incandescent bulbs that limit portability. Therefore, UV
phototherapy requires frequent office visits that patients often
find burdensome [11,12]. In contrast, light-emitting diode-
generated red light (LED-RL) phototherapy is a safe, non-
invasive, inexpensive, and portable treatment that may be
combined with existing treatment modalities. Furthermore,
the visible red light spectrum has superior depth of penetra-
tion, when compared to UV light, that allows it to penetrate
the epidermis and reach the dermis to affect fibroblast function
[13]. LED-RL is not known to cause thymidine dimer DNA
damage or to be associated with an increased incidence of skin
cancer [14]. However, the underlying biochemical mecha-
nisms and clinical effects of visible light photobiomodulation
of skin fibrosis are not well characterized.
The purpose of this review is to review the available evi-
dence on LED-RL phototherapy for the treatment of skin fi-
brosis, witha special emphasis on the key molecular pathways
involved. Herein, we also highlight several strengths and lim-
itations of visible red light phototherapy and suggest enhance-
ments and futuredirections to evaluate their clinical utility. We
anticipate that as the understanding of LED-RL’sbiochemical
mechanisms and clinical effects continue to advance, addi-
tional therapeutic targets in related pathways may emerge.
We believe that the use of LED-RL, in combination with
existing and new therapies, has the potential to alter the cur-
rent treatment paradigm of skin fibrosis.
Methods
A search of the published literature from 1 January 2000 to
present on the effects of visible red light on skin fibrosis and
related pathways was performed in January 2016. A search of
PubMed and EMBASE was done using specific keywords
and MeSH terms. BFibrosis^OR Bskin fibrosis^was com-
bined with (Blight emitting diode,^BLED,^Blaser,^or Bred
light^). The articles that were original research studies that
investigated the use of visible red light to treat skin fibrosis
or related pathways were selected for inclusion. Non-English
articles were excluded.
Results
A schematic of our search strategy is outlined in Fig. 2.Our
systematic search returned a total of 1376 articles. Duplicate
articles were removed resulting in 1189 unique articles, and
Fig. 1 a Normal fibroblast function. Fibroblasts are the primary resident
cell in the dermis and are the major contributor to skin fibrosis.
Fibroblasts typically proliferate and produce collagen at a basal rate to
maintain dermal integrity. bAbnormal fibroblast function increases
proliferation and collagen production leading to skin fibrosis.
Fibroblasts contributing to skin fibrosis have an increased proliferation
rate and an increased collagen production and deposition rate. These
cellular alterations are the hallmark of skin fibrosis, and thus are targets
of therapeutic interest. cLight-emitting diode-generated red light (LED-
RL) reduces fibroblast proliferation and collagen production. LED-RL
alters fibroblast function leading to decreased collagen production and
fibroblast proliferation. If LED-RL is capable of returning fibroblast ac-
tivity to basal levels, LED-RL may be a therapeutic option for the pre-
vention or treatment of skin fibrosis
Fig. 2 Schematic of the search
strategy listing the number of
articles matching inclusion or
exclusion criteria
Curr Derm Rep (2016) 5:121–128 123
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
133 non-English articles were excluded. From these articles,
we identified six articles related to LED effects on skin fibro-
sis and dermal fibroblasts. We augmented our discussion with
additional in vitro data on related pathways.
Discussion
Molecular Mechanism of Red Light Photobiomodulation
Although visible light makes up 44 % of the total solar energy
in our environment, its effect on cellular function and physiol-
ogy are not fully established [14]. There is emerging in vitro
mechanistic data demonstrating red light may be an effective
treatment for skin fibrosis; however, there is a paucity of evi-
dence for red light’s clinical effects. Visible light may represent
a safer therapeutic modality compared to UV light as it does
not generate DNA damage associated with skin cancer [14].
A potential mechanistic pathway demonstrating the cellular
effects of red light photobiomodulation in skin fibrosis is
diagrammed in Fig. 3. Key downstream targets for the modu-
lation of skin fibrosis include reducing cellular fibroblast pro-
liferation and migration speed, inhibiting pro-fibrotic cyto-
kines and their related pathways such as the transforming growth
factor-beta (TGF-beta) pathway, and decreasing synthesis and
deposition of collagen.
Mitochondrial Signaling
The molecular mechanism behind LED-RL’s
photobiomodulatory effects appearstoinitiateinthemitochon-
dria [28,29]. Red light stimulates the copper/heme-iron centers
on cytochrome C oxidase (CCO), an intramitochondrial com-
ponent of the electron transport chain (Fig. 3)[15,16]. CCO is a
protein complex containing two copper and heme-iron groups
that play a key role in the electron transport within the mito-
chondrial. LED-RL photostimulation of CCO directly influ-
ences reactive oxygen species (ROS) and adenosine triphos-
phate (ATP) production and results in increased ROS and
ATP lev e ls (Fi g . 3).
