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Sample records for neural crest-derived melanocytes

  1. Hepatocyte growth factor/scatter factor-MET signaling in neural crest-derived melanocyte development.

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    Kos, L; Aronzon, A; Takayama, H; Maina, F; Ponzetto, C; Merlino, G; Pavan, W

    1999-02-01

    The mechanisms governing development of neural crest-derived melanocytes, and how alterations in these pathways lead to hypopigmentation disorders, are not completely understood. Hepatocyte growth factor/scatter factor (HGF/SF) signaling through the tyrosine-kinase receptor, MET, is capable of promoting the proliferation, increasing the motility, and maintaining high tyrosinase activity and melanin synthesis of melanocytes in vitro. In addition, transgenic mice that ubiquitously overexpress HGF/SF demonstrate hyperpigmentation in the skin and leptomenigenes and develop melanomas. To investigate whether HGF/ SF-MET signaling is involved in the development of neural crest-derived melanocytes, transgenic embryos, ubiquitously overexpressing HGF/SF, were analyzed. In HGF/SF transgenic embryos, the distribution of melanoblasts along the characteristic migratory pathway was not affected. However, additional ectopically localized melanoblasts were also observed in the dorsal root ganglia and neural tube, as early as 11.5 days post coitus (p.c.). We utilized an in vitro neural crest culture assay to further explore the role of HGF/SF-MET signaling in neural crest development. HGF/SF added to neural crest cultures increased melanoblast number, permitted differentiation into pigmented melanocytes, promoted melanoblast survival, and could replace mast-cell growth factor/Steel factor (MGF) in explant cultures. To examine whether HGF/SF-MET signaling is required for the proper development of melanocytes, embryos with a targeted Met null mutation (Met-/-) were analysed. In Met-/- embryos, melanoblast number and location were not overtly affected up to 14 days p.c. These results demonstrate that HGF/SF-MET signaling influences, but is not required for, the initial development of neural crest-derived melanocytes in vivo and in vitro.

  2. Regeneration of neural crest derivatives in the Xenopus tadpole tail

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    Slack Jonathan MW

    2007-05-01

    Full Text Available Abstract Background After amputation of the Xenopus tadpole tail, a functionally competent new tail is regenerated. It contains spinal cord, notochord and muscle, each of which has previously been shown to derive from the corresponding tissue in the stump. The regeneration of the neural crest derivatives has not previously been examined and is described in this paper. Results Labelling of the spinal cord by electroporation, or by orthotopic grafting of transgenic tissue expressing GFP, shows that no cells emigrate from the spinal cord in the course of regeneration. There is very limited regeneration of the spinal ganglia, but new neurons as well as fibre tracts do appear in the regenerated spinal cord and the regenerated tail also contains abundant peripheral innervation. The regenerated tail contains a normal density of melanophores. Cell labelling experiments show that melanophores do not arise from the spinal cord during regeneration, nor from the mesenchymal tissues of the skin, but they do arise by activation and proliferation of pre-existing melanophore precursors. If tails are prepared lacking melanophores, then the regenerates also lack them. Conclusion On regeneration there is no induction of a new neural crest similar to that seen in embryonic development. However there is some regeneration of neural crest derivatives. Abundant melanophores are regenerated from unpigmented precursors, and, although spinal ganglia are not regenerated, sufficient sensory systems are produced to enable essential functions to continue.

  3. Modeling Cerebrovascular Pathophysiology in Amyloid-β Metabolism using Neural-Crest-Derived Smooth Muscle Cells

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    Christine Cheung

    2014-10-01

    Full Text Available Summary: There is growing recognition of cerebrovascular contributions to neurodegenerative diseases. In the walls of cerebral arteries, amyloid-beta (Aβ accumulation is evident in a majority of aged people and patients with cerebral amyloid angiopathy. Here, we leverage human pluripotent stem cells to generate vascular smooth muscle cells (SMCs from neural crest progenitors, recapitulating brain-vasculature-specific attributes of Aβ metabolism. We confirm that the lipoprotein receptor, LRP1, functions in our neural-crest-derived SMCs to mediate Aβ uptake and intracellular lysosomal degradation. Hypoxia significantly compromises the contribution of SMCs to Aβ clearance by suppressing LRP1 expression. This enabled us to develop an assay of Aβ uptake by using the neural crest-derived SMCs with hypoxia as a stress paradigm. We then tested several vascular protective compounds in a high-throughput format, demonstrating the value of stem-cell-based phenotypic screening for novel therapeutics and drug repurposing, aimed at alleviating amyloid burden. : The contribution of blood vessel pathologies to neurodegenerative disorders is relatively neglected, partly due to inadequate human tissues for research. By using human stem cells, Cheung et al. establish a method of generating vascular smooth muscle cells (SMCs from neural crest progenitors, the primary precursors that give rise to brain blood vessels. These stem-cell-derived SMCs display defective amyloid processing under chronic hypoxia, a phenomenon well documented in the cerebral vasculatures of aged people and patients with Alzheimer’s disease.

  4. Constitutively active Notch1 converts cranial neural crest-derived frontonasal mesenchyme to perivascular cells in vivo

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    Sophie R. Miller

    2017-03-01

    Full Text Available Perivascular/mural cells originate from either the mesoderm or the cranial neural crest. Regardless of their origin, Notch signalling is necessary for their formation. Furthermore, in both chicken and mouse, constitutive Notch1 activation (via expression of the Notch1 intracellular domain is sufficient in vivo to convert trunk mesoderm-derived somite cells to perivascular cells, at the expense of skeletal muscle. In experiments originally designed to investigate the effect of premature Notch1 activation on the development of neural crest-derived olfactory ensheathing glial cells (OECs, we used in ovo electroporation to insert a tetracycline-inducible NotchΔE construct (encoding a constitutively active mutant of mouse Notch1 into the genome of chicken cranial neural crest cell precursors, and activated NotchΔE expression by doxycycline injection at embryonic day 4. NotchΔE-targeted cells formed perivascular cells within the frontonasal mesenchyme, and expressed a perivascular marker on the olfactory nerve. Hence, constitutively activating Notch1 is sufficient in vivo to drive not only somite cells, but also neural crest-derived frontonasal mesenchyme and perhaps developing OECs, to a perivascular cell fate. These results also highlight the plasticity of neural crest-derived mesenchyme and glia.

  5. Neural Crest-Derived Mesenchymal Cells Require Wnt Signaling for Their Development and Drive Invagination of the Telencephalic Midline

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    Choe, Youngshik; Zarbalis, Konstantinos S.; Pleasure, Samuel J.

    2014-01-01

    Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs) leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis. PMID:24516524

  6. Neural crest-derived mesenchymal cells require Wnt signaling for their development and drive invagination of the telencephalic midline.

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    Youngshik Choe

    Full Text Available Embryonic neural crest cells contribute to the development of the craniofacial mesenchyme, forebrain meninges and perivascular cells. In this study, we investigated the function of ß-catenin signaling in neural crest cells abutting the dorsal forebrain during development. In the absence of ß-catenin signaling, neural crest cells failed to expand in the interhemispheric region and produced ectopic smooth muscle cells instead of generating dermal and calvarial mesenchyme. In contrast, constitutive expression of stabilized ß-catenin in neural crest cells increased the number of mesenchymal lineage precursors suggesting that ß-catenin signaling is necessary for the expansion of neural crest-derived mesenchymal cells. Interestingly, the loss of neural crest-derived mesenchymal stem cells (MSCs leads to failure of telencephalic midline invagination and causes ventricular system defects. This study shows that ß-catenin signaling is required for the switch of neural crest cells to MSCs and mediates the expansion of MSCs to drive the formation of mesenchymal structures of the head. Furthermore, loss of these structures causes striking defects in forebrain morphogenesis.

  7. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

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    Ignatius, Myron S; Unal Eroglu, Arife; Malireddy, Smitha; Gallagher, Glen; Nambiar, Roopa M; Henion, Paul D

    2013-01-01

    The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382) mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382) mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382) mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382) defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  8. Distinct functional and temporal requirements for zebrafish Hdac1 during neural crest-derived craniofacial and peripheral neuron development.

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    Myron S Ignatius

    Full Text Available The regulation of gene expression is accomplished by both genetic and epigenetic means and is required for the precise control of the development of the neural crest. In hdac1(b382 mutants, craniofacial cartilage development is defective in two distinct ways. First, fewer hoxb3a, dlx2 and dlx3-expressing posterior branchial arch precursors are specified and many of those that are consequently undergo apoptosis. Second, in contrast, normal numbers of progenitors are present in the anterior mandibular and hyoid arches, but chondrocyte precursors fail to terminally differentiate. In the peripheral nervous system, there is a disruption of enteric, DRG and sympathetic neuron differentiation in hdac1(b382 mutants compared to wildtype embryos. Specifically, enteric and DRG-precursors differentiate into neurons in the anterior gut and trunk respectively, while enteric and DRG neurons are rarely present in the posterior gut and tail. Sympathetic neuron precursors are specified in hdac1(b382 mutants and they undergo generic neuronal differentiation but fail to undergo noradrenergic differentiation. Using the HDAC inhibitor TSA, we isolated enzyme activity and temporal requirements for HDAC function that reproduce hdac1(b382 defects in craniofacial and sympathetic neuron development. Our study reveals distinct functional and temporal requirements for zebrafish hdac1 during neural crest-derived craniofacial and peripheral neuron development.

  9. In vivo impact of Dlx3 conditional inactivation in Neural Crest-Derived Craniofacial Bones

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    Duverger, Olivier; Isaac, Juliane; Zah, Angela; Hwang, Joonsung; Berdal, Ariane; Lian, Jane B.; Morasso, Maria I.

    2012-01-01

    Mutations in DLX3 in humans lead to defects in craniofacial and appendicular bones, yet the in vivo activity related to Dlx3 function during normal skeletal development have not been fully elucidated. Here we used a conditional knockout approach to analyze the effects of neural crest deletion of Dlx3 on craniofacial bones development. At birth, mutant mice exhibit a normal overall positioning of the skull bones, but a change in the shape of the calvaria was observed. Molecular analysis of the genes affected in the frontal bones and mandibles from these mice identified several bone markers known to affect bone development, with a strong prediction for increased bone formation and mineralization in vivo. Interestingly, while a subset of these genes were similarly affected in frontal bones and mandibles (Sost, Mepe, Bglap, Alp, Ibsp, Agt), several genes, including Lect1 and Calca, were specifically affected in frontal bones. Consistent with these molecular alterations, cells isolated from the frontal bone of mutant mice exhibited increased differentiation and mineralization capacities ex vivo, supporting cell autonomous defects in neural crest cells. However, adult mutant animals exhibited decreased bone mineral density in both mandibles and calvaria, as well as a significant increase in bone porosity. Together, these observations suggest that mature osteoblasts in the adult respond to signals that regulate adult bone mass and remodeling. This study provides new downstream targets for Dlx3 in craniofacial bone, and gives additional evidence of the complex regulation of bone formation and homeostasis in the adult skeleton. PMID:22886599

  10. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

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    Tan, Yu, E-mail: tanyu2048@163.com; Fu, Runqing, E-mail: furunqing@sjtu.edu.cn; Liu, Jiaqiang, E-mail: liujqmj@163.com; Wu, Yong, E-mail: wyonger@gmail.com; Wang, Bo, E-mail: wb228@126.com; Jiang, Ning, E-mail: 179639060@qq.com; Nie, Ping, E-mail: nieping1011@sina.com; Cao, Haifeng, E-mail: 0412chf@163.com; Yang, Zhi, E-mail: wcums1981@163.com; Fang, Bing, E-mail: fangbing@sjtu.edu.cn

    2016-07-08

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.

  11. ADAM10 is essential for cranial neural crest-derived maxillofacial bone development

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    Tan, Yu; Fu, Runqing; Liu, Jiaqiang; Wu, Yong; Wang, Bo; Jiang, Ning; Nie, Ping; Cao, Haifeng; Yang, Zhi; Fang, Bing

    2016-01-01

    Growth disorders of the craniofacial bones may lead to craniofacial deformities. The majority of maxillofacial bones are derived from cranial neural crest cells via intramembranous bone formation. Any interruption of the craniofacial skeleton development process might lead to craniofacial malformation. A disintegrin and metalloprotease (ADAM)10 plays an essential role in organ development and tissue integrity in different organs. However, little is known about its function in craniofacial bone formation. Therefore, we investigated the role of ADAM10 in the developing craniofacial skeleton, particularly during typical mandibular bone development. First, we showed that ADAM10 was expressed in a specific area of the craniofacial bone and that the expression pattern dynamically changed during normal mouse craniofacial development. Then, we crossed wnt1-cre transgenic mice with adam10-flox mice to generate ADAM10 conditional knockout mice. The stereomicroscopic, radiographic, and von Kossa staining results showed that conditional knockout of ADAM10 in cranial neural crest cells led to embryonic death, craniofacial dysmorphia and bone defects. Furthermore, we demonstrated that impaired mineralization could be triggered by decreased osteoblast differentiation, increased cell death. Overall, these findings show that ADAM10 plays an essential role in craniofacial bone development. -- Highlights: •We firstly reported that ADAM10 was essentially involved in maxillofacial bone development. •ADAM10 cKO mice present craniofacial dysmorphia and bone defects. •Impaired osteoblast differentiation,proliferation and apoptosis underlie the bone deformity.

  12. Interaction of adult human neural crest-derived stem cells with a nanoporous titanium surface is sufficient to induce their osteogenic differentiation

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    Matthias Schürmann

    2014-07-01

    Full Text Available Osteogenic differentiation of various adult stem cell populations such as neural crest-derived stem cells is of great interest in the context of bone regeneration. Ideally, exogenous differentiation should mimic an endogenous differentiation process, which is partly mediated by topological cues. To elucidate the osteoinductive potential of porous substrates with different pore diameters (30 nm, 100 nm, human neural crest-derived stem cells isolated from the inferior nasal turbinate were cultivated on the surface of nanoporous titanium covered membranes without additional chemical or biological osteoinductive cues. As controls, flat titanium without any topological features and osteogenic medium was used. Cultivation of human neural crest-derived stem cells on 30 nm pores resulted in osteogenic differentiation as demonstrated by alkaline phosphatase activity after seven days as well as by calcium deposition after 3 weeks of cultivation. In contrast, cultivation on flat titanium and on membranes equipped with 100 nm pores was not sufficient to induce osteogenic differentiation. Moreover, we demonstrate an increase of osteogenic transcripts including Osterix, Osteocalcin and up-regulation of Integrin β1 and α2 in the 30 nm pore approach only. Thus, transplantation of stem cells pre-cultivated on nanostructured implants might improve the clinical outcome by support of the graft adherence and acceleration of the regeneration process.

  13. In vitro cementoblast-like differentiation of postmigratory neural crest-derived p75{sup +} stem cells with dental follicle cell conditioned medium

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    Wen, Xiujie; Liu, Luchuan; Deng, Manjing; Liu, Rui; Zhang, Li; Nie, Xin, E-mail: dr.xinnie@gmail.com

    2015-09-10

    Cranial neural crest-derived cells (CNCCs) play important role in epithelial–mesenchymal interactions during tooth morphogenesis. However, the heterogeneity of CNCCs and their tendency to spontaneously differentiate along smooth muscle or osteoblast lineages in vitro limit further understanding of their biological properties. We studied the differentiation properties of isolated rat embryonic postmigratory CNCCs, expressing p75 neurotrophin receptor (p75NTR). These p75NTR positive (p75{sup +}) CNCCs, isolated using fluorescence activated cell sorter, exhibited fibroblast-like morphology and characteristics of mesenchymal stem cells. Incubation of p75{sup +} CNCCs in dental follicle cell conditioned medium (DFCCM) combined with dentin non-collagenous proteins (dNCPs), altered their morphological features to cementoblast-like appearance. These cells also showed low proliferative activity, high ALP activity and significantly increased calcified nodule formation. Markers related to mineralization or specific to cementoblast lineage were highly expressed in dNCPs/DFCCM-treated p75{sup +} cells, suggesting their differentiation along cementoblast-like lineage. p75{sup +} stem cells selected from postmigratory CNCCs represent a pure stem cell population and could be used as a stem cell model for in vitro studies due to their intrinsic ability to differentiate to neuronal cells and transform from neuroectoderm to ectomesenchyme. They can provide a potential stem cell resource for tooth engineering studies and help to further investigate mechanisms of epithelial–mesenchymal interactions in tooth morphogenesis. - Highlights: • Cranial neural crest-derived cells (CNCCs) take part in tooth morphogenesis. • positive (p75{sup +}) CNCCs are fibroblast-like and resemble mesenchymal stem cells. • p75{sup +} CNCCs in dental follicle cell medium (DFCCM/dNCP) appear like cementoblasts. • DFCCM/dNCP-treated p75{sup +} cells express cementoblast specific mineralization

  14. In vitro cementoblast-like differentiation of postmigratory neural crest-derived p75+ stem cells with dental follicle cell conditioned medium

    International Nuclear Information System (INIS)

    Wen, Xiujie; Liu, Luchuan; Deng, Manjing; Liu, Rui; Zhang, Li; Nie, Xin

    2015-01-01

    Cranial neural crest-derived cells (CNCCs) play important role in epithelial–mesenchymal interactions during tooth morphogenesis. However, the heterogeneity of CNCCs and their tendency to spontaneously differentiate along smooth muscle or osteoblast lineages in vitro limit further understanding of their biological properties. We studied the differentiation properties of isolated rat embryonic postmigratory CNCCs, expressing p75 neurotrophin receptor (p75NTR). These p75NTR positive (p75 + ) CNCCs, isolated using fluorescence activated cell sorter, exhibited fibroblast-like morphology and characteristics of mesenchymal stem cells. Incubation of p75 + CNCCs in dental follicle cell conditioned medium (DFCCM) combined with dentin non-collagenous proteins (dNCPs), altered their morphological features to cementoblast-like appearance. These cells also showed low proliferative activity, high ALP activity and significantly increased calcified nodule formation. Markers related to mineralization or specific to cementoblast lineage were highly expressed in dNCPs/DFCCM-treated p75 + cells, suggesting their differentiation along cementoblast-like lineage. p75 + stem cells selected from postmigratory CNCCs represent a pure stem cell population and could be used as a stem cell model for in vitro studies due to their intrinsic ability to differentiate to neuronal cells and transform from neuroectoderm to ectomesenchyme. They can provide a potential stem cell resource for tooth engineering studies and help to further investigate mechanisms of epithelial–mesenchymal interactions in tooth morphogenesis. - Highlights: • Cranial neural crest-derived cells (CNCCs) take part in tooth morphogenesis. • positive (p75 + ) CNCCs are fibroblast-like and resemble mesenchymal stem cells. • p75 + CNCCs in dental follicle cell medium (DFCCM/dNCP) appear like cementoblasts. • DFCCM/dNCP-treated p75 + cells express cementoblast specific mineralization markers. • p75 + cells are pure stem

  15. Decreased proliferative, migrative and neuro-differentiative potential of postnatal rat enteric neural crest-derived cells during culture in vitro

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    Yu, Hui; Pan, Wei-Kang; Zheng, Bai-Jun; Wang, Huai-Jie; Chen, Xin-Lin; Liu, Yong; Gao, Ya

    2016-01-01

    A growing body of evidence supports the potential use of enteric neural crest-derived cells (ENCCs) as a cell replacement therapy for Hirschsprung's disease. Based on previous observations of robust propagation of primary ENCCs, as opposed to their progeny, it is suggested that their therapeutic potential after in vitro expansion may be restricted. We therefore examined the growth and differentiation activities and phenotypic characteristics of continuous ENCC cultures. ENCCs were isolated from the intestines of postnatal rats and were identified using an immunocytochemical approach. During continuous ENCC culture expansion, proliferation, migration, apoptosis, and differentiation potentials were monitored. The Cell Counting Kit-8 was used for assessment of ENCC vitality, Transwell inserts for cell migration, immunocytochemistry for cell counts and identification, and flow cytometry for apoptosis. Over six continuous generations, ENCC proliferation potency was reduced and with prolonged culture, the ratio of migratory ENCCs was decreased. The percentage of apoptosis showed an upward trend with prolonged intragenerational culture, but showed a downward trend with prolonged culture of combined generations. Furthermore, the percentage of peripherin"+ cells decreased whilst the percentage of GFAP"+ cells increased with age. The results demonstrated that alterations in ENCC growth characteristics occur with increased culture time, which may partially account for the poor results of proposed cell therapies. - Highlights: • Differences were identified between primary and daughter ENCCs. • Daughter ENCCs had reduced proliferation, migration and differentiation. • Daughter ENCCs also had increased apoptosis. • These altered characteristics warrant further investigation.

  16. Renal excretion of iodine-131 labelled meta-iodobenzylguanidine and metabolites after therapeutic doses in patients suffering from different neural crest-derived tumours

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    Wafelman, A.R.; Hoefnagel, C.A.; Maessen, H.J.M.; Maes, R.A.A.; Beijnen, J.H.

    1997-01-01

    Iodine-131 labelled meta-iodobenzylguanidine ([ 131 I[MIBG) is used for diagnostic scintigraphy and radionuclide therapy of neural crest-derived tumours. After administration of therapeutic doses of [ 131 I[MIBG (3.1-7.5 GBq) to 17 patients (n=32 courses), aged 2-73 years, 56%±10%, 73%±11%, 80%±10% and 83%±10% of the dose was cumulatively excreted as total radioactivity in urine at t=24 h, 48 h, 72 h and 96 h, respectively. Except for two adult patients, who showed excretion of 14%-18% of [ 131 I[meta-iodohippuric acid ([ 131 I[MIHA), the cumulatively excreted radioactivity consisted of >85% [ 131 I[MIBG, with 6% of the dose excreted as free [ 131 I[iodide, 4% as [ 131 I[MIHA and 2.5% as an unknown iodine-131 labelled metabolite. Cumulative renal excretion rates of total radioactivity and of [ 131 I[MIBG appeared to be higher in neuroblastoma and phaeochromocytoma patients than in carcinoid patients. Based on the excretion of small amounts of [ 131 I[meta-iodobenzoic acid in two patients, a possible metabolic pathway for [ 131 I[MIBG is suggested. The degree of metabolism was not related to the extent of liver uptake of radioactivity. (orig.). With 2 figs., 5 tabs

  17. Combination of exogenous cell transplantation and 5-HT4 receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model.

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    Yu, Hui; Zheng, Bai-Jun; Pan, Wei-Kang; Wang, Huai-Jie; Xie, Chong; Zhao, Yu-Ying; Chen, Xin-Lin; Liu, Yong; Gao, Ya

    2017-02-01

    Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT 4 receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT 4 receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75 NTR and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT 4 receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. Copyright © 2016 Elsevier Inc. All rights reserved.

  18. Decreased proliferative, migrative and neuro-differentiative potential of postnatal rat enteric neural crest-derived cells during culture in vitro

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Pan, Wei-Kang; Zheng, Bai-Jun; Wang, Huai-Jie [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2016-05-01

    A growing body of evidence supports the potential use of enteric neural crest-derived cells (ENCCs) as a cell replacement therapy for Hirschsprung's disease. Based on previous observations of robust propagation of primary ENCCs, as opposed to their progeny, it is suggested that their therapeutic potential after in vitro expansion may be restricted. We therefore examined the growth and differentiation activities and phenotypic characteristics of continuous ENCC cultures. ENCCs were isolated from the intestines of postnatal rats and were identified using an immunocytochemical approach. During continuous ENCC culture expansion, proliferation, migration, apoptosis, and differentiation potentials were monitored. The Cell Counting Kit-8 was used for assessment of ENCC vitality, Transwell inserts for cell migration, immunocytochemistry for cell counts and identification, and flow cytometry for apoptosis. Over six continuous generations, ENCC proliferation potency was reduced and with prolonged culture, the ratio of migratory ENCCs was decreased. The percentage of apoptosis showed an upward trend with prolonged intragenerational culture, but showed a downward trend with prolonged culture of combined generations. Furthermore, the percentage of peripherin{sup +} cells decreased whilst the percentage of GFAP{sup +} cells increased with age. The results demonstrated that alterations in ENCC growth characteristics occur with increased culture time, which may partially account for the poor results of proposed cell therapies. - Highlights: • Differences were identified between primary and daughter ENCCs. • Daughter ENCCs had reduced proliferation, migration and differentiation. • Daughter ENCCs also had increased apoptosis. • These altered characteristics warrant further investigation.

  19. Differentiation defect in neural crest-derived smooth muscle cells in patients with aortopathy associated with bicuspid aortic valves

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    Jiao Jiao

    2016-08-01

    Full Text Available Individuals with bicuspid aortic valves (BAV are at a higher risk of developing thoracic aortic aneurysms (TAA than patients with trileaflet aortic valves (TAV. The aneurysms associated with BAV most commonly involve the ascending aorta and spare the descending aorta. Smooth muscle cells (SMCs in the ascending and descending aorta arise from neural crest (NC and paraxial mesoderm (PM, respectively. We hypothesized defective differentiation of the neural crest stem cells (NCSCs-derived SMCs but not paraxial mesoderm cells (PMCs-derived SMCs contributes to the aortopathy associated with BAV. When induced pluripotent stem cells (iPSCs from BAV/TAA patients were differentiated into NCSC-derived SMCs, these cells demonstrated significantly decreased expression of marker of SMC differentiation (MYH11 and impaired contraction compared to normal control. In contrast, the PMC-derived SMCs were similar to control cells in these aspects. The NCSC-SMCs from the BAV/TAA also showed decreased TGF-β signaling based on phosphorylation of SMAD2, and increased mTOR signaling. Inhibition of mTOR pathway using rapamycin rescued the aberrant differentiation. Our data demonstrates that decreased differentiation and contraction of patient's NCSC-derived SMCs may contribute to that aortopathy associated with BAV.

  20. Combination of exogenous cell transplantation and 5-HT{sub 4} receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model

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    Yu, Hui [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Zheng, Bai-Jun; Pan, Wei-Kang; Wang, Huai-Jie; Xie, Chong; Zhao, Yu-Ying [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China); Chen, Xin-Lin; Liu, Yong [Institute of Neurobiology, Environment and Genes Related to Diseases Key Laboratory of Chinese Ministry of Education, Xi’an Jiaotong University, No 96, Yan Ta Xi Road, Xi’an 710061, Shaanxi (China); Gao, Ya, E-mail: ygao@mail.xjtu.edu.cn [Department of Pediatric Surgery, the Second Affiliated Hospital, Xi’an Jiaotong University, No 157, Xi Wu Road, Xi’an 710004, Shaanxi (China)

    2017-02-01

    Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT{sub 4} receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT{sub 4} receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75{sup NTR} and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT{sub 4} receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. - Highlights: • Survival and differentiation of exogenous ENCCs in treated colons. • With longer times post-intervention, the number of ENCCs and their progeny cells gradually increased. • Exogenous ENCCs combined with the 5-HT4 receptor agonist ffectively induced ENCCs proliferation and differentiation.

  1. Combination of exogenous cell transplantation and 5-HT4 receptor agonism induce endogenous enteric neural crest-derived cells in a rat hypoganglionosis model

    International Nuclear Information System (INIS)

    Yu, Hui; Zheng, Bai-Jun; Pan, Wei-Kang; Wang, Huai-Jie; Xie, Chong; Zhao, Yu-Ying; Chen, Xin-Lin; Liu, Yong; Gao, Ya

    2017-01-01

    Enteric neural crest-derived cells (ENCCs) can migrate into endogenous ganglia and differentiate into progeny cells, and have even partially rescued bowel function; however, poor reliability and limited functional recovery after ENCC transplantation have yet to be addressed. Here, we investigated the induction of endogenous ENCCs by combining exogenous ENCC transplantation with a 5-HT 4 receptor agonist mosapride in a rat model of hypoganglionosis, established by benzalkonium chloride treatment. ENCCs, isolated from the gut of newborn rats, were labeled with a lentiviral eGFP reporter. ENCCs and rats were treated with the 5-HT 4 receptor agonist/antagonist. The labeled ENCCs were then transplanted into the muscular layer of benzalkonium chloride-treated colons. At given days post-intervention, colonic tissue samples were removed for histological analysis. ENCCs and neurons were detected by eGFP expression and immunoreactivity to p75 NTR and peripherin, respectively. eGFP-positive ENCCs and neurons could survive and maintain levels of fluorescence after transplantation. With longer times post-intervention, the number of peripherin-positive cells gradually increased in all groups. Significantly more peripherin-positive cells were found following ENCCs plus mosapride treatment, compared with the other groups. These results show that exogenous ENCCs combined with the 5-HT 4 receptor agonist effectively induced endogenous ENCCs proliferation and differentiation in a rat hypoganglionosis model. - Highlights: • Survival and differentiation of exogenous ENCCs in treated colons. • With longer times post-intervention, the number of ENCCs and their progeny cells gradually increased. • Exogenous ENCCs combined with the 5-HT4 receptor agonist ffectively induced ENCCs proliferation and differentiation.

  2. FGF8 signaling sustains progenitor status and multipotency of cranial neural crest-derived mesenchymal cells in vivo and in vitro

    Science.gov (United States)

    Shao, Meiying; Liu, Chao; Song, Yingnan; Ye, Wenduo; He, Wei; Yuan, Guohua; Gu, Shuping; Lin, Congxin; Ma, Liang; Zhang, Yanding; Tian, Weidong; Hu, Tao; Chen, YiPing

    2015-01-01

    The cranial neural crest (CNC) cells play a vital role in craniofacial development and regeneration. They are multi-potent progenitors, being able to differentiate into various types of tissues. Both pre-migratory and post-migratory CNC cells are plastic, taking on diverse fates by responding to different inductive signals. However, what sustains the multipotency of CNC cells and derivatives remains largely unknown. In this study, we present evidence that FGF8 signaling is able to sustain progenitor status and multipotency of CNC-derived mesenchymal cells both in vivo and in vitro. We show that augmented FGF8 signaling in pre-migratory CNC cells prevents cell differentiation and organogenesis in the craniofacial region by maintaining their progenitor status. CNC-derived mesenchymal cells with Fgf8 overexpression or control cells in the presence of exogenous FGF8 exhibit prolonged survival, proliferation, and multi-potent differentiation capability in cell cultures. Remarkably, exogenous FGF8 also sustains the capability of CNC-derived mesenchymal cells to participate in organogenesis such as odontogenesis. Furthermore, FGF8-mediated signaling strongly promotes adipogenesis but inhibits osteogenesis of CNC-derived mesenchymal cells in vitro. Our results reveal a specific role for FGF8 in the maintenance of progenitor status and in fate determination of CNC cells, implicating a potential application in expansion and fate manipulation of CNC-derived cells in stem cell-based craniofacial regeneration. PMID:26243590

  3. The Melanocyte Fate in Neural Crest is Triggered by Myb Proteins through Activation of c-kit

    Czech Academy of Sciences Publication Activity Database

    Karafiát, Vít; Dvořáková, Marta; Pajer, Petr; Čermák, Vladimír; Dvořák, Michal

    2007-01-01

    Roč. 64, č. 21 (2007), s. 2975-2984 ISSN 1420-682X R&D Projects: GA MŠk(CZ) LC06061; GA ČR GA204/06/1728 Institutional research plan: CEZ:AV0Z50520514 Keywords : c-myb proto-oncogene * v-mybAMV oncogene * neural crest * cell fate determination * melanocytes * c-kit signal Subject RIV: EB - Genetics ; Molecular Biology Impact factor: 5.239, year: 2007

  4. Transmembrane potential of GlyCl-expressing instructor cells induces a neoplastic-like conversion of melanocytes via a serotonergic pathway

    Directory of Open Access Journals (Sweden)

    Douglas Blackiston

    2011-01-01

    Understanding the mechanisms that coordinate stem cell behavior within the host is a high priority for developmental biology, regenerative medicine and oncology. Endogenous ion currents and voltage gradients function alongside biochemical cues during pattern formation and tumor suppression, but it is not known whether bioelectrical signals are involved in the control of stem cell progeny in vivo. We studied Xenopus laevis neural crest, an embryonic stem cell population that gives rise to many cell types, including melanocytes, and contributes to the morphogenesis of the face, heart and other complex structures. To investigate how depolarization of transmembrane potential of cells in the neural crest’s environment influences its function in vivo, we manipulated the activity of the native glycine receptor chloride channel (GlyCl. Molecular-genetic depolarization of a sparse, widely distributed set of GlyCl-expressing cells non-cell-autonomously induces a neoplastic-like phenotype in melanocytes: they overproliferate, acquire an arborized cell shape and migrate inappropriately, colonizing numerous tissues in a metalloprotease-dependent fashion. A similar effect was observed in human melanocytes in culture. Depolarization of GlyCl-expressing cells induces these drastic changes in melanocyte behavior via a serotonin-transporter-dependent increase of extracellular serotonin (5-HT. These data reveal GlyCl as a molecular marker of a sparse and heretofore unknown cell population with the ability to specifically instruct neural crest derivatives, suggest transmembrane potential as a tractable signaling modality by which somatic cells can control stem cell behavior at considerable distance, identify a new biophysical aspect of the environment that confers a neoplastic-like phenotype upon stem cell progeny, reveal a pre-neural role for serotonin and its transporter, and suggest a novel strategy for manipulating stem cell behavior.

  5. Pax7 lineage contributions to the mammalian neural crest.

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    Barbara Murdoch

    Full Text Available Neural crest cells are vertebrate-specific multipotent cells that contribute to a variety of tissues including the peripheral nervous system, melanocytes, and craniofacial bones and cartilage. Abnormal development of the neural crest is associated with several human maladies including cleft/lip palate, aggressive cancers such as melanoma and neuroblastoma, and rare syndromes, like Waardenburg syndrome, a complex disorder involving hearing loss and pigment defects. We previously identified the transcription factor Pax7 as an early marker, and required component for neural crest development in chick embryos. In mammals, Pax7 is also thought to play a role in neural crest development, yet the precise contribution of Pax7 progenitors to the neural crest lineage has not been determined.Here we use Cre/loxP technology in double transgenic mice to fate map the Pax7 lineage in neural crest derivates. We find that Pax7 descendants contribute to multiple tissues including the cranial, cardiac and trunk neural crest, which in the cranial cartilage form a distinct regional pattern. The Pax7 lineage, like the Pax3 lineage, is additionally detected in some non-neural crest tissues, including a subset of the epithelial cells in specific organs.These results demonstrate a previously unappreciated widespread distribution of Pax7 descendants within and beyond the neural crest. They shed light regarding the regionally distinct phenotypes observed in Pax3 and Pax7 mutants, and provide a unique perspective into the potential roles of Pax7 during disease and development.

  6. Neural crest stem cell population in craniomaxillofacial development and tissue repair

    Directory of Open Access Journals (Sweden)

    M La Noce

    2014-10-01

    Full Text Available Neural crest cells, delaminating from the neural tube during migration, undergo an epithelial-mesenchymal transition and differentiate into several cell types strongly reinforcing the mesoderm of the craniofacial body area – giving rise to bone, cartilage and other tissues and cells of this human body area. Recent studies on craniomaxillofacial neural crest-derived cells have provided evidence for the tremendous plasticity of these cells. Actually, neural crest cells can respond and adapt to the environment in which they migrate and the cranial mesoderm plays an important role toward patterning the identity of the migrating neural crest cells. In our experience, neural crest-derived stem cells, such as dental pulp stem cells, can actively proliferate, repair bone and give rise to other tissues and cytotypes, including blood vessels, smooth muscle, adipocytes and melanocytes, highlighting that their use in tissue engineering is successful. In this review, we provide an overview of the main pathways involved in neural crest formation, delamination, migration and differentiation; and, in particular, we concentrate our attention on the translatability of the latest scientific progress. Here we try to suggest new ideas and strategies that are needed to fully develop the clinical use of these cells. This effort should involve both researchers/clinicians and improvements in good manufacturing practice procedures. It is important to address studies towards clinical application or take into consideration that studies must have an effective therapeutic prospect for humans. New approaches and ideas must be concentrated also toward stem cell recruitment and activation within the human body, overcoming the classical grafting.

  7. Aebp2 as an epigenetic regulator for neural crest cells.

    Directory of Open Access Journals (Sweden)

    Hana Kim

    Full Text Available Aebp2 is a potential targeting protein for the mammalian Polycomb Repression Complex 2 (PRC2. We generated a mutant mouse line disrupting the transcription of Aebp2 to investigate its in vivo roles. Aebp2-mutant homozygotes were embryonic lethal while heterozygotes survived to adulthood with fertility. In developing mouse embryos, Aebp2 is expressed mainly within cells of neural crest origin. In addition, many heterozygotes display a set of phenotypes, enlarged colon and hypopigmentation, similar to those observed in human patients with Hirschsprung's disease and Waardenburg syndrome. These phenotypes are usually caused by the absence of the neural crest-derived ganglia in hindguts and melanocytes. ChIP analyses demonstrated that the majority of the genes involved in the migration and development process of neural crest cells are downstream target genes of AEBP2 and PRC2. Furthermore, expression analyses confirmed that some of these genes are indeed affected in the Aebp2 heterozygotes. Taken together, these results suggest that Aebp2 may regulate the migration and development of the neural crest cells through the PRC2-mediated epigenetic mechanism.

  8. Giant Congenital Melanocytic Nevus

    DEFF Research Database (Denmark)

    Rasmussen, Bo Sonnich; Henriksen, Trine Foged; Kølle, Stig-Frederik Trojahn

    2015-01-01

    Giant congenital melanocytic nevi (GCMN) occur in 1:20,000 livebirths and are associated with increased risk of malignant transformation. The treatment of GCMN from 1981 to 2010 in a tertiary referral center was reviewed evaluating the modalities used, cosmetic results, associated complications...

  9. Development of teeth in chick embryos after mouse neural crest transplantations.

    Science.gov (United States)

    Mitsiadis, Thimios A; Chéraud, Yvonnick; Sharpe, Paul; Fontaine-Pérus, Josiane

    2003-05-27

    Teeth were lost in birds 70-80 million years ago. Current thinking holds that it is the avian cranial neural crest-derived mesenchyme that has lost odontogenic capacity, whereas the oral epithelium retains the signaling properties required to induce odontogenesis. To investigate the odontogenic capacity of ectomesenchyme, we have used neural tube transplantations from mice to chick embryos to replace the chick neural crest cell populations with mouse neural crest cells. The mouse/chick chimeras obtained show evidence of tooth formation showing that avian oral epithelium is able to induce a nonavian developmental program in mouse neural crest-derived mesenchymal cells.

  10. Adipose stromal cells contain phenotypically distinct adipogenic progenitors derived from neural crest.

    Directory of Open Access Journals (Sweden)

    Yoshihiro Sowa

    Full Text Available Recent studies have shown that adipose-derived stromal/stem cells (ASCs contain phenotypically and functionally heterogeneous subpopulations of cells, but their developmental origin and their relative differentiation potential remain elusive. In the present study, we aimed at investigating how and to what extent the neural crest contributes to ASCs using Cre-loxP-mediated fate mapping. ASCs harvested from subcutaneous fat depots of either adult P0-Cre/or Wnt1-Cre/Floxed-reporter mice contained a few neural crest-derived ASCs (NCDASCs. This subpopulation of cells was successfully expanded in vitro under standard culture conditions and their growth rate was comparable to non-neural crest derivatives. Although NCDASCs were positive for several mesenchymal stem cell markers as non-neural crest derivatives, they exhibited a unique bipolar or multipolar morphology with higher expression of markers for both neural crest progenitors (p75NTR, Nestin, and Sox2 and preadipocytes (CD24, CD34, S100, Pref-1, GATA2, and C/EBP-delta. NCDASCs were able to differentiate into adipocytes with high efficiency but their osteogenic and chondrogenic potential was markedly attenuated, indicating their commitment to adipogenesis. In vivo, a very small proportion of adipocytes were originated from the neural crest. In addition, p75NTR-positive neural crest-derived cells were identified along the vessels within the subcutaneous adipose tissue, but they were negative for mural and endothelial markers. These results demonstrate that ASCs contain neural crest-derived adipocyte-restricted progenitors whose phenotype is distinct from that of non-neural crest derivatives.

  11. Oral melanocytic nevi: Report of two cases with immunohistochemical elaboration of their probable origin and maturation

    Directory of Open Access Journals (Sweden)

    Dipti Dutta

    2015-01-01

    Full Text Available Oral melanocytic nevi are localized developmental tissue malformations of nevus cells in the oral mucosa. Relatively rare in occurrence compared to their dermal counterparts, considerable debate exists in the literature related to their origin, development and maturation, and their relationship to oral melanocytes.We report two cases of oral melanocytic nevi with classical clinical presentation. The histopathology was consistent with the known patterns of oral melanocytic nevi. Special stains such as Masson Fontana, further substantiated the observation. S-100 and HMB-45 were applied to immunohistochemically elaborate the cell population. Interestingly two distinct cell populations were detected in the lesions. "Type A" cells in the center of the lesion were S-100 positive, indicating a neural origin and immaturity in development, while peripheral "type B" cells stained positive with HMB-45, indicating melanocytic origin and mature development.

  12. Neurally Derived Tissues in Xenopus laevis Embryos Exhibit a Consistent Bioelectrical Left-Right Asymmetry

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    Vaibhav P. Pai

    2012-01-01

    Full Text Available Consistent left-right asymmetry in organ morphogenesis is a fascinating aspect of bilaterian development. Although embryonic patterning of asymmetric viscera, heart, and brain is beginning to be understood, less is known about possible subtle asymmetries present in anatomically identical paired structures. We investigated two important developmental events: physiological controls of eye development and specification of neural crest derivatives, in Xenopus laevis embryos. We found that the striking hyperpolarization of transmembrane potential (Vmem demarcating eye induction usually occurs in the right eye field first. This asymmetry is randomized by perturbing visceral left-right patterning, suggesting that eye asymmetry is linked to mechanisms establishing primary laterality. Bilateral misexpression of a depolarizing channel mRNA affects primarily the right eye, revealing an additional functional asymmetry in the control of eye patterning by Vmem. The ATP-sensitive K+ channel subunit transcript, SUR1, is asymmetrically expressed in the eye primordia, thus being a good candidate for the observed physiological asymmetries. Such subtle asymmetries are not only seen in the eye: consistent asymmetry was also observed in the migration of differentiated melanocytes on the left and right sides. These data suggest that even anatomically symmetrical structures may possess subtle but consistent laterality and interact with other developmental left-right patterning pathways.

  13. Mammalian melanocytes and radiations

    International Nuclear Information System (INIS)

    Hirobe, Tomohisa

    2008-01-01

    Melanocytes (M) decide the skin and hair color through the synthesis of melanine pigment, which is transported via their melanosome to keratinocytes (K) for body color expression in animals. This paper describes mainly author's studies of M concerning effects of ultraviolet (UV), ionizing radiation and heavy ion (carbon ion) beam on their development and differentiation together with its mechanism. In vitro, studies of UV effect on proliferation and differentiation of M and melanoblast (MB) have been greatly advanced since their culturing in serum-free media became possible using cells from author's black-mouse (C57BL/10JHir strain): Their mixed culture with K firstly revealed that their proliferation and differentiation were enhanced by UV irradiation. The important K's factor to regulate M/MB cells was identified to be GMCSF (granulocyte-macrophage colony-stimulating factor). In vivo studies of the skin color of the black-mouse before and after birth were performed using radiations like 60 Co gamma ray and high linear energy transfer (LET) carbon ion beam and have revealed that abnormal proliferation and differentiation of M/MB, which were expressed as white spot formation, death and mal-differentiation of M/MB, were induced dose-, LET- and developmental stage-dependently. (R.T.)

  14. Bilateral diffuse uveal melanocytic proliferation

    DEFF Research Database (Denmark)

    Klemp, Kristian; Kiilgaard, Jens Folke; Heegaard, Steffen

    2017-01-01

    cataract formation and uveal melanocytic tumours. The awareness and documentation of BDUMP has increased during the past decade, and the increasing amount of data collected demonstrates the effect of treatment with plasmapheresis and the value of diagnostic tools in BDUMP such as genetic and immunologic...

  15. Ecto-mesenchymal stem cells from dental pulp are committed to differentiate into active melanocytes

    Directory of Open Access Journals (Sweden)

    F Paino

    2010-10-01

    Full Text Available Dental pulp stem cells (DPSCs are multipotent stem cells derived from neural crest and mesenchyme and have the capacity to differentiate into multiple cell lineages. It has already been demonstrated that DPSCs differentiate into melanocyte-like cells but only when cultivated in a specific melanocyte differentiating medium. In this study we have shown, for the first time, that DPSCs are capable of spontaneously differentiating into mature melanocytes, which display molecular and ultrastructural features of full development, including the expression of melanocyte specific markers and the presence of melanosomes up to the terminal stage of maturation. We have also compared the differentiating features of DPSCs grown in different culture conditions, following the timing of differentiation at molecular and cytochemical levels and found that in all culture conditions full development of these cells was obtained, although at different times. The spontaneous differentiating potential of these cells strongly suggests their possible applications in regenerative medicine.

  16. Development of teeth in chick embryos after mouse neural crest transplantations

    OpenAIRE

    Mitsiadis, Thimios A.; Chéraud, Yvonnick; Sharpe, Paul; Fontaine-Pérus, Josiane

    2003-01-01

    Teeth were lost in birds 70–80 million years ago. Current thinking holds that it is the avian cranial neural crest-derived mesenchyme that has lost odontogenic capacity, whereas the oral epithelium retains the signaling properties required to induce odontogenesis. To investigate the odontogenic capacity of ectomesenchyme, we have used neural tube transplantations from mice to chick embryos to replace the chick neural crest cell populations with mouse neural crest cells. The mouse/chick ...

  17. Melanocyte colonization and pigmentation of breast carcinoma

    DEFF Research Database (Denmark)

    Mele, Marco; Laurberg, Tinne; Engberg Damsgaard, Tine

    2012-01-01

    . The pathogenesis by which melanocyte migration takes place is not known, but a breached basement membrane is considered essential. Conclusion. Histological examination and additional staining of skin are essential to differentiate breast cancer melanosis from malignant melanoma.......Introduction. Melanocyte colonization of breast carcinoma by nonneoplastic melanocytes of epidermal origin is a rare and serious condition first described in 1977. We report on the exceptional clinical and pathological features of this migration phenomenon in a 74-year-old patient. Discussion...

