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Regulation of People Skin Pigmentation


In the body, your skin is the most significant organ, with it being truly a complicated epithelial and mesenchymal tissue. It contains an epidermis which is multilayered as well as buildings such as sebaceous and sweating glands, hair follicles, a dermis comprising elastic and collagen fibres. There is also a coating of subcutaneous extra fat. There's been a finding of over 1000 disease entities involved with your skin such as eczema, psoriasis, melanoma and urticaria. Around 15% of your human being adult's total body weight is accounted for by your skin with a surface area of approximately 2m2. The skin contains three layers; the epidermis, the dermis and the hypodermis.

The outer coating of the skin is recognized as the epidermis, which really is a stratified squamous epithelium, where 95% of its skin cells are keratinocytes. The rest of the cells in the epidermis are the melanocytes, merkel and langerhans skin cells. The role of the skin is to provide a defence hurdle against environments of inhospitable nature. The epidermis can be divided into four layers, to be able from outer layer to deepest level; stratum corneum (the cornified coating), stratum lucidum (the clear/translucent layer), stratum granulosum (the granular part), stratum spinosum (the spinous covering) and the stratum basale (the basal layer).

There is an individual part of keratinocytes in the basal covering, where daughter skin cells can be made by these to terminal differentiation via proliferation, leading to the formation of the cornified part, which may take around 40 days and nights, however this is shorter in various diseases, such psoriasis. About ten levels of corneocytes that are flattened make up the cornified part.

From the neural crest, dendritic cells can be derived which are known as melanocytes, that are also within the basal level. Melanosomes, that happen to be subcellular organelles, transportation melanin, that are synthesised by melanocytes, to the neighbouring basal keratinocytes. To be able to prevent harm to the nuclei of the basal keratinocytes from ultraviolet radiation, a 'melanin cap' is made by the melanosomes. Melanosome size and number, as well as melanin's aspect determine skin coloring or pigmentation. Langerhans skin cells are derived from the bone marrow and are antigen presenting dendritic cells founds in the epidermis. Sensory information is transmitted from your skin to the sensory nerves by merkel cells found in the epidermis.

The dermis is the coating under the epidermis, and it's thickness depends upon the region of your body. For example, on the eyelid, the dermis is thin, whilst the dermis is thick on someone's back. The dermis contains two layers; the papillary dermis and the reticular dermis. The papillary dermis is in contact with the basement membrane zone, which gives adhesion between your epidermis and dermis, where epidermis blistering may appear due to defects. Arteries as well as sensory nerve endings are richly supplied to the papillary dermis. The reticular dermis is in contact with the hypodermis which is the main component of the dermis.

Interstitial components, such as elastic and collagen fibres, and cellular components, such as fibroblasts and plasma and mast skin cells, are what constitute the structure of the dermis. Collagen makes up about around 70% of the dermis' dried up weight, where types I and III are predominant. The predominant cell type, however, is fibroblasts in the dermis, which derive from the mesenchyme.

The hypodermis is the deepest layer of the skin comprising lipocytes. The function of the hypodermis is to hook up your skin to the bone and muscle, thus supplying the bone with nerves and blood vessels. The arrangement of the is in excessive fat lobules, where the fibrous septae separates one from another. The connection between your dermis and the hypodermis is strengthened by fibre bundles actually from the dermis. Around 80% of the entire body fat is available within the hypodermis in those people who aren't obese.

As very briefly mentioned recently, melanocytes function would depend upon for pigmentation. These cells from melanoblasts during embryological development. Each basal melanocyte is connected functionally to the dermal fibroblasts as well regarding the basal keratinocytes. These three cell types interact and talk to each other to be able to regulate the skin's phenotype and function through the secreted factors and receptors in addition to cell to cell contact.

Stem cell keratinocytes and basal melanocytes has a slow-moving proliferation rate in normal circumstances, however the higher basal keratinocytes have a much swift proliferation rate, which holds them into the skin's surface alongside the ingested melanin thus forming a barrier. Which means skin's shade is not personified by only the melanin within melanocytes, but also in a conjunction with pigment within the superficial layers of the skin.