Red light has also been shown to modulate a number of
other mitochondrial functions, including increased
intramitochondrial calcium concentration, and alterations in
mitochondrial membrane potential, which may also play a role
in mediating downstream effects (Fig. 3)[16]. Furthermore,
while there is substantial data demonstrating the effects of
redox mechanisms on cellular health and function, there is a
paucity of data on how specific mitochondrial measures, such
as calcium concentration, might lead to downstream cellular
effects. The absence of precise mechanistic links between
these other mitochondrial alterations has led many researchers
to focus on studying the downstream cellular effects of
LED-RL and investigating the role of visible light-
associated alterations in ROS levels.
ROS-Related Intracellular Signaling and Transcriptional
Changes
For instance, altering ROS levels can release TGF-beta 1 and
TGF-beta 3 from their associated latency binding proteins
(Fig. 3). The interaction of these cytokines with their associ-
ated receptors is critical in the pathogenesis or prevention of
skin fibrosis. Altering the levels of TGF-beta 1 versus TGF-
Beta 3 bound to the TGF-beta receptor complex modulates the
pro-fibrotic cascade that leads to downstream activation of
key signaling molecules called SMADs and numerous growth
factors that ultimately result in fibroblast proliferation and
collagen biosynthesis [17,18,21,22].
It is believed that visible light-associated increases in ROS
levels within the cell trigger redox-sensitive transcription
factors such as AP-1, NF-kB, p53, and hypoxia inducible
factor 1 (HIF-1) [30]. Cellular redox changes also modulate
insulin-like growth factors (IGFs), Akt/PKB, and
phosphoinositide 3-kinase (PI3K) pathways, and activate
mammalian target of rapamycin (mTOR) [31]. ROS-initiated
alterations in these pathways often contribute to the
downstream effects on transcription, cellular proliferation,
migration speed, and extracellular matrix production. This
suggests that ROS may be the mechanistic link between
the mitochondrial effects of LED-RL and the resulting
downstream transcriptional and cellular effects.
In additional to these canonical transcriptional alterations,
some researchers believe that alterations in microRNA levels
also play a role in LED-RL photobiomodulation (Fig. 3).
However, there is currently a paucity of data investigating
the specific effects of LED-RL on microRNA levels.
Interestingly, research has demonstrated that laser-generated
visible red light leads to specific alterations in microRNA that
are associated with skin fibrosis, including microRNA-7a, 21,
29, 133b, and 192 [31,32]. Further research is warranted to
investigate the role these microRNA play in causing LED-RL-
associated downstream cellular effects.
Effects of Red Light on Cellular Functions Related
to Fibrosis
Cellular Proliferation
Modulation of mitochondrial, intracellular, and nuclear pro-
cesses ultimately alter downstream cellular processes involved
in skin fibroblast proliferation. For instance, fibroblast prolifera-
tion is a key contributor to the initiation and maintenance of
skin fibrosis, and control of fibroblast proliferation is a critical
therapeutic strategy for addressing skin fibrosis [33]. Our
124 Curr Derm Rep (2016) 5:121–128
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
group has found that LED-RL is capable of inhibiting fibro-
blast proliferation in a dose-dependent manner [34].
Furthermore, red light does not appear to affect fibroblast
viability, with no increases in apoptosis or necrosis observed
[34,35••]. This suggests that visible red light is likely modu-
lating fibroblast function through means other than direct
cellular cytotoxicity, such as through modulation of the cell
cycle or autophagy.
