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Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5.... more
Oculocutaneous albinism (OCA) 6 is a non‐syndromic type of OCA that has distinct ocular symptoms and variable cutaneous hypopigmentation. The causative gene of OCA6 is SLC24A5, which encodes NCKX5, a K+‐dependent Na+/Ca2+ exchanger 5. NCKX5 is involved in the maturation of melanosomes, but its function is still unclear. In this study, we characterized a Japanese patient with OCA6. Genetic analysis revealed compound heterozygous variants in SLC24A5, c.590 + 1dupG, and c.598G>A (p.G200R). To clarify the functional significance of the missense variant, we generated a knock‐in (KI) mouse model carrying the mouse homolog of the G200R variant using the CRISPR/Cas9 system. Chemical analysis showed decreased amounts of eumelanin in the hair and skin of KI mice, while levels of benzothiazine units in pheomelanin were significantly increased in their hair. Retinal pigment was also decreased in KI mice. Notably, a histopathologic study revealed a significant pigment loss in the retinal pigment epithelium (RPE) but not in the choroid. Immunohistochemically, the expression of NCKX5 in the RPE was decreased but was maintained in the choroid of KI mice. These findings could explain the difference in phenotypic severity between eye symptoms and hypopigmentation in the skin/hair.
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Understanding the mechanisms responsible for phenotypic diversification within and among species ultimately rests with linking naturally occurring mutations to functionally and ecologically significant traits. Colour polymorphisms are of... more
Understanding the mechanisms responsible for phenotypic diversification within and among species ultimately rests with linking naturally occurring mutations to functionally and ecologically significant traits. Colour polymorphisms are of great interest in this context because discrete colour patterns within a population are often controlled by just a few genes in a common environment. We investigated how and why phenotypic diversity arose and persists in the <i>Zosterops borbonicus</i> white-eye of Reunion (Mascarene archipelago), a colour polymorphic songbird in which all highland populations contain individuals belonging to either a brown or a grey plumage morph. Using extensive phenotypic and genomic data, we demonstrate that this melanin-based colour polymorphism is controlled by a single locus on chromosome 1 with two large-effect alleles, which was not previously described as affecting hair or feather colour. Differences between colour morphs appear to rely upon complex <i>cis</i>-regulatory variation that either prevents the synthesis of pheomelanin in grey feathers, or increases its production in brown ones. We used coalescent analyses to show that, from a 'brown' ancestral population, the dominant 'grey' allele spread quickly once it arose from a new mutation. Since colour morphs are always found in mixture, this implies that the selected allele does not go to fixation, but instead reaches an intermediate frequency, as would be expected under balancing selection.
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Understanding the mechanisms responsible for phenotypic diversification within and among species ultimately rests with linking naturally occurring mutations to functionally and ecologically significant traits. Colour polymorphisms are of... more
Understanding the mechanisms responsible for phenotypic diversification within and among species ultimately rests with linking naturally occurring mutations to functionally and ecologically significant traits. Colour polymorphisms are of great interest in this context because discrete colour patterns within a population are often controlled by just a few genes in a common environment. We investigated how and why phenotypic diversity arose and persists in the <i>Zosterops borbonicus</i> white-eye of Reunion (Mascarene archipelago), a colour polymorphic songbird in which all highland populations contain individuals belonging to either a brown or a grey plumage morph. Using extensive phenotypic and genomic data, we demonstrate that this melanin-based colour polymorphism is controlled by a single locus on chromosome 1 with two large-effect alleles, which was not previously described as affecting hair or feather colour. Differences between colour morphs appear to rely upon complex <i>cis</i>-regulatory variation that either prevents the synthesis of pheomelanin in grey feathers, or increases its production in brown ones. We used coalescent analyses to show that, from a 'brown' ancestral population, the dominant 'grey' allele spread quickly once it arose from a new mutation. Since colour morphs are always found in mixture, this implies that the selected allele does not go to fixation, but instead reaches an intermediate frequency, as would be expected under balancing selection.