Currently, pigmentation may be controlled in a direct or indirect fashion by over 125 different genes, with this amount potentially increasing 150-200 in under another 100 years. Out of these genes, the one's whose function is recognized, many of them affect functions that are involved in development that happen to be critical for melanoblasts. Some genes regulate melanocytes' differentiation and survival whilst others control processes impacting on pigmentation. Melanosomes functions or biogenesis is damaged by more than 25 of the genes. Some critical enzymes involved in the control of pigmentation include tyrosinase, tyrosinase related necessary protein 1 (TRP-1) and DCT (DOPAchrometautomerase). If these enzymes are mutated, melanins which can be synthesis could be afflicted in terms of these volume and quality. Some critical structural proteins required for the melanosomes to mature structurally include Pmel17 and MART1. Mutations in proteins that are involved in the sorting of melanosome protein can effect inherited disorders of hypopigmentary aspect.

This critical appraisal will look at in further detail different types of pigmentation, constitutive and facultative, and exactly how they are governed, including the roles of MC-1R, cyclic AMP (cAMP) pathway Agouti Signalling Health proteins, MITF and ultraviolet radiation. Also protected in this piece of work is CRH's and -endorphin's functions in rules of human skin area pigmentation.


Within the melanosomes, melanins are synthesises via the previously mentioned enzymes. The response which restricts the melanogenesis' rate becomes catalysed by tyrosinase, as is tyrosinase's hydroxylation leading to 3, 4-dihydroxyphenylalanine (DOPA), along with DOPA oxidising into DOPAquinone. The oxidation of 5, 6-dihydroxyindole-2-carboxylic acid (DHICA) take place in mice credited to TRP-1, however this same activity doesn't happen in humans. DOPAchrome is isomerised into DHICA by DCT. In human being, there is certainly productions of two types of melanin, eumelanin which is dark-colored or darkish and pheomelanin which is yellowish or red. Tyrosinase is vital for the synthesis of both types of melanin, whilst TRP1 and DCT more for the synthesis of eumelanin.

With respect to epidermis pigmentation, there are two types; Constitutive pigmentation and Facultative pigmentation.

Regulation of Constitutive Pigmentation

Depending upon the racial and ethnic background of the individual, the colour of human pores and skin can vary from extremely light to extremely dark. Several major chaperones, melanin, oxyhaemoglobin and deoxyhaemoglobin and carotenoids determine the color of human skin area.

In 1954, the first observation was made with respect to the pigmentary system of your skin by Szabo when an immunohistochemical approach was used to check tyrosinase's enzymatic activity via staining of tissue, where Caucasian epidermis was examined initially accompanied by other colors of epidermis. Along with many other studies as well as Szabo's it was shown that in several human skin types possessed similar melanocytes densities as well as circulation in similar body areas. They also found that there is less melanin content in lighter pores and skin, with melanosomes that are pigmented terribly being clustered above the nuclei within keratinocytes. There may be more melanin within darker skin area, with the syndication of melanosomes that are pigmented seriously being individual in keratinocytes alternatively than clustered, which heightens light absorption.

The denseness of melanocytes differs in distinct parts of the body. For example, the skin on a person's palms or soles is lighter compared to others areas of the body. Environmental factors can affect the density of constitutive melanocytes in your skin, including ultraviolet radiation (UVR), where in fact the thickness can be increase by 3 or 4 4 times of the norm. Another environmental factor that can improve the density are poisons, for example hydroquinone, resulting in the devastation of melanocytes. In increase of reduced melanocyte densities, pigmentary disorders that are inherited can end result, for example freckles or vitiligo respectively.

Due to Bcl2's high expression, epidermal keratinocytes are tolerant to apoptosis as they have a poor proliferation rate in normal circumstances. It has been shown that the hands and feet dermis have a high level of Dickkopf-1 (DKK1) secretion which in turn causes the Wnt/-catenin signalling pathway to become inhibited via the suppression of the expansion function of melanocytes, thus inhibiting the melanogenic pathway. This can have results on some transcriptional regulators, for example microphthalmia transcription factor (MITF), for some downstream melanogenic protein. Epidermal Keratinocytes also become damaged by DKK1 as melanin uptake is reduced, producing a skin phenotype which is a lot wider with less pigmentation.