  18. A subpopulation of smooth muscle cells, derived from melanocyte-competent precursors, prevents patent ductus arteriosus.

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    Ichiro Yajima

    Full Text Available BACKGROUND: Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA, a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2 and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes.

  19. A Subpopulation of Smooth Muscle Cells, Derived from Melanocyte-Competent Precursors, Prevents Patent Ductus Arteriosus

    Science.gov (United States)

    Puig, Isabel; Champeval, Delphine; Kumasaka, Mayuko; Belloir, Elodie; Bonaventure, Jacky; Mark, Manuel; Yamamoto, Hiroaki; Taketo, Mark M.; Choquet, Philippe; Etchevers, Heather C.; Beermann, Friedrich; Delmas, Véronique; Monassier, Laurent; Larue, Lionel

    2013-01-01

    Background Patent ductus arteriosus is a life-threatening condition frequent in premature newborns but also present in some term infants. Current mouse models of this malformation generally lead to perinatal death, not reproducing the full phenotypic spectrum in humans, in whom genetic inheritance appears complex. The ductus arteriosus (DA), a temporary fetal vessel that bypasses the lungs by shunting the aortic arch to the pulmonary artery, is constituted by smooth muscle cells of distinct origins (SMC1 and SMC2) and many fewer melanocytes. To understand novel mechanisms preventing DA closure at birth, we evaluated the importance of cell fate specification in SMC that form the DA during embryonic development. Upon specific Tyr::Cre-driven activation of Wnt/β-catenin signaling at the time of cell fate specification, melanocytes replaced the SMC2 population of the DA, suggesting that SMC2 and melanocytes have a common precursor. The number of SMC1 in the DA remained similar to that in controls, but insufficient to allow full DA closure at birth. Thus, there was no cellular compensation by SMC1 for the loss of SMC2. Mice in which only melanocytes were genetically ablated after specification from their potential common precursor with SMC2, demonstrated that differentiated melanocytes themselves do not affect DA closure. Loss of the SMC2 population, independent of the presence of melanocytes, is therefore a cause of patent ductus arteriosus and premature death in the first months of life. Our results indicate that patent ductus arteriosus can result from the insufficient differentiation, proliferation, or contractility of a specific smooth muscle subpopulation that shares a common neural crest precursor with cardiovascular melanocytes. PMID:23382837

  20. Conjunctival Melanocytic Tumors-New Developments

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    Hülya Gökmen Soysal

    2014-09-01

    Full Text Available Melanocytic lesions of the conjunctiva represent a wide spectrum of tumors that include benign, premalignant, and malignant tumors. There are many ongoing arguments about the definition, classification, and therapeutic options of the conjunctival melanocytic tumors with many different suggestions. Conjunctival nevi are the most common melanocytic tumors and their risk of malignant transformation is less than1%. Primary acquired melanosis (PAM histopathologically includes various types of lesions from increased melanin pigmentation without melanocyte proliferation to melanoma in situ and is accepted as a clinical definition, so that a new classification is recommended which is based on more objective criteria than before. Although conjunctival melanoma is seen rarely, it is associated with a high mortality rate. Management of these tumors mainly involves surgery and adjuvant topical chemotherapy, cryotherapy, and radiation therapy that help improving the survival, however, new options are being investigated related to genetic and molecular researches. (Turk J Ophthalmol 2014; 44: Supplement 15-21

  1. Sema4D, the ligand for Plexin B1, suppresses c-Met activation and migration and promotes melanocyte survival and growth.

    Science.gov (United States)

    Soong, Joanne; Chen, Yulin; Shustef, Elina M; Scott, Glynis A

    2012-04-01

    Semaphorins are secreted and membrane-bound proteins involved in neural pathfinding, organogenesis, and tumor progression, through Plexin and neuropilin receptors. We recently reported that Plexin B1, the Semaphorin 4D (Sema4D) receptor, is a tumor-suppressor protein for melanoma, which functions, in part, through inhibition of the oncogenic c-Met tyrosine kinase receptor. In this report, we show that Sema4D is a protective paracrine factor for normal human melanocyte survival in response to UV irradiation, and that it stimulates proliferation and regulates the activity of the c-Met receptor. c-Met receptor signaling stimulates melanocyte migration, partly through downregulation of the cell adhesion molecule E-cadherin. Sema4D suppressed activation of c-Met in response to its ligand, hepatocyte growth factor (HGF), and partially blocked the suppressive effects of HGF on E-cadherin expression in melanocytes and HGF-dependent migration. These data demonstrate a role for Plexin B1 in maintenance of melanocyte survival and proliferation in the skin, and suggest that Sema4D and Plexin B1 act cooperatively with HGF and c-Met to regulate c-Met-dependent effects in human melanocytes. Because our data show that Plexin B1 is profoundly downregulated by UVB in melanocytes, loss of Plexin B1 may accentuate HGF-dependent effects on melanocytes, including melanocyte migration.

  2. Human melanocytes form a PAX3-expressing melanocyte cluster on Matrigel by the cell migration process.

    Science.gov (United States)

    Choi, Hyunjung; Jin, Sun Hee; Han, Mi Hwa; Lee, Jinyoung; Ahn, Seyeon; Seong, Minjeong; Choi, Hyun; Han, Jiyeon; Cho, Eun-Gyung; Lee, Tae Ryong; Noh, Minsoo

    2014-10-01

    The interactions between human epidermal melanocytes and their cellular microenvironment are important in the regulation of human melanocyte functions or in their malignant transformation into melanoma. Although the basement membrane extracellular matrix (BM-ECM) is one of major melanocyte microenvironments, the effects of BM-ECM on the human melanocyte functions are not fully explained at a molecular level. This study was aimed to characterize the molecular and cellular interactions between normal human melanocytes (NHMs) and BM-ECM. We investigated cell culture models of normal human melanocytes or melanoma cells on three-dimensional (3D) Matrigel to understand the roles of the basement membrane microenvironment in human melanocyte functions. Melanogenesis and melanobast biomarker expression in both primary human melanocytes and melanoma cells on 3D Matrigel were evaluated. We found that NHMs migrated and formed reversible paired box 3 (PAX3) expressing cell clusters on three-dimensional (3D) Matrigel. The melanogenesis was significantly decreased in the PAX3 expressing cell cluster. The expression profile of PAX3, SOX10, and MITF in the melanocyte cluster on 3D Matrigel was similar to that of melanoblasts. Interestingly, PAX3 and SOX10 showed an inverse expression profile in NHMs, whereas the inverse expression pattern of PAX3 and SOX10 was disrupted in melanoma MNT1 and WM266-4 cells. The human melanocyte culture on 3D Matrigel provides an alternative model system to study functions of human melanoblasts. In addition, this system will contribute to the elucidation of PAX3-related tumorigenic mechanisms to understand human melanoma. Copyright © 2014 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  3. Neural crest contributions to the lamprey head

    Science.gov (United States)

    McCauley, David W.; Bronner-Fraser, Marianne

    2003-01-01

    The neural crest is a vertebrate-specific cell population that contributes to the facial skeleton and other derivatives. We have performed focal DiI injection into the cranial neural tube of the developing lamprey in order to follow the migratory pathways of discrete groups of cells from origin to destination and to compare neural crest migratory pathways in a basal vertebrate to those of gnathostomes. The results show that the general pathways of cranial neural crest migration are conserved throughout the vertebrates, with cells migrating in streams analogous to the mandibular and hyoid streams. Caudal branchial neural crest cells migrate ventrally as a sheet of cells from the hindbrain and super-pharyngeal region of the neural tube and form a cylinder surrounding a core of mesoderm in each pharyngeal arch, similar to that seen in zebrafish and axolotl. In addition to these similarities, we also uncovered important differences. Migration into the presumptive caudal branchial arches of the lamprey involves both rostral and caudal movements of neural crest cells that have not been described in gnathostomes, suggesting that barriers that constrain rostrocaudal movement of cranial neural crest cells may have arisen after the agnathan/gnathostome split. Accordingly, neural crest cells from a single axial level contributed to multiple arches and there was extensive mixing between populations. There was no apparent filling of neural crest derivatives in a ventral-to-dorsal order, as has been observed in higher vertebrates, nor did we find evidence of a neural crest contribution to cranial sensory ganglia. These results suggest that migratory constraints and additional neural crest derivatives arose later in gnathostome evolution.

  4. DNA methyltransferase 3b is dispensable for mouse neural crest development.

    Directory of Open Access Journals (Sweden)

    Bridget T Jacques-Fricke

    Full Text Available The neural crest is a population of multipotent cells that migrates extensively throughout vertebrate embryos to form diverse structures. Mice mutant for the de novo DNA methyltransferase DNMT3b exhibit defects in two neural crest derivatives, the craniofacial skeleton and cardiac ventricular septum, suggesting that DNMT3b activity is necessary for neural crest development. Nevertheless, the requirement for DNMT3b specifically in neural crest cells, as opposed to interacting cell types, has not been determined. Using a conditional DNMT3b allele crossed to the neural crest cre drivers Wnt1-cre and Sox10-cre, neural crest DNMT3b mutants were generated. In both neural crest-specific and fully DNMT3b-mutant embryos, cranial neural crest cells exhibited only subtle migration defects, with increased numbers of dispersed cells trailing organized streams in the head. In spite of this, the resulting cranial ganglia, craniofacial skeleton, and heart developed normally when neural crest cells lacked DNMT3b. This indicates that DNTM3b is not necessary in cranial neural crest cells for their development. We conclude that defects in neural crest derivatives in DNMT3b mutant mice reflect a requirement for DNMT3b in lineages such as the branchial arch mesendoderm or the cardiac mesoderm that interact with neural crest cells during formation of these structures.

  5. Gene expression analysis of zebrafish melanocytes, iridophores, and retinal pigmented epithelium reveals indicators of biological function and developmental origin.

    Directory of Open Access Journals (Sweden)

    Charles W Higdon

    Full Text Available In order to facilitate understanding of pigment cell biology, we developed a method to concomitantly purify melanocytes, iridophores, and retinal pigmented epithelium from zebrafish, and analyzed their transcriptomes. Comparing expression data from these cell types and whole embryos allowed us to reveal gene expression co-enrichment in melanocytes and retinal pigmented epithelium, as well as in melanocytes and iridophores. We found 214 genes co-enriched in melanocytes and retinal pigmented epithelium, indicating the shared functions of melanin-producing cells. We found 62 genes significantly co-enriched in melanocytes and iridophores, illustrative of their shared developmental origins from the neural crest. This is also the first analysis of the iridophore transcriptome. Gene expression analysis for iridophores revealed extensive enrichment of specific enzymes to coordinate production of their guanine-based reflective pigment. We speculate the coordinated upregulation of specific enzymes from several metabolic pathways recycles the rate-limiting substrate for purine synthesis, phosphoribosyl pyrophosphate, thus constituting a guanine cycle. The purification procedure and expression analysis described here, along with the accompanying transcriptome-wide expression data, provide the first mRNA sequencing data for multiple purified zebrafish pigment cell types, and will be a useful resource for further studies of pigment cell biology.

  6. Prostaglandin production by melanocytic cells and the effect of alpha-melanocyte stimulating hormone.

    Science.gov (United States)

    Nicolaou, Anna; Estdale, Sian E; Tsatmali, Marina; Herrero, Daniel Pascual; Thody, Anthony J

    2004-07-16

    Prostaglandins are potent mediators of the inflammatory response and are also involved in cancer development. In this study, we show that human melanocytes and FM55 melanoma cells express cyclooxygenase-1 and -2 (COX-1 and -2) and thus have the capability to produce prostaglandins. The FM55 cells produced predominantly PGE2 and PGF2alpha, whereas the HaCaT keratinocyte cell line produced mainly PGE2. The anti-inflammatory peptide, alpha-melanocyte stimulating hormone (alpha-MSH), reduced prostaglandin production in FM55 and HaCaT cells and reversed the effect of the pro-inflammatory cytokine TNF-alpha in the former. These results indicate that melanocytes produce prostaglandins and that alpha-MSH, by inhibiting this response, may play an important role in regulating inflammatory responses in the skin.

  7. Growth of melanocytes in human epidermal cell cultures

    International Nuclear Information System (INIS)

    Staiano-Coico, L.; Hefton, J.M.; Amadeo, C.; Pagan-Charry, I.; Madden, M.R.; Cardon-Cardo, C.

    1990-01-01

    Epidermal cell cultures were grown in keratinocyte-conditioned medium for use as burn wound grafts; the melanocyte composition of the grafts was studied under a variety of conditions. Melanocytes were identified by immunohistochemistry based on a monoclonal antibody (MEL-5) that has previously been shown to react specifically with melanocytes. During the first 7 days of growth in primary culture, the total number of melanocytes in the epidermal cultures decreased to 10% of the number present in normal skin. Beginning on day 2 of culture, bipolar melanocytes were present at a mean cell density of 116 +/- 2/mm2; the keratinocyte to melanocyte ratio was preserved during further primary culture and through three subpassages. Moreover, exposure of cultures to mild UVB irradiation stimulated the melanocytes to proliferate, suggesting that the melanocytes growing in culture maintained their responsiveness to external stimuli. When the sheets of cultured cells were enzymatically detached from the plastic culture flasks before grafting, melanocytes remained in the basal layer of cells as part of the graft applied to the patient

  8. Stage-specific control of neural crest stem cell proliferation by the small rho GTPases Cdc42 and Rac1

    DEFF Research Database (Denmark)

    Fuchs, Sebastian; Herzog, Dominik; Sumara, Grzegorz

    2009-01-01

    -renewal and proliferation of later stage, but not early migratory NCSCs. This stage-specific requirement for small Rho GTPases is due to changes in NCSCs that, during development, acquire responsiveness to mitogenic EGF acting upstream of both Cdc42 and Rac1. Thus, our data reveal distinct mechanisms for growth control......The neural crest (NC) generates a variety of neural and non-neural tissues during vertebrate development. Both migratory NC cells and their target structures contain cells with stem cell features. Here we show that these populations of neural crest-derived stem cells (NCSCs) are differentially...

  9. Spontaneous regression of a congenital melanocytic nevus

    Directory of Open Access Journals (Sweden)

    Amiya Kumar Nath

    2011-01-01

    Full Text Available Congenital melanocytic nevus (CMN may rarely regress which may also be associated with a halo or vitiligo. We describe a 10-year-old girl who presented with CMN on the left leg since birth, which recently started to regress spontaneously with associated depigmentation in the lesion and at a distant site. Dermoscopy performed at different sites of the regressing lesion demonstrated loss of epidermal pigments first followed by loss of dermal pigments. Histopathology and Masson-Fontana stain demonstrated lymphocytic infiltration and loss of pigment production in the regressing area. Immunohistochemistry staining (S100 and HMB-45, however, showed that nevus cells were present in the regressing areas.

  10. Melanocytic nevi and non-neoplastic hyperpigmentations.

    Science.gov (United States)

    Clemente, C

    2017-06-01

    This is the first of three chapters that will be progressively published on Pathologica as updating activity of the Italian Study Group of Dermatopathology (GISD), Italian Society of Pathology and Cytology (SIAPeC IAP). The first chapter concerns non-neoplastic hyperpigmented skin lesions and nevi, the second will address the topics of dysplastic nevus, borderline and low malignant potential melanocytic proliferations and the third melanoma in its variants and differential diagnoses with a supplement on the immunohistochemistry and molecular support to diagnostic and prognostic definition of nevi and melanomas. Although we believe that great advances were made in the application of ancillary genetic, immunohistochemical and molecular techniques, for the diagnosis and biological characterization of melanocytic tumors the morphology still remains the gold standard. These chapters are not intended as substitutes or even claim to be compared to the numerous and valuable texts that are also recently published, but they want to present, concisely and quickly available, all of those traits that we believe essential to the histopathological evaluation of a melanocytic lesion. No morphological parameter is exclusive and individually sufficient to make the correct diagnosis of nevus or melanoma but to reach a final conclusive and appropriate interpretation a set of morphological characters must be evaluated and compared. I was lucky enough to be able to examine several thousand cases and to draw lessons from each of these increasing my diagnostic experience. I had a great lesson by my teacher and good friend Prof. Martin C. Mihm Jr of Boston, dermato-pathologist with undisputed international reputation, who, with great passion, patience and friendship, transferred me much of his experience and knowledge and for which I always thank him. Special thanks I would like to address Dr. Agostino Crupi, dermatologist, skin-oncologist and brilliant dermatoscopist who taught me how the

  11. Neurotized congenital melanocytic nevus resembling a pigmented neurofibroma

    Directory of Open Access Journals (Sweden)

    Nidhi Singh

    2015-01-01

    Full Text Available Neurotized congenital melanocytic nevus and pigmented neurofibroma (PNF are close mimics and pose a clinicopathological challenge. We present a case of pigmented hypertrichotic plaque over lumbosacral region and discuss the differential diagnosis and its clinical, histopathological and immunohistochemistry features which may aid in differentiation. We highlight the difficulties faced in differentiating neurotized congenital melanocytic nevus from pigmented neurofibroma.

  12. Early diagnosis and successful treatment of paraneoplastic melanocytic proliferation.

    Science.gov (United States)

    Jansen, Joyce C G; Van Calster, Joachim; Pulido, Jose S; Miles, Sarah L; Vile, Richard G; Van Bergen, Tine; Cassiman, Catherine; Spielberg, Leigh H; Leys, Anita M

    2015-07-01

    Paraneoplastic melanocytic proliferation (bilateral diffuse uveal melanocytic proliferation, BDUMP) is a rare but devastating disease that causes progressive visual loss in patients who usually have an occult malignancy. Visual loss occurs as a result of paraneoplastic changes in the uveal tissue. In a masked fashion, the serum of two patients with BDUMP was evaluated for the presence of cultured melanocyte elongation and proliferation (CMEP) factor using cultured human melanocytes. We evaluated the efficacy of plasmapheresis as a treatment modality early in the disease in conjunction with radiation and chemotherapy. The serum of the first case patient was investigated after plasmapheresis and did not demonstrate proliferation of cultured human melanocytes. The serum of the second case was evaluated prior to treatment with plasmapheresis and did induce this proliferation. These findings are in accordance with the diminution of CMEP factor after plasmapheresis. Treatment with plasmapheresis managed to stabilise the ocular disease progression in both patients. In the past, visual loss due to paraneoplastic melanocytic proliferation was considered progressive and irreversible. We treated two patients successfully with plasmapheresis and demonstrated a relation between CMEP factor in the serum of these patients and proliferation of cultured melanocytes. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

  13. Diprosopia revisited in light of the recognized role of neural crest cells in facial development.

    Science.gov (United States)

    Carles, D; Weichhold, W; Alberti, E M; Léger, F; Pigeau, F; Horovitz, J

    1995-01-01

    The aim of this study is to compare the theory of embryogenesis of the face with human diprosopia. This peculiar form of conjoined twinning is of great interest because 1) only the facial structures are duplicated and 2) almost all cases have a rather monomorphic pattern. The hypothesis is that an initial duplication of the notochord leads to two neural plates and subsequently duplicated neural crests. In those conditions, derivatives of the neural crests will be partially or totally duplicated; therefore, in diprosopia, the duplicated facial structures would be considered to be neural crest derivatives. If these structures are identical to those that are experimentally demonstrated to be neural crest derivatives in animals, these findings are an argument to apply this theory of facial embryogenesis in man. Serial horizontal sections of the face of two diprosopic fetuses (11 and 21 weeks gestation) were studied macro- and microscopically to determine the external and internal structures that are duplicated. Complete postmortem examination was performed in search for additional malformations. The face of both fetuses showed a very similar morphologic pattern with duplication of ocular, nasal, and buccal structures. The nasal fossae and the anterior part of the tongue were also duplicated, albeit the posterior part and the pharyngolaryngeal structures were unique. Additional facial clefts were present in both fetuses. Extrafacial anomalies were represented by a craniorachischisis, two fused vertebral columns and, in the older fetus, by a complex cardiac malformation morphologically identical to malformations induced by removal or grafting of additional cardiac neural crest cells in animals. These pathological findings could identify the facial structures that are neural crest derivatives in man. They are similar to those experimentally demonstrated to be neural crest derivatives in animals. In this respect, diprosopia could be considered as the end of a spectrum

  14. Requirement for Foxd3 in the maintenance of neural crest progenitors.

    Science.gov (United States)

    Teng, Lu; Mundell, Nathan A; Frist, Audrey Y; Wang, Qiaohong; Labosky, Patricia A

    2008-05-01

    Understanding the molecular mechanisms of stem cell maintenance is crucial for the ultimate goal of manipulating stem cells for the treatment of disease. Foxd3 is required early in mouse embryogenesis; Foxd3(-/-) embryos fail around the time of implantation, cells of the inner cell mass cannot be maintained in vitro, and blastocyst-derived stem cell lines cannot be established. Here, we report that Foxd3 is required for maintenance of the multipotent mammalian neural crest. Using tissue-specific deletion of Foxd3 in the neural crest, we show that Foxd3(flox/-); Wnt1-Cre mice die perinatally with a catastrophic loss of neural crest-derived structures. Cranial neural crest tissues are either missing or severely reduced in size, the peripheral nervous system consists of reduced dorsal root ganglia and cranial nerves, and the entire gastrointestinal tract is devoid of neural crest derivatives. These results demonstrate a global role for this transcriptional repressor in all aspects of neural crest maintenance along the anterior-posterior axis, and establish an unprecedented molecular link between multiple divergent progenitor lineages of the mammalian embryo.

  15. Neural Crossroads in the Hematopoietic Stem Cell Niche.

    Science.gov (United States)

    Agarwala, Sobhika; Tamplin, Owen J

    2018-05-29

    The hematopoietic stem cell (HSC) niche supports steady-state hematopoiesis and responds to changing needs during stress and disease. The nervous system is an important regulator of the niche, and its influence is established early in development when stem cells are specified. Most research has focused on direct innervation of the niche, however recent findings show there are different modes of neural control, including globally by the central nervous system (CNS) and hormone release, locally by neural crest-derived mesenchymal stem cells, and intrinsically by hematopoietic cells that express neural receptors and neurotransmitters. Dysregulation between neural and hematopoietic systems can contribute to disease, however new therapeutic opportunities may be found among neuroregulator drugs repurposed to support hematopoiesis. Copyright © 2018 Elsevier Ltd. All rights reserved.

  16. Role of Melanin in Melanocyte Dysregulation of Reactive Oxygen Species

    Directory of Open Access Journals (Sweden)

    Noah C. Jenkins

    2013-01-01

    Full Text Available We have recently reported a potential alternative tumor suppressor function for p16 relating to its capacity to regulate oxidative stress and observed that oxidative dysregulation in p16-depleted cells was most profound in melanocytes, compared to keratinocytes or fibroblasts. Moreover, in the absence of p16 depletion or exogenous oxidative insult, melanocytes exhibited significantly higher basal levels of reactive oxygen species (ROS than these other epidermal cell types. Given the role of oxidative stress in melanoma development, we speculated that this increased susceptibility of melanocytes to oxidative stress (and greater reliance on p16 for suppression of ROS may explain why genetic compromise of p16 is more commonly associated with predisposition to melanoma rather than other cancers. Here we show that the presence of melanin accounts for this differential oxidative stress in normal and p16-depleted melanocytes. Thus the presence of melanin in the skin appears to be a double-edged sword: it protects melanocytes as well as neighboring keratinocytes in the skin through its capacity to absorb UV radiation, but its synthesis in melanocytes results in higher levels of intracellular ROS that may increase melanoma susceptibility.

  17. Melanogenesis in dermal melanocytes of Japanese Silky chicken embryos.

    Science.gov (United States)

    Ortolani-Machado, C F; Freitas, P F; Faraco, C D

    2009-08-01

    The Japanese Silky chicken (SK) shows dermal and visceral hyperpigmentation. This study characterizes ultrastructurally the melanin granules developing in dermal melanocytes of the dorsal skin of SK, in an attempt to better understand the processes of melanogenesis in these permanently ectopic cells. The steps of melanogenesis are similar to those described for epidermal melanocytes, with melanosomes going from stage I to IV but, in SK, the maturation occurs in the cell body, as well as in the cytoplasmic processes. At stage III, the deposition of melanin is cumulative and can aggregate in rounded structures, which combine to turn into the mature granule. The final destiny of mature melanosomes is still unclear, although it was observed that dermal macrophages can accumulate melanin granules in their phagosomes. Even with the close proximity between melanocytes and other dermal cells, the transference of melanosomes was not observed. Our findings indicate that melanogenesis in dermal melanocytes in SK has the same morphological characteristics found in epidermal melanocytes, but the functional aspect still remains to be elucidated.

  18. Hesperetin induces melanin production in adult human epidermal melanocytes.

    Science.gov (United States)

    Usach, Iris; Taléns-Visconti, Raquel; Magraner-Pardo, Lorena; Peris, José-Esteban

    2015-06-01

    One of the major sources of flavonoids for humans are citrus fruits, hesperidin being the predominant flavonoid. Hesperetin (HSP), the aglycon of hesperidin, has been reported to provide health benefits such as antioxidant, anti-inflammatory and anticarcinogenic effects. However, the effect of HSP on skin pigmentation is not clear. Some authors have found that HSP induces melanogenesis in murine B16-F10 melanoma cells, which, if extrapolated to in vivo conditions, might protect skin against photodamage. Since the effect of HSP on normal melanocytes could be different to that observed on melanoma cells, the described effect of HSP on murine melanoma cells has been compared to the effect obtained using normal human melanocytes. HSP concentrations of 25 and 50 µM induced melanin synthesis and tyrosinase activity in human melanocytes in a concentration-dependent manner. Compared to control melanocytes, 25 µM HSP increased melanin production and tyrosinase activity 1.4-fold (p melanin production in human melanocyte cultures could be reproduced on human skin. Copyright © 2015 Elsevier Ltd. All rights reserved.

  19. Does Melanoma Begin in a Melanocyte Stem Cell

    International Nuclear Information System (INIS)

    Hoerter, J. D.; Bradley, P.; Casillas, A.; Chambers, D.; Weiswasser, B.; Clements, L.; Gilbert, S.; Jiao, A.

    2012-01-01

    What is the cellular origin of melanoma? What role do melanocyte stem cells (MSC) and other melanocyte precursors play in the development of melanoma? Are MSCs and other latent melanocyte precursors more susceptible to solar radiation? These and many other questions can be very effectively addressed using the zebra fish model. Zebra fish have a robust regenerative capability, permitting the study of how MSCs are regulated and recruited at specific times and places to generate the pigment pattern following fin amputation or melanocyte ablation. They can be used to determine the effects of environmental radiation on the proliferation, survival, repair, and differentiation of MSCs. Our lab is using zebra fish to investigate how UVA- (320-400nm) and UVB- (290-320nm) induced damage to MSCs may contribute to the development of melanoma. A review is given of MSCs in zebrafish as well as experimental techniques and drugs for manipulating MSC populations. These techniques can be used to design experiments to help answer many questions regarding the role of MSCs or melanocyte precursors in the formation of melanoma stem cells and tumors following exposure to UVA/UVB radiation.

  20. Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects.

    NARCIS (Netherlands)

    Blokx, W.A.M.; Dijk, M.C.R.F. van; Ruiter, D.J.

    2010-01-01

    This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect

  1. Molecular cytogenetics of cutaneous melanocytic lesions - diagnostic, prognostic and therapeutic aspects

    NARCIS (Netherlands)

    Blokx, Willeke Am M.; van Dijk, Marcory C. R. F.; Ruiter, Dirk J.

    This review intends to update current knowledge regarding molecular cytogenetics in melanocytic tumours with a focus on cutaneous melanocytic lesions. Advantages and limitations of diverse, already established methods, such as (fluorescence) in situ hybridization and mutation analysis, to detect

  2. High-definition optical coherence tomography imaging of melanocytic lesions

    DEFF Research Database (Denmark)

    Boone, Marc A L M; Norrenberg, Sarah; Jemec, Gregor B E

    2014-01-01

    and cytologic features of melanocytic lesions. All lesions were examined by one observer clinically and using dermoscopy. Cross-sectional HD-OCT images were compared with histopathology. En face HD-OCT images were compared with reflectance confocal microscopy (RCM). Twenty-six melanocytic lesions of 26 patients...... with sufficient resolution and penetration depth to discriminate architectural patterns and cytologic features of pigmented cells in epidermis and dermis. The method appears to offer the possibility of additional three-dimensional structural information complementary to that of RCM, albeit at a slightly lower...

  3. The epidermal melanocyte system in individuals of Scandinavian origin, determined by DOPA-staining and TEM

    DEFF Research Database (Denmark)

    Drzewiecki, K T; Piltz-Drzewiecka, J

    1979-01-01

    The quantitative evaluation of DOPA-positive epidermal melanocytes in 16 patients of Scandinavian origin showed both individual and regional differences in the melanocyte count. Our data is in agreement with other published studies. The distribution in the number of melanocytes varies significant...

  4. FISH analysis for diagnostic evaluation of challenging melanocytic lesions.

    Science.gov (United States)

    Zimmermann, A K; Hirschmann, A; Pfeiffer, D; Paredes, B E; Diebold, J

    2010-09-01

    The differential diagnosis of malignant melanomas and atypical melanocytic nevi is still a diagnostic challenge. The currently accepted morphologic criteria show substantial interobserver variability, likewise immunohistochemical studies are often not able to discriminate these lesions reliably. Techniques that support diagnostic accuracy are of the greatest importance considering the growing incidence of malignant melanomas and their increase in younger patients. In this study we analyzed the feasibility of fluorescence in situ hybridization (FISH) analysis for the discrimination of malignant and benign melanocytic tumors. A panel of DNA probes was used to detect chromosomal aberrations of chromosomes 6 and 11. On a series of 5 clearly malignant and benign melanocytic tumors we confirmed the applicability of the test. Then we focused on examination of ambiguous melanocytic lesions, where atypical cells are often difficult to relocalize in the 4',6-Diamidino-2-phenylindol (DAPI)-fluorescence stain. FISH analyses were conducted on destained H&E-stained slides. By comparison of the DAPI-image with photos taken from the H&E stain, unambiguous assignment of the FISH results to the conspicuous groups of cells was possible. The results of FISH analysis were consistent with the conventional diagnosis in 11 of 14 small ambiguous lesions. Of the remaining 3 cases, 2 showed FISH-results close to the cut-off level. Comparison of FISH results on thin and thick sections revealed that the cut-off values have to be adapted for 2 microm destained sections. In conclusion, FISH analysis is a useful and applicable tool for assessment of even smallest melanocytic neoplasms, although there will remain unclear cases that cannot be solved even after additional FISH evaluation.

  5. Aberrant expression of HMB-45 in traumatized melanocytic nevi.

    Science.gov (United States)

    Leleux, Todd M; Prieto, Victor G; Diwan, A Hafeez

    2012-09-01

    Assessment of histologic and immunohistochemical maturation (with HMB-45 and anti-Ki-67) may be helpful in differentiating benign melanocytic nevi (BMN) from malignant melanoma. Recently, we reported loss of maturation and aberrant immunohistochemical findings in melanocytic nevi after liquid nitrogen cryotherapy (Adeniran et al, J Am Acad Dermatol 2009;61:341-5). Herein we report a similar phenomenon identified in traumatized melanocytic nevi (TMN). We sought to evaluate the histologic and immunohistochemical findings in early and late stages of traumatized nevi. Twenty-four cases of TMN were retrieved from the pathology archives. These were then assessed by two pathologists (T.L. and A.H.D.) using HMB-45 and MIB-1 (for Ki-67) antibodies. TMN showed some of the following findings: epidermal changes (parakeratosis, ulceration, serum crust, flattening of the epidermis) and dermal changes including fibrosis and the presence of melanophages. In some cases, there was architectural disorder of the overlying melanocytes, with crowding in the basal layer, but without significant pagetoid spread. Occasionally, the dermal scar contained larger, more epithelioid-appearing melanocytes than those beneath the scar. Fifty-four percent of TMN lacked obvious immunohistochemical maturation with HMB-45, since nevus cells within the scar or directly beneath it were strongly labeled. None of the TMN showed appreciable labeling for Ki-67. The exact clinical duration between trauma and biopsy could not be determined. Loss of maturation with HMB-45 in TMN can be a diagnostic pitfall in challenging cases. Concurrent evaluation of MIB-1 expression, along with the characteristic histologic features of trauma, should allow the correct diagnosis to be reached. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  6. AKT signaling displays multifaceted functions in neural crest development.

    Science.gov (United States)

    Sittewelle, Méghane; Monsoro-Burq, Anne H

    2018-05-31

    AKT signaling is an essential intracellular pathway controlling cell homeostasis, cell proliferation and survival, as well as cell migration and differentiation in adults. Alterations impacting the AKT pathway are involved in many pathological conditions in human disease. Similarly, during development, multiple transmembrane molecules, such as FGF receptors, PDGF receptors or integrins, activate AKT to control embryonic cell proliferation, migration, differentiation, and also cell fate decisions. While many studies in mouse embryos have clearly implicated AKT signaling in the differentiation of several neural crest derivatives, information on AKT functions during the earliest steps of neural crest development had remained relatively scarce until recently. However, recent studies on known and novel regulators of AKT signaling demonstrate that this pathway plays critical roles throughout the development of neural crest progenitors. Non-mammalian models such as fish and frog embryos have been instrumental to our understanding of AKT functions in neural crest development, both in neural crest progenitors and in the neighboring tissues. This review combines current knowledge acquired from all these different vertebrate animal models to describe the various roles of AKT signaling related to neural crest development in vivo. We first describe the importance of AKT signaling in patterning the tissues involved in neural crest induction, namely the dorsal mesoderm and the ectoderm. We then focus on AKT signaling functions in neural crest migration and differentiation. Copyright © 2018 Elsevier Inc. All rights reserved.

  7. Aqueous humor tyrosinase activity is indicative of iris melanocyte toxicity.

    Science.gov (United States)

    Mahanty, Sarmistha; Kawali, Ankush A; Dakappa, Shruthi Shirur; Mahendradas, Padmamalini; Kurian, Mathew; Kharbanda, Varun; Shetty, Rohit; Setty, Subba Rao Gangi

    2017-09-01

    Antibiotics such as fluoroquinolones (FQLs) are commonly used to treat ocular infections but are also known to cause dermal melanocyte toxicity. The release of dispersed pigments from the iris into the aqueous humor has been considered a possible ocular side effect of the systemic administration of FQLs such as Moxifloxacin, and this condition is known as bilateral acute iris transillumination (BAIT). Bilateral acute depigmentation of iris (BADI) is a similar condition, with iris pigment released into the aqueous, but it has not been reported as a side effect of FQL. Iris pigments are synthesized by the melanogenic enzyme tyrosinase (TYR) and can be detected but not quantified by using slit-lamp biomicroscopy. The correlation between dispersed pigments in the aqueous and the extent of melanocyte toxicity due to topical antibiotics in vivo is not well studied. Here, we aimed to study the effect of topical FQLs on iris tissue, the pigment release in the aqueous humor and the development of clinically evident iris atrophic changes. We evaluated this process by measuring the activity of TYR in the aqueous humor of 82 healthy eyes undergoing cataract surgery following topical application of FQLs such as Moxifloxacin (27 eyes, preservative-free) or Ciprofloxacin (29 eyes, with preservative) or the application of non-FQL Tobramycin (26 eyes, with preservative) as a control. In addition, the patients were questioned and examined for ocular side effects in pre- and post-operative periods. Our data showed a significantly higher mean TYR activity in the aqueous humor of Ciprofloxacin-treated eyes compared to Moxifloxacin- (preservative free, p iris melanocytes. However, the reduced TYR activity in the aqueous of Moxifloxacin-treated eyes was possibly due to the presence of a higher drug concentration, which inhibits TYR activity. Consistently, immunoblotting analysis of the aqueous humor from both Ciprofloxacin- and Moxifloxacin-treated eyes showed the presence of soluble

  8. Asymmetry and irregularity border as discrimination factor between melanocytic lesions

    Science.gov (United States)

    Sbrissa, David; Pratavieira, Sebastião.; Salvio, Ana Gabriela; Kurachi, Cristina; Bagnato, Vanderlei Salvadori; Costa, Luciano Da Fontoura; Travieso, Gonzalo

    2015-06-01

    Image processing tools have been widely used in systems supporting medical diagnosis. The use of mobile devices for the diagnosis of melanoma can assist doctors and improve their diagnosis of a melanocytic lesion. This study proposes a method of image analysis for melanoma discrimination from other types of melanocytic lesions, such as regular and atypical nevi. The process is based on extracting features related with asymmetry and border irregularity. It were collected 104 images, from medical database of two years. The images were obtained with standard digital cameras without lighting and scale control. Metrics relating to the characteristics of shape, asymmetry and curvature of the contour were extracted from segmented images. Linear Discriminant Analysis was performed for dimensionality reduction and data visualization. Segmentation results showed good efficiency in the process, with approximately 88:5% accuracy. Validation results presents sensibility and specificity 85% and 70% for melanoma detection, respectively.

  9. Ultraviolet radiation directly induces pigment production by cultured human melanocytes

    International Nuclear Information System (INIS)

    Friedmann, P.S.; Gilchrest, B.A.

    1987-01-01

    In humans the major stimulus for cutaneous pigmentation is ultraviolet radiation (UVR). Little is known about the mechanism underlying this response, in part because of the complexity of interactions in whole epidermis. Using a recently developed culture system, human melanocytes were exposed daily to a physiologic range of UVR doses from a solar simulator. Responses were determined 24 hours after the last exposure. There was a dose-related increase in melanin content per cell and uptake of 14 C-DOPA, accompanied by growth inhibition. Cells from donors of different racial origin gave proportionately similar increases in melanin, although there were approximately tenfold differences in basal values. Light and electron microscopy revealed UVR-stimulated increases in dendricity as well as melanosome number and degree of melanization, analogous to the well-recognized melanocyte changes following sun exposure of intact skin. Similar responses were seen with Cloudman S91 melanoma cells, although this murine cell line required lower UVR dosages and fewer exposures for maximal stimulation. These data establish that UVR is capable of directly stimulating melanogenesis. Because cyclic AMP elevation has been associated in some settings with increased pigment production by cultured melanocytes, preliminary experiments were conducted to see if the effects of UVR were mediated by cAMP. Both alpha-MSH and isobutylmethylxanthine (IBMX), as positive controls, caused a fourfold increase in cAMP level in human melanocytes and/or S91 cells, but following a dose of UVR sufficient to stimulate pigment production there was no change in cAMP level up to 4 hours after exposure. Thus, it appears that the UVR-induced melanogenesis is mediated by cAMP-independent mechanisms

  10. Automatic Classification of Specific Melanocytic Lesions Using Artificial Intelligence

    Directory of Open Access Journals (Sweden)

    Joanna Jaworek-Korjakowska

    2016-01-01

    Full Text Available Background. Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. Different computer-aided diagnosis (CAD systems have been proposed to increase the specificity and sensitivity of melanoma detection. Although such computer programs are developed for different diagnostic algorithms, to the best of our knowledge, a system to classify different melanocytic lesions has not been proposed yet. Method. In this research we present a new approach to the classification of melanocytic lesions. This work is focused not only on categorization of skin lesions as benign or malignant but also on specifying the exact type of a skin lesion including melanoma, Clark nevus, Spitz/Reed nevus, and blue nevus. The proposed automatic algorithm contains the following steps: image enhancement, lesion segmentation, feature extraction, and selection as well as classification. Results. The algorithm has been tested on 300 dermoscopic images and achieved accuracy of 92% indicating that the proposed approach classified most of the melanocytic lesions correctly. Conclusions. A proposed system can not only help to precisely diagnose the type of the skin mole but also decrease the amount of biopsies and reduce the morbidity related to skin lesion excision.

  11. Automatic Classification of Specific Melanocytic Lesions Using Artificial Intelligence.

    Science.gov (United States)

    Jaworek-Korjakowska, Joanna; Kłeczek, Paweł

    2016-01-01

    Given its propensity to metastasize, and lack of effective therapies for most patients with advanced disease, early detection of melanoma is a clinical imperative. Different computer-aided diagnosis (CAD) systems have been proposed to increase the specificity and sensitivity of melanoma detection. Although such computer programs are developed for different diagnostic algorithms, to the best of our knowledge, a system to classify different melanocytic lesions has not been proposed yet. In this research we present a new approach to the classification of melanocytic lesions. This work is focused not only on categorization of skin lesions as benign or malignant but also on specifying the exact type of a skin lesion including melanoma, Clark nevus, Spitz/Reed nevus, and blue nevus. The proposed automatic algorithm contains the following steps: image enhancement, lesion segmentation, feature extraction, and selection as well as classification. The algorithm has been tested on 300 dermoscopic images and achieved accuracy of 92% indicating that the proposed approach classified most of the melanocytic lesions correctly. A proposed system can not only help to precisely diagnose the type of the skin mole but also decrease the amount of biopsies and reduce the morbidity related to skin lesion excision.

  12. UVA phototransduction drives early melanin synthesis in human melanocytes.

    Science.gov (United States)

    Wicks, Nadine L; Chan, Jason W; Najera, Julia A; Ciriello, Jonathan M; Oancea, Elena

    2011-11-22

    Exposure of human skin to solar ultraviolet radiation (UVR), a powerful carcinogen [1] comprising ~95% ultraviolet A (UVA) and ~5% ultraviolet B (UVB) at the Earth's surface, promotes melanin synthesis in epidermal melanocytes [2, 3], which protects skin from DNA damage [4, 5]. UVB causes DNA lesions [6] that lead to transcriptional activation of melanin-producing enzymes, resulting in delayed skin pigmentation within days [7]. In contrast, UVA causes primarily oxidative damage [8] and leads to immediate pigment darkening (IPD) within minutes, via an unknown mechanism [9, 10]. No receptor protein directly mediating phototransduction in skin has been identified. Here we demonstrate that exposure of primary human epidermal melanocytes (HEMs) to UVA causes calcium mobilization and early melanin synthesis. Calcium responses were abolished by treatment with G protein or phospholipase C (PLC) inhibitors or by depletion of intracellular calcium stores. We show that the visual photopigment rhodopsin [11] is expressed in HEMs and contributes to UVR phototransduction. Upon UVR exposure, significant melanin production was measured within one hour; cellular melanin continued to increase in a retinal- and calcium-dependent manner up to 5-fold after 24 hr. Our findings identify a novel UVA-sensitive signaling pathway in melanocytes that leads to calcium mobilization and melanin synthesis and may underlie the mechanism of IPD in human skin. Copyright © 2011 Elsevier Ltd. All rights reserved.

  13. Melanoma and melanocytic nevi in decorative tattoos: three case reports.

    Science.gov (United States)

    Varga, Erika; Korom, Irma; Varga, János; Kohán, József; Kemény, Lajos; Oláh, Judit

    2011-12-01

    In response to the demands of style and fashion, the number of decorative tattoos has been increasing worldwide. This has been paralleled by a rising incidence of melanocytic proliferations, including melanoma. The coincidence of various dermatological diseases and skin tumors with tattoos has been documented with some frequency, but reports of melanoma associated with tattoos are exceedingly rare. To date, only 13 cases have been documented in the English language literature. The possibility of an association between melanocytic proliferations and tattoos remains an area for further study. This report presents two cases of melanocytic nevi and one of melanoma occurring in association with a decorative tattoos. At present, the pathogenesis of melanoma developing in a tattoo is unknown. Mere coincidence cannot be ruled out. However, trauma, ultraviolet light exposure, a photoallergic effect, or an inflammatory reaction may promote malignant transformation. Clinicians and histopathologists should be aware of the clinical and pathological features if they are to make a correct diagnosis. Copyright © 2011 John Wiley & Sons A/S.

  14. [Effect of Tribulus terrestris extract on melanocyte-stimulating hormone expression in mouse hair follicles].

    Science.gov (United States)

    Yang, Liu; Lu, Jian-wei; An, Jing; Jiang, Xuan

    2006-12-01

    To observe the effect of Tribulus terrestris extract on melanocyte stimulating hormone (MSH) expression in C57BL/6J mouse hair follicles, and investigate the role of Tribulus terrestris extract in activation, proliferation, epidermal migration of dormant hair follicle melanocytes. The aqueous extract of Tribulus terrestris was administered orally in specific pathogen-free C57BL/6J mouse at the daily dose equivalent to 1 g/1 kg in adult human, and the expression and distribution of MSH in the mouse hair follicles was observed with immunohistochemistry. The positivity rate of MSH expression in the hair follicle melanocytes was 75% in mice treated with the extract, significantly higher than the rate of only 18.75% in the control group (PTribulus terrestris can significantly increase MSH expression in the hair follicle melanocytes by activating tyrosinase activity and promoting melanocyte proliferation, melanine synthesis, and epidermal migration of dormant melanocytes.

  15. A rare case of unilateral diffuse melanocytic proliferation

    Directory of Open Access Journals (Sweden)

    Guruprasad Ayachit

    2018-01-01

    Full Text Available A 67-year-old woman presented with metamorphopsia in the right eye. Leopard mottling was seen temporal to the fovea oculus dexter with corresponding hyper- and hypo-autofluorescent lesions on fundus autofluorescence. Spectral domain-optical coherence tomography revealed hyperreflective dots in the retinal pigment epithelium and choroid with subretinal fluid (SRF. Intravitreal bevacizumab was administered with which SRF resolved, albeit with increase in the areas of mottling. The patient was diagnosed to have metastatic ductal carcinoma of the right breast. It is important to bear in mind that the well-known entity of bilateral diffuse uveal melanocytic proliferation can rarely present unilaterally.