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Pigment-producing melanocytes overcome frequent oxidative stress in their physiological role of protecting the skin against the deleterious effects of solar UV irradiation. This is accomplished by the activity of several endogenous... more
Pigment-producing melanocytes overcome frequent oxidative stress in their physiological role of protecting the skin against the deleterious effects of solar UV irradiation. This is accomplished by the activity of several endogenous antioxidant systems, including the thioredoxin antioxidant system, in which thioredoxin reductase 1 (TR1) plays an important part. To determine whether TR1 contributes to the redox regulation of melanocyte homeostasis, we have generated a selective melanocytic Txnrd1-knockout mouse model (Txnrd1mel‒/‒), which exhibits a depigmentation phenotype consisting of variable amelanotic ventral spotting and reduced pigmentation on the extremities (tail tip, ears, and paws). The antioxidant role of TR1 was further probed in the presence of acute neonatal UVB irradiation, which stimulates melanocyte activation and introduces a spike in oxidative stress in the skin microenvironment. Interestingly, we observed a significant reduction in overall melanocyte count and proliferation in the absence of TR1. Furthermore, melanocytes exhibited an elevated level of UV-induced DNA damage in the form of 8-oxo-2'-deoxyguanosine after acute UVB treatment. We also saw an engagement of compensatory antioxidant mechanisms through increased nuclear localization of transcription factor NRF2. Altogether, these data indicate that melanocytic TR1 positively regulates melanocyte homeostasis and pigmentation during development and protects against UVB-induced DNA damage and oxidative stress.
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Ornithology, Sexual Selection, Melanin, Biology, Plumage, and 4 morePigment, Barn, Feather, and Moulting
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Since human activities are responsible for anthropogenic greenhouse gases emissions, climate models project an increase in the global surface temperature of 0.9 C to 4.0 C by 2100. For human health, it is projected that global warming may... more
Since human activities are responsible for anthropogenic greenhouse gases emissions, climate models project an increase in the global surface temperature of 0.9 C to 4.0 C by 2100. For human health, it is projected that global warming may have a critical effect on the increased periods of severe heat stress in summer throughout the world. Global warming may have a critical issue on the increased periods of severe heat stress that have a potential impact on peroxidative damage in humans and animals. Lipid peroxidative damage is markedly related to GSH peroxidase activities, therefore the study was carried out to analyze the relationship between biochemical adaptability and the lipid peroxidative damage especially intracellular structure, such as mitochondria and endoplasmic reticulum depending on the exposure time of heat stress.
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Sex allocation is the parental resource allocation to sons versus daughters. Given the different benefits and costs of investments in sons and daughters, females should adjust the brood sex ratio according to their own quality to maximize... more
Sex allocation is the parental resource allocation to sons versus daughters. Given the different benefits and costs of investments in sons and daughters, females should adjust the brood sex ratio according to their own quality to maximize their fitness. In the barn swallow Hirundo rustica, as in many other passerines, females should increase the proportion of sons in their broods with increasing maternal body size, because rearing sons is particularly costly to small females with low feeding capacity, and because reproductive success in the barn swallow, which may depend on rearing conditions, varies more in males. However, evidence supporting this prediction is lacking, even in this model species of sex allocation. Using the Asian subspecies of the barn swallow H. r. gutturalis, we confirmed this prediction. Larger mothers with a longer keel had more sons in their brood. We found that male nestlings invested more in pheomelanin pigmentation compared with female nestlings, while they had shorter wing lengths, indicating that male nestlings are costly to rear compared with female nestlings. Smaller mothers that are at a disadvantage in provisioning may not retard the nestling period by producing daughters, which reduces their parental investment and thus saves their residual reproductive value. This breeding strategy might be particularly beneficial to Japanese barn swallows that breed in environments with high nest predation.