Melanocortin 1 Receptor (MC-1R), which is domain name receptor of seven transmembranes which binds to pro-opiomelanocortin peptides due to it being in conjunction with ±s G-protein, is a major epidermis pigment phenotype determinant. It regulated the quality and quantity of melanin creation. Two agonists regulate MC-1R function, which are ± melanocyte stimulating hormone (±-MSH) and adrenocorticotropic hormone (ACTH). An antagonist called Agouti signalling necessary protein (ASP) also regulates MC-1R function. When ±-MSH or ACTH activate MC-1R, melanogenic cascade expression is stimulated, leading to excitement of eumelanin synthesis. This can be reversed by ASP, resulting in stimulation of pheomelanin production. MC-1R gene appearance can be upregulated by ±-MSH and ACTH, which respond in a good responses loop.


Melanogenesis can be defined as the biosynthetic pathway of melanin in living skin cells, which is a intricate process with multiple steps that involves substrates, specific enzymes mentioned previously and various cofactors commencing with phenylalanine and/or tyrosinase resulting in melanin deposition on the melanosome's protein matrix. The understanding of melanogenesis was greatly increased in the 1950's onwards by Fitzpatrick et al.

During the cycle of hair regrowth in Agouti mice, melanogensis regulation occurs quantitatively as well as qualitatively. Pheomelanins are produced rather than eumelanins in the anagen period, a move incurred by the melanocytes in the hair roots, causing a yellow band on top of a brown track record. The regulation of this switch involves extension and agouti loci products that encode MC-1R and ASP respectively. Whenever a ligand binds to MC-1R it triggers, resulting in activation of adenylyl cyclase by the ±s G-protein, causing an increase in the intracellular cAMP significantly. When the extension locus incurs any mutations, the MC-1R reception will become non functional, therefore adenylate cyclase will stay inactive in ±-MSH presence, meaning mice will have a yellowish coat shade. The MC-1R receptor is destined by ASP, which results in the ±-MSH effects being antagonised, which include the adenylate cyclase activation triggered by the ±-MSH.

There is lots of evidence which shows that ±-MSH, ACTH and cAMP have key functions in pores and skin pigmentation rules in humans. For example, ±-MSH hypersecretrion has been reported to cause epidermis hyperpigmentation. Patients with severe fatness and locks pigmentation which is red have been shown to own pro opiomelanocortin gene mutations.

In individuals melanocytes that contain been cultured, dendricity and melanogenesis are upregulated by the pro opiomelanocortin peptides. Pharmalogical cAMP can also imitate these effects. All of this clearly suggests that ±-MSH, ACTH and cAMP have a vital role in melanogenesis regulation.

Role of cAMP

It is advised that cAMP has a pivotal role in melanogenic enzymes activity / expression regulation. This is because the enzyme activity of melanogenesis is diminished much more than TRP-1 and DCT. The melanogenic effects of the expert opiomelanocortin peptides seem to be to be mediated via the cAMP pathway upregulation through the activation of MC-1R as well as adenylate cyclase.

Within the cell, cAMP binds to protein kinase A (PKA), allowing activation of the catalytic subunit. PKA phosphorylates its substrates, then translocating to the nucleus, phosphorylating cAMP responsive element binding protein (CREB) transcription factors family. Specific genes have their appearance triggered by this family of proteins, which includes consensus cAMP reactive aspect (CRE) sequences of their promoters. CREB-binding proteins is also phosphorylated by PKA, where PKA reliant gene expression is required in order for the connections with the family of CREB protein.

MITF, which really is a helix loop helix transcription factor has been proven to be encoded by the mi locus. That is due to mice that have the mi mutation have a coating colour which is diluted, have white places, or complete pigmentation loss. They can likewise have a microphthalmic phenotype triggered by ocular development flaws. Within melanocytes, mast cells, pigment cells in the retina and osteoclasts, MITF has been found to be indicated. Also, the lack of melanocytes seems to be the cause of the defective pigmentation in mi mice. It's been set up that in the development and success of melanocytes, MITF takes on a key role, which is established by the cloning of the MITF homologue within humans. Patients who have type II Waardenburg syndrome have been known to have mutations in MITF present, where there is faulty pigmentation in your skin, hair and sight, as well as reading alterations.

It was shown by Bertolotto et al that there surely is some kind of connection between the cAMP pathway with MITF. In normal melanocytes and B16 melanoma cells, MITF manifestation was shown to be increased by cAMP. Tyrosinase manifestation stimulation that is induced by cAMP requires MITF as shown with a MITF absent the transactivation domain name by a prominent negative mutation.