  16. The slaty mutation affects the morphology and maturation of melanosomes in the mouse melanocytes.

    Science.gov (United States)

    Hirobe, Tomohisa; Abe, Hiroyuki

    2006-10-01

    The slaty (Dct(slt)) mutation is known to reduce the activity of dopachrome tautomerase in melanocytes and to reduce the melanin content in skin, hairs and eyes. Although the melanosomes in slaty melanocytes are reported to be eumelanosome-like, detailed melanosome biogenesis is not well studied. To address this point, melanosomes in neonatal epidermal melanocytes from wild-type (Dct+/Dct+) mice at the slaty locus as well as its congenic mouse mutant (Dct(slt)/Dct(slt)) in serum-free primary culture were observed under the electron microscope. Wild-type melanocytes possessed exclusively elliptical melanosomes with internal longitudinal structures, whereas in mutant melanocytes, numerous spherical melanosomes with globular depositions of pigment and elliptical melanosomes as well as mixed type of the two melanosomes were observed. Mature stage IV melanosomes were greatly decreased in mutant melanocytes, whereas immature stage III melanosomes were more numerous than in wild-type melanocytes. These results suggest that the slaty mutation affects the morphology and maturation of melanosomes in mouse melanocytes.

  17. Heme oxygenase-1 expression protects melanocytes from stress-induced cell death: implications for vitiligo

    NARCIS (Netherlands)

    Elassiuty, Yasser E.; Klarquist, Jared; Speiser, Jodi; Yousef, Randa M.; El Refaee, Abdelaziz A.; Hunter, Nahla S.; Shaker, Olfat G.; Gundeti, Mohan; Nieuweboer-Krobotova, Ludmila; Caroline Le Poole, I.

    2011-01-01

    To study protection of melanocytes from stress-induced cell death by heme oxygenases during depigmentation and repigmentation in vitiligo, expression of isoforms 1 and 2 was studied in cultured control and patient melanocytes and normal skin explants exposed to UV or bleaching agent 4-TBP.

  18. Inhibition of systemic inflammation by central action of the neuropeptide alpha-melanocyte- stimulating hormone.

    Science.gov (United States)

    Delgado Hernàndez, R; Demitri, M T; Carlin, A; Meazza, C; Villa, P; Ghezzi, P; Lipton, J M; Catania, A

    1999-01-01

    The neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) reduces fever and acute inflammation in the skin when administered centrally. The aim of the present research was to determine whether central alpha-MSH can also reduce signs of systemic inflammation in mice with endotoxemia. Increases in serum tumor necrosis factor-alpha and nitric oxide, induced by intraperitoneal administration of endotoxin, were modulated by central injection of a small concentration of alpha-MSH. Inducible nitric oxide synthase (iNOS) activity and iNOS mRNA in lungs and liver were likewise modulated by central alpha-MSH. Lung myeloperoxidase activity, a marker of neutrophil infiltration, was increased in endotoxemic mice; the increase was significantly less in lungs of mice treated with central alpha-MSH. Intraperitoneal administration of the small dose of alpha-MSH that was effective centrally did not alter any of the markers of inflammation. In experiments using immunoneutralization of central alpha-MSH, we tested the idea that endogenous peptide induced within the brain during systemic inflammation modulates host responses to endotoxic challenge in peripheral tissues. The data showed that proinflammatory agents induced by endotoxin in the circulation, lungs, and liver were significantly greater after blockade of central alpha-MSH. The results suggest that anti-inflammatory influences of neural origin that are triggered by alpha-MSH could be used to treat systemic inflammation.

  19. Melanocyte-secreted fibromodulin promotes an angiogenic microenvironment.

    Science.gov (United States)

    Adini, Irit; Ghosh, Kaustabh; Adini, Avner; Chi, Zai-Long; Yoshimura, Takeru; Benny, Ofra; Connor, Kip M; Rogers, Michael S; Bazinet, Lauren; Birsner, Amy E; Bielenberg, Diane R; D'Amato, Robert J

    2014-01-01

    Studies have established that pigmentation can provide strong, protective effects against certain human diseases. For example, angiogenesis-dependent diseases such as wet age-related macular degeneration and infantile hemangioma are more common in light-skinned individuals of mixed European descent than in African-Americans. Here we found that melanocytes from light-skinned humans and albino mice secrete high levels of fibromodulin (FMOD), which we determined to be a potent angiogenic factor. FMOD treatment stimulated angiogenesis in numerous in vivo systems, including laser-induced choroidal neovascularization, growth factor-induced corneal neovascularization, wound healing, and Matrigel plug assays. Additionally, FMOD enhanced vascular sprouting during normal retinal development. Deletion of Fmod in albino mice resulted in a marked reduction in the amount of neovascularization induced by retinal vein occlusion, corneal growth factor pellets, and Matrigel plugs. Our data implicate the melanocyte-secreted factor FMOD as a key regulator of angiogenesis and suggest an underlying mechanism for epidemiological differences between light-skinned individuals of mixed European descent and African-Americans. Furthermore, inhibition of FMOD in humans has potential as a therapeutic strategy for treating angiogenesis-dependent diseases.

  20. [Alpha-melanocyte-stimulating hormone. From bench to bedside].

    Science.gov (United States)

    Böhm, M; Luger, T A

    2010-06-01

    Alpha-melanocyte-stimulating hormone (alpha-MSH) is a tridecapeptide that is produced by the skin itself from the precursor proopiomelanocortin. It crucially mediates ultraviolet light-induced tanning after binding to melanocortin-1 receptors (MC-1R) expressed on the surface of epidermal melanocytes. The potent pigment-inducing and also cytoprotective actions of alpha-MSH are the rationale for the performance of first phase II clinical trials with Nle4-D-Phe7-alpha-MSH (NDP-alpha-MSH), a subcutaneously administered synthetic and superpotent alpha-MSH analogue, in patients with photodermatoses such as erythropoietic protoporphyria. Since alpha-MSH has shown promising anti-inflammatory and antifibrotic properties in numerous preclinical studies, it will be most interesting to evaluate these effects in further clinical pilot studies with NDP-alpha-MSH. In addition to alpha-MSH analogues, truncated tripeptides such as KDPT which do not bind to MC-1R but have sustained anti-inflammatory properties are currently emerging as another novel therapeutic strategy in dermatology.

  1. YY1 regulates melanocyte development and function by cooperating with MITF.

    Directory of Open Access Journals (Sweden)

    Juying Li

    Full Text Available Studies of coat color mutants have greatly contributed to the discovery of genes that regulate melanocyte development and function. Here, we generated Yy1 conditional knockout mice in the melanocyte-lineage and observed profound melanocyte deficiency and premature gray hair, similar to the loss of melanocytes in human piebaldism and Waardenburg syndrome. Although YY1 is a ubiquitous transcription factor, YY1 interacts with M-MITF, the Waardenburg Syndrome IIA gene and a master transcriptional regulator of melanocytes. YY1 cooperates with M-MITF in regulating the expression of piebaldism gene KIT and multiple additional pigmentation genes. Moreover, ChIP-seq identified genome-wide YY1 targets in the melanocyte lineage. These studies mechanistically link genes implicated in human conditions of melanocyte deficiency and reveal how a ubiquitous factor (YY1 gains lineage-specific functions by co-regulating gene expression with a lineage-restricted factor (M-MITF-a general mechanism which may confer tissue-specific gene expression in multiple lineages.

  2. Protective Effect of HemoHIM on Epidermal Melanocytes in Ultraviolet-B irradiated Mice

    Energy Technology Data Exchange (ETDEWEB)

    Lee, Hae June [Korea Institute of Radiological and Medical Science, Seoul (Korea, Republic of); Kim, Jong Choon; Moon, Chang Jong; Kim, Sung Ho [Chonnam National University, Gwangju (Korea, Republic of); Jung, U Hee; Park, Hae Ran; Jo, Sung Kee [Jeongeup Campus of Korea Atomic Energy Research Institute, Jeongeup (Korea, Republic of); Jang, Jong Sik; Kim, Tae Hwan [Kyungpook National University, Daegu (Korea, Republic of)

    2011-06-15

    We induced the activation of melanocytes in the epidermis of C57BL/6 mice by ultraviolet-B (UV-B) irradiation, and observed the effect of an herbal preparation (HemoHIM, HH) on the formation, and decrease of UV-B-induced epidermal melanocytes. C57BL/6 mice were irradiated by UV-B 80 mJ:cm{sup -2} (0.5 mW:sec{sup -1}) daily for 7 days, and HH was intraperitoneally, orally or topically applied pre- or post-irradiation. For the estimation of change of epidermal melanocytes, light microscopic observation with dihydroxyphenylalanine (DOPA) stain was performed. Split epidermal sheets prepared from the ear of untreated mice exhibited 13∼15 melanocytes:mm{sup -2}, and one week after UV irradiation, the applied areas showed an increased number of strongly DOPA-positive melanocytes with stout dendrites. But intraperitoneal, oral or topical treatment with HH before each irradiation interrupted UV-B-induced pigmentation and resulted in a marked reduction in the number of epidermal melanocytes as compared to the number found in UV-B-irradiated, untreated control skin. The number and size of DOPA-positive epidermal melanocytes were also significantly decreased in intraperitoneally injected or topically applicated group after irradiation with HH at 3rd and 6th weeks after irradiation. The present study suggests the HH as inhibitor of UV-B-induced pigmentation, and depigmenting agent.

  3. Melanocyte pigmentation inversely correlates with MCP-1 production and angiogenesis-inducing potential.

    Science.gov (United States)

    Adini, Irit; Adini, Avner; Bazinet, Lauren; Watnick, Randolph S; Bielenberg, Diane R; D'Amato, Robert J

    2015-02-01

    The incidence of certain angiogenesis-dependent diseases is higher in Caucasians than in African Americans. Angiogenesis is amplified in wound healing and cornea models in albino C57 mice compared with black C57 mice. Moreover, mouse and human melanocytes with low pigmentation stimulate endothelial cell (EC) proliferation and migration in vitro more than melanocytes with high pigmentation. This effect is due, in part, to the secretion of an angiogenic protein called fibromodulin (FMOD) from lowly pigmented melanocytes. Herein, we expand upon the mechanism contributing to increased angiogenesis in lighter skin and report that monocyte chemotactic protein-1 (MCP-1) is secreted by nonpigmented mouse melanocytes by 5- to 10-fold more than pigmented melanocytes. MCP-1 protein stimulates EC proliferation and migration in vitro and angiogenesis in vivo. Mechanistic studies determine that FMOD is upstream of MCP-1 and promotes its secretion from both melanocytes and activated ECs via stimulation of NF-κB activity. Mice injected with FMOD-neutralizing antibodies show 2.3-fold decreased levels of circulating MCP-1. Human studies confirmed that, on average, Caucasians have 2-fold higher serum levels of MCP-1 than African Americans. Taken together, this study implicates the FMOD/MCP-1 pathway in the regulation of angiogenesis by local melanocytes and suggests that melanogenic activity may protect against aberrant angiogenic diseases. © FASEB.

  4. PREFERENTIAL SECRETION OF INDUCIBLE HSP70 BY VITILIGO MELANOCYTES UNDER STRESS

    Science.gov (United States)

    Mosenson, Jeffrey A.; Flood, Kelsey; Klarquist, Jared; Eby, Jonathan M.; Koshoffer, Amy; Boissy, Raymond E.; Overbeck, Andreas; C.Tung, Rebecca; Poole, I. Caroline Le

    2014-01-01

    SUMMARY Inducible HSP70 (HSP70i) chaperones peptides from stressed cells, protecting them from apoptosis. Upon extracellular release, HSP70i serves an adjuvant function, enhancing immune responses to bound peptides. We questioned whether HSP70i differentially protects control and vitiligo melanocytes from stress and subsequent immune responses. We compared expression of HSP70i in skin samples, evaluated the viability of primary vitiligo and control melanocytes exposed to bleaching phenols, and measured secreted HSP70i. We determined whether HSP70i traffics to melanosomes to contact immunogenic proteins by cell fractionation, western blotting, electron microscopy and confocal microscopy. Viability of vitiligo and control melanocytes was equally affected under stress. However, vitiligo melanocytes secreted increased amounts of HSP70i in response to MBEH, corroborating with aberrant HSP70i expression in patient skin. Intracellular HSP70i colocalized with melanosomes, and more so in response to MBEH in vitiligo melanocytes. Thus whereas either agent is cytotoxic to melanocytes, MBEH preferentially induces immune responses to melanocytes. PMID:24354861

  5. Ocular Albinism Type 1 Regulates Melanogenesis in Mouse Melanocytes

    Directory of Open Access Journals (Sweden)

    Tianzhi Chen

    2016-09-01

    Full Text Available To investigate whether ocular albinism type 1 (OA1 is differentially expressed in the skin of mice with different coat colors and to determine its correlation with coat color establishment in mouse, the expression patterns and tissue distribution characterization of OA1 in the skin of mice with different coat colors were qualitatively and quantitatively analyzed by real-time quantitative PCR (qRT-PCR, immunofluorescence staining and Western blot. The qRT-PCR analysis revealed that OA1 mRNA was expressed in all mice skin samples tested, with the highest expression level in brown skin, a moderate expression level in black skin and the lowest expression level in gray skin. Positive OA1 protein bands were also detected in all skin samples by Western blot analysis. The relative expression levels of OA1 protein in both black and brown skin were significantly higher than that in gray skin, but there was no significant difference between black and brown mice. Immunofluorescence assays revealed that OA1 was mainly expressed in the hair follicle matrix, the inner and outer root sheath in the skin tissues with different coat colors. To get further insight into the important role of OA1 in the melanocytes’ pigmentation, we transfected the OA1 into mouse melanocytes and then detected the relative expression levels of pigmentation-related gene. Simultaneously, we tested the melanin content of melanocytes. As a result, the overexpression of OA1 significantly increased the expression levels of microphthalmia-associated transcription factor (MITF, tyrosinase (TYR, tyrosinase-related protein 1 (TRP1 and premelanosome protein (PMEL. However, the tyrosinase-related protein 2 (TRP2 level was attenuated. By contrast, the level of glycoprotein non-metastatic melanoma protein b (GPNMB was unaffected by OA1 overexpression. Furthermore, we observed a significant increase in melanin content in mouse melanocyte transfected OA1. Therefore, we propose that OA1 may

  6. Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

    International Nuclear Information System (INIS)

    Chantarawong, Wipa; Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki; Pradermwong, Kantimanee; Shibahara, Shigeki

    2014-01-01

    Highlights: • In human melanocytes, cadmium decreases the expression of MITF-M and tyrosinase and their mRNAs. • In human melanoma cells, cadmium decreases the expression of MITF-M protein and tyrosinase mRNA. • Expression of MITF-H is less sensitive to cadmium toxicity in melanocyte-linage cells. • Cadmium does not decrease the expression of MITF-H in retinal pigment epithelial cells. • MITF-M is the molecular target of cadmium toxicity in melanocytes. - Abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure

  7. Population-Based Analysis of Histologically Confirmed Melanocytic Proliferations Using Natural Language Processing.

    Science.gov (United States)

    Lott, Jason P; Boudreau, Denise M; Barnhill, Ray L; Weinstock, Martin A; Knopp, Eleanor; Piepkorn, Michael W; Elder, David E; Knezevich, Steven R; Baer, Andrew; Tosteson, Anna N A; Elmore, Joann G

    2018-01-01

    Population-based information on the distribution of histologic diagnoses associated with skin biopsies is unknown. Electronic medical records (EMRs) enable automated extraction of pathology report data to improve our epidemiologic understanding of skin biopsy outcomes, specifically those of melanocytic origin. To determine population-based frequencies and distribution of histologically confirmed melanocytic lesions. A natural language processing (NLP)-based analysis of EMR pathology reports of adult patients who underwent skin biopsies at a large integrated health care delivery system in the US Pacific Northwest from January 1, 2007, through December 31, 2012. Skin biopsy procedure. The primary outcome was histopathologic diagnosis, obtained using an NLP-based system to process EMR pathology reports. We determined the percentage of diagnoses classified as melanocytic vs nonmelanocytic lesions. Diagnoses classified as melanocytic were further subclassified using the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) reporting schema into the following categories: class I (nevi and other benign proliferations such as mildly dysplastic lesions typically requiring no further treatment), class II (moderately dysplastic and other low-risk lesions that may merit narrow reexcision with skin biopsies, performed on 47 529 patients, were examined. Nearly 1 in 4 skin biopsies were of melanocytic lesions (23%; n = 18 715), which were distributed according to MPATH-Dx categories as follows: class I, 83.1% (n = 15 558); class II, 8.3% (n = 1548); class III, 4.5% (n = 842); class IV, 2.2% (n = 405); and class V, 1.9% (n = 362). Approximately one-quarter of skin biopsies resulted in diagnoses of melanocytic proliferations. These data provide the first population-based estimates across the spectrum of melanocytic lesions ranging from benign through dysplastic to malignant. These results may serve as a foundation for future

  8. Microphthalmia-associated transcription factor as the molecular target of cadmium toxicity in human melanocytes

    Energy Technology Data Exchange (ETDEWEB)

    Chantarawong, Wipa [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Inter Departmental Multidisciplinary Graduate Program in Bioscience, Faculty of Science, Kasetsart University, Bangkok (Thailand); Takeda, Kazuhisa; Sangartit, Weerapon; Yoshizawa, Miki [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan); Pradermwong, Kantimanee [Department of Zoology, Faculty of Science, Kasetsart University, Bangkok (Thailand); Shibahara, Shigeki, E-mail: shibahar@med.tohoku.ac.jp [Department of Molecular Biology and Applied Physiology, Tohoku University School of Medicine, Sendai (Japan)

    2014-11-28

    Highlights: • In human melanocytes, cadmium decreases the expression of MITF-M and tyrosinase and their mRNAs. • In human melanoma cells, cadmium decreases the expression of MITF-M protein and tyrosinase mRNA. • Expression of MITF-H is less sensitive to cadmium toxicity in melanocyte-linage cells. • Cadmium does not decrease the expression of MITF-H in retinal pigment epithelial cells. • MITF-M is the molecular target of cadmium toxicity in melanocytes. - Abstract: Dietary intake of cadmium is inevitable, causing age-related increase in cadmium accumulation in many organs, including hair, choroid and retinal pigment epithelium (RPE). Cadmium has been implicated in the pathogenesis of hearing loss and macular degeneration. The functions of cochlea and retina are maintained by melanocytes and RPE, respectively, and the differentiation of these pigment cells is regulated by microphthalmia-associated transcription factor (MITF). In the present study, we explored the potential toxicity of cadmium in the cochlea and retina by using cultured human melanocytes and human RPE cell lines. MITF consists of multiple isoforms, including melanocyte-specific MITF-M and widely expressed MITF-H. Levels of MITF-M protein and its mRNA in human epidermal melanocytes and HMV-II melanoma cells were decreased significantly by cadmium. In parallel with the MITF reduction, mRNA levels of tyrosinase, the key enzyme of melanin biosynthesis that is regulated by MITF-M, were also decreased. In RPE cells, however, the levels of total MITF protein, constituting mainly MITF-H, were not decreased by cadmium. We thus identify MITF-M as the molecular target of cadmium toxicity in melanocytes, thereby accounting for the increased risk of disability from melanocyte malfunction, such as hearing and vision loss among people with elevated cadmium exposure.

  9. The relationship between Na+/H+ exchanger expression and tyrosinase activity in human melanocytes

    International Nuclear Information System (INIS)

    Smith, Dustin R.; Spaulding, Deborah T.; Glenn, Hayden M.; Fuller, Bryan B.

    2004-01-01

    The activity of melanosome-associated tyrosinase in human melanocytes differs based on racial skin type. In melanocytes from Black skin, tyrosinase activity is high while in White melanocytes the activity of the enzyme is low. Recent studies suggest that low tyrosinase activity in White melanocytes may be due to an acidic pH environment within the melanosome. Because sodium/hydrogen (Na + /H + ) exchangers (NHEs) are known to regulate intracellular pH, melanocytes were treated with NHE inhibitors to determine what effect this inhibition might have on tyrosinase activity. Treatment of Black melanocytes with ethyl-isopropyl amiloride (EIPA) caused a rapid dose-dependent inhibition of tyrosinase activity. This inhibition was not due to either direct enzyme inhibition or to a decrease in tyrosinase abundance. In contrast, treatment of White melanocytes with EIPA, cimetidine, or clonidine resulted in little inhibition of tyrosinase activity. Reverse transcriptase-polymerase chain reaction (RT-PCR) and Western blot analysis showed that both Black and White melanocytes expressed mRNA and protein for NHE-1, NHE-3, NHE-5, NHE-6, and NHE-7. Immunohistochemical analysis showed that NHE-7 and NHE-3 co-localized with the melanosomal protein, Tyrosinase Related Protein-1 (TRP-1). In addition, the vesicular proton pump, vesicular ATPase (V-ATPase), was found to be present in both White and Black melanosomes, indicating that organelles from both racial skin types are capable of being acidified. The results suggest that one or more NHEs may help regulate melanosome pH and tyrosinase activity in human melanocytes

  10. Expression of cytosolic NADP(+)-dependent isocitrate dehydrogenase in melanocytes and its role as an antioxidant.

    Science.gov (United States)

    Kim, Ji Young; Shin, Jae Yong; Kim, Miri; Hann, Seung-Kyung; Oh, Sang Ho

    2012-02-01

    Cytosolic NADP(+)-dependent ICDH (IDPc) has an antioxidant effect as a supplier of NADPH to the cytosol, which is needed for the production of glutathione. To evaluate the expression of IDPc in melanocytes and to elucidate its role as an antioxidant. The knock-down of IDPc expression in immortalized mouse melanocyte cell lines (melan-a) was performed using the short interfering RNA (siRNA)-targeted gene silencing method. After confirming the silencing of IDPc expression with mRNA and protein levels, viability, apoptosis and necrosis, as well as ROS production in IDPc-silenced melanocytes were monitored under conditions of oxidative stress and non-stress. Also, the ratio of oxidized glutathione to total glutathione was examined, and whether the addition of glutathione recovered cell viability, decreased by oxidant stress, was checked. The expression of IDPc in both primary human melanocytes and melan-a cells was confirmed by Western blot and RT-PCR. The silencing of IDPc expression by transfecting IDPc siRNA in melan-a cells was observed by Western blotting and real-time RT-PCR. IDPc knock-down cells showed significantly decreased cell viability and an increased number of cells under apoptosis and necrosis. IDPc siRNA-treated melanocytes demonstrated a higher intensity of DCFDA after the addition of H(2)O(2) compared with scrambled siRNA-treated melanocytes, and a lower ratio of reduced glutathione to oxidized glutathione were observed in IDPc siRNA transfected melanocytes. In addition, the addition of glutathione recovered cell viability, which was previously decreased after incubation with H(2)O(2). This study suggests that decreased IDPc expression renders melanocytes more vulnerable to oxidative stress, and IDPc plays an important antioxidant function in melanocytes. Copyright © 2011 Japanese Society for Investigative Dermatology. Published by Elsevier Ireland Ltd. All rights reserved.

  11. Association between melanocytic neoplasms and seborrheic keratosis: more than a coincidental collision?

    Science.gov (United States)

    DeFazio, Jennifer; Zalaudek, Iris; Busam, Klaus J.; Cota, Carlo; Marghoob, Ashfaq

    2012-01-01

    Clinical observations and an expanding knowledge of cell-to-cell communication have led us to speculate that the finding of a melanocytic nevus in conjunction with a seborrheic keratosis is more than a coincidental collision of two lesions. Here we present five cases demonstrating dermoscopic features of both melanocytic lesions and seborrheic keratoses with corresponding histology. Four cases demonstrate dermoscopic features of a melanocytic nevus and seborrheic keratosis, and the final case a melanoma arising in association with a seborrheic keratosis. PMID:23785597

  12. Isolation, Culture, and Motility Measurements of Epidermal Melanocytes from GFP-Expressing Reporter Mice.

    Science.gov (United States)

    Dagnino, Lina; Crawford, Melissa

    2018-03-27

    In this article, we provide a method to isolate primary epidermal melanocytes from reporter mice, which also allow targeted gene inactivation. The mice from which these cells are isolated are bred into a Rosa26 mT/mG reporter background, which results in GFP expression in the targeted melanocytic cell population. These cells are isolated and cultured to >95% purity. The cells can be used for gene expression studies, clonogenic experiments, and biological assays, such as capacity for migration. Melanocytes are slow moving cells, and we also provide a method to measure motility using individual cell tracking and data analysis.

  13. alpha-Melanocyte-stimulating-hormone precursors in the pig pituitary

    DEFF Research Database (Denmark)

    Fenger, M

    1986-01-01

    The occurrence of intermediates from the processing of ACTH-(1-39) [adrenocorticotropic hormone-(1-39)] to alpha-melanocyte-stimulating hormone was investigated in normal pig pituitaries by the use of sensitive and specific radioimmunoassays for ACTH-(1-13), ACTH-(1-14), ACTH-(1-13)-NH2 and ACTH-(1......) were detected in lower amounts in both the intermediate lobe and the anterior lobe. ACTH-(1-17), ACTH-(1-13) and their acetylated analogues could not be detected in the anterior lobe or the intermediate lobe. The results suggest that an endopeptidase initially cleaves ACTH-(1-39) at the Lys-16-Arg-17...... bond. ACTH-(1-16) is then processed by a pituitary carboxypeptidase to ACTH-(1-14) and ACTH-(17-39) by the aminopeptidase to ACTH-(18-39)....

  14. Isolation and culture of melanocytes from the arctic fox (Alopex lagopus

    Directory of Open Access Journals (Sweden)

    Jiarong Bao

    2015-09-01

    Full Text Available Coat colour is a phenotypic marker of fur animal species, which was determined by the pigment generated from melanocytes. In this study, we developed and validated a method for isolation, purification and passage culture of melanocytes from the arctic fox (Alopex lagopus. Skin biopsies were harvested from the dorsal region of adult foxes and enzyme digestion by Dispase II. The primary culture of melanocytes from arctic fox skin was obtained by using keratinocyte serum-free medium supplemented with epidermal growth factor and bovine pituitary extract with/without phorbol- 12-myristate-13-acetate, and by carrying out a medium change strategy. After serial passages, it yielded pure population of melanocytes, which become efficient tools for investigating the function of colour genes and unraveling the process of melanin synthesis.

  15. Coat-sleeve type giant congenital melanocytic nevus with intraoral blue nevus: A rare case report

    Directory of Open Access Journals (Sweden)

    Lata M Kale

    2017-01-01

    Full Text Available Congenital melanocytic nevi (CMN are visible hyperpigmented (melanocytic, benign, tumor like proliferations in the skin resulting from faulty development of pigment cell precursors in the embryo, and are composed of an abnormal mixture of skin elements. Giant congenital melanocytic nevus (GCMN is usually defined as a melanocytic lesion present at birth that will reach a larger size in adulthood. GCMN is a rare variety of CMN which is characterized by its size (diameter ≥20 cm and the potential for malignant transformation. It is infrequently associated with other findings, which makes the clinical picture complex. In this case, we report a rare association of GCMN with intraoral blue nevus in a 24-year-old male patient.

  16. Blood Supply--Susceptible Formation of Melanin Pigment in Hair Bulb Melanocytes of Mice

    Directory of Open Access Journals (Sweden)

    Shogo Maeda, MD

    2015-03-01

    Conclusions: Melanin pigment formation in the hair bulb melanocytes appeared to be susceptible to the blood supply, and melanocytosis was promoted in the follicles and in the epidermis of Kitl-Tg C57BL/6 mice.

  17. Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization

    OpenAIRE

    Poorman, Kelsey; Borst, Luke; Moroff, Scott; Roy, Siddharth; Labelle, Philippe; Motsinger-Reif, Alison; Breen, Matthew

    2014-01-01

    Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address t...

  18. Image enhancement of optical images for binary system of melanocytes and keratinocytes

    Science.gov (United States)

    Takanezawa, S.; Baba, A.; Sako, Y.; Ozaki, Y.; Date, A.; Toyama, K.; Morita, S.

    2013-05-01

    Automatic determination of the cell shapes of large numbers of melanocytes based on optical images of human skin models have been largely unsuccessful (the complexities introduced by dendrites and the melanin pigmentation over the keratinocytes to give unclear outlines). Here, we present an image enhancement procedure for enhancing the contrast of images with removing the non-uniformity of background. The brightness is normalized also for the non-uniform population density of melanocytes.

  19. Pigmentation, Melanocyte Colonization, and p53 Status in Basal Cell Carcinoma

    International Nuclear Information System (INIS)

    Frey, L. M.; Houben, R.; Brocker, E. B.

    2011-01-01

    Basal cell carcinoma (BCC) is the most common neoplasm in the Caucasian population. Only a fraction of BCC exhibits pigmentation. Lack of melanocyte colonization has been suggested to be due to p53-inactivating mutations in the BCC cells interfering with the p53-proopiomelanocortin pathway and the production of alpha melanocyte-stimulating hormone in the tumor. To evaluate this, we determined tumor pigmentation as well as expression of melan-A and of p53 in 49 BCC tissues by means of immunohistochemistry. As expected, we observed a positive relation between tumor pigmentation and melan-A positive intra-tumoral melanocytes. Melanocyte colonization and, to a lesser extent, p53 overexpression showed intraindividual heterogeneity in larger tumors. p53 overexpression, which is indicative of p53 mutations, was not correlated to melanocyte colonization of BCC. Sequencing of exon 5-8 of the p53 gene in selected BCC cases revealed that colonization by melanocytes and BCC pigmentation is neither ablated by p53 mutations nor generally present in BCCs with wild-type p53.

  20. Substantial Effect of Melanin Influencing Factors on Melanogenesis in Muzzle Melanocytes of Differently Colored Hanwoo

    Directory of Open Access Journals (Sweden)

    Touseef Amna

    2012-07-01

    Full Text Available The present study was designed to investigate the effect of α-melanocyte-stimulating hormone (α-MSH, nitric oxide (NO and L-cysteine on melanin production and expression of related genes MC1R, Tyr, Tyrp-1 and Tyrp-2 in muzzle melanocytes of differently colored three native Hanwoo cattle. Muzzle samples were taken from black, brindle and brown Hanwoo and purified melanocytes were cultured with α-MSH, nitric oxide and L-cysteine at 100 nM, 50 µM and 0.07 mg/ml of media respectively. The amounts of total melanin, eumelanin and mRNA expression at Tyr, Tyrp-1, Tyrp-2 and MC1R levels were quantified. α-MSH and nitric oxide significantly increased (p<0.05 the amount of total melanin in black and brindle whereas eumelanin production in brown Hanwoo muzzle melanocytes. On the contrary, L-cysteine greatly (p<0.05 depressed the eumelanin production in black color but increased in brown. Simultaneously, up regulation of Tyr by nitric oxide and α-MSH and down regulation of Tyr, Tyrp-2 and MC1R genes by L-cysteine were observed in muzzle melanocytes of all three phenotypes. The results of this study revealed nitric oxide and α-MSH contribute hyper-pigmentation by enhancing eumelanogenesis whereas L-cysteine contributes to pheomelanin production in different colored Hanwoo muzzle melanocytes.

  1. Melanocyte biology and function with reference to oral melanin hyperpigmentation in HIV-seropositive subjects.

    Science.gov (United States)

    Feller, Liviu; Chandran, Rakesh; Kramer, Beverley; Khammissa, Razia A G; Altini, Mario; Lemmer, Johan

    2014-09-01

    The color of normal skin and of oral mucosa is not determined by the number of melanocytes in the epithelium but rather by their melanogenic activity. Pigmented biopolymers or melanins are synthesized in melanosomes. Tyrosinase is the critical enzyme in the biosynthesis of both brown/black eumelanin and yellow/red pheomelanin. The number of the melanosomes within the melanocytes, the type of melanin within the melanosomes, and the efficacy of the transfer of melanosomes from the melanocytes to the neighboring keratinocytes all play an important role in tissue pigmentation. Melanin production is regulated by locally produced factors including proopiomelanocortin and its derivative peptides, particularly alpha-melanocyte-stimulating hormone (α-MSH), melanocortin 1 receptor (MC1R), adrenergic and cholinergic agents, growth factors, cytokines, and nitric oxide. Both eumelanin and pheomelanin can be produced by the same melanocytes, and the proportion of the two melanin types is influenced by the degree of functional activity of the α-MSH/MC1R intracellular pathway. The cause of HIV oral melanosis is not fully understood but may be associated with HIV-induced cytokine dysregulation, with the medications commonly prescribed to HIV-seropositive persons, and with adrenocortical dysfunction, which is not uncommon in HIV-seropositive subjects with AIDS. The purpose of this article is to discuss some aspects of melanocyte biology and HIV-associated oral melanin hyperpigmentation.

  2. Effect of nicotine on melanogenesis and antioxidant status in HEMn-LP melanocytes

    International Nuclear Information System (INIS)

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa

    2014-01-01

    Nicotine is a natural ingredient of tobacco plants and is responsible for the addictive properties of tobacco. Nowadays nicotine is also commonly used as a form of smoking cessation therapy. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn affect biochemical processes in human cells producing melanin. The aim of this study was to examine the effect of nicotine on melanogenesis and antioxidant status in cultured normal human melanocytes HEMn-LP. Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC 50 was determined to be 7.43 mM. Nicotine inhibited a melanization process in human light pigmented melanocytes and caused alterations of antioxidant defense system. Significant changes in cellular antioxidant enzymes: superoxide dismutase and catalase activities and in hydrogen peroxide content were stated. The obtained results may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long term exposition to nicotine. - Graphical abstract: Nicotine inhibits melanogenesis and induces oxidative stress in HEMn-LP melanocytes. - Highlights: • Nicotine induces concentration-dependent loss in melanocytes viability. • Nicotine in non-cytotoxic concentrations inhibits melanogenesis. • Nicotine in higher concentrations induces oxidative stress

  3. PPARalpha/gamma expression and activity in mouse and human melanocytes and melanoma cells.

    Science.gov (United States)

    Eastham, Linda L; Mills, Caroline N; Niles, Richard M

    2008-06-01

    We examined the expression of PPARs and the effects of PPARalpha and PPARgamma agonists on growth of mouse and human melanocytes and melanoma cells. PPARalpha,beta, and PPARgamma mRNA qualitative expression in melan-a mouse melanocytes, B16 mouse melanoma, human melanocytes, and A375 and SK-mel28 human melanoma cells was determined by RT-PCR, while quantitative PPARalpha mRNA levels were determined by QuantiGene assay. PPARalpha and PPARgamma protein was assessed by Western blotting. The effect of natural and synthetic PPAR ligands on cell growth was determined by either hemocytometer counting or crystal violet assay. PPAR transcriptional activity was determined by a PPRE-reporter gene assay, while knockdown of PPARalpha expression was achieved by transient transfection of siRNA. Both mouse and human melanoma cells produced more PPARalpha and PPARgamma protein compared to melanocytes. PPARalpha mRNA levels were elevated in human melanoma cells, but not in mouse melanoma cells relative to melanocytes. Silencing of PPARalpha in human melanoma cells did not alter cell proliferation or morphology. PPARgamma-selective agonists inhibited the growth of both mouse and human melanoma cells, while PPARalpha-selective agonists had limited effects. Increased expression of PPARalpha in melanoma relative to melanocytes may be a common occurrence, however its biologic significance remains to be determined. PPARgamma agonists may be useful for arresting the growth of some melanomas.

  4. Effect of norfloxacin and moxifloxacin on melanin synthesis and antioxidant enzymes activity in normal human melanocytes.

    Science.gov (United States)

    Beberok, Artur; Wrześniok, Dorota; Otręba, Michał; Miliński, Maciej; Rok, Jakub; Buszman, Ewa

    2015-03-01

    Fluoroquinolone antibiotics provide broad-spectrum coverage for a number of infectious diseases, including respiratory as well as urinary tract infections. One of the important adverse effects of these drugs is phototoxicity which introduces a serious limitation to their use. To gain insight the molecular mechanisms underlying the fluoroquinolones-induced phototoxic side effects, the impact of two fluoroquinolone derivatives with different phototoxic potential, norfloxacin and moxifloxacin, on melanogenesis and antioxidant enzymes activity in normal human melanocytes HEMa-LP was determined. Both drugs induced concentration-dependent loss in melanocytes viability. The value of EC50 for these drugs was found to be 0.5 mM. Norfloxacin and moxifloxacin suppressed melanin biosynthesis; antibiotics were shown to inhibit cellular tyrosinase activity and to reduce melanin content in melanocytes. When comparing the both analyzed fluoroquinolones, it was observed that norfloxacin possesses greater inhibitory effect on tyrosinase activity in melanocytes than moxifloxacin. The extent of oxidative stress in cells was assessed by measuring the activity of antioxidant enzymes: SOD, CAT, and GPx. It was observed that norfloxacin caused higher depletion of antioxidant status in melanocytes when compared with moxifloxacin. The obtained results give a new insight into the mechanisms of fluoroquinolones toxicity directed to pigmented tissues. Moreover, the presented differences in modulation of biochemical processes in melanocytes may be an explanation for various phototoxic activities of the analyzed fluoroquinolone derivatives in vivo.

  5. Oncogenic mutations in melanomas and benign melanocytic nevi of the female genital tract.

    Science.gov (United States)

    Tseng, Diane; Kim, Julie; Warrick, Andrea; Nelson, Dylan; Pukay, Marina; Beadling, Carol; Heinrich, Michael; Selim, Maria Angelica; Corless, Christopher L; Nelson, Kelly

    2014-08-01

    The genetic heterogeneity of melanomas and melanocytic nevi of the female genital tract is poorly understood. We aim to characterize the frequency of mutations of the following genes: BRAF, NRAS, KIT, GNA11, and GNAQ in female genital tract melanomas. We also characterize the frequency of BRAF mutations in female genital tract melanomas compared with melanocytic nevi. Mutational screening was performed on the following female genital tract melanocytic neoplasms: 25 melanomas, 7 benign melanocytic nevi, and 4 atypical melanocytic nevi. Of the 25 female genital tract melanoma specimens queried, KIT mutations were detected in 4 (16.0%), NRAS mutations in 4 (16.0%), and BRAF mutations in 2 (8.0%) samples. Two of the tumors with KIT mutations harbored double mutations in the same exon. No GNAQ or GNA11 mutations were identified among 11 melanomas screened. BRAF V600E mutations were detected in 7 of 7 benign melanocytic genital nevi (100%) and 3 of 4 atypical genital nevi (75%). Our study is limited by the small sample size of this rare subset of melanomas. KIT, NRAS, and BRAF mutations are found in a subset of female genital tract melanomas. Screening for oncogenic mutations is important for developing and applying clinical therapies for melanomas of the female genital tract. Copyright © 2014 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  6. Effect of nicotine on melanogenesis and antioxidant status in HEMn-LP melanocytes

    Energy Technology Data Exchange (ETDEWEB)

    Delijewski, Marcin; Beberok, Artur; Otręba, Michał; Wrześniok, Dorota; Rok, Jakub; Buszman, Ewa, E-mail: ebuszman@sum.edu.pl

    2014-10-15

    Nicotine is a natural ingredient of tobacco plants and is responsible for the addictive properties of tobacco. Nowadays nicotine is also commonly used as a form of smoking cessation therapy. It is suggested that nicotine may be accumulated in human tissues containing melanin. This may in turn affect biochemical processes in human cells producing melanin. The aim of this study was to examine the effect of nicotine on melanogenesis and antioxidant status in cultured normal human melanocytes HEMn-LP. Nicotine induced concentration-dependent loss in melanocytes viability. The value of EC{sub 50} was determined to be 7.43 mM. Nicotine inhibited a melanization process in human light pigmented melanocytes and caused alterations of antioxidant defense system. Significant changes in cellular antioxidant enzymes: superoxide dismutase and catalase activities and in hydrogen peroxide content were stated. The obtained results may explain a potential influence of nicotine on biochemical processes in melanocytes in vivo during long term exposition to nicotine. - Graphical abstract: Nicotine inhibits melanogenesis and induces oxidative stress in HEMn-LP melanocytes. - Highlights: • Nicotine induces concentration-dependent loss in melanocytes viability. • Nicotine in non-cytotoxic concentrations inhibits melanogenesis. • Nicotine in higher concentrations induces oxidative stress.

  7. Neural crest cells: from developmental biology to clinical interventions.

    Science.gov (United States)

    Noisa, Parinya; Raivio, Taneli

    2014-09-01

    Neural crest cells are multipotent cells, which are specified in embryonic ectoderm in the border of neural plate and epiderm during early development by interconnection of extrinsic stimuli and intrinsic factors. Neural crest cells are capable of differentiating into various somatic cell types, including melanocytes, craniofacial cartilage and bone, smooth muscle, and peripheral nervous cells, which supports their promise for cell therapy. In this work, we provide a comprehensive review of wide aspects of neural crest cells from their developmental biology to applicability in medical research. We provide a simplified model of neural crest cell development and highlight the key external stimuli and intrinsic regulators that determine the neural crest cell fate. Defects of neural crest cell development leading to several human disorders are also mentioned, with the emphasis of using human induced pluripotent stem cells to model neurocristopathic syndromes. © 2014 Wiley Periodicals, Inc.

  8. Prolonged Expansion Induces Spontaneous Neural Progenitor Differentiation from Human Gingiva-Derived Mesenchymal Stem Cells.

    Science.gov (United States)

    Rajan, Thangavelu Soundara; Scionti, Domenico; Diomede, Francesca; Piattelli, Adriano; Bramanti, Placido; Mazzon, Emanuela; Trubiani, Oriana

    2017-12-01

    Neural crest-derived mesenchymal stem cells (MSCs) obtained from dental tissues received considerable interest in regenerative medicine, particularly in nerve regeneration owing to their embryonic origin and ease of harvest. Proliferation efficacy and differentiation capacity into diverse cell lineages propose dental MSCs as an in vitro tool for disease modeling. In this study, we investigated the spontaneous differentiation efficiency of dental MSCs obtained from human gingiva tissue (hGMSCs) into neural progenitor cells after extended passaging. At passage 41, the morphology of hGMSCs changed from typical fibroblast-like shape into sphere-shaped cells with extending processes. Next-generation transcriptomics sequencing showed increased expression of neural progenitor markers such as NES, MEIS2, and MEST. In addition, de novo expression of neural precursor genes, such as NRN1, PHOX2B, VANGL2, and NTRK3, was noticed in passage 41. Immunocytochemistry results showed suppression of neurogenesis repressors TP53 and p21, whereas Western blot results revealed the expression of neurotrophic factors BDNF and NT3 at passage 41. Our results showed the spontaneous efficacy of hGMSCs to differentiate into neural precursor cells over prolonged passages and that these cells may assist in producing novel in vitro disease models that are associated with neural development.

  9. Tranexamic acid suppresses ultraviolet B eye irradiation-induced melanocyte activation by decreasing the levels of prohormone convertase 2 and alpha-melanocyte-stimulating hormone.

    Science.gov (United States)

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2014-12-01

    Tranexamic acid (trans-4-aminomethylcyclohexanecarboxylic acid) is a medicinal amino acid used in skin whitening care. This study examined the effects of tranexamic acid on the melanocyte activation of the skin induced by an ultraviolet (UV) B eye irradiation. The eye or ear was locally exposed to UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp after covering the remaining body surface with aluminum foil. UVB eye irradiation induced melanocyte activation of the skin, similar to that observed following UVB ear irradiation, which was suppressed by the administration of tranexamic acid treatment. The plasma α-melanocyte-stimulating hormone (α-MSH) content was increased by UVB irradiation of the eye; however, the increase in α-MSH was suppressed by tranexamic acid treatment. In addition, UVB eye irradiation induced the up-regulation of prohormone convertase (PC) 2 in the pituitary gland. Meanwhile, the increase in PC2 induced by UVB eye irradiation was suppressed by tranexamic acid treatment. These results clearly indicate that tranexamic acid decreases the expression of PC2, which cleavages from proopiomelanocortin to α-MSH in the pituitary gland, thereby suppressing melanocyte activation. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  10. Topography of Protein Kinase C βII in Benign and Malignant Melanocytic Lesions.

    Science.gov (United States)

    Krasagakis, Konstanin; Tsentelierou, Eleftheria; Chlouverakis, Gregory; Stathopoulos, Efstathios N

    2017-09-01

    Protein kinase C βII promotes melanogenesis and affects proliferation of melanocytic cells but is frequently absent or decreased in melanoma cells in vitro. To investigate PKC-βII expression and spatial distribution within a lesion in various benign and malignant melanocytic proliferations. Expression of PKC-βII was semiquantitatively assessed in the various existing compartments (intraepidermal [not nested], junctional [nested], and dermal) of benign (n = 43) and malignant (n = 28) melanocytic lesions by immunohistochemistry. Melanocytes in the basal layer of normal skin or in lentigo simplex stained strongly for PKC-βII. Common nevi lacked completely PKC-βII. All other lesions expressed variably PKC-βII, with cutaneous melanoma metastases displaying the lowest rate of positivity (14%). In the topographical analysis within a lesion, PKC-βII expression was largely retained in the intraepidermal and junctional part of all other lesions (dysplastic nevus, lentigo maligna, and melanoma). Reduced expression of PKC-βII was found in the dermal component of benign and malignant lesions ( P = .041 vs intraepidermal). PKC-βII expression in the various compartments did not differ significantly between benign and malignant lesions. The current study revealed a significant correlation between PKC-βII expression and spatial localization of melanocytes, with the lowest expression found in the dermal compartment and the highest in the epidermal compartment.

  11. Agreement Between Cytology and Histopathology for Regional Lymph Node Metastasis in Dogs With Melanocytic Neoplasms.

    Science.gov (United States)

    Grimes, Janet A; Matz, Brad M; Christopherson, Pete W; Koehler, Jey W; Cappelle, Kelsey K; Hlusko, Katelyn C; Smith, Annette

    2017-07-01

    Melanocytic neoplasms are common in dogs and frequently occur within the oral cavity or in haired skin. The behavior of melanocytic neoplasms is variable and depends on tumor location, size, and histopathologic features. This study compared cytopathology and histopathology of 32 lymph nodes from 27 dogs diagnosed with melanocytic neoplasms. Agreement between the original cytology report, cytology slide review, original histopathology report, and histopathology slide review was determined for each lymph node. A subset of lymph nodes was subjected to immunohistochemistry (Melan-A) and additional histochemical stains/techniques (Prussian blue, bleach) to assist in differentiation of melanocytes and melanophages. Agreement ranged from slight to fair for each of the variables evaluated with weighted kappa (κ w ) or kappa (κ) analysis (original cytology vs cytology review κ w = 0.24; original cytology vs original histopathology κ w = 0.007; original cytology vs histopathology review κ w = 0.23; cytology review vs original histopathology κ w = 0.008; cytology review vs histopathology review κ w = 0.006; and original histopathology vs histopathology review κ = 0.18). The diagnoses (metastatic, equivocal, or negative for metastasis) of the original report and slide review for both cytology and histopathology were not significantly correlated with survival in this population of patients. Overall, agreement between cytology and histopathology was poor even with a single clinical or anatomic pathologist performing slide review. Consensus between routine cytology and histopathology for staging of lymph nodes in patients with melanocytic neoplasms is poor and does not correlate with survival.