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In order to characterize the phenotype and to examine the effects of sun exposure on the color and structure of eumelanin (EM) and pheomelanin (PM) in alpaca fibers, we applied Soluene‐350 solubilization, alkaline hydrogen peroxide... more
In order to characterize the phenotype and to examine the effects of sun exposure on the color and structure of eumelanin (EM) and pheomelanin (PM) in alpaca fibers, we applied Soluene‐350 solubilization, alkaline hydrogen peroxide oxidation (AHPO) and hydroiodic acid (HI) hydrolysis to the base and tip fibers of 20 true‐black (TB) and 20 warm‐black (WB) alpacas. We analyzed absorbances at 500 nm (A500) and 650 nm (A650), Free and Total pyrrole‐2,3,5‐tricarboxylic acid (PTCA), 2,3,4,5‐tetracarboxylic acid (PTeCA) as degradative products from EM, and 4‐amino‐3‐hydroxyphenylalanine (4‐AHP), 3‐amino‐4‐hydroxyphenylalanine (3‐AHP) and thiazole‐2,4,5‐tricarboxylic acid (TTCA) as degradative products from PM. We found that the ratio of PTeCA/Total PTCA increased significantly from the base to the tip in both colors of alpaca fibers, while the ratios of A650/A500 and 4‐AHP/3‐AHP decreased significantly. These results show that structures made of both EM and PM in alpaca fibers are modified significantly by sun exposure inducing color change. This study indicates that the ratios of A650/A500, PTeCA/Total PTCA and 4‐AHP/3‐AHP are highly sensitive markers of color change and photodegradation of EM and PM, respectively.
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Along with the expansion of therapeutic options for metastatic melanoma, the development of useful biomarkers is urgently required to predict and monitor treatment response. Serum 5‐S‐cysteinyldopa (5‐S‐CD) has been identified as a... more
Along with the expansion of therapeutic options for metastatic melanoma, the development of useful biomarkers is urgently required to predict and monitor treatment response. Serum 5‐S‐cysteinyldopa (5‐S‐CD) has been identified as a diagnostic marker of malignant melanoma, but its utility as a biomarker for emerging therapeutic agents remains unknown. We assessed serum 5‐S‐CD in 12 metastatic melanoma patients (median age, 76 years; six men and six women) who had been treated with nivolumab (Nivo) at Shinshu University Hospital between 2014 and 2016. Serum 5‐S‐CD and lactate dehydrogenase levels before and at 3–6 weeks of Nivo treatment were obtained and their changes were compared with clinical responses as defined by the Response Evaluation Criteria in Solid Tumors criteria (version 1.1). A decrease of 10 nmol/L or more of serum 5‐S‐CD was observed only in partial response patients (2/3 cases, 67%), while an increase of 10 nmol/L or more of serum 5‐S‐CD was witnessed only in progressive disease patients (4/8 cases, 50%). Serum 5‐S‐CD changes were within ±10 nmol/L in the remaining six patients (partial response, one; stable disease, one; progressive disease, four). The results of the four moderately affected progressive disease patients were suspected to have been influenced by small‐sized metastatic lesions, a mixed response that included diminished and enlarged metastatic lesions, prior therapy to Nivo with BRAF inhibitors or radiation, or the development of brain metastasis. Serum 5‐S‐CD in the early phase of Nivo treatment may be helpful to predict therapeutic response in metastatic melanoma.
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Biology, Medicine, Liver, Female, Animals, and 7 moreMale, Hyperplasia, Wild edible plants, Plant extracts, Rats, Sex Factors, and Carcinogen
The nature of the carcinogen present in bracken fern has not yet been elucidated. Very recently, we succeeded in isolating ptaquiloside, a novel norsesquiterpene glucoside of the illudane type, from bracken. Ptaquiloside was shown to be a... more
The nature of the carcinogen present in bracken fern has not yet been elucidated. Very recently, we succeeded in isolating ptaquiloside, a novel norsesquiterpene glucoside of the illudane type, from bracken. Ptaquiloside was shown to be a carcinogenic principle of bracken fern. It induces mammary cancer and multiple ileal tumors in high incidences when given orally to female Sprague-Dawley rats.