PKA becomes activated by cAMP. PKA then continues on to phosphorylate and stimulate CREB. CREB binds to CRE after it is turned on. The CRE is in the microphthalmia promoter, which upregulates its transcription. Microphthalmia manifestation is therefore increased, which brings about amplified binding of microphthalmia to the M box motif within the tyrosinase promoter. Tyrosinase appearance is increased, as is the upregulation of the synthesis of melanin.

Agouti Signalling Protein

In cultured real human melanocytes, eumelanin synthesis and the activity of tyrosinase is inhibited by ASP. TRP-1 and the manifestation of tyrosinase is also reduced by ASP. Because of tyrosinase's slightest inhibition of activity as well as to the near lack of the appearance of TRP-1 and DCT, ASP decreases eumelanin synthesis. It has been discovered that genes were downregulated by ASP founds in tyrosinase and DCT, as well as upregulated genes which have some connection with a basic helix loop helix transcription factor (ITF2). This shows that ITF2 may have a role in melanogenesis rules, particularly in the previously mentioned move of eumelanin to pheomelanin.

Regulation of Facultative Pigmentation

Physiological regulation that triggers an increase in skin color can be defined as facultative epidermis pigmentation. There are several factors that controlled facultative skin coloring, including ultraviolet (UV) which is also called the tanning reaction which occurs in seafood as well as humans. The skin's respond to UV radiation is kinetically intricate triggering tanning of your skin over a period of several weeks.

The ramifications of UVR can be split into acute and chronic effects. The acute effects include erythema (sunburn), tanning and immunosuppression. The skin's noticeable pigmentation is added to by UV leading to erythema of the skin itself. You can find three different periods of tanning, two which occur swiftly, immediate and consistent tanning, and one which takes time in order for it to build up, delayed tanning. Immunosuppression can bring about a decreased amount and function of antigen delivering langerhans skin cells, as well morphological changes.

The chronic effects of UVR include photoaging and photocarcinogenesis. In photoaging, wrinkles and freckles commence to appear on the skin, where there's a leather type appearance. Photocarcinogenesis can be caused due to the indirect damage of DNA by reactive oxygen species generation.

There are three types of UVR:

  • UVA - which is 320 - 400nm long. It's the longest influx from all the types of UVR and can permeate deeply into the dermis.
  • UBV - is 280 - 320nm long. It can penetrate the skin and is 100 fold more energetic and mutagenic.
  • UVC - is 200 - 280nm long but does not reach the surface of Earth.

The reaction of immediate tanning may appear almost instantaneously, within a few minutes after being exposed to UV, where it still persists several hours later. Continual tanning is a separate second stage of the tanning effect whereupon it occurs within a few hours after exposure to UV, with it still being consistent several times later. Melanin and/or melanogenic precursors oxidation and polymerisation is thought to be behind both immediate and persistent tanning. The replies of both these kinds of tanning are greater to UVA than to UVB. Immediate tanning has a shade of grey to dark-colored whilst persistent tanning shows up brown. It's been shown that one week after exposure to UV, you can find very little production of more melanin.

Reported in 1986 was that immediate tanning can be educed by UVA in epidermal bed linens. Honigsmann's results recommended that existing melanin or melanin precursors chemical substance oxidation is reflected upon by immediate tanning alternatively than pigment granules physiological movements. Reactive oxygen kinds are able to cause the oxidation of tyrosine as well as DOPA to melanin which occurs in immediate tanning. Also, pigmentation's UVA induction is dependent after melanin which is soluble and there are two different kinds of melanin absorption which are involved in UVA photoxidation.

Delayed Tanning

The result of delayed tanning has a developmental time greater than several days. Pores and skin tanning seems to peak seven days after being exposed to UV, and tanning appears to diminish for another ten weeks, but doesn't return to the constitutive level after that time. Within the same time frame, Asian skin area pigmentation increase is relatively small. Therefore there is a higher level of hyperplasia in skin area which has smaller degrees of constitutive pigment, playing somewhat of an protective role in the reaction to UV than did the increased pigmentation the skin types that are lighter. Skin pigmentation increase over a long term triggered by UV are scheduled to lots of physiological facts being governed by UV, affecting the growth and differentiation of melanocytes. Pigmentation is also stimulated by DNA harm induced by UV exposure.