  12. Automated Estimation of Melanocytic Skin Tumor Thickness by Ultrasonic Radiofrequency Data.

    Science.gov (United States)

    Andrekute, Kristina; Valiukeviciene, Skaidra; Raisutis, Renaldas; Linkeviciute, Gintare; Makstiene, Jurgita; Kliunkiene, Renata

    2016-05-01

    High-frequency (>20-MHz) ultrasound (US) is a noninvasive preoperative tool for assessment of melanocytic skin tumor thickness. Ultrasonic melanocytic skin tumor thickness estimation is not always easy and is related to the experience of the clinician. In this article, we present an automated thickness measurement method based on time-frequency analysis of US radiofrequency signals. The study was performed on 52 thin (≤1-mm) melanocytic skin tumors (46 melanocytic nevi and 6 melanomas). Radiofrequency signals were obtained with a single-element focused transducer (fundamental frequency, 22 MHz; bandwidth, 12-28 MHz). The radiofrequency data were analyzed in the time-frequency domain to make the tumor boundaries more noticeable. The thicknesses of the tumors were evaluated by 3 different metrics: histologically measured Breslow thickness, manually measured US thickness, and automatically measured US thickness. The results showed a higher correlation coefficient between the automatically measured US thickness and Breslow thickness (r= 0.83; Pmeasured US thickness (r = 0.68; P measurement algorithm was 96.55%, and the specificity was 78.26% compared with histologic measurement. The sensitivity of the manually measured US thickness was 75.86%, and the specificity was 73.91%. The efficient automated tumor thickness measurement method developed could be used as a tool for preoperative assessment of melanocytic skin tumor thickness. © 2016 by the American Institute of Ultrasound in Medicine.

  13. Oxidative stress-induced overexpression of miR-25: the mechanism underlying the degeneration of melanocytes in vitiligo

    Science.gov (United States)

    Shi, Q; Zhang, W; Guo, S; Jian, Z; Li, S; Li, K; Ge, R; Dai, W; Wang, G; Gao, T; Li, C

    2016-01-01

    Oxidative stress has a critical role in the pathogenesis of vitiligo. However, the specific molecular mechanism involved in oxidative stress-induced melanocyte death is not well characterized. Given the powerful role of microRNAs (miRNAs) in the regulation of cell survival as well as the fact that the generation of miRNAs can be affected by oxidative stress, we hypothesized that miRNAs may participate in vitiligo pathogenesis by modulating the expression of vital genes in melanocytes. In the present study, we initially found that miR-25 was increased in both serum and lesion samples from vitiligo patients, and its serum level was correlated with the activity of vitiligo. Moreover, restoration of miR-25 promoted the H2O2-induced melanocyte destruction and led to the dysfunction of melanocytes. Further experiments proved that MITF, a master regulator in melanocyte survival and function, accounted for the miR-25-caused damaging impact on melanocytes. Notably, other than the direct role on melanocytes, we observed that miR-25 inhibited the production and secretion of SCF and bFGF from keratinocytes, thus impairing their paracrine protective effect on the survival of melanocytes under oxidative stress. At last, we verified that oxidative stress could induce the overexpression of miR-25 in both melanocytes and keratinocytes possibly by demethylating the promoter region of miR-25. Taken together, our study demonstrates that oxidative stress-induced overexpression of miR-25 in vitiligo has a crucial role in promoting the degeneration of melanocytes by not only suppressing MITF in melanocytes but also impairing the paracrine protective effect of keratinocytes. Therefore, it is worthy to investigate the possibility of miR-25 as a potential drug target for anti-oxidative therapy in vitiligo. PMID:26315342

  14. A reporter mouse model for in vivo tracing and in vitro molecular studies of melanocytic lineage cells and their diseases.

    Science.gov (United States)

    Crawford, Melissa; Leclerc, Valerie; Dagnino, Lina

    2017-08-15

    Alterations in melanocytic lineage cells give rise to a plethora of distinct human diseases, including neurocristopathies, cutaneous pigmentation disorders, loss of vision and hearing, and melanoma. Understanding the ontogeny and biology of melanocytic cells, as well as how they interact with their surrounding environment, are key steps in the development of therapies for diseases that involve this cell lineage. Efforts to culture and characterize primary melanocytes from normal or genetically engineered mouse models have at times yielded contrasting observations. This is due, in part, to differences in the conditions used to isolate, purify and culture these cells in individual studies. By breeding ROSA mT/mG and Tyr::CreER T2 mice, we generated animals in which melanocytic lineage cells are identified through expression of green fluorescent protein. We also used defined conditions to systematically investigate the proliferation and migration responses of primary melanocytes on various extracellular matrix (ECM) substrates. Under our culture conditions, mouse melanocytes exhibit doubling times in the range of 10 days, and retain exponential proliferative capacity for 50-60 days. In culture, these melanocytes showed distinct responses to different ECM substrates. Specifically, laminin-332 promoted cell spreading, formation of dendrites, random motility and directional migration. In contrast, low or intermediate concentrations of collagen I promoted adhesion and acquisition of a bipolar morphology, and interfered with melanocyte forward movements. Our systematic evaluation of primary melanocyte responses emphasizes the importance of clearly defining culture conditions for these cells. This, in turn, is essential for the interpretation of melanocyte responses to extracellular cues and to understand the molecular basis of disorders involving the melanocytic cell lineage. © 2017. Published by The Company of Biologists Ltd.

  15. A reporter mouse model for in vivo tracing and in vitro molecular studies of melanocytic lineage cells and their diseases

    Directory of Open Access Journals (Sweden)

    Melissa Crawford

    2017-08-01

    Full Text Available Alterations in melanocytic lineage cells give rise to a plethora of distinct human diseases, including neurocristopathies, cutaneous pigmentation disorders, loss of vision and hearing, and melanoma. Understanding the ontogeny and biology of melanocytic cells, as well as how they interact with their surrounding environment, are key steps in the development of therapies for diseases that involve this cell lineage. Efforts to culture and characterize primary melanocytes from normal or genetically engineered mouse models have at times yielded contrasting observations. This is due, in part, to differences in the conditions used to isolate, purify and culture these cells in individual studies. By breeding ROSAmT/mG and Tyr::CreERT2 mice, we generated animals in which melanocytic lineage cells are identified through expression of green fluorescent protein. We also used defined conditions to systematically investigate the proliferation and migration responses of primary melanocytes on various extracellular matrix (ECM substrates. Under our culture conditions, mouse melanocytes exhibit doubling times in the range of 10 days, and retain exponential proliferative capacity for 50-60 days. In culture, these melanocytes showed distinct responses to different ECM substrates. Specifically, laminin-332 promoted cell spreading, formation of dendrites, random motility and directional migration. In contrast, low or intermediate concentrations of collagen I promoted adhesion and acquisition of a bipolar morphology, and interfered with melanocyte forward movements. Our systematic evaluation of primary melanocyte responses emphasizes the importance of clearly defining culture conditions for these cells. This, in turn, is essential for the interpretation of melanocyte responses to extracellular cues and to understand the molecular basis of disorders involving the melanocytic cell lineage.

  16. Immunohistochemical expression of tenascin in melanocytic tumours of dogs.

    Science.gov (United States)

    Sevastre, B; van Ederen, A M; Terlou, M; Gruys, E; Nederbragt, H

    2007-01-01

    The aim of this study was to investigate tenascin-C (TN) immunolabelling and labelling for endothelium by von Willebrand Factor (vWF) in melanocytic tumours of dogs as compared with normal tissues, to evaluate the TN distribution in these types of tumours and to investigate whether a relation could be established between TN and angiogenesis in different types of tumour. Samples of normal dog skin (n=8), benign skin melanocytomas (n=10), malignant oral melanomas (n=9) and malignant toe melanomas (n=5) were studied. The percentages of TN and vWF immunolabelling per total microscopical area were analysed by morphometric methods. In normal skin, TN was found at dermo-epidermal junctions, around hair follicles, in the smooth muscles of hair follicles, and in the walls of blood vessels. TN immunolabelling (distribution and intensity) in melanocytomas was comparable with that found in normal skin. In melanomas, TN expression was considerably increased, its intensity in toe melanomas being twice that observed in oral melanomas. The degree of TN immunolabelling was not related to the histological malignancy of the melanomas. In melanomas, TN was found in the connective tissue surrounding the tumour cell nests and in narrow stromal strands inside the tumour. Regions infiltrated with lymphocytes were devoid of TN. The presence of TN around capillaries in melanocytomas and melanomas was investigated by double-immunolabelling (for TN and vWF). The intensity of vWF and TN immunolabelling was higher in melanomas than in melanocytomas, and higher in toe melanomas than in oral melanomas; however, no clear relation between TN expression and immunolabelling for vWF was found.

  17. Development and validation of a simple method for the extraction of human skin melanocytes.

    Science.gov (United States)

    Wang, Yinjuan; Tissot, Marion; Rolin, Gwenaël; Muret, Patrice; Robin, Sophie; Berthon, Jean-Yves; He, Li; Humbert, Philippe; Viennet, Céline

    2018-03-21

    Primary melanocytes in culture are useful models for studying epidermal pigmentation and efficacy of melanogenic compounds, or developing advanced therapy medicinal products. Cell extraction is an inevitable and critical step in the establishment of cell cultures. Many enzymatic methods for extracting and growing cells derived from human skin, such as melanocytes, are described in literature. They are usually based on two enzymatic steps, Trypsin in combination with Dispase, in order to separate dermis from epidermis and subsequently to provide a suspension of epidermal cells. The objective of this work was to develop and validate an extraction method of human skin melanocytes being simple, effective and applicable to smaller skin samples, and avoiding animal reagents. TrypLE™ product was tested on very limited size of human skin, equivalent of multiple 3-mm punch biopsies, and was compared to Trypsin/Dispase enzymes. Functionality of extracted cells was evaluated by analysis of viability, morphology and melanin production. In comparison with Trypsin/Dispase incubation method, the main advantages of TrypLE™ incubation method were the easier of separation between dermis and epidermis and the higher population of melanocytes after extraction. Both protocols preserved morphological and biological characteristics of melanocytes. The minimum size of skin sample that allowed the extraction of functional cells was 6 × 3-mm punch biopsies (e.g., 42 mm 2 ) whatever the method used. In conclusion, this new procedure based on TrypLE™ incubation would be suitable for establishment of optimal primary melanocytes cultures for clinical applications and research.

  18. Melanocytes and melanin represent a first line of innate immunity against Candida albicans.

    Science.gov (United States)

    Tapia, Cecilia V; Falconer, Maryanne; Tempio, Fabián; Falcón, Felipe; López, Mercedes; Fuentes, Marisol; Alburquenque, Claudio; Amaro, José; Bucarey, Sergio A; Di Nardo, Anna

    2014-07-01

    Melanocytes are dendritic cells located in the skin and mucosae that synthesize melanin. Some infections induce hypo- or hyperpigmentation, which is associated with the activation of Toll-like receptors (TLRs), especially TLR4. Candida albicans is an opportunist pathogen that can switch between blastoconidia and hyphae forms; the latter is associated with invasion. Our objectives in this study were to ascertain whether C. albicans induces pigmentation in melanocytes and whether this process is dependent on TLR activation, as well as relating this with the antifungal activity of melanin as a first line of innate immunity against fungal infections. Normal human melanocytes were stimulated with C. albicans supernatants or with crude extracts of the blastoconidia or hyphae forms, and pigmentation and TLR2/TLR4 expression were measured. Expression of the melanosomal antigens Melan-A and gp100 was examined for any correlation with increased melanin levels or antifungal activity in melanocyte lysates. Melanosomal antigens were induced earlier than cell pigmentation, and hyphae induced stronger melanization than blastoconidia. Notably, when melanocytes were stimulated with crude extracts of C. albicans, the cell surface expression of TLR2/TLR4 began at 48 h post-stimulation and peaked at 72 h. At this time, blastoconidia induced both TLR2 and TLR4 expression, whereas hyphae only induced TLR4 expression. Taken together, these results suggest that melanocytes play a key role in innate immune responses against C. albicans infections by recognizing pathogenic forms of C. albicans via TLR4, resulting in increased melanin content and inhibition of infection. © The Author 2014. Published by Oxford University Press on behalf of The International Society for Human and Animal Mycology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

  19. Giant melanocytic nevus with malignant melanoma: a rare disorder in a black African child.

    Science.gov (United States)

    Katibi, Oludolapo Sherifat; Ogunbiyi, Adebola; Brown, Biobele Jotham; Adeyemi, Oyedeji Oladele

    2014-10-01

    Giant congenital melanocytic nevus (GCMN) is rare in babies of African descent. Unfortunately, it has an increased potential for malignant transformation. A 3-year-old female child presented with a 6-month history of multiple nodules on an existing giant congenital melanocytic nevus and swelling in the right axilla of four weeks duration. Skin biopsy of the nodular skin lesions was in keeping with a metastatic malignant melanoma (Clark stage 4). She completed a full course of chemotherapy but subsequently died four months after presentation. Patients with large GCMN should be counseled and followed up appropriately to improve and prolong life. © 2014 The International Society of Dermatology.

  20. Investigation of cellular signalling responses to non-ionising radiation in melanocytes by microarray analysis

    International Nuclear Information System (INIS)

    Boyle, G.M.; Pedley, J.; Martyn, A.C.; Fraser, L.M.; Banducci, K.J.; Parsons, P.G.; Breit, S.N.

    2003-01-01

    Melanoma is a highly aggressive cancer resulting from the abnormal proliferation and spread of specialised pigment cells in the skin, known as melanocytes. Extensive epidemiological and molecular evidence suggests that a major risk factor for melanoma formation is exposure to non-ionising radiation in the form of solar ultra-violet (UV) light. However, the exact role of solar UV in the development of melanoma is unclear. To elucidate the molecular events that occur in melanocytes following solar UV exposure and determine how they lead to melanoma development, cDNA microarray analysis was used to analyse the gene expression profile of normal melanocytes, melanocytes exposed to simulated solar UV and melanoma cells. The development of cDNA microarray technology has allowed gene expression profiling at the mRNA level to be conducted for many thousands of genes simultaneously by hybridising an array of known sequences with labelled cDNA reverse transcribed form the sample RNA. Gene expression analysis was performed for over 13,000 genes. More than 500 genes were identified as differentially expressed in melanocytes following a single UV exposure, although overall there was a general suppression of transcription. Genes that were up-regulated included oncogenes and cytoskeletal genes; in contrast, genes encoding protein tyrosine kinases and apoptosis effectors were down-regulated. Many of the genes identified as being differentially expressed represent novel UV-regulated targets. Repeated exposure to solar UV resulted in the elevation in expression of a novel member of the transforming growth factor-b (TGF-b) superfamily, the Macrophage Inhibitory Cytokine-1 (MIC-1). Our results have shown that MIC-1 is up-regulated by solar UV in melanocytes, and is highly expressed (>3 fold) in a number of metastatic melanoma cell lines (31/61) in comparison to primary melanocytes. Furthermore functional, dimerised MIC-1 was found to be secreted by melanocytes, and secreted levels were

  1. Confocal laser scanning microscopy in vivo for diagnosing melanocytic skin neoplasms

    Directory of Open Access Journals (Sweden)

    A. A. Kubanova

    2014-01-01

    Full Text Available The authors discuss the use of confocal laser scanning microscopy in vivo (CLSM for diagnosing melanocytic skin neoplasms and its value for early diagnostics of melanoma. CLSM is an innovation noninvasive visual examination method for real-time multiple and painless examinations of the patient’s skin without injuring the skin integument. The method ensures early diagnostics of skin melanomas with high sensitivity and specificity, which makes it possible to use CLSM for screening melanocytic skin neoplasms for the sake of the early onset of treatment to save patient life and health.

  2. Immunopolarization of CD4(+) and CD8(+) T cells to type-1-like is associated with melanocyte loss in human vitiligo

    NARCIS (Netherlands)

    Wańkowicz-Kalińska, Anna; van den Wijngaard, René M. J. G. J.; Tigges, Bert J.; Westerhof, Wiete; Ogg, Graham S.; Cerundolo, Vincenzo; Storkus, Walter J.; Das, Pranab K.

    2003-01-01

    Vitiligo is an autoimmune condition characterized by loss of epidermal melanocytes. High frequencies of melanocyte-reactive cytotoxic T cells in the peripheral blood of vitiligo patients and the observed correlation between perilesional T-cell infiltration and melanocyte loss in situ suggest the

  3. The nuclear factor (erythroid-derived 2)-like 2 (NRF2) antioxidant response promotes melanocyte viability and reduces toxicity of the vitiligo-inducing phenol monobenzone.

    Science.gov (United States)

    Arowojolu, Omotayo A; Orlow, Seth J; Elbuluk, Nada; Manga, Prashiela

    2017-07-01

    Vitiligo, characterised by progressive melanocyte death, can be initiated by exposure to vitiligo-inducing phenols (VIPs). VIPs generate oxidative stress in melanocytes and activate the master antioxidant regulator NRF2. While NRF2-regulated antioxidants are reported to protect melanocytes from oxidative stress, the role of NRF2 in the melanocyte response to monobenzone, a clinically relevant VIP, has not been characterised. We hypothesised that activation of NRF2 may protect melanocytes from monobenzone-induced toxicity. We observed that knockdown of NRF2 or NRF2-regulated antioxidants NQO1 and PRDX6 reduced melanocyte viability, but not viability of keratinocytes and fibroblasts, suggesting that melanocytes were preferentially dependent upon NRF2 activity for growth compared to other cutaneous cells. Furthermore, melanocytes activated the NRF2 response following monobenzone exposure and constitutive NRF2 activation reduced monobenzone toxicity, supporting NRF2's role in the melanocyte stress response. In contrast, melanocytes from individuals with vitiligo (vitiligo melanocytes) did not activate the NRF2 response as efficiently. Dimethyl fumarate-mediated NRF2 activation protected normal and vitiligo melanocytes against monobenzone-induced toxicity. Given the contribution of oxidant-antioxidant imbalance in vitiligo, modulation of this pathway may be of therapeutic interest. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  4. Optical Coherence Tomography Angiography Characteristics of Iris Melanocytic Tumors

    Science.gov (United States)

    Skalet, Alison H.; Li, Yan; Lu, Chen D.; Jia, Yali; Lee, ByungKun; Husvogt, Lennart; Maier, Andreas; Fujimoto, James G.; Thomas, Charles R.; Huang, David

    2016-01-01

    -injection, cost-effective method for monitoring a variety of tumors including iris melanocytic lesions for growth and vascularity. This could be helpful in evaluating tumors for malignant transformation and response to treatment. Penetration of the OCT beam remains a limitation for highly pigmented tumors, as does the inability to image the entire iris in a single field. PMID:27856029

  5. Krox20 defines a subpopulation of cardiac neural crest cells contributing to arterial valves and bicuspid aortic valve.

    Science.gov (United States)

    Odelin, Gaëlle; Faure, Emilie; Coulpier, Fanny; Di Bonito, Maria; Bajolle, Fanny; Studer, Michèle; Avierinos, Jean-François; Charnay, Patrick; Topilko, Piotr; Zaffran, Stéphane

    2018-01-03

    Although cardiac neural crest cells are required at early stages of arterial valve development, their contribution during valvular leaflet maturation remains poorly understood. Here, we show in mouse that neural crest cells from pre-otic and post-otic regions make distinct contributions to the arterial valve leaflets. Genetic fate-mapping analysis of Krox20-expressing neural crest cells shows a large contribution to the borders and the interleaflet triangles of the arterial valves. Loss of Krox20 function results in hyperplastic aortic valve and partially penetrant bicuspid aortic valve formation. Similar defects are observed in neural crest Krox20 -deficient embryos. Genetic lineage tracing in Krox20 -/- mutant mice shows that endothelial-derived cells are normal, whereas neural crest-derived cells are abnormally increased in number and misplaced in the valve leaflets. In contrast, genetic ablation of Krox20 -expressing cells is not sufficient to cause an aortic valve defect, suggesting that adjacent cells can compensate this depletion. Our findings demonstrate a crucial role for Krox20 in arterial valve development and reveal that an excess of neural crest cells may be associated with bicuspid aortic valve. © 2018. Published by The Company of Biologists Ltd.

  6. Ultraviolet B, melanin and mitochondrial DNA: Photo-damage in human epidermal keratinocytes and melanocytes modulated by alpha-melanocyte-stimulating hormone [version 1; referees: 2 approved

    Directory of Open Access Journals (Sweden)

    Markus Böhm

    2016-05-01

    Full Text Available Alpha-melanocyte-stimulating hormone (alpha-MSH increases melanogenesis and protects from UV-induced DNA damage. However, its effect on mitochondrial DNA (mtDNA damage is unknown. We have addressed this issue in a pilot study using human epidermal keratinocytes and melanocytes incubated with alpha-MSH and irradiated with UVB. Real-time touchdown PCR was used to quantify total and deleted mtDNA. The deletion detected encompassed the common deletion but was more sensitive to detection. There were 4.4 times more mtDNA copies in keratinocytes than in melanocytes. Irradiation alone did not affect copy numbers. Alpha-MSH slightly increased copy numbers in both cell types in the absence of UVB and caused a similar small decrease in copy number with dose in both cell types. Deleted copies were nearly twice as frequent in keratinocytes as in melanocytes. Alpha-MSH reduced the frequency of deleted copies by half in keratinocytes but not in melanocytes. UVB dose dependently led to an increase in the deleted copy number in alpha-MSH-treated melanocytes. UVB irradiation had little effect on deleted copy number in alpha-MSH-treated keratinocytes. In summary, alpha-MSH enhances mtDNA damage in melanocytes presumably by increased melanogenesis, while α-MSH is protective in keratinocytes, the more so in the absence of irradiation.

  7. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation

    Science.gov (United States)

    Kadekaro, Ana Luisa; Leachman, Sancy; Kavanagh, Renny J.; Swope, Viki; Cassidy, Pamela; Supp, Dorothy; Sartor, Maureen; Schwemberger, Sandy; Babcock, George; Wakamatsu, Kazumasa; Ito, Shosuke; Koshoffer, Amy; Boissy, Raymond E.; Manga, Prashiela; Sturm, Richard A.; Abdel-Malek, Zalfa A.

    2010-01-01

    The melanocortin 1 receptor gene is a main determinant of human pigmentation, and a melanoma susceptibility gene, because its variants that are strongly associated with red hair color increase melanoma risk. To test experimentally the association between melanocortin 1 receptor genotype and melanoma susceptibility, we compared the responses of primary human melanocyte cultures naturally expressing different melanocortin 1 receptor variants to α-melanocortin and ultraviolet radiation. We found that expression of 2 red hair variants abolished the response to α-melanocortin and its photoprotective effects, evidenced by lack of functional coupling of the receptor, and absence of reduction in ultraviolet radiation-induced hydrogen peroxide generation or enhancement of repair of DNA photoproducts, respectively. These variants had different heterozygous effects on receptor function. Microarray data confirmed the observed differences in responses of melanocytes with functional vs. nonfunctional receptor to α-melanocortin and ultraviolet radiation, and identified DNA repair and antioxidant genes that are modulated by α-melanocortin. Our findings highlight the molecular mechanisms by which the melanocortin 1 receptor genotype controls genomic stability of and the mutagenic effect of ultraviolet radiation on human melanocytes.—Kadekaro, A. L., Leachman, S., Kavanagh, R. J., Swope, V., Cassidy, P., Supp, D., Sartor, M., Schwemberger, S., Babcock, G., Wakamatsu, K., Ito, S., Koshoffer, A., Boissy, R. E., Manga, P., Sturm, R. A., Abdel-Malek, Z. A. Melanocortin 1 receptor genotype: an important determinant of the damage response of melanocytes to ultraviolet radiation. PMID:20519635

  8. Ultraviolet Radiation and the Slug Transcription Factor Induce Proinflammatory and Immunomodulatory Mediator Expression in Melanocytes

    Directory of Open Access Journals (Sweden)

    Stephanie H. Shirley

    2012-01-01

    Full Text Available Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete proinflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce proinflammatory mediators and that Slug is important in this process. Microarray studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of proinflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.

  9. Molecular effects of 1-naphthyl-methylcarbamate and solar radiation exposures on human melanocytes.

    Science.gov (United States)

    Ferrucio, Bianca; Tiago, Manoela; Fannin, Richard D; Liu, Liwen; Gerrish, Kevin; Maria-Engler, Silvya Stuchi; Paules, Richard S; Barros, Silvia Berlanga de Moraes

    2017-02-01

    Carbaryl (1-naphthyl-methylcarbamate), a broad-spectrum insecticide, has recently been associated with the development of cutaneous melanoma in an epidemiological cohort study with U.S. farm workers also exposed to ultraviolet radiation, the main etiologic factor for skin carcinogenesis. We hypothesized that carbaryl exposure may increase deleterious effects of UV solar radiation on skin melanocytes. This study aimed to characterize human melanocytes after individual or combined exposure to carbaryl (100μM) and solar radiation (375mJ/cm 2 ). In a microarray analysis, carbaryl, but not solar radiation, induced an oxidative stress response, evidenced by the upregulation of antioxidant genes, such as Hemeoxygenase-1 (HMOX1), and downregulation of Microphtalmia-associated Transcription Factor (MITF), the main regulator of melanocytic activity; results were confirmed by qRT-PCR. Carbaryl and solar radiation induced a gene response suggestive of DNA damage and cell cycle alteration. The expression of CDKN1A, BRCA1/2 and MDM2 genes was notably more intense in the combined treatment group, in a synergistic manner. Flow cytometry assays demonstrated S-phase cell cycle arrest, reduced apoptosis levels and faster induction of cyclobutane pyrimidine dimers (CPD) lesions in carbaryl treated groups. Our data suggests that carbaryl is genotoxic to human melanocytes, especially when associated with solar radiation. Copyright © 2016 Elsevier B.V. All rights reserved.

  10. Ultraviolet Radiation and the Slug Transcription Factor Induce Pro inflammatory and Immunomodulatory Mediator Expression in Melanocytes

    International Nuclear Information System (INIS)

    Shirley, S. H.; Kusewitt, D. F.; Grimm, E. A.

    2012-01-01

    Despite extensive investigation, the precise contribution of the ultraviolet radiation (UVR) component of sunlight to melanoma etiology remains unclear. UVR induces keratinocytes to secrete pro inflammatory and immunomodulatory mediators that promote inflammation and skin tumor development; expression of the slug transcription factor in keratinocytes is required for maximal production of these mediators. In the present studies we examined the possibility that UVR-exposed melanocytes also produce pro inflammatory mediators and that Slug is important in this process. Micro array studies revealed that both UVR exposure and Slug overexpression altered transcription of a variety of pro inflammatory mediators by normal human melanocytes; some of these mediators are also known to stimulate melanocyte growth and migration. There was little overlap in the spectra of cytokines produced by the two stimuli. However IL-20 was similarly induced by both stimuli and the NFκB pathway appeared to be important in both circumstances. Further exploration of UVR-induced and Slug-dependent pathways of cytokine induction in melanocytes may reveal novel targets for melanoma therapy.

  11. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism

    DEFF Research Database (Denmark)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet

    2013-01-01

    in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted...

  12. Stimulation of cyclic GMP efflux in human melanocytes by hypergravity generated by centrifugal acceleration

    NARCIS (Netherlands)

    Ivanova, Krassimira; Zadeh, Nahid Hamidi; Block, Ingrid; Das, Pranab K.; Gerzer, Rupert

    2004-01-01

    Gravity alteration (micro- and hypergravity) is known to influence cell functions. As guanosine 3',5'-cyclic monophosphate (cGMP) plays an important role in human melanocyte functions and different guanylyl cyclase isoforms are responsible for cGMP synthesis in human non-metastatic and metastatic

  13. Overexpression of hepatoma-derived growth factor in melanocytes does not lead to oncogenic transformation

    International Nuclear Information System (INIS)

    Sedlmaier, Angela; Wernert, Nicolas; Gallitzendörfer, Rainer; Abouzied, Mekky M; Gieselmann, Volkmar; Franken, Sebastian

    2011-01-01

    HDGF is a growth factor which is overexpressed in a wide range of tumors. Importantly, expression levels were identified as a prognostic marker in some types of cancer such as melanoma. To investigate the presumed oncogenic/transforming capacity of HDGF, we generated transgenic mice overexpressing HDGF in melanocytes. These mice were bred with mice heterozygous for a defective copy of the Ink4a tumor suppressor gene and were exposed to UV light to increase the risk for tumor development both genetically and physiochemically. Mice were analyzed by immunohistochemistry and Western blotting. Furthermore, primary melanocytes were isolated from different strains created. Transgenic animals overexpressed HDGF in hair follicle melanocytes. Interestingly, primary melanocytes isolated from transgenic animals were not able to differentiate in vitro whereas cells isolated from wild type and HDGF-deficient animals were. Although, HDGF -/- /Ink4a +/- mice displayed an increased number of epidermoid cysts after exposure to UV light, no melanomas or premelanocytic alterations could be detected in this mouse model. The results therefore provide no evidence that HDGF has a transforming capacity in tumor development. Our results in combination with previous findings point to a possible role in cell differentiation and suggest that HDGF promotes tumor progression after secondary upregulation and may represent another protein fitting into the concept of non-oncogene addiction of tumor tissue

  14. (Pheo)melanin photosensitizes UVA-induced DNA damage in cultured human melanocytes

    NARCIS (Netherlands)

    Wenczl, E.; Schans, G.P. van der; Roza, L.; Kolb, R.M.; Timmerman, A.J.; Smit, N.P.M.; Pavel, S.; Schothorst, A.A.

    1998-01-01

    The question of whether melanins are photoprotecting and/or photosensitizing in human skin cells continues to be debated. To evaluate the role of melanin upon UVA irradiation, DNA single-strand breaks (ssb) were measured in human melanocytes differing only in the amount of pigment produced by

  15. Progressive Increase in Telomerase Activity From Benign Melanocytic Conditions to Malignant Melanoma

    Directory of Open Access Journals (Sweden)

    Ruben D. Ramirez

    1999-04-01

    Full Text Available The expression of telomerase activity and the in situ localization of the human telomerase RNA component (hTR in melanocytic skin lesions was evaluated in specimens from sixty-three patients. Specimens of melanocytic nevi, primary melanomas and subcutaneous metastases of melanoma were obtained from fifty-eight patients, whereas metastasized lymph nodes were obtained from five patients. Telomerase activity was determined in these specimens by using a Polymerase Chain Reaction—based assay (TRAP. High relative mean telomerase activity levels were detected in metastatic melanoma (subcutaneous metastasess = 54.5, lymph node metastasess = 56.5. Much lower levels were detected in primary melanomas, which increased with advancing levels of tumor cell penetration (Clark II = 0.02, Clark III = 1.1, and Clark IV = 1.9. Twenty-six formalin-fixed, paraffin-embedded melanocytic lesions were sectioned and analyzed for telomerase RNA with a radioactive in situ hybridization assay. In situ hybridization studies with a probe to the template RNA component of telomerase confirmed that expression was almost exclusively confined to tumor cells and not infiltrating lymphocytes. These results indicate that levels of telomerase activity and telomerase RNA in melanocytic lesions correlate well with clinical stage and could potentially assist in the diagnosis of borderline lesions.

  16. Clinical and histological responses of congenital melanocytic nevi after single treatment with Q-switched lasers

    NARCIS (Netherlands)

    Grevelink, JM; vanLeeuwen, RL; Anderson, RR; Byers, HR

    Background: Laser irradiation of congenital melanocytic nevi is a controversial treatment. Recurrence of lesions after laser treatment appears to be the rule, and the effects of laser irradiation on cellular biological behavior and the possible mutagenic responses of nevomelanocytes that have

  17. G2 accumulation and melanin overproduction in malignant melanocytes treated with a new nitrosourea.

    Science.gov (United States)

    Buchdahl, C; Papon, J; Communal, Y; Bourges, M; Madelmont, J C

    1998-12-01

    Cystemustine (N'-(2-chloroethyl)-N-(2-(methylsulphonyl)ethyl)-N'-nitrosourea), a new anticancer chloroethylnitrosourea (CENU) is being tested in a phase II clinical trial of disseminated melanoma. The antitumour effect of this drug is mainly due to DNA damage in malignant melanocytes. Recently, we have shown that this damage can induce apoptosis in some melanoma cell lines. In others, apoptosis is not clearly observed, although there is a strong cytostatic effect. In this paper, we have characterized the cytological effect of cystemustine on murine malignant melanocytes (B16 cell line) which are resistant to apoptosis induced by this CENU. The results show that 3 days after cystemustine treatment, these melanocytes had accumulated in phase G2 of the cell cycle. There was then a strong morphological modification during a long cytostatic phase up to 30 days after treatment. During this cytostatic phase, there was uncontrolled DNA synthesis and marked swelling. Also, tyrosinase activity, melanin content and the number of mature melanosomes were greatly increased. These results suggest that when malignant melanocytes are not able to undergo apoptosis after treatment with CENU, they accumulate in G2 and this is followed by enhancement of melanogenesis.

  18. Behandling og håndtering af kongenitte melanocytære naevi

    DEFF Research Database (Denmark)

    Bahn, Kamille-Amalie; Hædersdal, Merete; Schmidt, Grethe

    2016-01-01

    Congenital melanocytic naevi (CMN) appear in approximately 2.6% of Caucasians. There is a major demand for treatment but no vital indication. Laser therapy, curettage and excision are available treatment modalities, but there is no ideal treatment with documented long-term effect and without side...

  19. Applications of Mesenchymal Stem Cells and Neural Crest Cells in Craniofacial Skeletal Research

    Directory of Open Access Journals (Sweden)

    Satoru Morikawa

    2016-01-01

    Full Text Available Craniofacial skeletal tissues are composed of tooth and bone, together with nerves and blood vessels. This composite material is mainly derived from neural crest cells (NCCs. The neural crest is transient embryonic tissue present during neural tube formation whose cells have high potential for migration and differentiation. Thus, NCCs are promising candidates for craniofacial tissue regeneration; however, the clinical application of NCCs is hindered by their limited accessibility. In contrast, mesenchymal stem cells (MSCs are easily accessible in adults, have similar potential for self-renewal, and can differentiate into skeletal tissues, including bones and cartilage. Therefore, MSCs may represent good sources of stem cells for clinical use. MSCs are classically identified under adherent culture conditions, leading to contamination with other cell lineages. Previous studies have identified mouse- and human-specific MSC subsets using cell surface markers. Additionally, some studies have shown that a subset of MSCs is closely related to neural crest derivatives and endothelial cells. These MSCs may be promising candidates for regeneration of craniofacial tissues from the perspective of developmental fate. Here, we review the fundamental biology of MSCs in craniofacial research.

  20. The unfolded protein response in melanocytes: activation in response to chemical stressors of the endoplasmic reticulum and tyrosinase misfolding.

    Science.gov (United States)

    Manga, Prashiela; Bis, Sabina; Knoll, Kristen; Perez, Beremis; Orlow, Seth J

    2010-10-01

    Accumulation of proteins in the endoplasmic reticulum (ER) triggers the unfolded protein response (UPR), comprising three signaling pathways initiated by Ire1, Perk and Atf6 respectively. Unfolded protein response activation was compared in chemically stressed murine wildtype melanocytes and mutant melanocytes that retain tyrosinase in the ER. Thapsigargin, an ER stressor, activated all pathways in wildtype melanocytes, triggering Caspase 12-mediated apoptosis at toxic doses. Albino melanocytes expressing mutant tyrosinase showed evidence of ER stress with increased Ire1 expression, but the downstream effector, Xbp1, was not activated even following thapsigargin treatment. Attenuation of Ire1 signaling was recapitulated in wildtype melanocytes treated with thapsigargin for 8 days, with diminished Xbp1 activation observed after 4 days. Atf6 was also activated in albino melanocytes, with no response to thapsigargin, while the Perk pathway was not activated and thapsigargin treatment elicited robust expression of the downstream effector CCAAT-enhancer-binding protein homologous protein. Thus, melanocytes adapt to ER stress by attenuating two UPR pathways.

  1. Diagnosis and staging of female genital tract melanocytic lesions using pump-probe microscopy (Conference Presentation)

    Science.gov (United States)

    Robles, Francisco E.; Selim, Maria A.; Warren, Warren S.

    2016-02-01

    Melanoma of the vulva is the second most common type of malignancy afflicting that organ. This disease caries poor prognosis, and shows tendencies to recur locally and develop distant metastases through hematogenous dissemination. Further, there exists significant clinical overlap between early-stage melanomas and melanotic macules, benign lesions that are believed to develop in about 10% of the general female population. In this work we apply a novel nonlinear optical method, pump-probe microscopy, to quantitatively analyze female genitalia tract melanocytic lesions. Pump-probe microscopy provides chemical information of endogenous pigments by probing their electronic excited state dynamics, with subcellular resolution. Using unstained biopsy sections from 31 patients, we find significant differences between melanin type and structure in tissue regions with invasive melanoma, melanoma in-situ and non-malignant melanocytic proliferations (e.g., nevi, melanocytic macules). The molecular images of non-malignant lesion have a well-organized structure, with relatively homogenous pigment chemistry, most often consistent with that of eumelanin with large aggregate size or void of metals, such as iron. On the other hand, pigment type and structure observed in melanomas in-situ and invasive melanomas is typically much more heterogeneous, with larger contributions from pheomelanin, melanins with larger metal content, and/or melanins with smaller aggregate size. Of most significance, clear differences can be observed between melanocytic macules and vulvar melanoma in-situ, which, as discussed above, can be difficult to clinically distinguish. This initial study demonstrates pump-probe microscopy's potential as an adjuvant diagnostic tool by revealing systematic chemical and morphological differences in melanin pigmentation among invasive melanoma, melanoma in-situ and non-malignant melanocytic lesions.

  2. Childhood malignant blue nevus of the ear associated with two intracranial melanocytic tumors-metastases or neurocutaneous melanosis?

    Science.gov (United States)

    Popović, Mara; Dolenc-Strazar, Zvezdana; Anzic, Jozica; Luzar, Bostjan

    2004-10-01

    Blue nevus is an uncommon pigmented tumor of dermal melanocytes that has traditionally been classified into common and cellular variant. It is usually a skin tumor in adults but can become apparent in early childhood or even be present at birth. Malignant blue nevus is a rare melanocytic tumor of the skin arising from a preexisting cellular blue nevus. We report a multinodular blue nevus of the left ear in an 11-year-old girl who also had 2 intracranial melanocytic lesions. Differential diagnosis between metastases from malignant blue nevus and neurocutaneous melanosis is discussed.

  3. Role of cranial neural crest cells in visceral arch muscle positioning and morphogenesis in the Mexican axolotl, Ambystoma mexicanum.

    Science.gov (United States)

    Ericsson, Rolf; Cerny, Robert; Falck, Pierre; Olsson, Lennart

    2004-10-01

    The role of cranial neural crest cells in the formation of visceral arch musculature was investigated in the Mexican axolotl, Ambystoma mexicanum. DiI (1,1'-dioctadecyl-3,3,3',3'-tetramethylindocarbocyanine, perchlorate) labeling and green fluorescent protein (GFP) mRNA injections combined with unilateral transplantations of neural folds showed that neural crest cells contribute to the connective tissues but not the myofibers of developing visceral arch muscles in the mandibular, hyoid, and branchial arches. Extirpations of individual cranial neural crest streams demonstrated that neural crest cells are necessary for correct morphogenesis of visceral arch muscles. These do, however, initially develop in their proper positions also in the absence of cranial neural crest. Visceral arch muscles forming in the absence of neural crest cells start to differentiate at their origins but fail to extend toward their insertions and may have a frayed appearance. Our data indicate that visceral arch muscle positioning is controlled by factors that do not have a neural crest origin. We suggest that the cranial neural crest-derived connective tissues provide directional guidance important for the proper extension of the cranial muscles and the subsequent attachment to the insertion on the correct cartilage. In a comparative context, our data from the Mexican axolotl support the view that the cranial neural crest plays a fundamental role in the development of not only the skeleton of the vertebrate head but also in the morphogenesis of the cranial muscles and that this might be a primitive feature of cranial development in vertebrates. 2004 Wiley-Liss, Inc.

  4. The gender differences in the inhibitory action of UVB-induced melanocyte activation by the administration of tranexamic acid.

    Science.gov (United States)

    Hiramoto, Keiichi; Yamate, Yurika; Sugiyama, Daijiro; Takahashi, Yumi; Mafune, Eiichi

    2016-05-01

    Tranexamic acid has an inhibitory action on ultraviolet (UV) B-induced melanocyte activation. This study examined the sex differences in the inhibitory action of tranexamic acid on UVB-induced melanocyte activation. We irradiated the eye and ear of male and female mice with UVB at a dose of 1.0 kJ/m(2) using a 20SE sunlamp. We orally administered tranexamic acid (750 mg/kg/day) at 30 min before UVB exposure. Tranexamic acid inhibited the UVB-induced epidermal melanocyte activation, and the effect was more remarkable under UVB eye irradiation than under UVB ear irradiation. Furthermore, the melanocyte activity suppression effect was stronger in female mice than in male mice. Following the administration of tranexamic acid, the female displayed increased blood levels of β-endorphin and μ-opioid receptor and estradiol receptor β expression in comparison with the male. Furthermore, the effect of melanocyte activity suppression in the female mice was decreased by the administration of tamoxifen (antagonist of estrogen receptor) or naltrexone (antagonist of μ-opioid receptor). These results suggest that the suppression by tranexamic acid of the UVB-induced melanocyte activation (UVB sensitivity) is stronger in female mice than in male mice and that female hormones and β-endorphin play an important role in this sex difference. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  5. Substantial Effect of Melanin Influencing Factors on In vitro Melanogenesis in Muzzle Melanocytes of Differently Colored Hanwoo.

    Science.gov (United States)

    Amna, Touseef; Park, Kyoung Mi; Cho, In-Kyung; Choi, Tae Jeong; Lee, Seung Soo; Seo, Kang-Seok; Hwang, Inho

    2012-07-01

    The present study was designed to investigate the effect of α-melanocyte-stimulating hormone (α-MSH), nitric oxide (NO) and L-cysteine on melanin production and expression of related genes MC1R, Tyr, Tyrp-1 and Tyrp-2 in muzzle melanocytes of differently colored three native Hanwoo cattle. Muzzle samples were taken from black, brindle and brown Hanwoo and purified melanocytes were cultured with α-MSH, nitric oxide and L-cysteine at 100 nM, 50 µM and 0.07 mg/ml of media respectively. The amounts of total melanin, eumelanin and mRNA expression at Tyr, Tyrp-1, Tyrp-2 and MC1R levels were quantified. α-MSH and nitric oxide significantly increased (pmuzzle melanocytes. On the contrary, L-cysteine greatly (pmuzzle melanocytes of all three phenotypes. The results of this study revealed nitric oxide and α-MSH contribute hyper-pigmentation by enhancing eumelanogenesis whereas L-cysteine contributes to pheomelanin production in different colored Hanwoo muzzle melanocytes.

  6. Antimelanogenic Efficacy of Melasolv (3,4,5-Trimethoxycinnamate Thymol Ester) in Melanocytes and Three-Dimensional Human Skin Equivalent.

    Science.gov (United States)

    Lee, John Hwan; Lee, Eun-Soo; Bae, Il-Hong; Hwang, Jeong-Ah; Kim, Se-Hwa; Kim, Dae-Yong; Park, Nok-Hyun; Rho, Ho Sik; Kim, Yong Jin; Oh, Seong-Geun; Lee, Chang Seok

    2017-01-01

    Excessive melanogenesis often causes unaesthetic hyperpigmentation. In a previous report, our group introduced a newly synthesized depigmentary agent, Melasolv™ (3,4,5-trimethoxycinnamate thymol ester). In this study, we demonstrated the significant whitening efficacy of Melasolv using various melanocytes and human skin equivalents as in vitro experimental systems. The depigmentary effect of Melasolv was tested in melan-a cells (immortalized normal murine melanocytes), α-melanocyte-stimulating hormone (α-MSH)-stimulated B16 murine melanoma cells, primary normal human melanocytes (NHMs), and human skin equivalent (MelanoDerm). The whitening efficacy of Melasolv was further demonstrated by photography, time-lapse microscopy, Fontana-Masson (F&M) staining, and 2-photon microscopy. Melasolv significantly inhibited melanogenesis in the melan-a and α-MSH-stimulated B16 cells. In human systems, Melasolv also clearly showed a whitening effect in NHMs and human skin equivalent, reflecting a decrease in melanin content. F&M staining and 2-photon microscopy revealed that Melasolv suppressed melanin transfer into multiple epidermal layers from melanocytes as well as melanin synthesis in human skin equivalent. Our study showed that Melasolv clearly exerts a whitening effect on various melanocytes and human skin equivalent. These results suggest the possibility that Melasolv can be used as a depigmentary agent to treat pigmentary disorders as well as an active ingredient in cosmetics to increase whitening efficacy. © 2017 S. Karger AG, Basel.

  7. Histomorphologic spectrum of BAP1 negative melanocytic neoplasms in a family with BAP1-associated cancer susceptibility syndrome.