It is likely that these alterations in proliferation are a result
of alterations in the redox state of fibroblasts treated with
LED-RL. While mild elevations in free radicals have been
shown to increase proliferation, we have found that the
Fig. 3 Theoretical mechanism of LED red light photobiomodulation. 1
Light has optimal tissue penetration when its wavelength is within the
Boptical window,^(600–1070 nm). Red light (620–750 nm) takes
advantage of this penetration window [15]. 2LED-RL stimulates the
photo-acceptor copper complex in cytochrome C oxidase, stimulating
the photodissociation of nitric oxide (NO), leading to upregulation of
the electron transport chain [15,16]. 3This stimulation of the electron
transport leads to the following intramitochondrial changes: increased
generation of ATP and reactive oxygen species (ROS), increased
intramitochondrial calcium concentration, and an increase in the
mitochondrial membrane potential [16]. 4TGF-Betas are secreted asso-
ciated with latency-associated peptide (LAP). These associated latency
peptides determine the activity TGF-Beta subtypes [17]. Reactive oxygen
species have been shown to trigger a conformational change in LAP, thus
freeing TGF-Beta 1 from its latency peptide [17–20]. It has been
suggested that activation of TGF-Beta 3 may function by a similar
ROS-induced release of LAP [20]. 5TGF-B1, upon being released from
its latency complex, binds to the TGF-Beta receptor II (TGF-BRII)
stimulating activation [21]. TGF-B3 inhibits activation of the TGF-BRII
and antagonizes TGF-B1 signaling [21]. 6TGF-BRII then forms a
heteromeric complex with TGF-BRI, causing the phosphorylation of
specific serine residues [21,22]. 7When activated, the intracytoplasmic
domain of the TGF-Beta receptor complex phosphorylates SMAD
proteins. Once phosphorylated, pSMAD2/3 has the ability to migrate to
the nucleus and associates with DNA-binding partners to cause changes
in target gene expression [22]. SMAD7 activation functions as a negative
feedback loop, inhibiting TGF-B1 signaling [23]. 8SMAD signaling
alters COL1A1 gene expression leading to changes in extracellular col-
lagen deposition and changes in fibroblast proliferation [24]. In addition,
SMAD signaling contributes to the collagen deposition and pathogenesis
of skin fibrosis [25]. These pathways, and related pathways such as Akt,
are believed to contribute to skin fibrosis through modulation offibroblast
proliferation and migration speed [26]. 9TGF-B1 has been shown to
increase cell proliferation at low levels; however, high levels of
TGF-B1 inhibits dermal fibroblast proliferation, supporting the idea that
modulation of levels of TGF-B1 may contribute to LED-RL’s modulation
of proliferation [27]. In addition, the release of TGF-B1 or TGF-B3 from
their LAP has been suggested as a possible mechanism behind the
photobiomodulation of LED-RL [20]. Figure legend: ψm, mitochondrial
membrane potential; [Ca]m,intramitochondrial calcium concentration;
ATP, adenosine triphosphate; ROS, reactive oxygen species; LAP/LTBP,
latency-associate peptide/latent transforming growth factor beta binding
protein; TGF-B1, transforming growth factor beta-1; TGF-B3,
transforming growth factor beta-3; BR2, transforming growth factor
receptor II; BR1, transforming growth factor receptor I; miRNA,
microRNA
Curr Derm Rep (2016) 5:121–128 125
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
dose-dependent decreases in fibroblast proliferation are
associated with a dose-dependent sustained increase in
ROS [35••,36]. Therefore, it is likely that the sustained
alterations in the redox state of fibroblasts treated with
LED-RL and the subsequent redox-initiated alterations
in the TGF-beta pathway and related pathways are con-
tributing to the dose-dependent decrease in fibroblast
proliferation.
Cellular Migration
Furthermore, some believe that cellular migration speed may
play a role in the recruitment of fibroblasts to sites of increased
collagen production [3,4]. This finding is supported by the
fact that fibroblasts derived from skin affected by skin fibrosis
demonstrate increased motility when compared to fibroblasts
derived from normal healthy skin [37,38]. Few studies have
sought to address this potential therapeutic avenue and so the
clinical effect of decreasing fibroblast motility is still unclear.
Researchers have demonstrated that the PI3K/Akt and
MAPK/ERK pathways play crucial roles in the regulation of
fibroblast migration, and that visible light is capable of direct-
ly activating or inhibiting the phosphorylation state of these
key cell signaling molecules [32,39–44]. Our group recently
found that LED-RL increased ROS levels and decreased fi-
broblast migration speed in a dose-dependent manner (Fig. 3)
[35••]. Additionally, we found that LED-RL also altered
phospho-Akt levels (unpublished data by Jagdeo Lab).
Furthermore, migration speed returned to control levels when
ROS increases were blocked by the pretreatment of fibroblasts
with the antioxidant resveratrol or when cells were pretreated
with the PI3K/Akt inhibitor LY294002 [35••]. This suggests
that LED-RL’s effects on migration may be largely mediated
by increased ROS that lead to modulation of phospho-Akt
levels and subsequent alterations in fibroblast migration
speed. Further research is needed to investigate the role cellu-
lar migration speed plays in the pathogenesis of skin fibrosis
and the clinical effects of therapeutically targeting fibroblast
motility.
Collagen Production
Fundamentally, the pathogenesis of all forms of skin fibrosis
involves an increased deposition of skin collagen [33].
Therefore, suppression of collagen production is a fundamen-
tal component of any effective anti-fibrotic therapy [33].