The degrees of eumelanin and pheomelanin slowly and gradually increase along after being exposed to UV on human skin. This implies that by UV, they are not regulated separately. In a variety of ethnic origins skin area pigmentation, there are around two fold distinctions in melanin's chemical substance content and the melanosomes distribution and size of the particle are important to the obvious colour of skin area. In comparison with skin area which is guarded to pores and skin which is continually radiated with UV, there is only significantly less than a two-fold increase again. All of this shows that apart from the quantity of melanin, other factors are necessary for skin area pigmentation.

An increase in their appearance of ±-MSH and ACTH is a reply by epidermal keratinocytes and melanocytes to UV vulnerability. This MC-1R's function and manifestation to become upregulated, increasing the response of melanocytes to melanocortins. The weakly functioning MC-1R variants can be positioned in people with reasonable pores and skin with red hair who have more pheomelanin with an failure to get a tan. The manifestation of Endothelin-1 by keratinocytes is enhanced by UV, thus enhancing MC-1R's expression also, but endothelin-1 works via its receptor on the melanocytes. The secretion of interleukin-1 by keratinocytes is also brought on by UV, stimulating endothelin-1, ±-MSH and ACTH secretion by keratinocytes. In keratinocytes, p53's excitement by the contact with UV triggers increased POMC gene expression resulting in a rise in ±-MSH secretion as well as MC-1R function activation in the neighbouring melanocytes.

-endorphin/-opiate receptor

It was reported for the first time by Kauser et al that -endorphin and the -opiate receptor system is expressed in epidermal melanocytes, they're associated closely with melanosomes, and that in melanocyte biology legislation, this system is active because of its pigmentation, dendricity and proliferation upregulating ability. In the epidermal melanocytes and keratinocytes, the existence of both aforementioned ligand and receptor provides system for both autocrine and paracrine mechanisms for the regulation of melanocyte behaviour. -endorphin and -lipotropic levels are increased being exposed to UVR, further recommending that -endorphin has a role in epidermal melanocytes. Kauser et al also demonstrated that -endorphin that has been supplied exogenously can cause a rise in melanogenesis and proliferation in epidermal melanocyte ethnicities. -endorphin also offers an association with melanosomes recommending that melanogenesis might be regulated locally in the secretory granule.

Corticotropin Releasing Hormone

It has been established that Corticotropin Releasing Hormone (CRH) does have some kind of role in pigmentation. MC-1R action as well as the -opiate receptor moderates melanocytes behaviour in hair follicles where there is complete manifestation of the pro opiomelanocortin system within the pigmentary product. The manifestation of CRH is low differs melanogenic zones, whilst there exists differentiated syndication of melanocytes in the same area. CRH Receptor 1 seems to be more important in follicular melanocytes for the arousal of melanogenesis, proliferation and dendricity. However, the role of CRH is skin area pigmentation is not 100% full proven, and is an area that definitely required further research in order to get some clarification.


As people grow older, pigmentation is constantly on the increase until adolescence or adulthood. Once they've come to this aspect, pigmented lesions often start to seem, and the locks starts to turn gray. It was found in 1979 that the quantity of melanocytes was decreased by about 10% with each ten years the age went up by. This is verified by two other researches, where one was completed on darker pores and skin also. Another study compared very reasonable pores and skin with Caucasian skin, discovering that melanocyte density was greatly improved following continuous exposure to sunshine in the darker pores and skin, however langerhans cell densities were reduced in the same time framework in both epidermis types after exposure to UV. . It had been suggested by Stierner et al that being exposed to UV may have some role in the development of melanoma in both revealed and protected skin area, as well to be exposed to aberrant UV profoundly can be a lot more hazardous than normal vulnerability, which includes since been confirmed by various other studies.

Disruption of Regulation

From time to time, different kinds of pigmentary disorders may appear due to disruption of the standard regulation of pores and skin pigmentation. Tyrosine function rules lays importance on intracellular pH as catalytic functions are afflicted by the intramelanosomal pH as well as melanosomal protein delivery needing the sorting pathway to really have the right pH gradient. It is also considered that pigment production is regulating in some part by intracellular pH in several types of epidermis depending after the racial or cultural origin.