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    Marušić, Zlatko; Buljan, Marija; Busam, Klaus J

    2015-06-01

    Multiple BAP1 negative melanocytic neoplasms are a hallmark of familial cancer susceptibility syndrome caused by BAP1 germline mutation. The syndrome is characterized by increased incidence of renal cell carcinoma, mesothelioma, cholangiocarcinoma, cutaneous and uveal melanoma and some other neoplasms. We report histomorphologic characteristics of six cutaneous melanocytic neoplasms with loss of BAP1 expression in two members of a family with BAP1-associated cancer susceptibility syndrome. The neoplasms were dermal melanocytic nevi characterized by a proliferation of large epithelioid (spitzoid) melanocytes, and adipocytic metaplasia. Nuclear pseudoinclusions and multinucleated melanocytes were present in most neoplasms. In two of the cases, a nodular melanoma was found associated with a dermal nevus. None of the melanomas recurred or metastasized after 6 and 3 years of follow up. We report two new cases of melanoma arising in a BAP1-deficient melanocytic nevus in the setting of familial tumor predisposition syndrome. Adipocytic metaplasia and nuclear pseudoinclusions may be additional morphologic clues to a BAP1-deficient nevus. It remains to be seen whether these features are more common in familial than sporadic lesions. © 2015 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Pseudomelanocytic nests mimicking atypical melanocytic proliferations: first reported cases in the oral cavity.

    Science.gov (United States)

    Boros, Audrey L; Handlers, Janice P; Melrose, Raymond J

    2014-10-01

    The concept of pseudomelanocytic nests has been recently described in the dermatology literature. To our knowledge, this entity has yet to be published in the oral pathology literature. We report 2 cases with features of pseudomelanocytic nests. In both instances, nests of cells suspicious for melanocytes were observed. Interpretation of melan-A was negative. Both cases showed strong and diffuse immunoreactivity of the nested cells to CD68. This immunohistochemical staining pattern is most consistent with a melanophage identity. Pseudomelanocytic nests are a recently described entity that represents a potential diagnostic pitfall. Distinguishing pseudomelanocytic nests from an authentic atypical melanocytic proliferation can be challenging and is important for appropriate patient management. Clinicopathologic correlation with cautious interpretation of immunohistochemistry may be necessary to arrive at the correct diagnosis. These cases represent the first reports of pseudomelanocytic nests in the oral pathology literature. Copyright © 2014 Elsevier Inc. All rights reserved.

  9. A case of melanocytic cervical adenosquamous carcinoma complicated with Cushing's syndrome.

    Science.gov (United States)

    Chen, Y; Zhang, Y; Wang, L; Yang, X

    2017-01-01

    To date, cervical carcinoma complicated with Cushing's syndrome were all diagnosed as small cell carcinoma histo- logically, but not adenosquamous carcinoma. Here the authors present the diagnosis, management, and prognosis of a case of melanocytic cervical adenosquamous carcinoma complicated with Cushing's syndrome. A 28-year-old woman was admitted with the chief complaint of post-coital bleeding for one month. Gynecological examination revealed a nodular yellowish-pigmented vegetation (6x5 cm) on the cervix. Laboratory findings proved the diagnosis of Cushing's syndrome. Histopathological diagnosis showed the adenosquamous carcinoma with melanoma differentiation. Immunohistochemical stainings for melanoma A and anti- adrenocorticotropic hormone (ACTH) were positive in the majority of the tumor cells, which indicated that this melanocytic cervical carcinoma lesion was the source of ectopic ACTH production resulting in Cushing's syndrome. This is a unique case of a rare type of cervical carcinoma.

  10. Malignant melanoma arising in congenital melanocytic nevi: clinical and dermoscopic challenges

    Directory of Open Access Journals (Sweden)

    Fatma Pelin Cengiz

    2017-01-01

    Full Text Available Congenital melanocytic nevi (CMN are visible pigmented lesions in the skin that are present at birth. CMN are benign malformations resulting from defective development of melanocyte precursors in the embryo. Six MMs from six patients were analyzed by clinical and dermoscopic examination. Of the patients, 33.3% were female (N = 2 and 66.6% were male (N = 4. Of the MMs, four (66.6% were superficial spreading MM and two (33.3 % were in situ MM. A reticular pattern was present in the MMs of three patients (50%, a homogeneous pattern was present in the other patients (50% at the base of the MMs. Superficial spreading melanomas and in situ melanomas with atypical dots and globules and a blue-white veil were the most common dermoscopic features of MMs found in CMN.

  11. Deep learning based classification of morphological patterns in RCM to guide noninvasive diagnosis of melanocytic lesions (Conference Presentation)

    Science.gov (United States)

    Kose, Kivanc; Bozkurt, Alican; Ariafar, Setareh; Alessi-Fox, Christi A.; Gill, Melissa; Dy, Jennifer G.; Brooks, Dana H.; Rajadhyaksha, Milind

    2017-02-01

    In this study we present a deep learning based classification algorithm for discriminating morphological patterns that appear in RCM mosaics of melanocytic lesions collected at the dermal epidermal junction (DEJ). These patterns are classified into 6 distinct types in the literature: background, meshwork, ring, clod, mixed, and aspecific. Clinicians typically identify these morphological patterns by examination of their textural appearance at 10X magnification. To mimic this process we divided mosaics into smaller regions, which we call tiles, and classify each tile in a deep learning framework. We used previously acquired DEJ mosaics of lesions deemed clinically suspicious, from 20 different patients, which were then labelled according to those 6 types by 2 expert users. We tried three different approaches for classification, all starting with a publicly available convolutional neural network (CNN) trained on natural image, consisting of a series of convolutional layers followed by a series of fully connected layers: (1) We fine-tuned this network using training data from the dataset. (2) Instead, we added an additional fully connected layer before the output layer network and then re-trained only last two layers, (3) We used only the CNN convolutional layers as a feature extractor, encoded the features using a bag of words model, and trained a support vector machine (SVM) classifier. Sensitivity and specificity were generally comparable across the three methods, and in the same ranges as our previous work using SURF features with SVM . Approach (3) was less computationally intensive to train but more sensitive to unbalanced representation of the 6 classes in the training data. However we expect CNN performance to improve as we add more training data because both the features and the classifier are learned jointly from the data. *First two authors share first authorship.

  12. Intracranial melanocytic meningeal tumours and melanosis oculi: case report and literature review

    International Nuclear Information System (INIS)

    Doglietto, Francesco; Colosimo, Cesare; Lauriola, Libero; Balducci, Mario; De Bonis, Pasquale; Montano, Nicola; Zadeh, Gelareh; Maira, Giulio; Pallini, Roberto

    2012-01-01

    Melanocytic meningeal tumours are rare extra-axial neoplasms of the nervous system, with only three reported cases in the cavernous sinus. Herein we describe for the first time the association of ocular melanosis and multiple intracranial melanocytic meningeal tumours, with the presenting lesion being in the cavernous sinus. The importance of this association is discussed together with the diagnostic and therapeutic challenges of the case. A 20-year-old man presented with a left sixth cranial nerve deficit; general examination documented only congenital melanosis of the homolateral eye. MRI examination showed a space occupying lesion in the left cavernous sinus, which was followed conservatively for 2 years, until a new space occupying lesion was evident at the level of the right frontal convexity: both lesions presented with neuroradiological characteristics suggestive of melanin content. The frontal convexity lesion was removed: intraoperatively the dura was markedly and diffusely melanotic. Histological examination documented a melanocytic meningeal tumour, with a proliferative index of 3 %. The patient underwent 3D-Conformal Radiation Therapy on the lesion of the cavernous sinus (total dose 5040 cGy), with initial tumour reduction. Three years later, due to a symptomatic growth, he underwent partial removal of the lesion in the cavernous sinus. Histological examination was unchanged. He then received adjuvant Temozolomide with Low Dose Fractionated Radiation Therapy (LD-FRT). Due to further disease progression cisplatin plus fotemustine were administered, concomitant with LD-FRT: after two cycles MRI documented significant disease regression. After a period of apparent disease control, the patient presented with persistent cough and evidence of multiple thoracic metastases, which lead to his death, seven years after presentation. Intracranial melanocytic meningeal tumours are challenging lesions, both from a diagnostic and therapeutic point of view; though rare

  13. Giant Congenital Melanocytic Nevus (GCMN - A New Hope for Targeted Therapy?

    Directory of Open Access Journals (Sweden)

    Georgi Tchernev

    2017-07-01

    Full Text Available We present a 6-month-old male patient, who was consulted with dermatologist by his parents, because of a pigmented lesion, present since birth, covering almost the all skin of the back and buttocks.  A sharply bordered, unequally coloured congenital pigmented nevus, measuring approximately 21 cm in diameter was observed in the whole body skin examination. The lesion was affecting the lower 2/3 of the skin of the back and the top half of the gluteus area, extending to the lateral part of the tors, forward the abdomen and the upper lateral part of the hips, composed by multiple darker-pigmented nests and several lighter areas, with single depigmented zones, hairy surface, irregularly infiltrated on palpation. Congenital melanocytic nevi are presented in approximately 1% of newborns, while giant congenital melanocytic nevi (GCMN are the most uncommon subtype of them; with occurrence rate 1 in 50,000 births. They affect 2% of a total body surface or presenting in a diameter larger than 20 cm in older children. Although not common, the possible malignant transformation remains one of the most important considerations related to them, as the related lifetime risk of melanoma is 4% to 10%. Treatment recommendations include non-surgical methods as dermabrasion only within the first two weeks of life, for prevention the possible melanocytic deeper migration, while serial surgical excisions or tissue expanders could be useful treatment tool even in later stages. Nevertheless, cosmetic result is not always satisfactory, and the risk of malignant changes remains, in cases of previous melanocytic migration in deeper layer. Recent article suggests the potential role in the treatment of GCMN with NRAS inhibitor trametinib, approved for treatment of advanced melanoma, associated with underlying NRAS mutations. Although promising, the drug could be useful in paediatric patients, only with associated NRAS gene mutation. It is still unclear whether it could be

  14. Expression of monocarboxylate transporter 1 in oral and ocular canine melanocytic tumors.

    Science.gov (United States)

    Shimoyama, Y; Akihara, Y; Kirat, D; Iwano, H; Hirayama, K; Kagawa, Y; Ohmachi, T; Matsuda, K; Okamoto, M; Kadosawa, T; Yokota, H; Taniyama, H

    2007-07-01

    Solid tumors are composed of a heterogeneous population of cells surviving in various concentrations of oxygen. In a hypoxic environment, tumor cells generally up-regulate glycolysis and, therefore, generate more lactate that must be expelled from the cell through proton transporters to prevent intracellular acidosis. Monocarboxylate transporter 1 (MCT1) is a major proton transporter in mammalian cells that transports monocarboxylates, such as lactate and pyruvate, together with a proton across the plasma membrane. Melanocytic neoplasia occurs frequently in dogs, but the prognosis is highly site-dependent. In this study, 50 oral canine melanomas, which were subdivided into 3 histologic subtypes, and 17 ocular canine melanocytic neoplasms (14 melanocytomas and 3 melanomas) were used to examine and compare MCT1 expression. Immunohistochemistry using a polyclonal chicken anti-rat MCT1 antibody showed that most oral melanoma exhibited cell membrane staining, although there were no significant differences observed among the 3 histologic subtypes. In contrast, the majority of ocular melanocytic tumors were not immunoreactive. Additionally, we documented the presence of a 45-kDa band in cell membrane protein Western blots, and sequencing of a reverse transcriptase polymerase chain reaction band of expected size confirmed its identity as a partial canine MCT1 transcript in 3 oral tumors. Increased MCT1 expression in oral melanomas compared with ocular melanocytic tumors may reflect the very different biology between these tumors in dogs. These results are the first to document canine MCT1 expression in canine tumors and suggest that increased MCT1 expression may provide a potential therapeutic target for oral melanoma.

  15. Resolution of vitiligo following excision of halo congenital melanocytic nevus: a rare case report.

    Science.gov (United States)

    Wang, Kai; Wang, Zhi; Huang, Weiqing

    2016-05-01

    Halo congenital melanocytic nevus (CMN) associated with vitiligo is rare, especially with regard to CMN excision. Only two reports of excision of halo CMN following repigmentation of vitiligo are found in the literature. We present a case of a girl with halo CMN and periorbital vitiligo. The halo CMN was excised and followed by spontaneous improvement of vitiligo. The result suggests excision of the inciting lesion may be a promising way to control vitiligo. © 2015 Wiley Periodicals, Inc.

  16. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

    Science.gov (United States)

    Choi, Hyunjung; Shin, Ji Hyun; Kim, Eun Sung; Park, So Jung; Bae, Il-Hong; Jo, Yoon Kyung; Jeong, In Young; Kim, Hyoung-June; Lee, Youngjin; Park, Hea Chul; Jeon, Hong Bae; Kim, Ki Woo; Lee, Tae Ryong; Cho, Dong-Hyung

    2016-01-01

    The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH)-smoothened (Smo) signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

  17. DMEM enhances tyrosinase activity in B16 mouse melanoma cells and human melanocytes

    Directory of Open Access Journals (Sweden)

    Panpen Diawpanich

    2008-07-01

    Full Text Available Media components may affect the activities of cultured cells. In this study, tyrosinase activity was evaluated by using B16-F10 mouse melanoma cell lines (B16-F10 and primary human melanocytes cultured in different media. An optical density measurement and a L-dopa reaction assay were used as the determination of the tyrosinase activity. The study of B16-F10 found the optical density to be 2010, 2246 and 2961 in cells cultured in RPMI Medium 1640 (RPMI1640,Minimum Essential Medium (MEM and Dulbecco’s Modified Eagle Medium (DMEM, respectively. Moreover, compared to RPMI 1640 and MEM, DMEM showed the darkest color of melanin formation in culture media and in cells after the L-dopa reaction assay. Addition of kojic acid showed a significant inhibitory effect on tyrosinase activity in all media.Whereas MCDB153 showed no significant effect on human melanocytes, DMEM caused a dramatic increase in tyrosinase activity after 4 days of cultivation. Addition of kojic acid showed a significant tyrosinase inhibitory effect in DMEM only. Furthermore, an active ingredient in green tea, epigallocathechin gallate (EGCG could inhibit tyrosinase activity in both B16-F10 and human melanocytes cultured in DMEM. In summary, these results suggest that DMEM is a suitable medium that provides high detection sensitivity in a tyrosinase inhibition assay.

  18. Primary Cilia Negatively Regulate Melanogenesis in Melanocytes and Pigmentation in a Human Skin Model.

    Directory of Open Access Journals (Sweden)

    Hyunjung Choi

    Full Text Available The primary cilium is an organelle protruding from the cell body that senses external stimuli including chemical, mechanical, light, osmotic, fluid flow, and gravitational signals. Skin is always exposed to the external environment and responds to external stimuli. Therefore, it is possible that primary cilia have an important role in skin. Ciliogenesis was reported to be involved in developmental processes in skin, such as keratinocyte differentiation and hair formation. However, the relation between skin pigmentation and primary cilia is largely unknown. Here, we observed that increased melanogenesis in melanocytes treated with a melanogenic inducer was inhibited by a ciliogenesis inducer, cytochalasin D, and serum-free culture. However, these inhibitory effects disappeared in GLI2 knockdown cells. In addition, activation of sonic hedgehog (SHH-smoothened (Smo signaling pathway by a Smo agonist, SAG inhibited melanin synthesis in melanocytes and pigmentation in a human skin model. On the contrary, an inhibitor of primary cilium formation, ciliobrevin A1, activated melanogenesis in melanocytes. These results suggest that skin pigmentation may be regulated partly by the induction of ciliogenesis through Smo-GLI2 signaling.

  19. Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion.

    Science.gov (United States)

    Ando, Hideya; Niki, Yoko; Ito, Masaaki; Akiyama, Kaoru; Matsui, Mary S; Yarosh, Daniel B; Ichihashi, Masamitsu

    2012-04-01

    Recent studies have described the role of shedding vesicles as physiological conveyers of intracellular components between neighboring cells. Here we report that melanosomes are one example of shedding vesicle cargo, but are processed by a previously unreported mechanism. Pigment globules were observed to be connected to the filopodia of melanocyte dendrites, which have previously been shown to be conduits for melanosomes. Pigment globules containing multiple melanosomes were released from various areas of the dendrites of normal human melanocytes derived from darkly pigmented skin. The globules were then captured by the microvilli of normal human keratinocytes, also derived from darkly pigmented skin, which incorporated them in a protease-activated receptor-2 (PAR-2)-dependent manner. After the pigment globules were ingested by the keratinocytes, the membrane that surrounded each melanosome cluster was gradually degraded, and the individual melanosomes then spread into the cytosol and were distributed primarily in the perinuclear area of each keratinocyte. These results suggest a melanosome transfer pathway wherein melanosomes are transferred from melanocytes to keratinocytes via the shedding vesicle system. This packaging system generates pigment globules containing multiple melanosomes in a unique manner.

  20. Infrared A radiation promotes survival of human melanocytes carrying ultraviolet radiation-induced DNA damage.

    Science.gov (United States)

    Kimeswenger, Susanne; Schwarz, Agatha; Födinger, Dagmar; Müller, Susanne; Pehamberger, Hubert; Schwarz, Thomas; Jantschitsch, Christian

    2016-06-01

    The link between solar radiation and melanoma is still elusive. Although infrared radiation (IR) accounts for over 50% of terrestrial solar energy, its influence on human skin is not well explored. There is increasing evidence that IR influences the expression patterns of several molecules independently of heat. A previous in vivo study revealed that pretreatment with IR might promote the development of UVR-induced non-epithelial skin cancer and possibly of melanoma in mice. To expand on this, the aim of the present study was to evaluate the impact of IR on UVR-induced apoptosis and DNA repair in normal human epidermal melanocytes. The balance between these two effects is a key factor of malignant transformation. Human melanocytes were exposed to physiologic doses of IR and UVR. Compared to cells irradiated with UVR only, simultaneous exposure to IR significantly reduced the apoptotic rate. However, IR did not influence the repair of UVR-induced DNA damage. IR partly reversed the pro-apoptotic effects of UVR via modification of the expression and activity of proteins mainly of the extrinsic apoptotic pathway. In conclusion, IR enhances the survival of melanocytes carrying UVR-induced DNA damage and thereby might contribute to melanomagenesis. © 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  1. Loss of 5-hydroxymethylcytosine correlates with increasing morphologic dysplasia in melanocytic tumors.

    Science.gov (United States)

    Larson, Allison R; Dresser, Karen A; Zhan, Qian; Lezcano, Cecilia; Woda, Bruce A; Yosufi, Benafsha; Thompson, John F; Scolyer, Richard A; Mihm, Martin C; Shi, Yujiang G; Murphy, George F; Lian, Christine Guo

    2014-07-01

    DNA methylation is the most well-studied epigenetic modification in cancer biology. 5-hydroxymethylcytosine is an epigenetic mark that can be converted from 5-methylcytosine by the ten-eleven translocation gene family. We recently reported the loss of 5-hydroxymethylcytosine in melanoma compared with benign nevi and suggested that loss of this epigenetic marker is correlated with tumor virulence based on its association with a worse prognosis. In this study, we further characterize the immunoreactivity patterns of 5-hydroxymethylcytosine in the full spectrum of melanocytic lesions to further validate the potential practical application of this epigenetic marker. One hundred and seventy-five cases were evaluated: 18 benign nevi, 20 dysplastic nevi (10 low-grade and 10 high-grade lesions), 10 atypical Spitz nevi, 20 borderline tumors, 5 melanomas arising within nevi, and 102 primary melanomas. Progressive loss of 5-hydroxymethylcytosine from benign dermal nevi to high-grade dysplastic nevi to borderline melanocytic neoplasms to melanoma was observed. In addition, an analysis of the relationship of nuclear diameter with 5-hydroxymethylcytosine staining intensity within lesional cells revealed a significant correlation between larger nuclear diameter and decreased levels of 5-hydroxymethylcytosine. Furthermore, borderline lesions uniquely exhibited a diverse spectrum of staining of each individual case. This study further substantiates the association of 5-hydroxymethylcytosine loss with dysplastic cytomorphologic features and tumor progression and supports the classification of borderline lesions as a biologically distinct category of melanocytic lesions.

  2. UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6

    Energy Technology Data Exchange (ETDEWEB)

    Miyata, Maiko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Ichihara, Masatoshi; Tajima, Orie; Sobue, Sayaka; Kambe, Mariko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Sugiura, Kazumitsu [Department of Dermatology, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Furukawa, Koichi, E-mail: koichi@med.nagoya-u.ac.jp [Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan); Furukawa, Keiko [Department of Life and Medical Sciences, Chubu University Faculty of Life and Health Sciences, Matsumoto, Kasugai 487-8501 (Japan); Department of Biochemistry II, Nagoya University Graduate School of Medicine, 65 Tsurumai, Showa-ku, Nagoya 466-0065 (Japan)

    2014-03-07

    Highlights: • Melanocytes showed low ST8SIA1 and high B3GALT4 levels in contrast with melanomas. • Direct UVB irradiation of melanocytes did not induce ganglioside synthase genes. • Culture supernatants of UVB-irradiated keratinocytes induced ST8SIA1 in melanocytes. • TNFα and IL-6 secreted from keratinocytes enhanced ST8SIA1 expression in melanocytes. • Inflammatory cytokines induced melanoma-related ST8SIA1 in melanocytes. - Abstract: Although expression of gangliosides and their synthetic enzyme genes in malignant melanomas has been well studied, that in normal melanocytes has been scarcely analyzed. In particular, changes in expression levels of glycosyltransferase genes responsible for ganglioside synthesis during evolution of melanomas from melanocytes are very important to understand roles of gangliosides in melanomas. Here, expression of glycosyltransferase genes related to the ganglioside synthesis was analyzed using RNAs from cultured melanocytes and melanoma cell lines. Quantitative RT-PCR revealed that melanomas expressed high levels of mRNA of GD3 synthase and GM2/GD2 synthase genes and low levels of GM1/GD1b synthase genes compared with melanocytes. As a representative exogenous stimulation, effects of ultraviolet B (UVB) on the expression levels of 3 major ganglioside synthase genes in melanocytes were analyzed. Although direct UVB irradiation of melanocytes caused no marked changes, culture supernatants of UVB-irradiated keratinocytes (HaCaT cells) induced definite up-regulation of GD3 synthase and GM2/GD2 synthase genes. Detailed examination of the supernatants revealed that inflammatory cytokines such as TNFα and IL-6 enhanced GD3 synthase gene expression. These results suggest that inflammatory cytokines secreted from UVB-irradiated keratinocytes induced melanoma-associated ganglioside synthase genes, proposing roles of skin microenvironment in the promotion of melanoma-like ganglioside profiles in melanocytes.

  3. UVB-irradiated keratinocytes induce melanoma-associated ganglioside GD3 synthase gene in melanocytes via secretion of tumor necrosis factor α and interleukin 6

    International Nuclear Information System (INIS)

    Miyata, Maiko; Ichihara, Masatoshi; Tajima, Orie; Sobue, Sayaka; Kambe, Mariko; Sugiura, Kazumitsu; Furukawa, Koichi; Furukawa, Keiko

    2014-01-01

    Highlights: • Melanocytes showed low ST8SIA1 and high B3GALT4 levels in contrast with melanomas. • Direct UVB irradiation of melanocytes did not induce ganglioside synthase genes. • Culture supernatants of UVB-irradiated keratinocytes induced ST8SIA1 in melanocytes. • TNFα and IL-6 secreted from keratinocytes enhanced ST8SIA1 expression in melanocytes. • Inflammatory cytokines induced melanoma-related ST8SIA1 in melanocytes. - Abstract: Although expression of gangliosides and their synthetic enzyme genes in malignant melanomas has been well studied, that in normal melanocytes has been scarcely analyzed. In particular, changes in expression levels of glycosyltransferase genes responsible for ganglioside synthesis during evolution of melanomas from melanocytes are very important to understand roles of gangliosides in melanomas. Here, expression of glycosyltransferase genes related to the ganglioside synthesis was analyzed using RNAs from cultured melanocytes and melanoma cell lines. Quantitative RT-PCR revealed that melanomas expressed high levels of mRNA of GD3 synthase and GM2/GD2 synthase genes and low levels of GM1/GD1b synthase genes compared with melanocytes. As a representative exogenous stimulation, effects of ultraviolet B (UVB) on the expression levels of 3 major ganglioside synthase genes in melanocytes were analyzed. Although direct UVB irradiation of melanocytes caused no marked changes, culture supernatants of UVB-irradiated keratinocytes (HaCaT cells) induced definite up-regulation of GD3 synthase and GM2/GD2 synthase genes. Detailed examination of the supernatants revealed that inflammatory cytokines such as TNFα and IL-6 enhanced GD3 synthase gene expression. These results suggest that inflammatory cytokines secreted from UVB-irradiated keratinocytes induced melanoma-associated ganglioside synthase genes, proposing roles of skin microenvironment in the promotion of melanoma-like ganglioside profiles in melanocytes

  4. MC1R and the response of melanocytes to ultraviolet radiation

    International Nuclear Information System (INIS)

    Rouzaud, Francois; Kadekaro, Ana Luisa; Abdel-Malek, Zalfa A.; Hearing, Vincent J.

    2005-01-01

    The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists α-melanocyte-stimulating hormone (αMSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of αMSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is considered a

  5. MC1R and the response of melanocytes to ultraviolet radiation

    Energy Technology Data Exchange (ETDEWEB)

    Rouzaud, Francois [Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 2132, Bethesda, MD 20892 (United States); Kadekaro, Ana Luisa [Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267 (United States); Abdel-Malek, Zalfa A. [Department of Dermatology, University of Cincinnati, College of Medicine, Cincinnati, OH 45267 (United States); Hearing, Vincent J. [Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Building 37, Room 2132, Bethesda, MD 20892 (United States)]. E-mail: hearingv@nih.gov

    2005-04-01

    The constitutive color of our skin plays a dramatic role in our photoprotection from solar ultraviolet radiation (UVR) that reaches the Earth and in minimizing DNA damage that gives rise to skin cancer. More than 120 genes have been identified and shown to regulate pigmentation, one of the key genes being melanocortin 1 receptor (MC1R) that encodes the melanocortin 1 receptor (MC1R), a seven-transmembrane G protein-coupled receptor expressed on the surface of melanocytes. Modulation of MC1R function regulates melanin synthesis by melanocytes qualitatively and quantitatively. The MC1R is regulated by the physiological agonists {alpha}-melanocyte-stimulating hormone ({alpha}MSH) and adrenocorticotropic hormone (ACTH), and antagonist agouti signaling protein (ASP). Activation of the MC1R by binding of an agonist stimulates the synthesis of eumelanin primarily via activation of adenylate cyclase. The significance of cutaneous pigmentation lies in the photoprotective effect of melanin, particularly eumelanin, against sun-induced carcinogenesis. Epidermal melanocytes and keratinocytes respond to UVR by increasing their expression of {alpha}MSH and ACTH, which up-regulate the expression of MC1R, and consequently enhance the response of melanocytes to melanocortins. Constitutive skin pigmentation dramatically affects the incidence of skin cancer. The pigmentary phenotype characterized by red hair, fair complexion, inability to tan and tendency to freckle is an independent risk factor for all skin cancers, including melanoma. The MC1R gene is highly polymorphic in human populations, and allelic variation at this locus accounts, to a large extent, for the variation in pigmentary phenotypes and skin phototypes (SPT) in humans. Several allelic variants of the MC1R gene are associated with the red hair and fair skin (RHC) phenotype, and carrying one of these variants is thought to diminish the ability of the epidermis to respond to DNA damage elicited by UVR. The MC1R gene is

  6. Vitiligo inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8

    Science.gov (United States)

    Toosi, Siavash; Orlow, Seth J.; Manga, Prashiela

    2012-01-01

    Vitiligo is characterized by depigmented skin patches due to loss of epidermal melanocytes. Oxidative stress may play a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol (4-TBP) and monobenzyl ether of hydroquinone (MBEH), known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box binding protein 1 (XBP1), are increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators interleukin-6 (IL6) and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while over-expression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity. PMID:22696056

  7. Vitiligo-inducing phenols activate the unfolded protein response in melanocytes resulting in upregulation of IL6 and IL8.

    Science.gov (United States)

    Toosi, Siavash; Orlow, Seth J; Manga, Prashiela

    2012-11-01

    Vitiligo is characterized by depigmented skin patches caused by loss of epidermal melanocytes. Oxidative stress may have a role in vitiligo onset, while autoimmunity contributes to disease progression. In this study, we sought to identify mechanisms that link disease triggers and spreading of lesions. A hallmark of melanocytes at the periphery of vitiligo lesions is dilation of the endoplasmic reticulum (ER). We hypothesized that oxidative stress results in redox disruptions that extend to the ER, causing accumulation of misfolded peptides, which activates the unfolded protein response (UPR). We used 4-tertiary butyl phenol and monobenzyl ether of hydroquinone, known triggers of vitiligo. We show that expression of key UPR components, including the transcription factor X-box-binding protein 1 (XBP1), is increased following exposure of melanocytes to phenols. XBP1 activation increases production of immune mediators IL6 and IL8. Co-treatment with XBP1 inhibitors reduced IL6 and IL8 production induced by phenols, while overexpression of XBP1 alone increased their expression. Thus, melanocytes themselves produce cytokines associated with activation of an immune response following exposure to chemical triggers of vitiligo. These results expand our understanding of the mechanisms underlying melanocyte loss in vitiligo and pathways linking environmental stressors and autoimmunity.

  8. A role for chemokine signaling in neural crest cell migration and craniofacial development

    Science.gov (United States)

    Killian, Eugenia C. Olesnicky; Birkholz, Denise A.; Artinger, Kristin Bruk

    2009-01-01

    Neural crest cells (NCCs) are a unique population of multipotent cells that migrate along defined pathways throughout the embryo and give rise to many diverse cell types including pigment cells, craniofacial cartilage and the peripheral nervous system (PNS). Aberrant migration of NCCs results in a wide variety of congenital birth defects including craniofacial abnormalities. The chemokine Sdf1 and its receptors, Cxcr4 and Cxcr7, have been identified as key components in the regulation of cell migration in a variety of tissues. Here we describe a novel role for the zebrafish chemokine receptor Cxcr4a in the development and migration of cranial NCCs (CNCCs). We find that loss of Cxcr4a, but not Cxcr7b results in aberrant CNCC migration, defects in the neurocranium, as well as cranial ganglia dismorphogenesis. Moreover, overexpression of either Sdf1b or Cxcr4a causes aberrant CNCC migration and results in ectopic craniofacial cartilages. We propose a model in which Sdf1b signaling from the pharyngeal arch endoderm and optic stalk to Cxcr4a expressing CNCCs is important for both the proper condensation of the CNCCs into pharyngeal arches and the subsequent patterning and morphogenesis of the neural crest derived tissues. PMID:19576198

  9. Influence of melanocytes in the ex-vivo reconstructed epidermal melanin unit following an acute UV irradiation; Role des melanocytes dans l'unite epidermique de melanisation reconstruite ex-vivo apres une irradiation UV aigue

    Energy Technology Data Exchange (ETDEWEB)

    Cario-Andre, M

    2000-11-15

    Influence of melanocytes in skin pigmentation is well documented, however its photo-protective role has given rise to controversy. The role of melanocytes have been investigated on reconstructed epidermis with 100 % of keratinocytes or 95 % of keratinocytes and 5 % of melanocytes. In a first time, the effect of an acute UVB dose has been studied on both reconstructed epidermis, next we have investigated UVA and UVA+B effects on these epidermis. Following irradiation, the presence of melanocytes in reconstructed epidermis protects against apoptosis without protecting significantly against DNA damage formation (CPD, 6-4PP) and protects against UV-induced unbalance of the SOD/catalase ratio (antioxidants enzymes). On the contrary, the presence of melanocytes in reconstructed epidermis amplifies lipids and proteins oxidations but seems to protect against DNA oxidations. Melanocytes differ from keratinocytes by their melanin content and their more important concentration in polyunsaturated fatty acids. To evaluate what is the part of melanin and the part of polyunsaturated fatty acids in epidermal UV responses, reconstructed epidermis with keratinocytes have been supplemented with polyunsaturated fatty acid. This study indicates that polyunsaturated fatty acids are responsible for lipids and proteins oxidations and that melanin protect against DNA oxidation induced by lipid peroxidation. All these studies demonstrate that, model of reconstructed epidermis and epidermis in-vivo have the same behaviour following UV irradiation. In the last part, sunscreens and antioxidants have been tested on reconstructed epidermis and have demonstrated that model of reconstructed epidermis is suitable for photo-protective molecules screening. (author)

  10. Influence of melanocytes in the ex-vivo reconstructed epidermal melanin unit following an acute UV irradiation; Role des melanocytes dans l'unite epidermique de melanisation reconstruite ex-vivo apres une irradiation UV aigue

    Energy Technology Data Exchange (ETDEWEB)

    Cario-Andre, M

    2000-11-15

    Influence of melanocytes in skin pigmentation is well documented, however its photo-protective role has given rise to controversy. The role of melanocytes have been investigated on reconstructed epidermis with 100 % of keratinocytes or 95 % of keratinocytes and 5 % of melanocytes. In a first time, the effect of an acute UVB dose has been studied on both reconstructed epidermis, next we have investigated UVA and UVA+B effects on these epidermis. Following irradiation, the presence of melanocytes in reconstructed epidermis protects against apoptosis without protecting significantly against DNA damage formation (CPD, 6-4PP) and protects against UV-induced unbalance of the SOD/catalase ratio (antioxidants enzymes). On the contrary, the presence of melanocytes in reconstructed epidermis amplifies lipids and proteins oxidations but seems to protect against DNA oxidations. Melanocytes differ from keratinocytes by their melanin content and their more important concentration in polyunsaturated fatty acids. To evaluate what is the part of melanin and the part of polyunsaturated fatty acids in epidermal UV responses, reconstructed epidermis with keratinocytes have been supplemented with polyunsaturated fatty acid. This study indicates that polyunsaturated fatty acids are responsible for lipids and proteins oxidations and that melanin protect against DNA oxidation induced by lipid peroxidation. All these studies demonstrate that, model of reconstructed epidermis and epidermis in-vivo have the same behaviour following UV irradiation. In the last part, sunscreens and antioxidants have been tested on reconstructed epidermis and have demonstrated that model of reconstructed epidermis is suitable for photo-protective molecules screening. (author)

  11. Mutations in c10orf11, a melanocyte-differentiation gene, cause autosomal-recessive albinism.

    Science.gov (United States)

    Grønskov, Karen; Dooley, Christopher M; Østergaard, Elsebet; Kelsh, Robert N; Hansen, Lars; Levesque, Mitchell P; Vilhelmsen, Kaj; Møllgård, Kjeld; Stemple, Derek L; Rosenberg, Thomas

    2013-03-07

    Autosomal-recessive albinism is a hypopigmentation disorder with a broad phenotypic range. A substantial fraction of individuals with albinism remain genetically unresolved, and it has been hypothesized that more genes are to be identified. By using homozygosity mapping of an inbred Faroese family, we identified a 3.5 Mb homozygous region (10q22.2-q22.3) on chromosome 10. The region contains five protein-coding genes, and sequencing of one of these, C10orf11, revealed a nonsense mutation that segregated with the disease and showed a recessive inheritance pattern. Investigation of additional albinism-affected individuals from the Faroe Islands revealed that five out of eight unrelated affected persons had the nonsense mutation in C10orf11. Screening of a cohort of autosomal-recessive-albinism-affected individuals residing in Denmark showed a homozygous 1 bp duplication in C10orf11 in an individual originating from Lithuania. Immunohistochemistry showed localization of C10orf11 in melanoblasts and melanocytes in human fetal tissue, but no localization was seen in retinal pigment epithelial cells. Knockdown of the zebrafish (Danio rerio) homolog with the use of morpholinos resulted in substantially decreased pigmentation and a reduction of the apparent number of pigmented melanocytes. The morphant phenotype was rescued by wild-type C10orf11, but not by mutant C10orf11. In conclusion, we have identified a melanocyte-differentiation gene, C10orf11, which when mutated causes autosomal-recessive albinism in humans. Copyright © 2013 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

  12. Comparative cytogenetic characterization of primary canine melanocytic lesions using array CGH and fluorescence in situ hybridization.

    Science.gov (United States)

    Poorman, Kelsey; Borst, Luke; Moroff, Scott; Roy, Siddharth; Labelle, Philippe; Motsinger-Reif, Alison; Breen, Matthew

    2015-06-01

    Melanocytic lesions originating from the oral mucosa or cutaneous epithelium are common in the general dog population, with up to 100,000 diagnoses each year in the USA. Oral melanoma is the most frequent canine neoplasm of the oral cavity, exhibiting a highly aggressive course. Cutaneous melanocytomas occur frequently, but rarely develop into a malignant form. Despite the differential prognosis, it has been assumed that subtypes of melanocytic lesions represent the same disease. To address the relative paucity of information about their genomic status, molecular cytogenetic analysis was performed on the three recognized subtypes of canine melanocytic lesions. Using array comparative genomic hybridization (aCGH) analysis, highly aberrant distinct copy number status across the tumor genome for both of the malignant melanoma subtypes was revealed. The most frequent aberrations included gain of dog chromosome (CFA) 13 and 17 and loss of CFA 22. Melanocytomas possessed fewer genome wide aberrations, yet showed a recurrent gain of CFA 20q15.3-17. A distinctive copy number profile, evident only in oral melanomas, displayed a sigmoidal pattern of copy number loss followed immediately by a gain, around CFA 30q14. Moreover, when assessed by fluorescence in situ hybridization (FISH), copy number aberrations of targeted genes, such as gain of c-MYC (80 % of cases) and loss of CDKN2A (68 % of cases), were observed. This study suggests that in concordance with what is known for human melanomas, canine melanomas of the oral mucosa and cutaneous epithelium are discrete and initiated by different molecular pathways.

  13. Premalignant quiescent melanocytic nevi do not express the MHC class I chain-related protein A

    Directory of Open Access Journals (Sweden)

    Mercedes B. Fuertes

    2011-08-01

    Full Text Available The MHC class I chain-related protein A (MICA is an inducible molecule almost not expressed by normal cells but strongly up-regulated in tumor cells. MICA-expressing cells are recognized by natural killer (NK cells, CD8+ aßTCR and ?dTCR T lymphocytes through the NKG2D receptor. Engagement of NKG2D by MICA triggers IFN-? secretion and cytotoxicity against malignant cells. Although most solid tumors express MICA and this molecule is a target during immune surveillance against tumors, it has been observed that high grade tumors from different histotypes express low amounts of cell surface MICA due to a metalloprotease- induced shedding. Also, melanomas develop after a complex process of neotransformation of normal melanocytes. However, the expression of MICA in premalignant stages (primary human quiescent melanocytic nevi remains unknown. Here, we assessed expression of MICA by flow cytometry using cell suspensions from 15 primary nevi isolated from 11 patients. When collected material was abundant, cell lysates were prepared and MICA expression was also analyzed by Western blot. We observed that MICA was undetectable in the 15 primary nevi (intradermic, junction, mixed, lentigo and congenital samples as well as in normal skin, benign lesions (seborrheic keratosis, premalignant lesions (actinic keratosis and benign basocellular cancer. Conversely, a primary recently diagnosed melanoma showed intense cell surface MICA. We conclude that the onset of MICA expression is a tightly regulated process that occurs after melanocytes trespass the stage of malignant transformation. Thus, analysis of MICA expression in tissue sections of skin samples may constitute a useful marker to differentiate between benign and malignant nevi.

  14. Constitutive activation of the ERK pathway in melanoma and skin melanocytes in Grey horses.

    Science.gov (United States)

    Jiang, Lin; Campagne, Cécile; Sundström, Elisabeth; Sousa, Pedro; Imran, Saima; Seltenhammer, Monika; Pielberg, Gerli; Olsson, Mats J; Egidy, Giorgia; Andersson, Leif; Golovko, Anna

    2014-11-21

    Constitutive activation of the ERK pathway, occurring in the vast majority of melanocytic neoplasms, has a pivotal role in melanoma development. Different mechanisms underlie this activation in different tumour settings. The Grey phenotype in horses, caused by a 4.6 kb duplication in intron 6 of Syntaxin 17 (STX17), is associated with a very high incidence of cutaneous melanoma, but the molecular mechanism behind the melanomagenesis remains unknown. Here, we investigated the involvement of the ERK pathway in melanoma development in Grey horses. Grey horse melanoma tumours, cell lines and normal skin melanocytes were analyzed with help of indirect immunofluorescence and immunoblotting for the expression of phospho-ERK1/2 in comparison to that in non-grey horse and human counterparts. The mutational status of BRAF, RAS, GNAQ, GNA11 and KIT genes in Grey horse melanomas was determined by direct sequencing. The effect of RAS, RAF and PI3K/AKT pathways on the activation of the ERK signaling in Grey horse melanoma cells was investigated with help of specific inhibitors and immunoblotting. Individual roles of RAF and RAS kinases on the ERK activation were examined using si-RNA based approach and immunoblotting. We found that the ERK pathway is constitutively activated in Grey horse melanoma tumours and cell lines in the absence of somatic activating mutations in BRAF, RAS, GNAQ, GNA11 and KIT genes or alterations in the expression of the main components of the pathway. The pathway is mitogenic and is mediated by BRAF, CRAF and KRAS kinases. Importantly, we found high activation of the ERK pathway also in epidermal melanocytes, suggesting a general predisposition to melanomagenesis in these horses. These findings demonstrate that the presence of the intronic 4.6 kb duplication in STX17 is strongly associated with constitutive activation of the ERK pathway in melanocytic cells in Grey horses in the absence of somatic mutations commonly linked to the activation of this

  15. Relative contributions of decay accelerating factor (DAF), membrane cofactor protein (MCP) and CD59 in the protection of melanocytes from homologous complement

    NARCIS (Netherlands)

    Venneker, G. T.; Vodegel, R. M.; Okada, N.; Westerhof, W.; Bos, J. D.; Asghar, S. S.

    1998-01-01

    Complement regulatory molecules, membrane cofactor protein (MCP), decay accelerating factor (DAF) and CD59, protect body cells from autologous complement. They have wide tissue distribution but nothing is known about the expression of these molecules on human melanocytes. Since melanocytes are lysed

  16. MicroRNA expression in melanocytic nevi: the usefulness of formalin-fixed, paraffin-embedded material for miRNA microarray profiling

    DEFF Research Database (Denmark)

    Glud, M.; Klausen, M.; Gniadecki, R.

    2009-01-01

    surgical specimens are formalin fixed and paraffin embedded (FFPE). To explore whether FFPE material would be suitable for miRNA profiling in melanocytic lesions, we compared miRNA expression patterns in FFPE versus fresh frozen samples, obtained from 15 human melanocytic nevi. Out of microarray data, we...

  17. Influence of melanocytes in the ex-vivo reconstructed epidermal melanin unit following an acute UV irradiation

    International Nuclear Information System (INIS)

    Cario-Andre, M.

    2000-11-01

    Influence of melanocytes in skin pigmentation is well documented, however its photo-protective role has given rise to controversy. The role of melanocytes have been investigated on reconstructed epidermis with 100 % of keratinocytes or 95 % of keratinocytes and 5 % of melanocytes. In a first time, the effect of an acute UVB dose has been studied on both reconstructed epidermis, next we have investigated UVA and UVA+B effects on these epidermis. Following irradiation, the presence of melanocytes in reconstructed epidermis protects against apoptosis without protecting significantly against DNA damage formation (CPD, 6-4PP) and protects against UV-induced unbalance of the SOD/catalase ratio (antioxidants enzymes). On the contrary, the presence of melanocytes in reconstructed epidermis amplifies lipids and proteins oxidations but seems to protect against DNA oxidations. Melanocytes differ from keratinocytes by their melanin content and their more important concentration in polyunsaturated fatty acids. To evaluate what is the part of melanin and the part of polyunsaturated fatty acids in epidermal UV responses, reconstructed epidermis with keratinocytes have been supplemented with polyunsaturated fatty acid. This study indicates that polyunsaturated fatty acids are responsible for lipids and proteins oxidations and that melanin protect against DNA oxidation induced by lipid peroxidation. All these studies demonstrate that, model of reconstructed epidermis and epidermis in-vivo have the same behaviour following UV irradiation. In the last part, sunscreens and antioxidants have been tested on reconstructed epidermis and have demonstrated that model of reconstructed epidermis is suitable for photo-protective molecules screening. (author)

  18. Significance of the Melanocortin 1 and Endothelin B Receptors in Melanocyte Homeostasis and Prevention of Sun-Induced Genotoxicity

    Directory of Open Access Journals (Sweden)

    Zalfa A. Abdel-Malek

    2016-08-01

    Full Text Available The membrane bound melanocortin 1 receptor (MC1R, and the endothelin B receptor (ENDBR are two G-protein coupled receptors that play important roles in constitutive regulation of melanocytes and their response to ultraviolet radiation (UVR, the main etiological factor for melanoma. The human MC1R is a Gs protein-coupled receptor, which is activated by its agonists α-melanocyte stimulating hormone (α-melanocortin; α-MSH and adrenocorticotropic hormone (ACTH. The ENDBR is a Gq coupled-receptor, which is activated by Endothelin (ET-3 during embryonic development, and ET-1 postnatally. Pigmentation and the DNA repair capacity are two major factors that determine the risk for melanoma. Activation of the MC1R by its agonists stimulates the synthesis of eumelanin, the dark brown photoprotective pigment. In vitro studies showed that α-MSH and ET-1 interact synergistically in the presence of basic fibroblast growth factor (bFGF to stimulate human melanocyte proliferation and melanogenesis, and to inhibit UVR-induced apoptosis. An important function of the MC1R is reduction of oxidative stress and activation of DNA repair pathways. The human MC1R is highly polymorphic, and MC1R variants, particularly those that cause loss of function of the expressed receptor, are associated with increased melanoma risk independently of pigmentation. These variants compromise the DNA repair and antioxidant capacities of human melanocytes. Recently, activation of ENDBR by ET-1 was reported to reduce the induction and enhance the repair of UVR-induced DNA photoproducts. We conclude that α-MSH and ET-1 and their cognate receptors MC1R and ENDBR reduce the risk for melanoma by maintaining genomic stability of melanocytes via modulating the DNA damage response to solar UVR. Elucidating the response of melanocytes to UVR should improve our understanding of the process of melanomagenesis, and lead to effective melanoma chemoprevention, as well as therapeutic strategies.