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Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the... more
Mutations of the mouse Attractin (Atrn; formerly mahogany) gene were originally recognized because they suppress Agouti pigment type switching. More recently, effects independent of Agouti have been recognized: mice homozygous for the Atrn(mg-3J) allele are resistant to diet-induced obesity and also develop abnormal myelination and vacuolation in the central nervous system. To better understand the pathophysiology and relationship of these pleiotropic effects, we further characterized the molecular abnormalities responsible for two additional Atrn alleles, Atrn(mg) and Atrn(mg-L), and examined in parallel the phenotypes of homozygous and compound heterozygous animals. We find that the three alleles have similar effects on pigmentation and neurodegeneration, with a relative severity of Atrn(mg-3J) > Atrn(mg) > Atrn(mg-L), which also corresponds to the effects of the three alleles on levels of normal Atrn mRNA. Animals homozygous for Atrn(mg-3J) or Atrn(mg), but not Atrn(mg-L), show reduced body weight, reduced adiposity, and increased locomotor activity, all in the presence of normal food intake. These results confirm that the mechanism responsible for the neuropathological alteration is a loss--rather than gain--of function, indicate that abnormal body weight in Atrn mutant mice is caused by a central process leading to increased energy expenditure, and demonstrate that pigmentation is more sensitive to levels of Atrn mRNA than are nonpigmentary phenotypes.
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Genetics, Science, Biology, Medicine, Multidisciplinary, and 4 moreNatural Selection, Phenotype, Genotype, and Allele
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Sunlight-induced melanomas contain UV-signature mutations, which are caused by cyclobutane pyrimidine dimers (CPD). These photoproducts are typically created picoseconds after a UV photon is absorbed at adjacent thymines or cytosines.... more
Sunlight-induced melanomas contain UV-signature mutations, which are caused by cyclobutane pyrimidine dimers (CPD). These photoproducts are typically created picoseconds after a UV photon is absorbed at adjacent thymines or cytosines. However, using immunohistochemistry, mass spectrometry, and RNAi, we find that melanocytes generate CPD for &gt;3 hours after exposure to UVA or UVB, wavelengths found in sunlight and in tanning beds; these “dark CPD” constitute the majority of CPD induced. Using pharmacologic inhibitors, single-photon counting, and specific energy acceptors, we elucidated the mechanism. The process begins when UV-induced superoxide and nitric oxide combine to form peroxynitrite, one of the few biological molecules capable of exciting an electron. Excitation creates a quantum triplet state in the skin pigment melanin that has the energy of a UV photon but induces CPD by transferring its energy to DNA in a radiation-independent manner. Melanin is evidently carcinogenic as well as protective. These findings may underlie the dependence of UV-induced and spontaneous skin cancers on melanin type. The results also validate the long-standing suggestion that chemical generation of excited electronic states - the source of bioluminescence in lower organisms - is important in mammalian biology. Citation Format: Sanjay Premi, Silvia Wallisch, Camila Mano, Adam Weiner, Antonella Bacchiocchi, Kazumasa Wakamatsu, Etelvino Bechara, Ruth Halaban, Thierry Douki, Douglas E. Brash. Excited electrons in melanin induce cyclobutane dimers in the dark. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr LB-104. doi:10.1158/1538-7445.AM2015-LB-104
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ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full... more
ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
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Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for... more
Post‐inflammatory hyperpigmentation (PIH) is a common cutaneous condition that can cause a disfigured appearance. However, the pathophysiology of PIH remains poorly understood, at least in part, because an appropriate animal model for research has not been established. In order to analyze the pathomechanism of PIH, we successfully induced PIH in a hairless version of transgenic mice (hk14‐SCF Tg/HRM) that have a human‐type epidermis containing melanin by repeated hapten application of 2,4‐dinitrofluorobenzene. Histopathologic observation showed epidermal hyperplasia, predominant infiltrations of inflammatory cells, and melanin‐containing cells in the dermis just after elicitation of the atopic dermatitis‐like condition. At week 2, the findings were similar to the characteristics of PIH, that is, an increase of melanin without spongiosis or liquid degeneration in the epidermis and an increase in dermal melanophages. Dynamic analysis of melanin showed that the melanin in the dermis remained for a longer duration than in the epidermis. Furthermore, immunohistochemical staining revealed that the majority of cells containing melanin were positive for the anti‐CD68 antibody, but negative for the anti‐F4/80 antibody. These data suggest that novel treatments of PIH should be targeted against macrophages and should eventually lead to the development of new treatment modalities.
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ABSTRACT