Every solo form of albinism is caused by tyrosine dysfunction or other styles of melanogenic proteins, which can cause skin area pigmentation to be blemished. Another pigmentary disorder is Hermansky - Pudlak syndrome. This disorder have pleiotropic medical effects.

Pigmentary disorders that are brought on by the acquiring of melanin involve your skin becoming lighter or darker. Skin area colour which reduced is normally caused from epidermal melanin content declining. The skin may become darker scheduled to an exceptionally large numbers of melanin being produced credited to there being truly a an enhanced quantity of melanocytes, however it may also be due to melanin syndication becoming irregular.


To summarise, in several skin shades and racial backgrounds, the density of melanocytes is near identical. The number and distribution of melanin is basically dependent after for constitutive epidermis pigmentation. Less DNA harm occurs to melanocytes within darker epidermis than those within lighter skin. The experience of melanogenesis increases in darker skin in a far more effective manner than in lighter skin area.

The dedication of constitutive epidermis pigmentation is attained by:

  • Melanoblasts migration during development
  • Melanoblasts differentiation and success to melanocytes
  • Melanocyte density
  • Melanosomal enzymes and their structural components appearance and function
  • Eumelanin and pheomelanin synthesis
  • Melanosome move to the dendrites
  • Melanosomes being moved into keratinocytes
  • Melanin syndication in the skin's suprabasal layers.

MITF appears to respond to UV really quickly, with a response after 1 to 2 2 days and nights. Some melanosomal protein reply slower, such as tyrosinase, TRP-1 and DCT, with a reply being elicited after about a week, where 3 weeks later a rise in the synthesis in melanin can be viewed, whereas melanocyte density is increased around 4 to 5 weeks.

Cyclic AMP causes the complex induction of intracellular operations which seem to be interconnected. The sub-pathway where PKA is activated, MITF is upregulated as is some of the enzymes involved in melanogenesis, causes melanogenesis stimulation. A cAMP turned on pathway, through ERK activation inducing the degradation and phosphorylation of MITF, regulated melanogenesis negatively, where PKA is impartial upon.

The skin's melanin syndication plays a key role in pigmentation that is seen. After around a week, the prevailing pigments migration towards the epidermal surface is increased, after which recently synthesis melanin restores the balance in the syndication of pigment around 4 to 5 weeks later. It is also apparent that when the syndication in this content of melanin goes through small changes, it can bring about major changes in noticeable pigmentation, impacting constitutive pigmentation as well as facultative pigmentation or the responses to exposure to UV.

After studying the literature to carry out this critical appraisal, it is obvious a large number of studies have opposing and conflicting results as well as conclusions which might be incoherent, where the same group of writers may diverge from something which they have previously stated. That is most probably credited to plenty of variants when conducting these kinds of in vivo and in situ physiological studies. These variants most definitely include:

  • UV source types
  • How much dose amount and frequency that is applied
  • The sites which have been uncovered and their locations
  • The time which is assessed after exposure to UV
  • The background of the themes, and if they have been exposed to the same / higher levels of UV conducted in the experiments previously
  • The capacity of an individual DNA repairing
  • Very notably, the racial and / or ethnic source of the subject matter.

There are numerous areas which require clarification in field, that happen to be definite area of potential future research. For instance; Is melanocyte function affected eumelanin against pheomelanin development? As facultative pigmentation is increased, will there be further protection against damage induced by UV? Does DNA repair have a role in lowering the skin's long-term damage?

Also, photocarcinogenesis understanding must be enhanced, a few of the variables that are critical to it, plus some strategies on how to lessen its dangers. Research into which pathways take part in melanogenesis induced by UV and MSH still appears to be under way. Any innovations could help in breakthrough of new potential means of treating certain pigmentary disorders.

The regulating mechanisms in the synthesis on melanin aren't understood as evidently as required, where it's been speculate that research into this might lead to topical melanogens finding that can cause the development of melanin when UV irradiation is absent, which in turn causes photo aging as well as some skin cancers.

Further studies are essential about the pigmentary role of -endorphin, which seems to be the forgotten melanocortin in relation to pigmentation. In the same way, the role of CRH in pigmentation must also be increased further. Additionally it is shown that some human hormones are likely involved in rules of pigmentation including some oestrogens and androgens, which are areas that could used for even more research to increase our understanding.

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