  19. Influence and timing of arrival of murine neural crest on pancreatic beta cell development and maturation.

    Science.gov (United States)

    Plank, Jennifer L; Mundell, Nathan A; Frist, Audrey Y; LeGrone, Alison W; Kim, Thomas; Musser, Melissa A; Walter, Teagan J; Labosky, Patricia A

    2011-01-15

    Interactions between cells from the ectoderm and mesoderm influence development of the endodermally-derived pancreas. While much is known about how mesoderm regulates pancreatic development, relatively little is understood about how and when the ectodermally-derived neural crest regulates pancreatic development and specifically, beta cell maturation. A previous study demonstrated that signals from the neural crest regulate beta cell proliferation and ultimately, beta cell mass. Here, we expand on that work to describe timing of neural crest arrival at the developing pancreatic bud and extend our knowledge of the non-cell autonomous role for neural crest derivatives in the process of beta cell maturation. We demonstrated that murine neural crest entered the pancreatic mesenchyme between the 26 and 27 somite stages (approximately 10.0 dpc) and became intermingled with pancreatic progenitors as the epithelium branched into the surrounding mesenchyme. Using a neural crest-specific deletion of the Forkhead transcription factor Foxd3, we ablated neural crest cells that migrate to the pancreatic primordium. Consistent with previous data, in the absence of Foxd3, and therefore the absence of neural crest cells, proliferation of insulin-expressing cells and insulin-positive area are increased. Analysis of endocrine cell gene expression in the absence of neural crest demonstrated that, although the number of insulin-expressing cells was increased, beta cell maturation was significantly impaired. Decreased MafA and Pdx1 expression illustrated the defect in beta cell maturation; we discovered that without neural crest, there was a reduction in the percentage of insulin-positive cells that co-expressed Glut2 and Pdx1 compared to controls. In addition, transmission electron microscopy analyses revealed decreased numbers of characteristic insulin granules and the presence of abnormal granules in insulin-expressing cells from mutant embryos. Together, these data demonstrate that

  20. Comparison of growth factor signalling pathway utilisation in cultured normal melanocytes and melanoma cell lines

    International Nuclear Information System (INIS)

    Kim, Ji Eun; Stones, Clare; Joseph, Wayne R; Leung, Euphemia; Finlay, Graeme J; Shelling, Andrew N; Phillips, Wayne A; Shepherd, Peter R; Baguley, Bruce C

    2012-01-01

    The phosphatidylinositol-3-kinase (PI3K-PKB), mitogen activated protein kinase (MEK-ERK) and the mammalian target of rapamycin (mTOR- p70S6K), are thought to regulate many aspects of tumour cell proliferation and survival. We have examined the utilisation of these three signalling pathways in a number of cell lines derived from patients with metastatic malignant melanoma of known PIK3CA, PTEN, NRAS and BRAF mutational status. Western blotting was used to compare the phosphorylation status of components of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways, as indices of pathway utilisation. Normal melanocytes could not be distinguished from melanoma cells on the basis of pathway utilisation when grown in the presence of serum, but could be distinguished upon serum starvation, where signalling protein phosphorylation was generally abrogated. Surprisingly, the differential utilisation of individual pathways was not consistently associated with the presence of an oncogenic or tumour suppressor mutation of genes in these pathways. Utilisation of the PI3K-PKB, MEK-ERK and mTOR-p70S6K signalling pathways in melanoma, as determined by phosphorylation of signalling components, varies widely across a series of cell lines, and does not directly reflect mutation of genes coding these components. The main difference between cultured normal melanocytes and melanoma cells is not the pathway utilisation itself, but rather in the serum dependence of pathway utilisation

  1. Refractometry of melanocyte cell nuclei using optical scatter images recorded by digital Fourier microscopy.

    Science.gov (United States)

    Seet, Katrina Y T; Nieminen, Timo A; Zvyagin, Andrei V

    2009-01-01

    The cell nucleus is the dominant optical scatterer in the cell. Neoplastic cells are characterized by cell nucleus polymorphism and polychromism-i.e., the nuclei exhibits an increase in the distribution of both size and refractive index. The relative size parameter, and its distribution, is proportional to the product of the nucleus size and its relative refractive index and is a useful discriminant between normal and abnormal (cancerous) cells. We demonstrate a recently introduced holographic technique, digital Fourier microscopy (DFM), to provide a sensitive measure of this relative size parameter. Fourier holograms were recorded and optical scatter of individual scatterers were extracted and modeled with Mie theory to determine the relative size parameter. The relative size parameter of individual melanocyte cell nuclei were found to be 16.5+/-0.2, which gives a cell nucleus refractive index of 1.38+/-0.01 and is in good agreement with previously reported data. The relative size parameters of individual malignant melanocyte cell nuclei are expected to be greater than 16.5.

  2. Abundance of the benign melanocytic universe: Dermoscopic-histopathological correlation in nevi.

    Science.gov (United States)

    Woltsche, Nora; Schmid-Zalaudek, Karin; Deinlein, Teresa; Rammel, Katrin; Hofmann-Wellenhof, Rainer; Zalaudek, Iris

    2017-05-01

    The broad universe of "melanocytic nevi" includes a variety of different subtypes, which can be classified either due to their morphology, epidemiology, genetic alterations or risk for developing melanoma. Regarding morphology, on the one hand macroscopic/clinical and on the other hand histopathological appearance were used to subdivide in the past, often resulting in confusion and poor interobserver agreement, while nowadays dermoscopy presents the clinician's precious bridge between naked-eye examination and histopathological diagnostics, allowing prediction of the lesions' histopathology, follow up and monitoring over time without need of excision. The non-invasive dermoscopic examination relies on the assessment of colors, patterns and the distribution of both within a cutaneous lesion. Until today, the correspondence of certain dermoscopic colors and patterns to certain histopathological correlates has been reported for a huge amount of different cutaneous lesions. Moreover, the correspondence of certain dermoscopic features to certain body sites, age groups and pigmentary traits, but also to specific genetic alterations in lesions, has been broadly investigated. Dermoscopy has led us to a new understanding of melanocytic nevi's biology and evolution and, last but not least, to a new classification system, which we want to present herein. © 2017 Japanese Dermatological Association.

  3. Multidirectional Vector Excision Leads to Better Outcomes than Traditional Elliptical Excision of Facial Congenital Melanocytic Nevus

    Directory of Open Access Journals (Sweden)

    Seung Il Oh

    2013-09-01

    Full Text Available Background The elliptical excision is the standard method of removing benign skin lesions,such as congenital melanocytic nevi. This technique allows for primary closure, with little to nodog-ear deformity, but may sacrifice normal tissue adjacent to the lesion, resulting in scarswhich are unnecessarily long. This study was designed to compare the predicted results ofelliptical excision with those resulting from our excision technique.Methods Eighty-two patients with congenital melanocytic nevus on the face were prospectivelystudied. Each lesion was examined and an optimal ellipse was designed and marked onthe skin. After an incision on one side of the nevus margin, subcutaneous undermining wasperformed in the appropriate direction. The skin flap was pulled up and approximated alongseveral vectors to minimize the occurrence of dog-ear deformity.Results Overall, the final wound length was 21.1% shorter than that achieved by ellipticalexcision. Only 8.5% of the patients required dog-ear repair. There was no significant distortionof critical facial structures. All of the scars were deemed aesthetically acceptable based ontheir Patient and Observer Scar Assessment Scale scores.Conclusions When compared to elliptical excision, our technique appears to minimize dogeardeformity and decrease the final wound length. This technique should be considered analternative method for excision of facial nevi.

  4. Malignant Tumor Derived from Skin Melanocytes of a Bovine of Unusual Presentation: A Case Study

    Directory of Open Access Journals (Sweden)

    Carlos Alberto Chaves Velásquez

    2015-05-01

    Full Text Available Melanocytic tumors and melanomas in domestic animals include neoplasms composed of melanin-producing cells. In cattle, these tumors are rare and mostly benign, while malignant tumors are almost non-existent. The article reports the case of a female crossbred cow 38 months of age with a fluctuating mass located between the mandibular border and the left parotid region, about three months duration, with evident growth in the last thirty days. After surgical excision, a sample preserved in buffered formalin (10% was sent to the Laboratory of Pathology (University of Nariño—consisting of a fragment of 7.0 × 10.5 × 8.0 cm, ellipsoid, with skin and hair on one side, irregular surface, blackish brown, semi-soft consistency, and presence of shear translucent slimy content—for processing and inclusion in paraffin, cut to 5 μm thickness and stained with hematoxylin-eosin coloration. The forwarded tissue was classified as a neoplasm of malignant behavior derived from melanocytes, due to its cellular characteristics: growth pattern, pattern of distribution, severe cellular pleomorphism, anisocytosis, megalocytosis, nuclear pleomorphism, anisokaryosis, megalokaryosis, and involvement of blood vessel walls; additionally, the paraffin block was cut for immunohistochemical processing using monoclonal markers (S-100 DAKO® and Melan A DAKO®, contrasted with Mayer’s hematoxylin. Strong immunostaining of neoplastic cells is evident, and it constitutes the first reported case of this disease in Nariño (Colombia.

  5. Altered expression of versican and hyaluronan in melanocytic tumors of dogs.

    Science.gov (United States)

    Docampo, María-José; Rabanal, Rosa M; Miquel-Serra, Laia; Hernández, Daniel; Domenzain, Clelia; Bassols, Anna

    2007-12-01

    To analyze the expression of versican and hyaluronan in melanocytomas and malignant melanomas of dogs, to correlate their expression with expression of the hyaluronan receptor CD44, and to identify enzymes responsible for the synthesis and degradation of hyaluronan in canine dermal fibroblasts and canine melanoma cell lines. 35 biopsy specimens from melanocytic tumors of dogs, canine primary dermal fibroblasts, and 3 canine melanoma cell lines. Versican, hyaluronan, and CD44 were detected in tumor samples by use of histochemical or immunohistochemical methods. Expression of hyaluronan-metabolizing enzymes was analyzed with a reverse transcriptase-PCR assay. Versican was found only in some hair follicles and around some blood vessels in normal canine skin, whereas hyaluronan was primarily found within the dermis. Hyaluronan was found in connective tissue of the oral mucosa. Versican and, to a lesser extent, hyaluronan were significantly overexpressed in malignant melanomas, compared with expression in melanocytomas. No significant difference was found between malignant tumors from oral or cutaneous origin. The expression of both molecules was correlated, but hyaluronan had a more extensive distribution than versican. Versican and hyaluronan were mainly associated with tumor stroma. Canine fibroblasts and melanoma cell lines expressed hyaluronan synthase 2 and 3 (but not 1) and hyaluronidase 1 and 2. Versican may be useful as a diagnostic marker for melanocytic tumors in dogs. Knowledge of the enzymes involved in hyaluronan metabolism could reveal new potential therapeutic targets.

  6. Adaptable pattern recognition system for discriminating Melanocytic Nevi from Malignant Melanomas using plain photography images from different image databases.

    Science.gov (United States)

    Kostopoulos, Spiros A; Asvestas, Pantelis A; Kalatzis, Ioannis K; Sakellaropoulos, George C; Sakkis, Theofilos H; Cavouras, Dionisis A; Glotsos, Dimitris T

    2017-09-01

    The aim of this study was to propose features that evaluate pictorial differences between melanocytic nevus (mole) and melanoma lesions by computer-based analysis of plain photography images and to design a cross-platform, tunable, decision support system to discriminate with high accuracy moles from melanomas in different publicly available image databases. Digital plain photography images of verified mole and melanoma lesions were downloaded from (i) Edinburgh University Hospital, UK, (Dermofit, 330moles/70 melanomas, under signed agreement), from 5 different centers (Multicenter, 63moles/25 melanomas, publicly available), and from the Groningen University, Netherlands (Groningen, 100moles/70 melanomas, publicly available). Images were processed for outlining the lesion-border and isolating the lesion from the surrounding background. Fourteen features were generated from each lesion evaluating texture (4), structure (5), shape (4) and color (1). Features were subjected to statistical analysis for determining differences in pictorial properties between moles and melanomas. The Probabilistic Neural Network (PNN) classifier, the exhaustive search features selection, the leave-one-out (LOO), and the external cross-validation (ECV) methods were used to design the PR-system for discriminating between moles and melanomas. Statistical analysis revealed that melanomas as compared to moles were of lower intensity, of less homogenous surface, had more dark pixels with intensities spanning larger spectra of gray-values, contained more objects of different sizes and gray-levels, had more asymmetrical shapes and irregular outlines, had abrupt intensity transitions from lesion to background tissue, and had more distinct colors. The PR-system designed by the Dermofit images scored on the Dermofit images, using the ECV, 94.1%, 82.9%, 96.5% for overall accuracy, sensitivity, specificity, on the Multicenter Images 92.0%, 88%, 93.7% and on the Groningen Images 76.2%, 73.9%, 77

  7. Loss of Oca2 disrupts the unfolded protein response and increases resistance to endoplasmic reticulum stress in melanocytes.

    Science.gov (United States)

    Cheng, Tsing; Orlow, Seth J; Manga, Prashiela

    2013-11-01

    Accumulation of proteins in the endoplasmic reticulum (ER) typically induces stress and initiates the unfolded protein response (UPR) to facilitate recovery. If homeostasis is not restored, apoptosis is induced. However, adaptation to chronic UPR activation can increase resistance to subsequent acute ER stress. We therefore investigated adaptive mechanisms in Oculocutaneous albinism type 2 (Oca2)-null melanocytes where UPR signaling is arrested despite continued tyrosinase accumulation leading to resistance to the chemical ER stressor thapsigargin. Although thapsigargin triggers UPR activation, instead of Perk-mediated phosphorylation of eIF2α, in Oca2-null melanocytes, eIF2α was rapidly dephosphorylated upon treatment. Dephosphorylation was mediated by the Gadd34-PP1α phosphatase complex. Gadd34-complex inhibition blocked eIF2α dephosphorylation and significantly increased Oca2-null melanocyte sensitivity to thapsigargin. Thus, Oca2-null melanocytes adapt to acute ER stress by disruption of pro-apoptotic Perk signaling, which promotes cell survival. This is the first study to demonstrate rapid eIF2α dephosphorylation as an adaptive mechanism to ER stress. © 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Cutaneous lasers and skin camouflage make-up: a useful alternative intervention for periorbital hairy congenital melanocytic naevus.

    Science.gov (United States)

    Townley, William A; Bragg, Thomas W H; Wright, Philip A; Cole, Richard P

    2013-12-01

    Periorbital congenital melanocytic naevi can be very disfiguring and difficult to treat effectively. Although surgical excision and reconstruction is the most widely accepted treatment strategy, we describe a case in which cutaneous lasers treatment followed by the application of cosmetic skin camouflage make-up provided an alternative solution delivering a good cosmetic improvement.

  9. Ginsenosides Rb1 and Rg1 Stimulate Melanogenesis in Human Epidermal Melanocytes via PKA/CREB/MITF Signaling

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    Mao Lin

    2014-01-01

    Full Text Available Reduced or defective melanin skin pigmentation may cause many hypopigmentation disorders and increase the risk of damage to the skin triggered by UV irradiation. Ginsenosides Rb1 and Rg1 have many molecular targets including the cAMP-response element-binding protein (CREB, which is involved in melanogenesis. This study aimed to investigate the effects of ginsenosides Rb1 and Rg1 on melanogenesis in human melanocytes and their related mechanisms. The effects of Rb1 and Rg1 on cell viability, tyrosinase activity, cellular melanin content and protein levels of tyrosinase, microphthalmia-associated transcription factor (MITF, and activation of CREB in melanocytes were assessed. Results showed that Rb1 or Rg1 significantly increased cellular melanin content and tyrosinase activity in a dose-dependent manner. By contrast, the cell viability of melanocytes remained unchanged. After exposure to Rb1 or Rg1, the protein levels of tyrosinase, MITF, and phosphorylated CREB were significantly increased. Furthermore, pretreatment with the selective PKA inhibitor H-89 significantly blocked the Rb1- or Rg1-induced increase of melanin content. These findings indicated that Rb1 and Rg1 increased melanogenesis and tyrosinase activity in human melanocytes, which was associated with activation of PKA/CREB/MITF signaling. The effects and mechanisms of Rb1 or Rg1 on skin pigmentation deserve further study.

  10. Melanin offers protection against induction of cyclobutane pyrimidine dimers and 6-4 photoproducts by UVB in cultured human melanocytes

    NARCIS (Netherlands)

    Smit, N.P.M.; Vink, A.A.; Kolb, R.M.; Steenwinkel, M.J.S.T.; Berg, P.T.M. van den; Nieuwpoort, F. van; Roza, L.; Pavel, S.

    2001-01-01

    The goal of this investigation was to correlate the melanin content in human pigmentary cells with the generation of UVB-induced photoproducts and to examine the relationship between the melanin content and the removal of the photoproducts. Cultured melanocytes from light-skinned individuals

  11. Label-Free Imaging of Female Genital Tract Melanocytic Lesions With Pump-Probe Microscopy: A Promising Diagnostic Tool.

    Science.gov (United States)

    Robles, Francisco E; Deb, Sanghamitra; Fischer, Martin C; Warren, Warren S; Selim, Maria Angelica

    2017-04-01

    Melanomas of the female genital tract present a unique clinical challenge. Not only are these lesions in an anatomically sensitive area, but also they tend to be multifocal and have high recurrence rates. Furthermore, several benign melanocytic proliferations resemble early-stage melanoma clinically and/or histopathologically. Thus, there is a significant need for additional tools that can help correctly diagnose and stage these lesions. Here, we quantitatively and nondestructively analyze the chemical composition of melanin in excised pigmented lesions of the female genital tract using pump-probe microscopy, a high-resolution optical imaging technique that is sensitive to many biochemical properties of melanin. Thirty-one thin (~5 μm) tissue sections previously excised from female genital tract melanocytic lesions were imaged with pump-probe microscopy and analyzed. We find significant quantitative differences in melanin type and structure between melanoma and nonmalignant melanocytic proliferations. Our analysis also suggests a link between the molecular signatures of melanins and lesion-specific genetic mutations. Finally, significant differences are found between metastatic and nonmetastatic melanomas. The limitations of this work include the fact that molecular information is restricted to melanin pigment and the sample size is relatively small. Pump-probe microscopy provides unique information regarding the biochemical composition of genital tract melanocytic lesions, which can be used to improve the diagnosis and staging of vulvar melanomas.

  12. Structural studies of α-melanocyte-stimulating hormone and a novel β-melanocyte-stimulating hormone from the neurointermediate lobe of the pituitary of the dogfish Squalus acanthias

    Science.gov (United States)

    Bennett, Hugh P. J.; Lowry, Philip J.; McMartin, Colin; Scott, Alexander P.

    1974-01-01

    A melanocyte-stimulating hormone (MSH) has been isolated from extracts of the neurointermediate lobe of the pituitary of the dogfish Squalus acanthias by gel-filtration and ion-exchange chromatography. It had approximately 1% of the potency of mammalian α-MSH on bioassays in vitro on frog skin and dogfish skin. Sequence analysis revealed it to be a hexadecapeptide with the following primary structure: Asp-Gly-Asp-Asp-Tyr-Lys-Phe-Gly-His-Phe-Arg-Trp-Ser-Val-Pro-Leu. It appears to be related to the β-MSH species of mammalian species but has only the sequence -His-Phe-Arg-Trp- in common with the heptapeptide core -Met-Glu-His-Phe-Arg-Trp-Gly- which is characteristic not only of the MSH peptides but also of the adrenocorticotrophins and lipotrophins studied so far. An α-MSH was also isolated, 50% of which was amidated at the C-terminus group. Sequence data from this study taken in conjunction with those from a previous study (Lowry & Chadwick, 1970b) revealed it to be a tridecapeptide which is identical with the N-terminal sequence of dogfish adrenocorticotrophin. PMID:4375978

  13. Aspirin reduces serum anti-melanocyte antibodies and soluble interleukin-2 receptors in vitiligo patients

    International Nuclear Information System (INIS)

    Zailaie, Mohamad Z.

    2005-01-01

    Increased serum levels of certain immunologic markers including immunoglobulin G (IgG) anti-melanocyte/ vitiligo antibodies (V-IgG) and soluble interleukin-2 receptors (sIL-2R) are associated with augmented humoral and cellular immunity involved in melanocyte cytotoxicity during the active phase of non-segmental vitiligo. Recent reports have shown that, aspirin possesses a wide range of immunomodulatory and antioxidant properties. Therefore, the aim of the present study is to investigate the effect of long-term treatment of vitiligo patients with low-dose oral aspirin on serum V-IgG activity and sIL-2R concentration. The present study was carried out at the Vitiligo Unit, King Abdul-Aziz University Medical Center, Jeddah, Kingdom of Saudi Arabia between March and October 2003. Eighteen female and 14 male patients with a recent onset of non-segmental vitiligo were divided into 2 equal groups. One group received a daily single dose of oral aspirin (300 mg) and the second group received only placebo for a period of 12 weeks. Serum V-IgG activity and sIL-2R concentration were determined before and at the end of treatment period. The V-IgG activity was measured using cellular enzyme-linked immunosorbent assay (ELISA) following incubation of IgG antibodies with an adult cultured melanocytes. Serum sIL-2R concentration was measured using the highly sensitive quantitative sandwich ELISA utilizing a commercially available kit. As expected, the serum V-IgG activity and sIL-2R concentration of the active vitiligo patients (0.81 +/- 0.23 optical density (O.D.), 1428 +/- 510 pg/ml) were significantly increased compared with that of controls (0.27 +/- 0.1 O.D., 846 +/- 312 pg/ml; p<0.05, p<0.01). Aspirin-treated vitiligo patients showed significant decrease in serum V-IgG activity and sIL-2R concentration (0.32 +/- 0.08 O.D., 756 +/- 216 pg/ml) compared with that of placebo-treated patients (0.83 +/- 0.19 O.D., 1327 +/- 392 pg/ml; p<0.01). Low-dose oral aspirin treatment of

  14. Neural networks

    International Nuclear Information System (INIS)

    Denby, Bruce; Lindsey, Clark; Lyons, Louis

    1992-01-01

    The 1980s saw a tremendous renewal of interest in 'neural' information processing systems, or 'artificial neural networks', among computer scientists and computational biologists studying cognition. Since then, the growth of interest in neural networks in high energy physics, fueled by the need for new information processing technologies for the next generation of high energy proton colliders, can only be described as explosive

  15. Gene Duplication of the zebrafish kit ligand and partitioning of melanocyte development functions to kit ligand a.

    Directory of Open Access Journals (Sweden)

    Keith A Hultman

    2007-01-01

    Full Text Available The retention of particular genes after the whole genome duplication in zebrafish has given insights into how genes may evolve through partitioning of ancestral functions. We examine the partitioning of expression patterns and functions of two zebrafish kit ligands, kit ligand a (kitla and kit ligand b (kitlb, and discuss their possible coevolution with the duplicated zebrafish kit receptors (kita and kitb. In situ hybridizations show that kitla mRNA is expressed in the trunk adjacent to the notochord in the middle of each somite during stages of melanocyte migration and later expressed in the skin, when the receptor is required for melanocyte survival. kitla is also expressed in other regions complementary to kita receptor expression, including the pineal gland, tail bud, and ear. In contrast, kitlb mRNA is expressed in brain ventricles, ear, and cardinal vein plexus, in regions generally not complementary to either zebrafish kit receptor ortholog. However, like kitla, kitlb is expressed in the skin during stages consistent with melanocyte survival. Thus, it appears that kita and kitla have maintained congruent expression patterns, while kitb and kitlb have evolved divergent expression patterns. We demonstrate the interaction of kita and kitla by morpholino knockdown analysis. kitla morphants, but not kitlb morphants, phenocopy the null allele of kita, with defects for both melanocyte migration and survival. Furthermore, kitla morpholino, but not kitlb morpholino, interacts genetically with a sensitized allele of kita, confirming that kitla is the functional ligand to kita. Last, we examine kitla overexpression in embryos, which results in hyperpigmentation caused by an increase in the number and size of melanocytes. This hyperpigmentation is dependent on kita function. We conclude that following genome duplication, kita and kitla have maintained their receptor-ligand relationship, coevolved complementary expression patterns, and that

  16. Keratinocyte-Melanocyte graft technique followed by PUVA therapy for stable vitiligo

    Directory of Open Access Journals (Sweden)

    Kachhawa Dilip

    2008-01-01

    Full Text Available Background: Various surgical procedures for correcting stable vitiligo exist but these have their own limitations. Autologous, non-cultured, non-trypsinized, melanocyte plus keratinocyte grafting is a new and simple method of vitiligo surgery. Objective: The study aimed to evaluate efficacy of a new grafting technique in vitiligo patches. Methods: Eighteen vitiligo patches underwent this procedure. The upper layer of epidermis was removed by superficial dermabrasion using a dermabrader micromotor until the epidermis appeared wet and shiny. Then, antibiotic ointment was applied and dermabrasion was continued up to the whitish area of the upper dermis. The paste-like material (ointment with entangled epidermal particles was collected and spread over the dermabraded recipient site. Results: Pigmentation usually started at 4-6 weeks. Complete uniform pigmentation took 16-20 weeks. Conclusion: For smaller vitiligo patches this method gives cosmetically acceptable results. It is easy to perform and does not require specific laboratory setup.

  17. Small Dysplastic Congenital Melanocytic Nevi in Childhood as Possible Melanoma Imitators

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    Georgi Tchernev

    2018-01-01

    Full Text Available Small pigmented lesions in children can represent a significant diagnostic challenge. If the diagnostic features and therapeutic approach are relatively well established in large and giant nevi, there is still much controversy regarding small and intermediate-sized congenital pigmented lesions that can lead to significant diagnostic challenges, both clinically and dermoscopically, and consequently to difficulty in defining the optimal approach in such cases. Although dermoscopy can be useful in the diagnosis of pigmented lesions, the diversity of clinical and dermoscopic features of pigmented nevi in children usually hinder the differentiation between them and melanoma. Histological findings after resection often show surprising results that do not correspond either to the clinical nor the dermoscopic features. With the present case, we want to emphasise the variable natural behaviour of melanocytic lesions in children, which sometimes leads to unnecessary surgical excisions, which should be avoided in pediatric patients.

  18. Grafting Of Autologous Non-Cultured Melanocytes For The Treatment Of Vitiligo : A Pilot Study

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    kumar Sudhir

    2003-01-01

    Full Text Available Vitiligo is a common, often heritable, acquired disorder. Although vitiligo does not cause any physical problem but it surely is a psychosocial disaster. Depigmented patches resistant to medical treatment need to be managed surgically. Surgically. Surgical procedures usually performed lead to unsatisfactory results and that too at the cost of scarring of normal donor site. Here we describe our experience with grafting of non-cultured autologous melanocytes, which is not associated with any scarring. We tried this method in 16 lesions in 8 patients of stable vitiligo. Due to its advantages, like no scarring at recipient sites, ability to re-pigment large area with small piece of skin graft, simplicity and feasibility in Indian conditions, this is a good alternative in the treatment of vitiligo.

  19. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Directory of Open Access Journals (Sweden)

    Cécile eCoste

    2015-06-01

    Full Text Available Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL12-abundant reticular (CAR cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs, which have been recently identified as neural crest-derived cells (NCSCs. Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-to-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  20. Are neural crest stem cells the missing link between hematopoietic and neurogenic niches?

    Science.gov (United States)

    Coste, Cécile; Neirinckx, Virginie; Gothot, André; Wislet, Sabine; Rogister, Bernard

    2015-01-01

    Hematopoietic niches are defined as cellular and molecular microenvironments that regulate hematopoietic stem cell (HSC) function together with stem cell autonomous mechanisms. Many different cell types have been characterized as contributors to the formation of HSC niches, such as osteoblasts, endothelial cells, Schwann cells, and mesenchymal progenitors. These mesenchymal progenitors have themselves been classified as CXC chemokine ligand (CXCL) 12-abundant reticular (CAR) cells, stem cell factor expressing cells, or nestin-positive mesenchymal stem cells (MSCs), which have been recently identified as neural crest-derived cells (NCSCs). Together, these cells are spatially associated with HSCs and believed to provide appropriate microenvironments for HSC self-renewal, differentiation, mobilization and hibernation both by cell-cell contact and soluble factors. Interestingly, it appears that regulatory pathways governing the hematopoietic niche homeostasis are operating in the neurogenic niche as well. Therefore, this review paper aims to compare both the regulation of hematopoietic and neurogenic niches, in order to highlight the role of NCSCs and nervous system components in the development and the regulation of the hematopoietic system.

  1. Melan-A/Mart-1- or HMB-45-positive melanocytes are not present in calcifying cystic odontogenic tumors (calcifying odontogenic cysts): a study in 13 Caucasian patients.

    Science.gov (United States)

    Tosios, Konstantinos I; Prountzos, Nikolaos; Katsoulas, Nikolaos; Koutlas, Ioannis G; Sklavounou-Andrikopoulou, Alexandra

    2012-03-01

    Melanin pigment and melanocytes may be found in odontogenic cysts and tumors, particularly calcifying cystic odontogenic tumor (CCOT). In the present study we investigated the immunohistochemical expression of the Melan-A/Mart-1 and HMB-45 antigens in 13 Caucasians patients with CCOT. Melan-A/Mart-1- and HMB-45-positive melanocytes were not seen in any of the cases. Our findings are in agreement with the assumption that pigmentation in odontogenic lesions may be a racial phenomenon.

  2. Evaluation of the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) classification scheme for diagnosis of cutaneous melanocytic neoplasms: Results from the International Melanoma Pathology Study Group.

    Science.gov (United States)

    Lott, Jason P; Elmore, Joann G; Zhao, Ge A; Knezevich, Stevan R; Frederick, Paul D; Reisch, Lisa M; Chu, Emily Y; Cook, Martin G; Duncan, Lyn M; Elenitsas, Rosalie; Gerami, Pedram; Landman, Gilles; Lowe, Lori; Messina, Jane L; Mihm, Martin C; van den Oord, Joost J; Rabkin, Michael S; Schmidt, Birgitta; Shea, Christopher R; Yun, Sook Jung; Xu, George X; Piepkorn, Michael W; Elder, David E; Barnhill, Raymond L

    2016-08-01

    Pathologists use diverse terminology when interpreting melanocytic neoplasms, potentially compromising quality of care. We sought to evaluate the Melanocytic Pathology Assessment Tool and Hierarchy for Diagnosis (MPATH-Dx) scheme, a 5-category classification system for melanocytic lesions. Participants (n = 16) of the 2013 International Melanoma Pathology Study Group Workshop provided independent case-level diagnoses and treatment suggestions for 48 melanocytic lesions. Individual diagnoses (including, when necessary, least and most severe diagnoses) were mapped to corresponding MPATH-Dx classes. Interrater agreement and correlation between MPATH-Dx categorization and treatment suggestions were evaluated. Most participants were board-certified dermatopathologists (n = 15), age 50 years or older (n = 12), male (n = 9), based in the United States (n = 11), and primary academic faculty (n = 14). Overall, participants generated 634 case-level diagnoses with treatment suggestions. Mean weighted kappa coefficients for diagnostic agreement after MPATH-Dx mapping (assuming least and most severe diagnoses, when necessary) were 0.70 (95% confidence interval 0.68-0.71) and 0.72 (95% confidence interval 0.71-0.73), respectively, whereas correlation between MPATH-Dx categorization and treatment suggestions was 0.91. This was a small sample size of experienced pathologists in a testing situation. Varying diagnostic nomenclature can be classified into a concise hierarchy using the MPATH-Dx scheme. Further research is needed to determine whether this classification system can facilitate diagnostic concordance in general pathology practice and improve patient care. Copyright © 2016 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  3. Integrated genomic classification of melanocytic tumors of the central nervous system using mutation analysis, copy number alterations and DNA methylation profiling.

    Science.gov (United States)

    Griewank, Klaus; Koelsche, Christian; van de Nes, Johannes A P; Schrimpf, Daniel; Gessi, Marco; Möller, Inga; Sucker, Antje; Scolyer, Richard A; Buckland, Michael E; Murali, Rajmohan; Pietsch, Torsten; von Deimling, Andreas; Schadendorf, Dirk

    2018-06-11

    In the central nervous system, distinguishing primary leptomeningeal melanocytic tumors from melanoma metastases and predicting their biological behavior solely using histopathologic criteria can be challenging. We aimed to assess the diagnostic and prognostic value of integrated molecular analysis. Targeted next-generation-sequencing, array-based genome-wide methylation analysis and BAP1 immunohistochemistry was performed on the largest cohort of central nervous system melanocytic tumors analyzed to date, incl. 47 primary tumors of the central nervous system, 16 uveal melanomas. 13 cutaneous melanoma metastasis and 2 blue nevus-like melanomas. Gene mutation, DNA-methylation and copy-number profiles were correlated with clinicopathological features. Combining mutation, copy-number and DNA-methylation profiles clearly distinguished cutaneous melanoma metastases from other melanocytic tumors. Primary leptomeningeal melanocytic tumors, uveal melanomas and blue nevus-like melanoma showed common DNA-methylation, copy-number alteration and gene mutation signatures. Notably, tumors demonstrating chromosome 3 monosomy and BAP1 alterations formed a homogeneous subset within this group. Integrated molecular profiling aids in distinguishing primary from metastatic melanocytic tumors of the central nervous system. Primary leptomeningeal melanocytic tumors, uveal melanoma and blue nevus-like melanoma share molecular similarity with chromosome 3 and BAP1 alterations markers of poor prognosis. Copyright ©2018, American Association for Cancer Research.

  4. Acral melanocytic lesions in the United States: Prevalence, awareness, and dermoscopic patterns in skin-of-color and non-Hispanic white patients.

    Science.gov (United States)

    Madankumar, Reshmi; Gumaste, Priyanka V; Martires, Kathryn; Schaffer, Panta R; Choudhary, Sonal; Falto-Aizpurua, Leyre; Arora, Harleen; Kallis, Penelope J; Patel, Shailee; Damanpour, Shadi; Sanchez, Margaret I; Yin, Natalie; Chan, Aegean; Sanchez, Miguel; Polsky, David; Kanavy, Holly; Grichnik, James M; Stein, Jennifer A

    2016-04-01

    Acral lentiginous melanoma has increased mortality compared with other melanoma subtypes and disproportionately affects ethnic minorities. Acral melanocytic lesions have not been well studied in diverse populations of the United States. We sought to assess the prevalence, awareness, and dermoscopic patterns of acral melanocytic lesions in skin-of-color and non-Hispanic white patients. We prospectively examined the palms and soles of 1052 patients presenting to dermatology clinics in New York, NY, and Miami, FL, from October 2013 to April 2015. Acral melanocytic lesions were observed in 36% of our cohort. Skin-of-color patients were more likely to have acral melanocytic lesions than non-Hispanic white patients (P < .01). Acral melanocytic lesions correlated with increased mole counts, particularly on non-Hispanic white patients. The majority of lesions demonstrated benign dermoscopic patterns. We observed 2 lesions with the parallel ridge pattern in our cohort, both found to be atypical nevi on biopsy specimen. Patients often lacked awareness of the presence of their lesions. Interobserver variability in assessing dermoscopic patterns is a limitation. Melanocytic lesions of the palms and soles are common, particularly in a cohort of multiple ethnicities from the United States. Dermoscopy of acral lesions is an important clinical tool for diagnosis and management of these lesions. Copyright © 2015 American Academy of Dermatology, Inc. Published by Elsevier Inc. All rights reserved.

  5. Usefulness of confocal microscopy in distinguishing between basal cell carcinoma and intradermal melanocytic nevus on the face.

    Science.gov (United States)

    Gamo, R; Floristan, U; Pampín, A; Caro, D; Pinedo, F; López-Estebaranz, J L

    2015-10-01

    The clinical distinction between basal cell carcinoma (BCC) and intradermal melanocytic nevus lesions on the face can be difficult, particularly in young patients or patients with multiple nevi. Dermoscopy is a useful tool for analyzing characteristic dermoscopic features of BCC, such as cartwheel structures, maple leaf-like areas, blue-gray nests and dots, and ulceration. It also reveals arborizing telangiectatic vessels and prominent curved vessels, which are typical of BCC, and comma vessels, which are typical of intradermal melanocytic nevi. It is, however, not always easy to distinguish between these 2 conditions, even when dermoscopy is used. We describe 2 facial lesions that posed a clinical and dermoscopic challenge in two 38-year-old patients; confocal microscopy showed separation between tumor nests and stroma and polarized nuclei, which are confocal microscopy features of basal cell carcinoma. Copyright © 2014 Elsevier España, S.L.U. y AEDV. All rights reserved.

  6. Parameterization using Fourier series expansion of the diffuse reflectance of human skin to vary the concentration of the melanocytes

    Science.gov (United States)

    Narea, J. Freddy; Muñoz, Aarón A.; Castro, Jorge; Muñoz, Rafael A.; Villalba, Caroleny E.; Martinez, María. F.; Bravo, Kelly D.

    2013-11-01

    Human skin has been studied in numerous investigations, given the interest in knowing information about physiology, morphology and chemical composition. These parameters can be determined using non invasively optical techniques in vivo, such as the diffuse reflectance spectroscopy. The human skin color is determined by many factors, but primarily by the amount and distribution of the pigment melanin. The melanin is produced by the melanocytes in the basal layer of the epidermis. This research characterize the spectral response of the human skin using the coefficients of Fourier series expansion. Simulating the radiative transfer equation for the Monte Carlo method to vary the concentration of the melanocytes (fme) in a simplified model of human skin. It fits relating the Fourier series coefficient a0 with fme. Therefore it is possible to recover the skin biophysical parameter.

  7. Analytical validation of a melanoma diagnostic gene signature using formalin-fixed paraffin-embedded melanocytic lesions.

    Science.gov (United States)

    Warf, M Bryan; Flake, Darl D; Adams, Doug; Gutin, Alexander; Kolquist, Kathryn A; Wenstrup, Richard J; Roa, Benjamin B

    2015-01-01

    These studies were to validate the analytical performance of a gene expression signature that differentiates melanoma and nevi, using RNA expression from 14 signature genes and nine normalization genes that generates a melanoma diagnostic score (MDS). Formalin-fixed paraffin-embedded melanocytic lesions were evaluated in these studies. The overall SD of the assay was determined to be 0.69 MDS units. Individual amplicons within the signature had an average amplification efficiency of 92% and a SD less than 0.5 CT. The MDS was reproducible across a 2000-fold dilution range of input RNA. Melanin, an inhibitor of PCR, does not interfere with the signature. These studies indicate this signature is robust and reproducible and is analytically validated on formalin-fixed paraffin-embedded melanocytic lesions.

  8. Rhododenol and raspberry ketone impair the normal proliferation of melanocytes through reactive oxygen species-dependent activation of GADD45.

    Science.gov (United States)

    Kim, Minjeong; Baek, Heung Soo; Lee, Miri; Park, Hyeonji; Shin, Song Seok; Choi, Dal Woong; Lim, Kyung-Min

    2016-04-01

    Rhododenol or rhododendrol (RD, 4-(4-hydroxyphenyl)-2-butanol) occurs naturally in many plants along with raspberry ketone (RK, 4-(4-hydroxyphenyl)-2-butanone), a ketone derivative, which include Nikko maple tree (Acer nikoense) and white birch (Betula platyphylla). De-pigmenting activity of RD was discovered and it was used as a brightening ingredient for the skin whitening cosmetics. Recently, cosmetics containing RD were withdrawn from the market because a number of consumers developed leukoderma, inflammation and erythema on their face, neck and hands. Here, we explored the mechanism underlying the toxicity of RD and RK against melanocytes using B16F10 murine melanoma cells and human primary epidermal melanocytes. Treatment with RD or RK resulted in the decreased cell viability in a dose-dependent manner which appeared from cell growth arrest. Consistently, ROS generation was significantly increased by RD or RK as determined by DCF-enhanced fluorescence. An antioxidant enzyme, glutathione peroxidase was depleted as well. In line with ROS generation, oxidative damages and the arrest of normal cell proliferation, GADD genes (Growth Arrest and DNA Damage) that include GADD45 and GADD153, were significantly up-regulated. Prevention of ROS generation with an anti-oxidant, N-acetylcysteine (NAC) significantly rescued RD and RK-suppressed melanocyte proliferation. Consistently, up-regulation of GADD45 and GADD153 was significantly attenuated by NAC, suggesting that increased ROS and the resultant growth arrest of melanocytes may contribute to RD and RK-induced leukoderma. Copyright © 2016 Elsevier Ltd. All rights reserved.

  9. UVB-Stimulated TNFα Release from Human Melanocyte and Melanoma Cells Is Mediated by p38 MAPK

    Directory of Open Access Journals (Sweden)

    Visalini Muthusamy

    2013-08-01

    Full Text Available Ultraviolet (UV radiation activates cell signaling pathways in melanocytes. As a result of altered signaling pathways and UV-induced cellular damage, melanocytes can undergo oncogenesis and develop into melanomas. In this study, we investigated the effect of UV-radiation on p38 MAPK (mitogen-activated protein kinase, JNK and NFκB pathways to determine which plays a major role in stimulating TNFα secretion in human HEM (melanocytes and MM96L (melanoma cells. MM96L cells exhibited 3.5-fold higher p38 activity than HEM cells at 5 min following UVA + B radiation and 1.6-fold higher JNK activity at 15–30 min following UVB+A radiation, while NFκB was minimally activated in both cells. Irradiated HEM cells had the greatest fold of TNFα secretion (UVB: 109-fold, UVA + B: 103-fold & UVB+A: 130-fold when co-exposed to IL1α. The p38 inhibitor, SB202190, inhibited TNFα release by 93% from UVB-irradiated HEM cells. In the UVB-irradiated MM96L cells, both SB202190 and sulfasalazine (NFκB inhibitor inhibited TNFα release by 52%. Although, anisomycin was a p38 MAPK activator, it inhibited TNFα release in UV-irradiated cells. This suggests that UV-mediated TNFα release may occur via different p38 pathway intermediates compared to those stimulated by anisomycin. As such, further studies into the functional role p38 MAPK plays in regulating TNFα release in UV-irradiated melanocyte-derived cells are warranted.

  10. Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

    Energy Technology Data Exchange (ETDEWEB)

    Dasgupta, Amrita [Hampton University Skin of Color Research Institute, Hampton, VA 23668 (United States); Katdare, Meena, E-mail: mkatdare@gmail.com [Hampton University Skin of Color Research Institute, Hampton, VA 23668 (United States); Department of Dermatology, Eastern Virginia Medical School, Norfolk, VA 23507 (United States)

    2015-08-14

    Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics.

  11. Ultraviolet Radiation-Induced Cytogenetic Damage in White, Hispanic and Black Skin Melanocytes: A Risk for Cutaneous Melanoma

    International Nuclear Information System (INIS)

    Dasgupta, Amrita; Katdare, Meena

    2015-01-01

    Cutaneous Melanoma (CM) is a leading cause of cancer deaths, with reports indicating a rising trend in the incidence rate of melanoma among Hispanics in certain U.S. states. The level of melanin pigmentation in the skin is suggested to render photoprotection from the DNA-damaging effects of Ultraviolet Radiation (UVR). UVR-induced DNA damage leads to cytogenetic defects visualized as the formation of micronuclei, multinuclei and polymorphic nuclei in cells, and a hallmark of cancer risk. The causative relationship between Sun exposure and CM is controversial, especially in Hispanics and needs further evaluation. This study was initiated with melanocytes from White, Hispanic and Black neonatal foreskins which were exposed to UVR to assess their susceptibility to UVR-induced modulation of cellular growth, cytogenetic damage, intracellular and released melanin. Our results show that White and Hispanic skin melanocytes with similar levels of constitutive melanin are susceptible to UVR-induced cytogenetic damage, whereas Black skin melanocytes are not. Our data suggest that the risk of developing UVR-induced CM in a skin type is correlated with the level of cutaneous pigmentation and its ethnic background. This study provides a benchmark for further investigation on the damaging effects of UVR as risk for CM in Hispanics

  12. Rab11b mediates melanin transfer between donor melanocytes and acceptor keratinocytes via coupled exo/endocytosis.

    Science.gov (United States)

    Tarafder, Abul K; Bolasco, Giulia; Correia, Maria S; Pereira, Francisco J C; Iannone, Lucio; Hume, Alistair N; Kirkpatrick, Niall; Picardo, Mauro; Torrisi, Maria R; Rodrigues, Inês P; Ramalho, José S; Futter, Clare E; Barral, Duarte C; Seabra, Miguel C

    2014-04-01

    The transfer of melanin from melanocytes to keratinocytes is a crucial process underlying maintenance of skin pigmentation and photoprotection against UV damage. Here, we present evidence supporting coupled exocytosis of the melanin core, or melanocore, by melanocytes and subsequent endocytosis by keratinocytes as a predominant mechanism of melanin transfer. Electron microscopy analysis of human skin samples revealed three lines of evidence supporting this: (1) the presence of melanocores in the extracellular space; (2) within keratinocytes, melanin was surrounded by a single membrane; and (3) this membrane lacked the melanosomal membrane protein tyrosinase-related protein 1 (TYRP1). Moreover, co-culture of melanocytes and keratinocytes suggests that melanin exocytosis is specifically induced by keratinocytes. Furthermore, depletion of Rab11b, but not Rab27a, caused a marked decrease in both keratinocyte-stimulated melanin exocytosis and transfer to keratinocytes. Thus, we propose that the predominant mechanism of melanin transfer is keratinocyte-induced exocytosis, mediated by Rab11b through remodeling of the melanosome membrane, followed by subsequent endocytosis by keratinocytes.

  13. Generation of a double binary transgenic zebrafish model to study myeloid gene regulation in response to oncogene activation in melanocytes.