Several studies support that visible red light is capable of
modulating collagen production in vitro. Our group has dem-
onstrated that LED-RL is capable of suppressing collagen
production in human skin fibroblast cultures. In this study,
fibroblasts were treated with LED-RL, and then collagen
was measured using the collagen stain, picrosirius red (unpub-
lished data by Jagdeo Lab). LED-RL resulted in decreased
collagen production in a dose-dependent manner (Fig. 3).
Furthermore, procollagen 1A1 levels were found to be de-
creased following LED-RL treatment, suggesting that this de-
crease in collagen levels may be due in large part to decreases
in collagen subunits.
Another study investigated the effect of visible red light
generated by a diode laser on murine NIH/3T3 fibroblasts
[45]. They found that red light treatment inhibited TGF-beta
induced fibroblast to myofibroblast differentiation and de-
creased collagen 1 expression. Furthermore, they found that
red light was capable of upregulating matrix metalloprotein-
ases (MMP)-2 and MMP-9, while downregulating tissue in-
hibitor of metalloproteinase (TIMP)-1 and TIMP-2 [45]. This
suggests that red light may not only decrease collagen produc-
tion, but may also change overall extracellular matrix remod-
eling profile. Further studies are needed evaluating the effects
of red light phototherapy on in vivo collagen content and
homeostasis; however, these early in vitro findings are
promising.
Limitations and Future Directions
However, red light phototherapy does possess several limita-
tions. First, the current understanding of the biochemical
mechanisms underlying visible light photobiomodulation is
limited. More laboratory research is needed to characterize
the key pathways involved in initiating the downstream cellu-
lar effects observed. Another limitation of the field of visible
light phototherapy is that many in vitro studies are done on
cultured skin fibroblasts. Fibroblast monocultures do not
completely recapitulate the complex fibroblast phenotype or
the extracellular milieu that contributes to skin fibrosis pathol-
ogy. Thus, randomized clinical trials are needed to demon-
strate visible red light’seffectonskinfibrosis.
Perhaps, one of the most critical challenges facing visible
light phototherapy is the selection of appropriate dosimetry.
Visible light does not have sufficient measures for evaluating
the pharmacokinetics of light or its effect on in vivo tissue.
Therefore, many dosing protocols are based upon observed
effects. However, the fluence delivered depends on the dura-
tion of treatment, the power density of the light source, and the
distance of the source from its target tissue. Differing any one
variable can at times lead to different photobiomodulatory
effects. For instance, while red light at fluences above 320 J/
cm2 inhibit fibroblast proliferation, red light at fluences below
50 J/cm2 often promote fibroblast proliferation. Therefore,
establishing standardized dosing ranges and thresholds for
future basic science and clinical research studies may improve
the comparability of different clinical studies.
We believe the use of commercially available LEDs as a
visible light source is an exciting avenue of future research.
LED-RL devices are safe, economic, and portable, and we
126 Curr Derm Rep (2016) 5:121–128
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
believe are the optimal devices for future research and clinical
use of visible red light.
Conclusions
Visible light phototherapy is an emerging therapeutic modal-
ity for treatment of skin fibrosis. There is a growing body of
evidence demonstrating that visible red light is capable of
modulating key cellular characteristic associated with skin
fibrosis. We believe that further laboratory research may elu-
cidate the underlying mechanisms and effects involved in vis-
ible light photobiomodulation. LED-based devices are the op-
timal devices for red visible light phototherapy. There is a
current lack of clinical trials investigating the efficacy of
LED-RL to treat skin fibrosis. Randomized clinical trials are
needed to demonstrate visible red light’sclinicalefficacyon
different types of skin fibrosis.
Acknowledgments This study was funded by the National Center for
Advancing Translational Sciences, National Institutes of Health, through
grant number UL1 TR000002 and linked awards TL1 TR000133 and
KL2 TR000134.
Compliance with Ethical Standards
Conflict of Interest The authors declare that they have no conflict of
interest.
Human and Animal Rights and Informed Consent This article does
not contain any studies with human or animal subjects performed by any
of the authors.
Disclaimer The contents herein do not represent the views of the US
Department of Veterans Affairs or the US Government. The content is
solely the responsibility of the authors and does not necessarily represent
the official views of the National Institutes of Health.
Open Access This article is distributed under the terms of the Creative
Commons Attribution 4.0 International License (http://
creativecommons.org/licenses/by/4.0/), which permits unrestricted use,
distribution, and reproduction in any medium, provided you give appro-
priate credit to the original author(s) and the source, provide a link to the
Creative Commons license, and indicate if changes were made.
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