    Science.gov (United States)

    Kenyon, Amy; Gavriouchkina, Daria; Zorman, Jernej; Chong-Morrison, Vanessa; Napolitani, Giorgio; Cerundolo, Vincenzo; Sauka-Spengler, Tatjana

    2018-04-06

    A complex network of inflammatory genes is closely linked to somatic cell transformation and malignant disease. Immune cells and their associated molecules are responsible for detecting and eliminating cancer cells as they establish themselves as the precursors of a tumour. By the time a patient has a detectable solid tumour, cancer cells have escaped the initial immune response mechanisms. Here, we describe the development of a double binary zebrafish model that enables regulatory programming of the myeloid cells as they respond to oncogene-activated melanocytes to be explored, focussing on the initial phase when cells become the precursors of cancer. A hormone-inducible binary system allows for temporal control of expression of different Ras oncogenes ( NRas Q61K , HRas G12V and KRas G12V ) in melanocytes, leading to proliferation and changes in morphology of the melanocytes. This model was coupled to binary cell-specific biotagging models allowing in vivo biotinylation and subsequent isolation of macrophage or neutrophil nuclei for regulatory profiling of their active transcriptomes. Nuclear transcriptional profiling of neutrophils, performed as they respond to the earliest precursors of melanoma in vivo , revealed an intricate landscape of regulatory factors that may promote progression to melanoma, including Serpinb1l4, Fgf1, Fgf6, Cathepsin H, Galectin 1 and Galectin 3. The model presented here provides a powerful platform to study the myeloid response to the earliest precursors of melanoma. © 2018. Published by The Company of Biologists Ltd.

  14. Silencing of GPNMB by siRNA Inhibits the Formation of Melanosomes in Melanocytes in a MITF-Independent Fashion

    Science.gov (United States)

    Zhu, Cansheng; Yuan, Xiaoying; Li, Dongguang; Gu, Weijie; Ma, Huimin; Xie, Xin; Gao, Tianwen

    2012-01-01

    Background Melanosomes are specialized membrane-surrounded organelles, which are involved in the synthesis, storage and transport of melanin. Glycoprotein (transmembrane) non-metastatic melanoma protein b (GPNMB), a melanosome-specific structural protein, shares significant amino acid sequence homology with Pmel-17. Proteomic analysis demonstrated that GPNMB is present in all stages (I-IV) of melanosomes. However, little is known about the role of GPNMB in melanosomes. Methodology/Principal Findings Using real-time quantitative PCR, Western blotting and immunofluorescence analysis, we demonstrated that the expression of GPNMB in PIG1 melanocytes was up-regulated by ultraviolet B (UVB) radiation. Transmission electron microscopy analysis showed that the total number of melanosomes in PIG1 melanocytes was sharply reduced by GPNMB-siRNA transfection. Simultaneously, the expression levels of tyrosinase (Tyr), tyrosinase related protein 1 (Trp1), Pmel17/gp100 and ocular albinism type 1 protein (OA1) were all significantly attenuated. But the expression of microphthalmia-associated transcription factor (MITF) was up-regulated. Intriguingly, in GPNMB silenced PIG1 melanocytes, UVB radiation sharply reduced MITF expression. Conclusion Our present work revealed that the GPNMB was critical for the formation of melanosomes. And GPNMB expression down-regulation attenuated melanosome formation in a MITF-independent fashion. PMID:22912767

  15. Neural Networks

    International Nuclear Information System (INIS)

    Smith, Patrick I.

    2003-01-01

    Physicists use large detectors to measure particles created in high-energy collisions at particle accelerators. These detectors typically produce signals indicating either where ionization occurs along the path of the particle, or where energy is deposited by the particle. The data produced by these signals is fed into pattern recognition programs to try to identify what particles were produced, and to measure the energy and direction of these particles. Ideally, there are many techniques used in this pattern recognition software. One technique, neural networks, is particularly suitable for identifying what type of particle caused by a set of energy deposits. Neural networks can derive meaning from complicated or imprecise data, extract patterns, and detect trends that are too complex to be noticed by either humans or other computer related processes. To assist in the advancement of this technology, Physicists use a tool kit to experiment with several neural network techniques. The goal of this research is interface a neural network tool kit into Java Analysis Studio (JAS3), an application that allows data to be analyzed from any experiment. As the final result, a physicist will have the ability to train, test, and implement a neural network with the desired output while using JAS3 to analyze the results or output. Before an implementation of a neural network can take place, a firm understanding of what a neural network is and how it works is beneficial. A neural network is an artificial representation of the human brain that tries to simulate the learning process [5]. It is also important to think of the word artificial in that definition as computer programs that use calculations during the learning process. In short, a neural network learns by representative examples. Perhaps the easiest way to describe the way neural networks learn is to explain how the human brain functions. The human brain contains billions of neural cells that are responsible for processing

  16. Evolvable synthetic neural system

    Science.gov (United States)

    Curtis, Steven A. (Inventor)

    2009-01-01

    An evolvable synthetic neural system includes an evolvable neural interface operably coupled to at least one neural basis function. Each neural basis function includes an evolvable neural interface operably coupled to a heuristic neural system to perform high-level functions and an autonomic neural system to perform low-level functions. In some embodiments, the evolvable synthetic neural system is operably coupled to one or more evolvable synthetic neural systems in a hierarchy.

  17. NEAR-INFRARED AUTOFLUORESCENCE IN BILATERAL DIFFUSE UVEAL MELANOCYTIC PROLIFERATION ASSOCIATED WITH ESOPHAGEAL CARCINOMA AND CHOROIDAL METASTASIS.

    Science.gov (United States)

    Golshahi, Azadeh; Bornfeld, Norbert; Weinitz, Silke; Kellner, Ulrich

    2016-01-01

    To investigate the advantage of near-infrared autofluorescence (787 nm) for the detection of melanocytic lesions in a patient with bilateral diffuse uveal melanocytic proliferation in association with esophageal carcinoma complicated by most likely unilateral choroidal metastasis. In this retrospective case report, a 55-year-old woman referred for the evaluation of sudden visual loss underwent normal ophthalmological evaluation and, in addition, was examined with near-infrared reflectance, near-infrared autofluorescence, fundus autofluorescence (Heidelberg Retina Angiograph II [HRA2; Heidelberg Engineering]), spectral domain optical coherence tomography (Spectralis OCT; Heidelberg Engineering), and multifocal electroretinography (RetiScan; Roland Consult). The patient had been diagnosed with esophageal carcinoma 3 months before the onset of visual symptoms. The visual acuity was 20/40 in the right eye and 20/20 in the left eye. Bilateral patchy melanocytic proliferation was detected on ophthalmoscopy. The extent of lesions was best detected with near-infrared reflectance and near-infrared autofluorescence, whereas fundus autofluorescence and spectral domain optical coherence tomography did not reveal alterations of the outer retina or retinal pigment epithelium in this early stage of bilateral diffuse uveal melanocytic proliferation. The right eye showed in addition to the findings on the left eye choroidal folds in the fovea and an elevated lesion inferotemporal of the fovea suspicious of a choroidal metastasis. In the B-scan ultrasonography, a homogenous lesion was seen. Spectral domain optical coherence tomography demonstrated a mild accumulation of subretinal fluid adjacent to and over the choroidal metastasis. Transretinal biopsy of this elevated lesion revealed a low differentiated carcinoma of squamous epithelium, compatible with choroidal metastasis of the esophageal carcinoma. The choroidal metastasis increased within 3 months after the first visit. The

  18. Review: the role of neural crest cells in the endocrine system.

    Science.gov (United States)

    Adams, Meghan Sara; Bronner-Fraser, Marianne

    2009-01-01

    The neural crest is a pluripotent population of cells that arises at the junction of the neural tube and the dorsal ectoderm. These highly migratory cells form diverse derivatives including neurons and glia of the sensory, sympathetic, and enteric nervous systems, melanocytes, and the bones, cartilage, and connective tissues of the face. The neural crest has long been associated with the endocrine system, although not always correctly. According to current understanding, neural crest cells give rise to the chromaffin cells of the adrenal medulla, chief cells of the extra-adrenal paraganglia, and thyroid C cells. The endocrine tumors that correspond to these cell types are pheochromocytomas, extra-adrenal paragangliomas, and medullary thyroid carcinomas. Although controversies concerning embryological origin appear to have mostly been resolved, questions persist concerning the pathobiology of each tumor type and its basis in neural crest embryology. Here we present a brief history of the work on neural crest development, both in general and in application to the endocrine system. In particular, we present findings related to the plasticity and pluripotency of neural crest cells as well as a discussion of several different neural crest tumors in the endocrine system.

  19. The Alpha-Melanocyte Stimulating Hormone Induces Conversion of Effector T Cells into Treg Cells

    Directory of Open Access Journals (Sweden)

    Andrew W. Taylor

    2011-01-01

    Full Text Available The neuropeptide alpha-melanocyte stimulating hormone (α-MSH has an important role in modulating immunity and homeostasis. The production of IFN-γ by effector T cells is suppressed by α-MSH, while TGF-β production is promoted in the same cells. Such α-MSH-treated T cells have immune regulatory activity and suppress hypersensitivity, autoimmune diseases, and graft rejection. Previous characterizations of the α-MSH-induced Treg cells showed that the cells are CD4+ T cells expressing the same levels of CD25 as effector T cells. Therefore, we further analyzed the α-MSH-induced Treg cells for expression of effector and regulatory T-cell markers. Also, we examined the potential for α-MSH-induced Treg cells to be from the effector T-cell population. We found that the α-MSH-induced Treg cells are CD25+  CD4+ T cells that share similar surface markers as effector T cells, except that they express on their surface LAP. Also, the α-MSH treatment augments FoxP3 message in the effector T cells, and α-MSH induction of regulatory activity was limited to the effector CD25+ T-cell population. Therefore, α-MSH converts effector T cells into Treg cells, which suppress immunity targeting specific antigens and tissues.

  20. Oral delivery of Bifidobacterium longum expressing α-melanocyte-stimulating hormone to combat ulcerative colitis.

    Science.gov (United States)

    Wei, Pijin; Yang, Yan; Ding, Qing; Li, Xiuying; Sun, Hanxiao; Liu, Zhaobing; Huang, Junli; Gong, Yahui

    2016-02-01

    α-Melanocyte-stimulating hormone (α-MSH) is a tridecapeptide derived from pro-opiomelanocortin that exhibits potent anti-inflammatory properties by regulating the production of inflammatory mediators. This peptide has been well established in several inflammatory models, including inflammatory bowel disease (IBD). However, its extremely short duration in vivo limits its clinical application. To address this limitation, Bifidobacterium was used here as a carrier to deliver α-MSH. We utilized α-MSH-engineered Bifidobacterium against IBD, which is closely linked to immune and intestinal microbiota dysfunction. First, we constructed a Bifidobacterium longum secreting α-MSH (B. longum-α-MSH). We then tested the recombinant α-MSH expression and determined its bioactivity in HT-29 cells. To assess its effectiveness, B. longum-α-MSH was used against an ulcerative colitis (UC) model in rats induced by dextran sulfate sodium. The data showed that α-MSH expression in B. longum-α-MSH was effective, and its biological activity was similar to the synthesized one. This UC model experiment indicated that B. longum-α-MSH successfully colonized the intestinal gut, expressed bioactive α-MSH and had a significant anti-inflammatory effect. The results demonstrate the feasibility of preventing IBD by using B. longum-α-MSH.

  1. Knowledge and perception of melanocytic nevi and sunburn in young children.

    Science.gov (United States)

    Richtig, Erika; Jung, Erika; Asbäck, Katharina; Trapp, Michael; Hofmann-Wellenhof, Rainer

    2009-01-01

    Understanding the public's perception of nevi and sunburn is crucial to melanoma prevention efforts. We investigated the knowledge and perception of melanocytic nevi and sunburns in 77 children 6 to 10 years old (mean 8.2) in two elementary schools in Styria, Austria. The children were interviewed by specially trained psychologists about the number of their moles and how they felt having them. Additionally questions about sunburn history and sunburn perception were asked. The spontaneous answers of the children were recorded, there were no pregiven answers. Afterwards the children were examined by dermatologists clinically and with dermatoscopes. The 96% of the children could describe a nevus (the term "mole" was translated to "nevus") and 91% did not feel bothered about theirs. Only 26% had noted the appearance of new nevi within the last year. The 67% of all children had at least one sunburn and remembered the clinical features. The 20% of the children knew that sunburns could provoke skin cancer. All children felt comfortable during the clinical and dermatoscopic examination. Children aged from 6 to 10 years know exactly why they had suffered from sunburn, can describe the sunburn and how to avoid it. They do not feel bothered by their nevi and are alert to the appearance of new nevi.

  2. A Case of Iris Melanocytoma Demonstrating Diffuse Melanocytic Proliferation with Uncontrolled Intraocular Pressure

    Directory of Open Access Journals (Sweden)

    Mami Kusunose

    2017-03-01

    Full Text Available We report a rare case with histologically proven melanocytoma of the iris that demonstrated diffuse melanocytic proliferation with uncontrolled secondary glaucoma and investigate the etiology of the intraocular pressure elevation. The patient was a 78-year-old man with a history of darkened iris of his left eye. The intraocular pressure was 39 mm Hg. A slit-lamp examination showed a diffuse darkened iris, and a gonioscopic examination revealed open angle with circumferential heavy pigmentation. There was no pigment dispersion of the anterior chamber and no pigment deposition of the cornea. We suspected malignant ring melanoma in the left eye and enucleated it. The globe was examined with light and electron microscopy. Light microscopy revealed the presence of heavily pigmented tumor cells in the iris, ciliary body, trabecular meshwork, and Schlemm’s canal. A bleached preparation showed large tumor cells with central and paracentral nuclei without mitosis. Electron microscopy of the trabecular meshwork revealed melanin-bearing tumor cells invading the intertrabecular spaces, and the melanin granules were not phagocytosed in the trabecular cells. The mechanical obstruction of the aqueous flow by the tumor cells may be a major cause of secondary glaucoma in eyes with iris melanocytoma presenting diffuse proliferation.

  3. L-tyrosine and L-DOPA as hormone-like regulators of melanocytes functions

    Science.gov (United States)

    Slominski, Andrzej; Zmijewski, Michal; Pawelek, John

    2011-01-01

    Summary Evidence reveals that L-tyrosine and L-DOPA, besides serving as substrates and intermediates of melanogenesis, are also bioregulatory agents acting not only as inducers and positive regulators of melanogenesis but also as regulators of other cellular functions. These can be mediated through action on specific receptors or through non-receptor mediated mechanisms. The substrate induced (L-tyrosine and/or L-DOPA) melanogenic pathway would autoregulate itself as well as it would regulate the melanocyte functions through activity of its structural or regulatory proteins and through intermediates of melanogenesis and melanin itself. Dissection of regulatory and autoregulatory elements of this process may elucidate how substrate induced autoregulatory pathways have evolved from prokaryotic or simple eukaryotic organisms to complex systems in vertebrates. This could substantiate older theory proposing that receptors for amino-acid derived hormones arose from the receptors for those amino acids, and that nuclear receptors evolved from primitive intracellular receptors binding nutritional factors or metabolic intermediates. PMID:21834848

  4. Dermoscopic patterns of melanocytic nevi in children and adolescents: a cross-sectional study*

    Science.gov (United States)

    Piazza, Christiane Donato; Yamada, Sergio; Marcassi, Aline P; Maciel, Marina G; Seize, Maria P; Cestari, Silmara C P

    2017-01-01

    Background Childhood is a dynamic period regarding nevogenesis. Dermoscopy is a noninvasive technique, recommended for the evaluation of pigmented cutaneous lesions. Objectives The purpose of this study was to describe the structures and dermoscopic patterns of melanocytic nevi observed in children and adolescents. Methods Dermoscopy with photographic documentation was used for nevi located on the face, trunk, and extremities of 38 patients aged from one to 16 years examined at the Pediatric Dermatology Outpatient Clinic of the Federal University of São Paulo. Results The study included 201 skin lesions that were diagnosed as nevi during clinic examination. Upon evaluation of the global dermoscopic pattern of the lesions, the most frequently observed nevi were reticular (39.0%), followed by homogeneous (23.9%) and globular nevi (16.4%). During evaluation of the dermoscopic structures, according to the body site, the pigment network was the most observed in the extremities. Study limitations A limitation to be considered is that the inclusion of small or new lesions may hinder the differentiation between dots and globules. Conclusions In our study, the most observed pattern was reticular. There was a difference in the predominance of structures dependent on the anatomical location. PMID:29186245

  5. Double optical fibre-probe device for the diagnosis of melanocytic lesions

    Science.gov (United States)

    Cicchi, Riccardo; Cosci, Alessandro; Rossari, Susanna; De Giorgi, Vincenzo; Kapsokalyvas, Dimitrios; Massi, Daniela; Pavone, Francesco S.

    2012-06-01

    We have designed and developed an optical fiber-probe for spectroscopic measurements on human tissues. The experimental setup combines fluorescence spectroscopy and Raman spectroscopy in a multidimensional approach. Concerning fluorescence spectroscopy, the excitation is provided by two laser diodes, one emitting in the UV (378 nm) and the other emitting in the visible (445 nm). These two lasers are used to selectively excite fluorescence from NADH and FAD, which are among the brightest endogenous fluorophores in human tissues. For Raman and NIR spectroscopy, the excitation is provided by a third laser diode with 785 nm excitation wavelength. Laser light is delivered to the tissue through the central optical fiber of a fiber bundle. The surrounding 48 fibers of the bundle are used for collecting fluorescence and Raman and for delivering light to the spectrograph. Fluorescence and Raman spectra are acquired on a cooled CCD camera. The instrument has been tested on fresh human skin biopsies clinically diagnosed as malignant melanoma, melanocytic nevus, or healthy skin, finding an optimal correlation with the subsequent histological exam. In some cases our examination was not in agreement with the clinical observation, but it was with the histological exam, demonstrating that the system can potentially contribute to improve clinical diagnostic capabilities and hence reduce the number of unnecessary biopsies.

  6. The effect of simultaneous exposure of HEMn-DP and HEMn-LP melanocytes to nicotine and UV-radiation on the cell viability and melanogenesis

    International Nuclear Information System (INIS)

    Delijewski, Marcin; Wrześniok, Dorota; Beberok, Artur; Rok, Jakub; Otręba, Michał; Buszman, Ewa

    2016-01-01

    Nicotine is a main compound of tobacco plants and may affect more than a billion people all over the world that are permanently exposed to nicotine from cigarettes, various forms of smoking cessation therapies, electronic cigarettes or second-hand smoke. It is known that nicotine forms complexes with melanin what may lead to accumulation of this alkaloid in tissues of living organisms containing the pigment. This may affect the viability of cells and process of melanin biosynthesis that takes place in melanocytes. Although UV radiation is known to be a particular inductor of melanin biosynthesis, its simultaneous effect with nicotine on this process as well as the viability of human cells containing melanin have not been assessed so far. The aim of this study was to examine the simultaneous impact of nicotine and UV radiation on viability and melanogenesis in cultured normal human melanocytes dark (HEMn-DP) and light (HEMn-LP) pigmented. Nicotine together with UV radiation induced concentration-dependent loss in melanocytes viability. The higher cell loss was observed in dark pigmented melanocytes in comparison to light pigmented cells. Simultaneous exposure of cells to nicotine and UV radiation also caused changes in melanization process in both tested cell lines. The data suggest that simultaneous exposure of melanocytes to nicotine and UV radiation up-regulates melanogenesis and affects cell viability. Observed processes are more pronounced in dark pigmented cells. - Highlights: • Nicotine and UVA induced concentration-dependent loss in melanocytes viability. • Nicotine and UVA modulated melanization process in melanocytes. • Changes in viability and melanization were more pronounced in dark pigmented cells.

  7. The effect of simultaneous exposure of HEMn-DP and HEMn-LP melanocytes to nicotine and UV-radiation on the cell viability and melanogenesis

    Energy Technology Data Exchange (ETDEWEB)

    Delijewski, Marcin; Wrześniok, Dorota; Beberok, Artur; Rok, Jakub; Otręba, Michał; Buszman, Ewa, E-mail: ebuszman@sum.edu.pl

    2016-11-15

    Nicotine is a main compound of tobacco plants and may affect more than a billion people all over the world that are permanently exposed to nicotine from cigarettes, various forms of smoking cessation therapies, electronic cigarettes or second-hand smoke. It is known that nicotine forms complexes with melanin what may lead to accumulation of this alkaloid in tissues of living organisms containing the pigment. This may affect the viability of cells and process of melanin biosynthesis that takes place in melanocytes. Although UV radiation is known to be a particular inductor of melanin biosynthesis, its simultaneous effect with nicotine on this process as well as the viability of human cells containing melanin have not been assessed so far. The aim of this study was to examine the simultaneous impact of nicotine and UV radiation on viability and melanogenesis in cultured normal human melanocytes dark (HEMn-DP) and light (HEMn-LP) pigmented. Nicotine together with UV radiation induced concentration-dependent loss in melanocytes viability. The higher cell loss was observed in dark pigmented melanocytes in comparison to light pigmented cells. Simultaneous exposure of cells to nicotine and UV radiation also caused changes in melanization process in both tested cell lines. The data suggest that simultaneous exposure of melanocytes to nicotine and UV radiation up-regulates melanogenesis and affects cell viability. Observed processes are more pronounced in dark pigmented cells. - Highlights: • Nicotine and UVA induced concentration-dependent loss in melanocytes viability. • Nicotine and UVA modulated melanization process in melanocytes. • Changes in viability and melanization were more pronounced in dark pigmented cells.

  8. Neural Crest Cells Isolated from the Bone Marrow of Transgenic Mice Express JCV T-Antigen.

    Directory of Open Access Journals (Sweden)

    Jennifer Gordon

    Full Text Available JC virus (JCV, a common human polyomavirus, is the etiological agent of the demyelinating disease, progressive multifocal leukoencephalopathy (PML. In addition to its role in PML, studies have demonstrated the transforming ability of the JCV early protein, T-antigen, and its association with some human cancers. JCV infection occurs in childhood and latent virus is thought to be maintained within the bone marrow, which harbors cells of hematopoietic and non-hematopoietic lineages. Here we show that non-hematopoietic mesenchymal stem cells (MSCs isolated from the bone marrow of JCV T-antigen transgenic mice give rise to JCV T-antigen positive cells when cultured under neural conditions. JCV T-antigen positive cells exhibited neural crest characteristics and demonstrated p75, SOX-10 and nestin positivity. When cultured in conditions typical for mesenchymal cells, a population of T-antigen negative cells, which did not express neural crest markers arose from the MSCs. JCV T-antigen positive cells could be cultured long-term while maintaining their neural crest characteristics. When these cells were induced to differentiate into neural crest derivatives, JCV T-antigen was downregulated in cells differentiating into bone and maintained in glial cells expressing GFAP and S100. We conclude that JCV T-antigen can be stably expressed within a fraction of bone marrow cells differentiating along the neural crest/glial lineage when cultured in vitro. These findings identify a cell population within the bone marrow permissible for JCV early gene expression suggesting the possibility that these cells could support persistent viral infection and thus provide clues toward understanding the role of the bone marrow in JCV latency and reactivation. Further, our data provides an excellent experimental model system for studying the cell-type specificity of JCV T-antigen expression, the role of bone marrow-derived stem cells in the pathogenesis of JCV-related diseases

  9. The neural crest is a source of mesenchymal stem cells with specialized hematopoietic stem cell niche function.

    Science.gov (United States)

    Isern, Joan; García-García, Andrés; Martín, Ana M; Arranz, Lorena; Martín-Pérez, Daniel; Torroja, Carlos; Sánchez-Cabo, Fátima; Méndez-Ferrer, Simón

    2014-09-25

    Mesenchymal stem cells (MSCs) and osteolineage cells contribute to the hematopoietic stem cell (HSC) niche in the bone marrow of long bones. However, their developmental relationships remain unclear. In this study, we demonstrate that different MSC populations in the developing marrow of long bones have distinct functions. Proliferative mesoderm-derived nestin(-) MSCs participate in fetal skeletogenesis and lose MSC activity soon after birth. In contrast, quiescent neural crest-derived nestin(+) cells preserve MSC activity, but do not generate fetal chondrocytes. Instead, they differentiate into HSC niche-forming MSCs, helping to establish the HSC niche by secreting Cxcl12. Perineural migration of these cells to the bone marrow requires the ErbB3 receptor. The neonatal Nestin-GFP(+) Pdgfrα(-) cell population also contains Schwann cell precursors, but does not comprise mature Schwann cells. Thus, in the developing bone marrow HSC niche-forming MSCs share a common origin with sympathetic peripheral neurons and glial cells, and ontogenically distinct MSCs have non-overlapping functions in endochondrogenesis and HSC niche formation.

  10. Topical application of dimethylbenz[a]anthracene results in the generation of multiple melanocytic nevi in C3H/HeN mice

    International Nuclear Information System (INIS)

    Elmets, Craig A.; Yusuf, Nabiha; Hamza, Sate; Iranikakh, Nasser; Smith, Jeffrey; Volk, Andrea L.; Skelton, Henry; Smith, Kathy

    2004-01-01

    Melanocytic nevi are a common dermatological problem for which there are few in vivo models. It has been postulated that environmental factors contribute to their development. Experiments were therefore conducted to determine whether application of dimethylbenz[a]anthracene (DMBA) to the skin of mice would result in the development of melanocytic nevi. One hundred microliters of a 0.1%, 0.5%, or 1.0% solution of DMBA was applied to the dorsal skin of C3H/HeN mice. The mice were then observed for the appearance of pigmented lesions. Histological examination revealed perifollicular accumulations of nevus cells, which were S-100-protein and HMB-45-positive, confirming their melanocytic origin. Pigmented lesions did not occur in animals treated with vehicle alone. Dose response studies revealed both greater numbers of nevi and lesions with larger diameters as the dose of DMBA was increased from 0.1% to 0.5%. In no instance was an invasive melanoma observed even after 40 weeks. The fact that melanocytic nevi can be produced by topical application of DMBA suggests that xenobiotics may play a previously unrecognized role in the development of this common benign neoplasm. Because this is one of the only animal models for melanocytic nevi, further examination of this model may facilitate identification of the molecular and biochemical mechanisms that lead to the development of pigmented nevi and the factors that promote their evolution into invasive melanomas

  11. Ultraviolet stimulated melanogenesis by human melanocytes is augmented by di-acyl glycerol but not TPA

    International Nuclear Information System (INIS)

    Friedmann, P.S.; Wren, F.E.; Matthews, J.N.

    1990-01-01

    Epidermal melanocytes (MC) synthesize melanin in response to ultraviolet radiation (UVR). The mechanisms mediating the UV-induced activation of melanogenesis are unknown but since UVR induces turnover of membrane phospholipids generating prostaglandins (PGs) and other products, it is possible that one of these might provide the activating signal. We have examined the effects of prostaglandins (PGs) E1, E2, D2, F2 alpha, and di-acyl glycerol upon the UV-induced responses of cultured human MC and the Cloudman S91 melanoma cell line. The PGs had little effect on unirradiated cells and did not alter the response to UVR in either human MC or S91 melanoma cells. However, a synthetic analogue of di-acyl glycerol, 1-oleyl 2-acetyl glycerol (OAG), caused a significant (P less than 0.0001), dose-related augmentation of melanin content both in human MC (seven-fold) and S91 cells (three-fold). UVR caused a significant augmentation of the OAG-induced melanogenesis of both human MC and S91 cells. Since OAG is known to activate protein kinase C, it was possible that the observed modulation of the UVR signal could be via that pathway. Di-octanoyl glycerol, another di-acyl glycerol, which activates kinase C, caused a small (70%) increase in melanogenesis in MC which was not altered by UVR. However, 12-0 tetradecanoyl phorbol 13-acetate (TPA), a potent activator of protein kinase C, had no significant effect on either basal or UV-induced melanin synthesis in either cell type. These data suggest that the UV-induced signal activating melanogenesis could be mediated by di-acyl glycerol. Furthermore, they imply that the signal is transduced via an alternative, pathway that might be independent of protein kinase C

  12. Melanocytic Nevi Prevalence and the Relationship with Sun Exposure Among School Children

    Directory of Open Access Journals (Sweden)

    Neslihan Şendur

    2009-12-01

    Full Text Available Background and Design: Melanocytic nevi (MN count is known as the strongest risk factor for melanoma development. So it is important to know the MN count in public. We aimed to determine the MN prevalence in schoolchildren and also clarify the possible relation between MN counts, constitutional variables and sun exposure. Material and Method: In this randomized, cross-sectional study, a questionnaire asking skin phenotypes and sun exposure in previous summer was prepared for primary-school children. Nine hundred and sixty questionnaires distributed to the parents. Children who were given permission by parents for examination were examined for whole body MN. Results: Questionnaires were answered by parents of 939 children and 622 children (316 boys and 306 girls were examined. Mean age of children was 8.8±1.5 (6-12. Mean MN count was 19.6±16.6 and this count was increasing with age (p<0.001. MN count was significantly related with sex, skin phototype and skin colour. More MN were found in boys (p<0.001, children with sun sensitive phototypes (p=0.03 and light skin colour (p<0.001. Time spent outside on midday in previous summer was not related with the MN count (p=0.35. Sunburns experienced in previous summer were not related with MN count (p=0.11. MN were most densely located on the face, and then on upper extremity, trunk and lower extremity in decreasing order. There were more MN on the more sun exposed sites of the arms, hands and feet. Conclusion: It was found that previous summer sun exposure had no effect on MN count in schoolchildren. However, relation between MN count and skin phenotype and distribution of the MN on the body suggest that sun exposure could affect MN count and this effect could be seen in a long period of time.

  13. The significance of crystalline/chrysalis structures in the diagnosis of melanocytic and nonmelanocytic lesions.

    Science.gov (United States)

    Balagula, Yevgeniy; Braun, Ralph P; Rabinovitz, Harold S; Dusza, Stephen W; Scope, Alon; Liebman, Tracey N; Mordente, Ines; Siamas, Katherine; Marghoob, Ashfaq A

    2012-08-01

    Crystalline/chrysalis structures (CS) are white shiny streaks that can only be seen with polarized dermatoscopy. We sought to estimate the prevalence and assess the clinical significance of CS in melanocytic and nonmelanocytic lesions. This was a prospective observational study in which dermatoscopic assessment of lesions was recorded in consecutive patients examined during a 6-month period. In addition, a data set of biopsy-proven melanomas was retrospectively analyzed. In all, 11,225 lesions in 881 patients were prospectively examined. Retrospectively, 229 melanomas imaged with polarized dermatoscopy were analyzed. In the prospective data set, a median of 12.7 lesions (range, 1-54) were evaluated per patient. None of clinically diagnosed Clark nevi (n = 9750, 86.8%) demonstrated CS. Overall, CS were observed in 206 (1.8%) lesions, most commonly dermatofibromas and scars among nonbiopsied lesions. A total of 265 (2.4%) lesions were biopsied, including 20 melanomas and 36 nevi. Among biopsied malignant lesions, CS were most commonly observed in basal cell carcinoma (47.6%) and invasive melanomas (84.6%). Melanomas were more likely to have CS than biopsied nevi (odds ratio = 9.7, 95% confidence interval 2.7-34.1). In the retrospective data set, CS were more commonly observed among invasive melanomas (41%) compared with in situ melanomas (17%) (odds ratio = 3.4, 95% confidence interval 1.9-6.3, P < .001). The prevalence of CS correlated with increased melanoma thickness (P = .001). Biopsied lesions represent a small percentage of the total number of lesions evaluated. Among biopsied malignant lesions, CS are most commonly observed in basal cell carcinoma and invasive melanomas and rarely seen in nevi. In melanoma, CS may reflect increased tumor thickness and progression. Copyright © 2011 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  14. HGF/SF increases number of skin melanocytes but does not alter quality or quantity of follicular melanogenesis.

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    Agnieszka Wolnicka-Glubisz

    Full Text Available Melanins are an important factor determining the vulnerability of mammalian skin to UV radiation and thus to UV-induced skin cancers. Transgenic mice overexpressing hepatocyte growth factor/scatter factor (HGF/SF have extra-follicular dermal melanocytes, notably in the papillary upper dermis, and are susceptible to UV-induced melanoma. Pigmented HGF/SF neonatal mice are more susceptible than albino HGF/SF animals to UVA -induced melanoma, indicating an involvement of melanin in melanoma formation. This raises the question of the effect of transgenic HGF/SF on melanization. We developed a methodology to accurately quantitate both the production of melanin and the efficiency of melanogenesis in normal, and HGF/SF transgenic mice in vivo. Skin and hair shafts of 5 day old and adult (3 week old C57BL/6-HGF/SF and corresponding C57BL/6 wild type mice were investigated by electron paramagnetic resonance spectroscopy (EPR to quantitate melanin, by transmission electron microscopy (TEM for the presence of melanosomes, and by standard histology and by Western blotting and zymography to determine the expression and activity of melanogenesis-related proteins. Eumelanin but no phaeomelanin was detected in transgenic C57BL/6-HGF and C57BL/6 wild type mice. Transgenic HGF/SF overexpression did not change the type of melanin produced in the skin or hair, did not affect the terminal content of melanin production in standard samples of hair and did not influence hair cycle/morphogenesis-related changes in skin thickness. No melanocytes were found in the epidermis and no melanosomes were found in epidermal keratinocytes. HGF/SF transgenic mice thus lack the epidermal melanin UV-protection found in constitutively dark human skin. We conclude that melanocytes in the HGF/SF transgenic mouse, particularly in the papillary dermis, are vulnerable to UVA which interacts with eumelanin but not phaeomelanin to induce melanoma.

  15. Uncovering the Role of BMP Signaling in Melanocyte Development and Melanoma Tumorigenesis

    Science.gov (United States)

    2016-09-01

    specifiers’, genes that are initially expressed broadly in the neural crest and help to maintain neural crest identity (Fig. 2G ) (6). As development...melanoma cells, GDF6 and the BMP pathway negatively regulated SOX9 expression (Fig. 3G ; Fig. S13A-C). Epistasis analyses showed that SOX9 knockdown rescued...criteria, if the tumor volume reached >1,000 mm3; if tumor size or location affected the mobility or general health of animal, the animal was euthanized

  16. Melanocytes from patients affected by Ullrich congenital muscular dystrophy and Bethlem myopathy have dysfunctional mitochondria that can be rescued with cyclophilin inhibitors

    Directory of Open Access Journals (Sweden)

    Alessandra eZulian

    2014-11-01

    Full Text Available Ullrich congenital muscular dystrophy and Bethlem myopathy are caused by mutations in collagen VI genes, which encode an extracellular matrix protein; yet mitochondria play a major role in disease pathogenesis through a short circuit caused by inappropriate opening of the permeability transition pore, a high conductance channel which causes a shortage in ATP production. We find that melanocytes do not produce collagen VI yet they bind it at the cell surface, suggesting that this protein may play a trophic role and that its absence may cause lesions similar to those seen in skeletal muscle. We show that mitochondria in melanocytes of Ullrich congenital muscular dystrophy and Bethlem myooathy patients display increased size, reduced matrix density and disrupted cristae, findings that suggest a functional impairment. In keeping with this hypothesis, mitochondria (i underwent anomalous depolarization after inhibition of the F-ATP synthase with oligomycin, and (ii displayed decreased respiratory reserve capacity. The non-immunosuppressive cyclophilin inhibitor NIM811 prevented mitochondrial depolarization in response to oligomycin in melanocytes from both Ullrich congenital muscular dystrophy and Bethlem myopathy patients, and partially restored the respiratory reserve of melanocytes from one Bethlem myopathy patient. These results match our recent findings on melanocytes from patients affected by Duchenne muscular dystrophy (Pellegrini et al., 2013 Melanocytes--a novel tool to study mitochondrial dysfunction in Duchenne muscular dystrophy. J Cell Physiol 228, 1323-1331, and suggest that skin biopsies may represent a minimally invasive tool to investigate mitochondrial dysfunction and to evaluate drug efficacy in collagen VI-related myopathies and possibly in other muscle wasting conditions like aging sarcopenia.

  17. Neural Networks

    Directory of Open Access Journals (Sweden)

    Schwindling Jerome

    2010-04-01

    Full Text Available This course presents an overview of the concepts of the neural networks and their aplication in the framework of High energy physics analyses. After a brief introduction on the concept of neural networks, the concept is explained in the frame of neuro-biology, introducing the concept of multi-layer perceptron, learning and their use as data classifer. The concept is then presented in a second part using in more details the mathematical approach focussing on typical use cases faced in particle physics. Finally, the last part presents the best way to use such statistical tools in view of event classifers, putting the emphasis on the setup of the multi-layer perceptron. The full article (15 p. corresponding to this lecture is written in french and is provided in the proceedings of the book SOS 2008.

  18. Plasma concentrations of alpha-melanocyte-stimulating hormone are elevated in patients on chronic haemodialysis.

    Science.gov (United States)

    Airaghi, L; Garofalo, L; Cutuli, M G; Delgado, R; Carlin, A; Demitri, M T; Badalamenti, S; Graziani, G; Lipton, J M; Catania, A

    2000-08-01

    Clinical and/or laboratory signs of systemic inflammation occur frequently in patients undergoing long-term haemodialysis. It is likely, therefore, that a compensatory release of endogenous anti-inflammatory molecules occurs to limit host reactions. The aim of the present research was to determine if the potent anti-inflammatory peptide alpha-melanocyte-stimulating hormone (alpha-MSH), a pro-opiomelanocortin derivative, is increased in plasma of haemodialysis patients. Because endotoxin and cytokines induce alpha-MSH in vivo and in vitro, we also measured plasma concentrations of endotoxin, interleukin-6 (IL-6), and tumour necrosis factor alpha (TNF-alpha), and the two circulating products of activated monocytes, nitric oxide (NO) and neopterin. Thirty-five chronic haemodialysis patients, 20 patients with chronic renal failure not yet on dialysis, and 35 normal controls were included in the study. In the haemodialysis group, blood samples were obtained before and at the end of a dialysis session. Plasma alpha-MSH was measured using a double antibody radioimmunoassay, and IL-6, TNF-alpha, and neopterin using specific enzyme-linked immunosorbent assays. Plasma nitrites were determined by a colorimetric method, and endotoxin with the quantitative chromogenic LAL (limulus amoebocyte lysate) method. Mean plasma alpha-MSH was higher in haemodialysis patients than in control subjects, with the peptide concentrations being particularly elevated in dialysed patients with detectable endotoxin. High alpha-MSH concentrations were observed in the pre-dialysis samples, with no substantial change at the end of the dialysis session. Plasma concentrations of IL-6, TNF-alpha, neopterin, and NO were generally elevated in chronic haemodialysis patients and there was a negative correlation between circulating alpha-MSH and IL-6. In patients with renal failure not yet on dialysis, mean plasma alpha-MSH was similar to that of normal subjects. alpha-MSH is increased in the circulation of

  19. Melanoma Therapy with Rhenium-Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs

    Energy Technology Data Exchange (ETDEWEB)

    Thomas P Quinn

    2005-11-22

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with {sup 188}Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, {sup 188}Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The {sup 177}Lu

  20. Melanome Therapy with Rhenium Cyclized Alpha Melanocyte Stimulating Hormone Peptide Analogs. Final report

    International Nuclear Information System (INIS)

    Quinn, Thomas P.

    2005-01-01

    Malignant melanoma is the 6th most commonly diagnosed cancer with increasing incidence in the United States. It is estimated that 54,200 cases of malignant melanoma will be newly diagnosed and 7,600 cases of death will occur in the United States in the year 2003 (1). At the present time, more than 1.3% of Americans will develop malignant melanoma during their lifetime (2). The average survival for patients with metastatic melanoma is about 6-9 months (3). Moreover, metastatic melanoma deposits are resistant to conventional chemotherapy and external beam radiation therapy (3). Systematic chemotherapy is the primary therapeutic approach to treat patients with metastatic melanoma. Dacarbazine is the only single chemotherapy agent approved by FDA for metastatic melanoma treatment (5). However, the response rate to Dacarbazine is only approximately 20% (6). Therefore, there is a great need to develop novel treatment approaches for metastatic melanoma. The global goal of this research program is the rational design, characterization and validation of melanoma imaging and therapeutic radiopharmaceuticals. Significant progress has been made in the design and characterization of metal-cyclized radiolabeled alpha-melanocyte stimulating hormone peptides. Therapy studies with 188 Re-CCMSH demonstrated the therapeutic efficacy of the receptor-targeted treatment in murine and human melanoma bearing mice (previous progress report). Dosimetry calculations, based on biodistribution data, indicated that a significant dose was delivered to the tumor. However, 188 Re is a very energetic beta-particle emitter. The longer-range beta-particles theoretically would be better for larger tumors. In the treatment of melanoma, the larger primary tumor is usually surgically removed leaving metastatic disease as the focus of targeted radiotherapy. Isotopes with lower beta-energies and/or shorter particle lengths should be better suited for targeting metastases. The 177 Lu-DOTA-Re(Arg11)CCMSH and

  1. Genetic Background of Iris Melanomas and Iris Melanocytic Tumors of Uncertain Malignant Potential.

    Science.gov (United States)

    van Poppelen, Natasha M; Vaarwater, Jolanda; Mudhar, Hardeep S; Sisley, Karen; Rennie, Ian G; Rundle, Paul; Brands, Tom; van den Bosch, Quincy C C; Mensink, Hanneke W; de Klein, Annelies; Kiliç, Emine; Verdijk, Robert M

    2018-01-19

    BAP1 expression as seen in choroidal melanoma. Consequently, iris melanoma is a distinct molecular subgroup of UM. Histologic borderline malignant iris nevi can harbor BAP1 mutations and may be designated iris melanocytic tumors of uncertain malignant potential. Copyright © 2017 American Academy of Ophthalmology. Published by Elsevier Inc. All rights reserved.

  2. Melanoma transition is frequently accompanied by a loss of cytoglobin expression in melanocytes: a novel expression site of cytoglobin.

    Directory of Open Access Journals (Sweden)

    Yoshihiko Fujita

    Full Text Available The tissue distribution and function of hemoglobin or myoglobin are well known; however, a newly found cytoglobin (CYGB, which also belongs to the globin family, remains to be characterized. To assess its expression in human malignancies, we sought to screen a number of cell lines originated from many tissues using northern blotting and real time PCR techniques. Unexpectedly, we found that several, but not all, melanoma cell lines expressed CYGB mRNA and protein at much higher levels than cells of other origins. Melanocytes, the primary origin of melanoma, also expressed CYGB at a high level. To verify these observations, immunostaining and immunoblotting using anti-CYGB antibody were also performed. Bisulfite-modified genomic sequencing revealed that several melanoma cell lines that abrogated CYGB expression were found to be epigenetically regulated by hypermethylation in the promoter region of CYGB gene. The RNA interference-mediated knockdown of the CYGB transcript in CYGB expression-positive melanoma cell lines resulted in increased proliferation in vitro and in vivo. Flow cytometric analysis using 2'-, 7'-dichlorofluorescein diacetate (DCFH-DA, an indicator of reactive oxygen species (ROS, revealed that the cellular ROS level may be involved in the proliferative effect of CYGB. Thus, CYGB appears to play a tumor suppressive role as a ROS regulator, and its epigenetic silencing, as observed in CYGB expression-negative melanoma cell lines, might function as an alternative pathway in the melanocyte-to-melanoma transition.

  3. Recent Updates in Melanocyte Function: The Use of Promising Bioactive Compounds for the Treatment of Hypopigmentary Disorders.

    Science.gov (United States)

    Ali, Sharique A; Naaz, Ishrat; Zaidi, Kamal Uddin; Ali, Ayesha S

    2017-01-01

    Skin pigmentation is a broadly appearing phenomenon in nature which plays an important task of determining the appearance and biology of all vertebrates including human beings. Skin color is a crucial attribute, determined by the synthesis of melanin pigment within melanocytes by the process of melanogenesis and is regulated by many extrinsic as well as intrinsic factors. Tyrosinase catalyzes the key step of melanogenesis, dysfunction of tyrosinase leads to reduce melanin production which results in severe clinical and aesthetical problems of hypopigmentation. Therefore, the regulation of melanin production is an important strategy in the treatment of abnormal skin pigmentation for cosmetic and medicinal purpose. The present review covers the various aspects of mammalian melanocyte biology which will help in the identification of key regulators of melanogenesis from pharmaceutical and pharmacological point of view. Further sections of the review focus on the dysfunctions of melanogenic pathways, which result in severe clinical and aesthetical problems of hypopigmentation. We have also attempted to highlight the ability of available scientifically validated plant extracts to naturally enhance melanin synthesis in order to cure hypopigmentation. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

  4. New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes

    Directory of Open Access Journals (Sweden)

    Rong-Dih Lin

    2015-12-01

    Full Text Available Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9 and 3,4-dihydroxy-5-methoxybiphenyl-2ʹ-O-β-d-glucopyranoside (13, as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver–Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics.

  5. Melanocytic Nevi and Sun Exposure in a Cohort of Colorado Children: Anatomic Distribution and Site-Specific Sunburn

    Science.gov (United States)

    Dodd, Athena T.; Morelli, Joseph; Mokrohisky, Stefan T.; Asdigian, Nancy; Byers, Tim E.; Crane, Lori A.

    2010-01-01

    Sun exposure and high prevalence of melanocytic nevi are major risk factors for melanoma, but the relationship between them is not well understood. This study examines the relationship between sun exposure (detailed by anatomic location and history of site-specific sunburns) and the presence of melanocytic nevi on 743 White children in Denver, Colorado. Parental reports of site-specific sunburns were collected annually for 2 years starting at ages 5 to 6 years. In the third year, nevi were counted and mapped by anatomic location. Nevus density was higher for boys (36.0 nevi/m2) than for girls (31.0 nevi/m2; P = 0.04). Nevus density was highest on the face, neck, and lateral forearms and was significantly higher in chronically versus intermittently sun-exposed areas (P sunburn. The face, shoulders, and back were the most frequently sunburned areas of the body. When adjusted for host factors, total number of sunburns was significantly associated with higher total nevus prevalence (P = 0.01 for one burn). Site-specific sunburns were significantly associated with nevus prevalence on the back (P = 0.03 for three or more sunburns), but not on the face, arms, or legs. In this high-risk population, there is evidence for two pathways to nevus accumulation: by chronic sun exposure and by intermittent exposure related to sunburns. PMID:17932362

  6. New Whitening Constituents from Taiwan-Native Pyracantha koidzumii: Structures and Tyrosinase Inhibitory Analysis in Human Epidermal Melanocytes

    Science.gov (United States)

    Lin, Rong-Dih; Chen, Mei-Chuan; Liu, Yan-Ling; Lin, Yi-Tzu; Lu, Mei-Kuang; Hsu, Feng-Lin; Lee, Mei-Hsien

    2015-01-01

    Nontoxic natural products useful in skin care cosmetics are of considerable interest. Tyrosinase is a rate-limiting enzyme for which its inhibitor is useful in developing whitening cosmetics. Pyracantha koidzumii (Hayata) Rehder is an endemic species in Taiwan that exhibits tyrosinase-inhibitory activity. To find new active natural compounds from P. koidzumii, we performed bioguided isolation and studied the related activity in human epidermal melanocytes. In total, 13 compounds were identified from P. koidzumii in the present study, including two new compounds, 3,6-dihydroxy-2,4-dimethoxy-dibenzofuran (9) and 3,4-dihydroxy-5-methoxybiphenyl-2ʹ-O-β-d-glucopyranoside (13), as well as 11 known compounds. The new compound 13 exhibited maximum potency in inhibiting cellular tyrosinase activity, the protein expression of cellular tyrosinase and tyrosinase-related protein-2, as well as the mRNA expression of Paired box 3 and microphthalmia-associated transcription factor in a concentration-dependent manner. In the enzyme kinetic assay, the new compound 13 acted as an uncompetitive mixed-type inhibitor against the substrate l-3,4-dihydroxyphenylalanine and had a Km value against this substrate of 0.262 mM, as calculated using the Lineweaver–Burk plots. Taken together, our findings show compound 13 exhibits tyrosinase inhibition in human melanocytes and compound 13 may be a potential candidate for use in cosmetics. PMID:26633381

  7. Evaluation of treatment response to autologous transplantation of noncultured melanocyte/keratinocyte cell suspension in patients with stable vitiligo.

    Science.gov (United States)

    Ramos, Mariana Gontijo; Ramos, Daniel Gontijo; Ramos, Camila Gontijo

    2017-01-01

    Vitiligo is a chronic disease characterized by the appearance of achromic macules caused by melanocyte destruction. Surgical treatments with melanocyte transplantation can be used for stable vitiligo cases. To evaluate treatment response to the autologous transplantation of noncultured epidermal cell suspension in patients with stable vitiligo. Case series study in patients with stable vitiligo submitted to noncultured epidermal cell suspension transplantation and evaluated at least once, between 3 and 6 months after the procedure, to observe repigmentation and possible adverse effects. The maximum follow-up period for some patients was 24 months. Of the 20 patients who underwent 24 procedures, 25% showed an excellent rate of repigmentation, 50% good repigmentation, 15% regular, and 10% poor response. The best results were observed in face and neck lesions, while the worst in extremity lesions (88% and 33% of satisfactory responses, respectively). Patients with segmental vitiligo had a better response (84%) compared to non-segmental ones (63%). As side effects were observed hyperpigmentation of the treated area and the appearance of Koebner phenomenon in the donor area. Some limitations of the study included the small number of patients, a subjective evaluation, and the lack of long-term follow-up on the results. CONCLUSION: Noncultured epidermal cell suspension transplantation is efficient and well tolerated for stable vitiligo treatment, especially for segmental vitiligo on the face and neck.

  8. Lack of the central nervous system- and neural crest-expressed forkhead gene Foxs1 affects motor function and body weight.

    Science.gov (United States)

    Heglind, Mikael; Cederberg, Anna; Aquino, Jorge; Lucas, Guilherme; Ernfors, Patrik; Enerbäck, Sven

    2005-07-01

    To gain insight into the expression pattern and functional importance of the forkhead transcription factor Foxs1, we constructed a Foxs1-beta-galactosidase reporter gene "knock-in" (Foxs1beta-gal/beta-gal) mouse, in which the wild-type (wt) Foxs1 allele has been inactivated and replaced by a beta-galactosidase reporter gene. Staining for beta-galactosidase activity reveals an expression pattern encompassing neural crest-derived cells, e.g., cranial and dorsal root ganglia as well as several other cell populations in the central nervous system (CNS), most prominently the internal granule layer of cerebellum. Other sites of expression include the lachrymal gland, outer nuclear layer of retina, enteric ganglion neurons, and a subset of thalamic and hypothalamic nuclei. In the CNS, blood vessel-associated smooth muscle cells and pericytes stain positive for Foxs1. Foxs1beta-gal/beta-gal mice perform significantly better (P fat diet, and we speculate that dorsomedial hypothalamic neurons, expressing Foxs1, could play a role in regulating body weight via regulation of sympathetic outflow. In support of this, we observed increased levels of uncoupling protein 1 mRNA in Foxs1beta-gal/beta-gal mice. This points toward a role for Foxs1 in the integration and processing of neuronal signals of importance for energy turnover and motor function.

  9. Towards a "free radical theory of graying": melanocyte apoptosis in the aging human hair follicle is an indicator of oxidative stress induced tissue damage.

    Science.gov (United States)

    Arck, Petra Clara; Overall, Rupert; Spatz, Katharina; Liezman, Christiane; Handjiski, Bori; Klapp, Burghard F; Birch-Machin, Mark A; Peters, Eva Milena Johanne

    2006-07-01

    Oxidative stress is generated by a multitude of environmental and endogenous challenges such as radiation, inflammation, or psychoemotional stress. It also speeds the aging process. Graying is a prominent but little understood feature of aging. Intriguingly, the continuous melanin synthesis in the growing (anagen) hair follicle generates high oxidative stress. We therefore hypothesize that hair bulb melanocytes are especially susceptible to free radical-induced aging. To test this hypothesis, we subjected human scalp skin anagen hair follicles from graying individuals to macroscopic and immunohistomorphometric analysis and organ culture. We found evidence of melanocyte apoptosis and increased oxidative stress in the pigmentary unit of graying hair follicles. The "common" deletion, a marker mitochondrial DNA-deletion for accumulating oxidative stress damage, occurred most prominently in graying hair follicles. Cultured unpigmented hair follicles grew better than pigmented follicles of the same donors. Finally, cultured pigmented hair follicles exposed to exogenous oxidative stress (hydroquinone) showed increased melanocyte apoptosis in the hair bulb. We conclude that oxidative stress is high in hair follicle melanocytes and leads to their selective premature aging and apoptosis. The graying hair follicle, therefore, offers a unique model system to study oxidative stress and aging and to test antiaging therapeutics in their ability to slow down or even stop this process.

  10. Stereological estimation of nuclear volume in benign and malignant melanocytic lesions of the skin. Inter- and intraobserver variability of malignancy grading

    DEFF Research Database (Denmark)

    Sørensen, Flemming Brandt; Ottosen, P D

    1991-01-01

    The volume-weighted, mean nuclear volume (nuclear vv) may be estimated without any assumptions regarding nuclear shape using modern stereological techniques. As a part of an investigation concerning the prospects of nuclear vv for classification and malignancy grading of cutaneous melanocytic tum...

  11. Human Adipose Mesenchymal Cells Inhibit Melanocyte Differentiation and the Pigmentation of Human Skin via Increased Expression of TGF-β1.

    Science.gov (United States)

    Klar, Agnes S; Biedermann, Thomas; Michalak, Katarzyna; Michalczyk, Teresa; Meuli-Simmen, Claudia; Scherberich, Arnaud; Meuli, Martin; Reichmann, Ernst

    2017-12-01

    There is accumulating evidence that interactions between epidermal melanocytes and stromal cells play an important role in the regulation of skin pigmentation. In this study we established a pigmented dermo-epidermal skin model, melDESS, of human origin to investigate the effects of distinct stromal cells on melanogenesis. melDESS is a complex, clinically relevant skin equivalent composed of an epidermis containing both melanocytes and keratinocytes. Its dermal compartment consists either of adipose tissue-derived stromal cells, dermal fibroblasts (Fbs), or a mixture of both cell types. These skin substitutes were transplanted for 5 weeks on the backs of immuno-incompetent rats and analyzed. Gene expression and Western blot analyses showed a significantly higher expression of transforming growth factor-β1 by adipose tissue-derived stromal cells compared with dermal Fbs. In addition, we showed that melanocytes responded to the increased levels of transforming growth factor-β1 by down-regulating the expression of key melanogenic enzymes such as tyrosinase. This caused decreased melanin synthesis and, consequently, greatly reduced pigmentation of melDESS. The conclusions are of utmost clinical relevance, namely that adipose tissue-derived stromal cells derived from the hypodermis fail to appropriately interact with epidermal melanocytes, thus preventing the sustainable restoration of the patient's native skin color in bioengineered skin grafts. Copyright © 2017 The Authors. Published by Elsevier Inc. All rights reserved.

  12. Effects of Extremely Low Frequency Electromagnetic Fields on Melanogenesis through p-ERK and p-SAPK/JNK Pathways in Human Melanocytes

    Directory of Open Access Journals (Sweden)

    Yu-Mi Kim

    2017-10-01

    Full Text Available This study evaluated frequency-dependent effects of extremely low frequency electromagnetic fields (ELF-EMFs on melanogenesis by melanocytes in vitro. Melanocytes were exposed to 2 mT EMFs at 30–75 Hz for 3 days before melanogenesis was examined. Exposure to ELF-EMFs at 50 and 60 Hz induced melanogenic maturation without cell damage, without changing cell proliferation and mitochondrial activity. Melanin content and tyrosinase activity of cells exposed to 50 Hz were higher than in controls, and mRNA expression of tyrosinase-related protein-2 was elevated relative to controls at 50 Hz. Phosphorylated cyclic adenosine monophosphate response element-binding protein (p-CREB levels were higher than controls in cells exposed to ELF-EMFs at 50–75 Hz. Immunohistochemical staining showed that melanocyte-specific markers (HMB45, Melan-A were strongly expressed in cells exposed to EMFs at 50 and 60 Hz compared to controls. Thus, exposure to ELF-EMFs at 50 Hz could stimulate melanogenesis in melanocytes, through activation of p-CREB and p-p38 and inhibition of phosphorylated extracellular signal-regulated protein kinase and phosphorylated stress-activated protein kinase/c-Jun N-terminal kinase. The results may form the basis of an appropriate anti-gray hair treatment or be applied in a therapeutic device for inducing repigmentation in the skin of vitiligo patients.

  13. MicroRNA expression in melanocytic nevi: the usefulness of formalin-fixed, paraffin-embedded material for miRNA microarray profiling.

    Science.gov (United States)

    Glud, Martin; Klausen, Mikkel; Gniadecki, Robert; Rossing, Maria; Hastrup, Nina; Nielsen, Finn C; Drzewiecki, Krzysztof T

    2009-05-01

    MicroRNAs (miRNAs) are small, noncoding RNA molecules that regulate cellular differentiation, proliferation, and apoptosis. MiRNAs are expressed in a developmentally regulated and tissue-specific manner. Aberrant expression may contribute to pathological processes such as cancer, and miRNA may therefore serve as biomarkers that may be useful in a clinical environment for diagnosis of various diseases. Most miRNA profiling studies have used fresh tissue samples. However, in some types of cancer, including malignant melanoma, fresh material is difficult to obtain from primary tumors, and most surgical specimens are formalin fixed and paraffin embedded (FFPE). To explore whether FFPE material would be suitable for miRNA profiling in melanocytic lesions, we compared miRNA expression patterns in FFPE versus fresh frozen samples, obtained from 15 human melanocytic nevi. Out of microarray data, we identified 84 miRNAs that were expressed in both types of samples and represented an miRNA profile of melanocytic nevi. Our results showed a high correlation in miRNA expression (Spearman r-value of 0.80) between paired FFPE and fresh frozen material. The data were further validated by quantitative RT-PCR. In conclusion, FFPE specimens of melanocytic lesions are suitable as a source for miRNA microarray profiling.

  14. A de novo SOX10 mutation causing severe type 4 Waardenburg syndrome without Hirschsprung disease.

    Science.gov (United States)

    Sznajer, Yves; Coldéa, Cristina; Meire, Françoise; Delpierre, Isabelle; Sekhara, Tayeb; Touraine, Renaud L

    2008-04-15

    Type 4 Waardenburg syndrome represents a well define entity caused by neural crest derivatives anomalies (melanocytes, intrinsic ganglion cells, central, autonomous and peripheral nervous systems) leading, with variable expressivity, to pigmentary anomalies, deafness, mental retardation, peripheral neuropathy, and Hirschsprung disease. Autosomal dominant mode of inheritance is prevalent when Sox10 gene mutation is identified. We report the natural history of a child who presented with synophrys, vivid blue eye, deafness, bilateral complete semicircular canals agenesis with mental retardation, subtle signs for peripheral neuropathy and lack of Hirschsprung disease. SOX10 gene sequencing identified "de novo" splice site mutation (c.698-2A > C). The present phenotype and the genotype findings underline the wide spectrum of SOX10 gene implication in unusual type 4 Waardenburg syndrome patient. Copyright 2008 Wiley-Liss, Inc.

  15. Noncultured keratinocyte/melanocyte cosuspension: effect on reepithelialization and repigmentation--a randomized, placebo-controlled study.

    Science.gov (United States)

    Back, Christopher; Dearman, Bronwyn; Li, Amy; Neild, Tim; Greenwood, John E

    2009-01-01

    Randomized controlled trials in the literature investigating the efficacy of noncultured keratinocyte/melanocyte suspensions are scarce; however, the advocates of such techniques press the value of their application based largely on case studies and anecdote. Caucasian patients with burn hypopigmentation seldom request cosmetic revision making worthwhile clinical trials difficult so that informal case treatments with new therapies generate anecdotal results. A randomized, placebo-controlled trial was carried out to evaluate whether cosuspensions of noncultured skin cells are capable of (1) decreasing the time to reepithelialization and (2) reestablishing pigmentation in vitiligo leukoderma following epidermal/superficial dermal ablation (in the knowledge that a positive result would make the technique likely to be successful in burn hypopigmentation). Vitiligo is common and is socially more debilitating such that suitable trial subjects for new therapies from this pool are more forthcoming. This study demonstrated that suspensions of noncultured keratinocytes and melanocytes do not decrease the time to epithelialization of superficial partial thickness wounds compared with controls. It also suggested that the achievement, quality, and duration of any pigmentation were unpredictable and largely disappointing. Some pigmentation was recorded in placebo-treated areas indicating an effect of the method of epidermal ablation in these patients. These findings have mandated a complete review of the use of these techniques in burn care at the Royal Adelaide Hospital; they have been omitted from surgical protocols where the aim of use was to speed reepithelialization. Their infrequent use in burns hypopigmentation will continue contingent on the successful repigmentation of a test patch.

  16. Association of Multiple Melanocytic Naevi with Education, Sex and Skin Type. A Northern Finland Birth Cohort 1966 Study with 46 Years Follow-up.

    Science.gov (United States)

    Sinikumpu, Suvi-Päivikki; Huilaja, Laura; Jokelainen, Jari; Auvinen, Juha; Timonen, Markku; Tasanen, Kaisa

    2017-02-08

    Having multiple melanocytic naevi (sex, socioeconomic status (education) in childhood and adulthood, skin type and sunbathing habits. The prevalence of multiple melanocytic naevi was 11.6% (223/1,930). Higher education (odds ratio (OR) 2.11, 95% confidence interval (95% CI) 1.51-2.96), male sex (OR 1.48, 95% CI 1.07-2.06), sun-sensitive skin type (OR 2.09, 95% CI 1.34-3.27) and regular use of sunscreen (OR 2.03, 95% CI 1.23-3.37) were associated with increased risk of multiple naevi. Inflammatory skin diseases decreased (OR 0.49, 95 CI% 0.33-0.72) the risk of multiple naevi. In conclusion, several risk factors were found for multiple naevi among adults living in high latitudes, in Northern Finland.

  17. Melanocytic lesions in a private pathology practice. Comparison of histologic features in different tumor types with particular reference to dysplastic nevi.

    Science.gov (United States)

    Hastrup, N; Hou-Jensen, K

    1993-11-01

    This study reviews a total of 1000 melanocytic lesions--two separate 500 consecutive sample groupings from 1980 and 1989, respectively--diagnosed in a private non-hospital-associated pathology practice. Lesions were classified as lentigo simplex, congenital nevus, "common" nevus, dysplastic nevus, blue nevus, Spitz's nevus or malignant melanoma. A comparison of the two periods reveals an increase in dysplastic nevi from one in 1980 to nine in 1989. The histologic changes in these nevi were compared to those of the other tumors. Pronounced cytologic atypia was seen in the melanocytes of a few "common" nevi, but more often in the dysplastic nevi and in all of the melanomas. Slight nuclear atypia was usual in "common" nevi and lentigines, and also fibroplasia, lymphocytic infiltration, vessel proliferation and pigment incontinence were seen in both "common" nevi and dysplastic nevi. It is concluded that no single histologic variable was specific for dysplastic nevi.

  18. Fibronectin promotes differentiation of neural crest progenitors endowed with smooth muscle cell potential

    International Nuclear Information System (INIS)

    Costa-Silva, Bruno; Coelho da Costa, Meline; Melo, Fernanda Rosene; Neves, Cynara Mendes; Alvarez-Silva, Marcio; Calloni, Giordano Wosgrau; Trentin, Andrea Goncalves

    2009-01-01

    The neural crest (NC) is a model system used to investigate multipotency during vertebrate development. Environmental factors control NC cell fate decisions. Despite the well-known influence of extracellular matrix molecules in NC cell migration, the issue of whether they also influence NC cell differentiation has not been addressed at the single cell level. By analyzing mass and clonal cultures of mouse cephalic and quail trunk NC cells, we show for the first time that fibronectin (FN) promotes differentiation into the smooth muscle cell phenotype without affecting differentiation into glia, neurons, and melanocytes. Time course analysis indicated that the FN-induced effect was not related to massive cell death or proliferation of smooth muscle cells. Finally, by comparing clonal cultures of quail trunk NC cells grown on FN and collagen type IV (CLIV), we found that FN strongly increased both NC cell survival and the proportion of unipotent and oligopotent NC progenitors endowed with smooth muscle potential. In contrast, melanocytic progenitors were prominent in clonogenic NC cells grown on CLIV. Taken together, these results show that FN promotes NC cell differentiation along the smooth muscle lineage, and therefore plays an important role in fate decisions of NC progenitor cells

  19. A Macrocyclic Agouti-Related Protein/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Sub-nanomolar Melanocortin Receptor Ligands

    OpenAIRE

    Ericson, Mark D.; Freeman, Katie T.; Schnell, Sathya M.; Haskell-Luevano, Carrie

    2017-01-01

    The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4, DPhe7]α-Melanocyte Stimulating Hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp repl...

  20. A modified fluorimetric host cell reactivation assay to determine the repair capacity of primary keratinocytes, melanocytes and fibroblasts

    Directory of Open Access Journals (Sweden)

    Gebhard Daniel

    2010-06-01

    Full Text Available Abstract Background The Host Cell Reactivation Assay (HCRA is widely used to identify circumstances and substances affecting the repair capacity of cells, however, it is restricted by the transfection procedure used and the sensitivity of the detection method. Primary skin cells are particularly difficult to transfect, and therefore sensitive methods are needed to detect any variations due to the cell-type or inter-individual differences or changes induced by diverse substances. A sensitive and repeatable method to detect the repair capacity of skin cells would be useful in two different aspects: On the one hand, to identify substances influencing the repair capacity in a positive manner (these substances could be promising ingredients for cosmetic products and on the other hand, to exclude the negative effects of substances on the repair capacity (this could serve as one step further towards replacing or at least reducing animal testing. Results In this paper, we present a rapid and sensitive assay to determine the repair capacity of primary keratinocytes, melanocytes and fibroblasts based on two wave-length Green Fluorescent Protein (GFP and DsRed reporter technology in order to test different substances and their potential to influence the DNA repair capacity. For the detection of plasmid restoration, we used FACS technology, which, in comparison to luminometer technology, is highly sensitive and allows single cell based analysis. The usefulness of this assay and studying the repair capacity is demonstrated by the evidence that DNA repair is repressed by Cyclosporin A in fibroblasts. Conclusions The methodology described in this paper determines the DNA repair capacity in different types of human skin cells. The described transfection protocol is suitable for the transfection of melanocytes, keratinocytes and fibroblasts, reaching efficacies suitable for the detection of the restored plasmids by FACS technology. Therefore the repair capacity

  1. Effect of Novel Marine Nutraceuticals on IL-1α-Mediated TNF-α Release from UVB-Irradiated Human Melanocyte-Derived Cells

    Directory of Open Access Journals (Sweden)

    Visalini Muthusamy

    2011-01-01

    Full Text Available UV-induced inflammation and reactive oxygen species formation are involved in the development of melanoma. Natural products like 5β-scymnol and CO2-supercritical fluid extract (CO2-SFE of mussel oil contain anti-inflammatory and antioxidant properties that may aid in reducing the deleterious effects of UV radiation. Therefore, their effect on the release of the proinflammatory cytokine, tumour necrosis factor-α (TNF-α, from UVB-irradiated human melanocytic cells was examined. Human epidermal melanocytes (HEM and MM96L melanoma cells were exposed to UVB radiation and IL-1α. Cell viability and TNF-α levels were determined 24 hours after-irradiation while p38 mitogen-activated protein kinase (MAPK activation was observed at 15 min after-irradiation. When α-tocopherol, CO2-SFE mussel oil, and 5β-scymnol were added to the UVB-irradiated HEM cells treated with IL-1α, TNF-α levels fell by 53%, 65%, and 76%, respectively, while no inhibition was evident in MM96L cells. This effect was not due to inhibition of the intracellular p38 MAPK signalling pathway. These compounds may be useful in preventing inflammation-induced damage to normal melanocytes.

  2. Morphological neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Ritter, G.X.; Sussner, P. [Univ. of Florida, Gainesville, FL (United States)

    1996-12-31

    The theory of artificial neural networks has been successfully applied to a wide variety of pattern recognition problems. In this theory, the first step in computing the next state of a neuron or in performing the next layer neural network computation involves the linear operation of multiplying neural values by their synaptic strengths and adding the results. Thresholding usually follows the linear operation in order to provide for nonlinearity of the network. In this paper we introduce a novel class of neural networks, called morphological neural networks, in which the operations of multiplication and addition are replaced by addition and maximum (or minimum), respectively. By taking the maximum (or minimum) of sums instead of the sum of products, morphological network computation is nonlinear before thresholding. As a consequence, the properties of morphological neural networks are drastically different than those of traditional neural network models. In this paper we consider some of these differences and provide some particular examples of morphological neural network.

  3. Neural Tube Defects

    Science.gov (United States)

    Neural tube defects are birth defects of the brain, spine, or spinal cord. They happen in the ... that she is pregnant. The two most common neural tube defects are spina bifida and anencephaly. In ...

  4. Neural tissue-spheres

    DEFF Research Database (Denmark)

    Andersen, Rikke K; Johansen, Mathias; Blaabjerg, Morten

    2007-01-01

    By combining new and established protocols we have developed a procedure for isolation and propagation of neural precursor cells from the forebrain subventricular zone (SVZ) of newborn rats. Small tissue blocks of the SVZ were dissected and propagated en bloc as free-floating neural tissue...... content, thus allowing experimental studies of neural precursor cells and their niche...

  5. Towards optimization of odonto/osteogenic bioengineering: in vitro comparison of simvastatin, sodium fluoride, melanocyte-stimulating hormone.

    Science.gov (United States)

    Zijah, Vahid; Salehi, Roya; Aghazadeh, Marziyeh; Samiei, Mohammad; Alizadeh, Effat; Davaran, Soodabeh

    2017-06-01

    Tissue engineering has emerged as a potential therapeutic option for dental problems in recent years. One of the policies in tissue engineering is to use both scaffolds and additive factors for enhancing cell responses. This study aims to evaluate and compare the effect of three types of biofactors on poly-caprolactone-poly-ethylene glycol-poly caprolactone (PCL-PEG-PCL) nanofibrous scaffold on human dental pulp stem cell (hDPSCs) engineering. The PCL-PEG-PCL copolymer was synthesized with ring opening polymerization method, and its nanofiber scaffold was prepared by electrospinning method. Nanofibrous scaffold-seeded hDPSCs were treated with sodium fluoride (NaF), melanocyte-stimulating hormone (MSH), or simvastatin (SIM). Non-treated nanofiber seeded cells were utilized as control. The viability, biocompatibility, adhesion, proliferation rate, morphology, osteo/odontogenic potential, and the expression of tissue-specific genes were studied. The results showed that significant higher results demonstrated significant higher adhesive behavior, viability, alizarin red activity, and dentin specific gene expression in MSH- and SIM-treated cells (p < 0.05). This study is unique; in that, it compares the effects of different treatments for optimization of dental tissue engineering.

  6. Fluorine-18-labeled [Nle4,D-Phe7]-α-MSH, an α-melanocyte stimulating hormone analogue

    International Nuclear Information System (INIS)

    Vaidyanathan, Ganesan; Zalutsky, Michael R.

    1997-01-01

    The α-melanocyte stimulating hormone (α-MSH) analogue [N1e 4 ,D-Phe 7 ]-α-MSH was labeled with 18 F using N-succinimidyl 4-[ 18 F]fluorobenzoate ([ 18 F]SFB) in >80% radiochemical yield. The IC 50 values of [N1e 4 ,D-Phe 7 ]-α-MSH and para-fluorobenzoyl-[N1e 4 ,D-Phe 7 ]-α-MSH ([N1e 4 ,D-Phe 7 ,Lys 11 -( 18 F)PFB]-α-MSH) for inhibiting the binding of meta-[ 131 I]iodobenzoyl-[N1e 4 ,D-Phe 7 ]-α-MSH ([N1e 4 ,D-Phe 7 ,Lys 11 -( 131 I)MIB]-α-MSH) to B16-F1 murine melanoma cells were 89 ± 9 pM and 112 ± 22 pM, respectively, suggesting that addition of 4-fluorobenzoate did not compromise α-MSH receptor binding affinity. Binding of [N1e 4 ,D-Phe 7 ,Lys 11 -( 18 F)PFB]-α-MSH was influenced by the specific activity of the preparation (400-1000 Ci/mmol). The normal tissue clearance of [N1e 4 ,D-Phe 7 ,Lys 11 -( 18 F)PFB]-α-MSH in mice was quite rapid, with little evidence for defluorination

  7. Regulation of pigmentation by substrate elasticity in normal human melanocytes and melanotic MNT1 human melanoma cells.

    Science.gov (United States)

    Choi, Hyunjung; Kim, Mina; Ahn, Song Ih; Cho, Eun-Gyung; Lee, Tae Ryong; Shin, Jennifer H

    2014-03-01

    The elasticity of the cellular microenvironment is a key regulator of cellular physiology in many cell types. To investigate the effects of substrate stiffness on the pigmentation process, we cultured normal human melanocytes (NHM) and MNT1 melanoma cells on laminin-coated polydimethylsiloxane (PDMS) substrates of different stiffness. The dendricity of NHM and MNT1 cells was reduced as the substrate stiffness decreased, and the degree of melanosome transfer from NHM or MNT1 cells to normal human keratinocytes was decreased on softer substrates with the reduced dendricity. Gene and protein expressions of MITF, tyrosinase, TRP2, and gp100/PMEL17 exhibited a consistent decreasing trend with the decreasing stiffness. Because the stiffness sensing is mediated by focal adhesion complex through integrin receptors, we checked laminin specific integrin alpha 6 and p-FAK for MNT1 cells to observe that the substrate adhesion was weakened as the substrate stiffness decreased. Weaker adhesion on a softer substrate was accompanied by dynamic shape changes in MNT1 cells with higher speed and larger scattering. Dendritic MNT1 cells cultured on a stiffer substrate exhibited lower migration with smaller root mean squared displacement. These results demonstrate the possibility that skin pigmentation can be influenced by mechanical properties of the cellular microenvironment and can increase when the skin becomes stiff. © 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

  8. Long-term follow-up of patients undergoing autologous noncultured melanocyte-keratinocyte transplantation for vitiligo and other leukodermas.

    Science.gov (United States)

    Silpa-Archa, Narumol; Griffith, James L; Huggins, Richard H; Henderson, Marsha D; Kerr, Holly A; Jacobsen, Gordon; Mulekar, Sanjeev V; Lim, Henry W; Hamzavi, Iltefat H

    2017-08-01

    Persistence of pigmentation after a melanocyte-keratinocyte transplantation procedure (MKTP) is an important consideration for efficacy. We sought to determine long-term repigmentation of MKTP in vitiligo and other leukodermas. A retrospective review of electronic medical records was conducted for all MKTPs performed at Henry Ford Hospital between January 2009 and April 2014. Repigmentation was assessed by a 5-point grading scale (poor to excellent) and Vitiligo Area Scoring Index (VASI). One hundred patients had MKTP performed at 236 anatomically-based lesions (ABLs); 63 patients with 157 ABLs had long-term data available (12-72 months; median, 24 months). Segmental vitiligo, nonsegmental vitiligo, and physical leukoderma demonstrated improvement in VASI scores: -75.6 ± 24.6%, -59.2 ± 36.6%, and -32.4 ± 33.5%, respectively. In vitiligo, at 24, 48, and 72 months after MKTP, 53%, 64%, and 53% of ABLs, respectively, maintained >75% repigmentation. Skin phototype, age, and anatomic location of ABLs had no significant effect on the outcome of treatment. Limitations of the study include the retrospective design with uncontrolled, postoperative adjuvant treatments and inconsistent compliance to scheduled follow-up evaluations. MKTP provides satisfactory long-term repigmentation in the majority of appropriately selected patients with leukoderma. MKTP can maintain repigmentation for at least 72 months. Copyright © 2017. Published by Elsevier Inc.

  9. Combined fluorescence-Raman spectroscopy measurements with an optical fiber probe for the diagnosis of melanocytic lesions

    Science.gov (United States)

    Cosci, Alessandro; Cicchi, Riccardo; Rossari, Susanna; De Giorgi, Vincenzo; Massi, Daniela; Pavone, Francesco S.

    2012-02-01

    We have designed and developed an optical fiber-probe for spectroscopic measurements on human tissues. The experimental setup combines fluorescence spectroscopy and Raman spectroscopy in a multidimensional approach. Concerning fluorescence spectroscopy, the excitation is provided by two laser diodes, one emitting in the UV (378 nm) and the other emitting in the visible (445 nm). These two lasers are used to selectively excite fluorescence from NADH and FAD, which are among the brightest endogenous fluorophores in human tissues. For Raman and NIR spectroscopy, the excitation is provided by a third laser diode with 785 nm excitation wavelength. Laser light is delivered to the tissue through the central optical fiber of a fiber bundle. The surrounding 48 fibers of the bundle are used for collecting fluorescence and Raman and for delivering light to the spectrograph. Fluorescence and Raman spectra are acquired on a cooled CCD camera. The instrument has been tested on fresh human skin biopsies clinically diagnosed as malignant melanoma, melanocytic nevus, or healthy skin, finding an optimal correlation with the subsequent histological exam. In some cases our examination was not in agreement with the clinical observation, but it was with the histological exam, demonstrating that the system can potentially contribute to improve clinical diagnostic capabilities and hence reduce the number of unnecessary biopsies.

  10. Neural electrical activity and neural network growth.

    Science.gov (United States)

    Gafarov, F M

    2018-05-01

    The development of central and peripheral neural system depends in part on the emergence of the correct functional connectivity in its input and output pathways. Now it is generally accepted that molecular factors guide neurons to establish a primary scaffold that undergoes activity-dependent refinement for building a fully functional circuit. However, a number of experimental results obtained recently shows that the neuronal electrical activity plays an important role in the establishing of initial interneuronal connections. Nevertheless, these processes are rather difficult to study experimentally, due to the absence of theoretical description and quantitative parameters for estimation of the neuronal activity influence on growth in neural networks. In this work we propose a general framework for a theoretical description of the activity-dependent neural network growth. The theoretical description incorporates a closed-loop growth model in which the neural activity can affect neurite outgrowth, which in turn can affect neural activity. We carried out the detailed quantitative analysis of spatiotemporal activity patterns and studied the relationship between individual cells and the network as a whole to explore the relationship between developing connectivity and activity patterns. The model, developed in this work will allow us to develop new experimental techniques for studying and quantifying the influence of the neuronal activity on growth processes in neural networks and may lead to a novel techniques for constructing large-scale neural networks by self-organization. Copyright © 2018 Elsevier Ltd. All rights reserved.

  11. Chaotic diagonal recurrent neural network

    International Nuclear Information System (INIS)

    Wang Xing-Yuan; Zhang Yi

    2012-01-01

    We propose a novel neural network based on a diagonal recurrent neural network and chaos, and its structure and learning algorithm are designed. The multilayer feedforward neural network, diagonal recurrent neural network, and chaotic diagonal recurrent neural network are used to approach the cubic symmetry map. The simulation results show that the approximation capability of the chaotic diagonal recurrent neural network is better than the other two neural networks. (interdisciplinary physics and related areas of science and technology)

  12. Comparative Functional Alanine Positional Scanning of the α-Melanocyte Stimulating Hormone and NDP-Melanocyte Stimulating Hormone Demonstrates Differential Structure-Activity Relationships at the Mouse Melanocortin Receptors.

    Science.gov (United States)

    Todorovic, Aleksandar; Ericson, Mark D; Palusak, Ryan D; Sorensen, Nicholas B; Wood, Michael S; Xiang, Zhimin; Haskell-Luevano, Carrie

    2016-07-20

    The melanocortin system has been implicated in the regulation of various physiological functions including melanogenesis, steroidogenesis, energy homeostasis, and feeding behavior. Five melanocortin receptors have been identified to date and belong to the family of G protein-coupled receptors (GPCR). Post-translational modification of the proopiomelanocortin (POMC) prohormone leads to the biosynthesis of the endogenous melanocortin agonists, including α-melanocyte stimulating hormone (α-MSH), β-MSH, γ-MSH, and adrenocorticotropic hormone (ACTH). All the melanocortin agonists derived from the POMC prohormone contain a His-Phe-Arg-Trp tetrapeptide sequence that has been implicated in eliciting the pharmacological responses at the melanocortin receptors. Herein, an alanine (Ala) positional scan is reported for the endogenous α-MSH ligand and the synthetic, more potent, NDP-MSH peptide (Ac-Ser(1)-Tyr(2)-Ser(3)-Nle(4)-Glu(5)-His(6)-DPhe(7)-Arg(8)-Trp(9)-Gly(10)-Lys(11)-Pro(12)-Val(13)-NH2) at the cloned mouse melanocortin receptors to test the assumption that the structure-activity relationships of one ligand would apply to the other. Several residues outside of the postulated pharmacophore altered potency at the melanocortin receptors, most notably the 1560-, 37-, and 15-fold potency loss when the Glu(5) position of α-MSH was substituted with Ala at the mMC1R, mMC3R, and mMC4R, respectively. Importantly, the altered potencies due to Ala substitutions in α-MSH did not necessarily correlate with equivalent Ala substitutions in NDP-MSH, indicating that structural modifications and corresponding biological activities in one of these melanocortin ligands may not be predictive for the other agonist.

  13. Evolvable Neural Software System

    Science.gov (United States)

    Curtis, Steven A.

    2009-01-01

    The Evolvable Neural Software System (ENSS) is composed of sets of Neural Basis Functions (NBFs), which can be totally autonomously created and removed according to the changing needs and requirements of the software system. The resulting structure is both hierarchical and self-similar in that a given set of NBFs may have a ruler NBF, which in turn communicates with other sets of NBFs. These sets of NBFs may function as nodes to a ruler node, which are also NBF constructs. In this manner, the synthetic neural system can exhibit the complexity, three-dimensional connectivity, and adaptability of biological neural systems. An added advantage of ENSS over a natural neural system is its ability to modify its core genetic code in response to environmental changes as reflected in needs and requirements. The neural system is fully adaptive and evolvable and is trainable before release. It continues to rewire itself while on the job. The NBF is a unique, bilevel intelligence neural system composed of a higher-level heuristic neural system (HNS) and a lower-level, autonomic neural system (ANS). Taken together, the HNS and the ANS give each NBF the complete capabilities of a biological neural system to match sensory inputs to actions. Another feature of the NBF is the Evolvable Neural Interface (ENI), which links the HNS and ANS. The ENI solves the interface problem between these two systems by actively adapting and evolving from a primitive initial state (a Neural Thread) to a complicated, operational ENI and successfully adapting to a training sequence of sensory input. This simulates the adaptation of a biological neural system in a developmental phase. Within the greater multi-NBF and multi-node ENSS, self-similar ENI s provide the basis for inter-NBF and inter-node connectivity.

  14. Effects of alpha-melanocyte-stimulating hormone on mitochondrial energy metabolism in rats of different age-groups.

    Science.gov (United States)

    Feichtinger, René G; Pétervári, Erika; Zopf, Michaela; Vidali, Silvia; Aminzadeh-Gohari, Sepideh; Mayr, Johannes A; Kofler, Barbara; Balaskó, Márta

    2017-08-01

    Hypothalamic alpha-melanocyte-stimulating hormone (α-MSH) is a key catabolic mediator of energy homeostasis. Its anorexigenic and hypermetabolic effects show characteristic age-related alterations that may be part of the mechanism of middle-aged obesity and geriatric anorexia/cachexia seen in humans and other mammals. We aimed to investigate the role of α-MSH in mitochondrial energy metabolism during the course of aging in a rodent model. To determine the role of α-MSH in mitochondrial energy metabolism in muscle, we administered intracerebroventricular (ICV) infusions of α-MSH for 7-days to different age-groups of male Wistar rats. The activities of oxidative phosphorylation complexes I to V and citrate synthase were determined and compared to those of age-matched controls. We also quantified mitochondrial DNA (mtDNA) copy number and measured the expression of the master regulators of mitochondrial biogenesis, peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) and peroxisome proliferator-activated receptor gamma (PPARγ). The peptide reduced weight gain in juvenile rats to one fifth of that of controls and increased the weight loss in older animals by about five fold. Mitochondrial DNA copy number inversely correlated with changes in body weight in controls, but not in α-MSH-treated animals. The strong increase in body weight in young rats was associated with a low mtDNA copy number and high PPARγ mRNA levels in controls. Expression of PGC-1α and PPARγ declined with age, whereas OXPHOS and citrate synthase enzyme activities were unchanged. In contrast, α-MSH treatment suppressed OXPHOS enzyme and citrate synthase activity. In conclusion, our results showed age-related differences in the metabolic effects of α-MSH. In addition, administration of α-MSH suppressed citrate synthase and OXPHOS activities independent of age. These findings suggest that α-MSH exposure may inhibit mitochondrial biogenesis. Copyright © 2016 Elsevier

  15. Alpha-Melanocyte Stimulating Hormone Protects against Cytokine-Induced Barrier Damage in Caco-2 Intestinal Epithelial Monolayers.

    Directory of Open Access Journals (Sweden)

    Judit Váradi

    Full Text Available Alpha-melanocyte-stimulating hormone (α-MSH is a potent anti-inflammatory peptide with cytoprotective effect in various tissues. The present investigation demonstrates the ability of α-MSH to interact with intestinal epithelial cell monolayers and mitigate inflammatory processes of the epithelial barrier. The protective effect of α-MSH was studied on Caco-2 human intestinal epithelial monolayers, which were disrupted by exposure to tumor necrosis factor-α and interleukin-1β. The barrier integrity was assessed by measuring transepithelial electric resistance (TEER and permeability for marker molecules. Caco-2 monolayers were evaluated by immunohistochemistry for expression of melanocortin-1 receptor and tight junction proteins ZO-1 and claudin-4. The activation of nuclear factor kappa beta (NF-κB was detected by fluorescence microscopy and inflammatory cytokine expression was assessed by flow cytometric bead array cytokine assay. Exposure of Caco-2 monolayers to proinflammatory cytokines lowered TEER and increased permeability for fluorescein and albumin, which was accompanied by changes in ZO-1 and claudin-4 immunostaining. α-MSH was able to prevent inflammation-associated decrease of TEER in a dose-dependent manner and reduce the increased permeability for paracellular marker fluorescein. Further immunohistochemistry analysis revealed proinflammatory cytokine induced translocation of the NF-κB p65 subunit into Caco-2 cell nuclei, which was inhibited by α-MSH. As a result the IL-6 and IL-8 production of Caco-2 monolayers were also decreased with different patterns by the addition of α-MSH to the culture medium. In conclusion, Caco-2 cells showed a positive immunostaining for melanocortin-1 receptor and α-MSH protected Caco-2 cells against inflammatory barrier dysfunction and inflammatory activation induced by tumor necrosis factor-α and interleukin-1β cytokines.

  16. Number and size of acquired melanocytic nevi and affecting risk factors in cases admitted to the dermatology clinic

    Directory of Open Access Journals (Sweden)

    Ayşegül Yalçınkaya İyidal

    2016-10-01

    Full Text Available Introduction: The size and number of acquired melanocytic nevi (AMN and presence of dysplastic nevi are the leading risk factors that should be recognized in the development of malignant melanoma. Aim: To evaluate AMN and risk factors in the development of AMN in all age groups admitted to a dermatology outpatient clinic. Material and methods : Four hundred and twelve patients who were admitted to the dermatology outpatient clinic for any dermatological symptom and who accepted to participate in the study were randomly included in the study. For each case, background-family history and dermatological findings were recorded. All AMN observed in the patients were dermatoscopically examined. Results : The presence of more than 50 nevi was significantly higher in males, in individuals who had a history of sunburn and smokers. The number of nevi that were 5 mm and below was found to be higher in individuals who regularly sunbathed their face/body, in individuals using sunscreen, in individuals who had a history of sunburn, smokers and alcohol users. The number of nevi that were above 5 mm was higher in smokers. The total dermatoscopy score between 4.75 and 5.45 was found to be higher in individuals who had more than 50 nevi, in individuals exposed to more than one chemical substance and in alcohol users. Conclusions : When determining the patient’s risk factors, factors such as the patient’s sunbathing habits and chemical substance exposure features should be taken into consideration besides the number and size of nevi.

  17. Spontaneous CD8 T cell responses against the melanocyte differentiation antigen RAB38/NY-MEL-1 in melanoma patients.

    Science.gov (United States)

    Walton, Senta M; Gerlinger, Marco; de la Rosa, Olga; Nuber, Natko; Knights, Ashley; Gati, Asma; Laumer, Monika; Strauss, Laura; Exner, Carolin; Schäfer, Niklaus; Urosevic, Mirjana; Dummer, Reinhard; Tiercy, Jean-Marie; Mackensen, Andreas; Jaeger, Elke; Lévy, Frédéric; Knuth, Alexander; Jäger, Dirk; Zippelius, Alfred

    2006-12-01

    The melanocyte differentiation Ag RAB38/NY-MEL-1 was identified by serological expression cloning (SEREX) and is expressed in the vast majority of melanoma lesions. The immunogenicity of RAB38/NY-MEL-1 has been corroborated previously by the frequent occurrence of specific Ab responses in melanoma patients. To elucidate potential CD8 T cell responses, we applied in vitro sensitization with overlapping peptides spanning the RAB38/NY-MEL-1 protein sequence and the reverse immunology approach. The identified peptide RAB38/NY-MEL-1(50-58) exhibited a marked response in ELISPOT assays after in vitro sensitization of CD8 T cells from HLA-A *0201(+) melanoma patients. In vitro digestion assays using purified proteasomes provided evidence of natural processing of RAB38/NY-MEL-1(50-58) peptide. Accordingly, monoclonal RAB38/NY-MEL-1(50-58)-specific T cell populations were capable of specifically recognizing HLA-A2(+) melanoma cell lines expressing RAB38/NY-MEL-1. Applying fluorescent HLA-A2/RAB38/NY-MEL-1(50-58) multimeric constructs, we were able to document a spontaneously developed memory/effector CD8 T cell response against this peptide in a melanoma patient. To elucidate the Ag-processing pathway, we demonstrate that RAB38/NY-MEL-1(50-58) is produced efficiently by the standard proteasome and the immunoproteasome. In addition to the identification of a RAB38/NY-MEL-1-derived immunogenic CD8 T cell epitope, this study is instrumental for both the onset and monitoring of future RAB38/NY-MEL-1-based vaccination trials.

  18. Single treatment with 100-microsecond alexandrite laser clears selected acquired melanocytic nevi in type IV asian facial skin

    Directory of Open Access Journals (Sweden)

    Etienne CE Wang

    2013-01-01

    Full Text Available Context: Small common acquired melanocytic nevi (AMNs are common on Asian facial skin. Aims: To show that the 755 nm Alexandrite laser stacked at the 100-μs long-pulsed mode (μsAL is an effective modality for the removal of selected AMNs. Settings and Design: This was a retrospective case series, followed up with a telephone interview. Materials and Methods: A retrospective analysis of all patients treated between January 2010 and April 2012 with the μsAL laser for small AMNs was conducted. Pre- and post-treatment facial photographs and photographs of the individual lesions were analyzed by two independent dermatological surgeons for degree of clearance and complications. A telephone interview was conducted with the patients to assess their satisfaction with the procedure. Results: A total of 18 patients with 53 lesions were included. 7/18 (38.9% of patients had ′excellent′ results. No patients had ′mild′ or ′poor′ results. At 4 week post-treatment, 49/53 (92.5% were totally cleared, with 14/53 (26.4% reporting mild atrophy, and 11/53 (20.8% reporting mild post-inflammatory hypopigmentation. The majority of lesions had negligible complications. 9/18 (50% judged the procedure to be ′excellent′, and all patients reported that they would recommend this procedure to a friend seeking removal of small facial AMNs. Conclusion: The μsAL is an effective modality for the removal of small facial AMNs.

  19. A neural flow estimator

    DEFF Research Database (Denmark)

    Jørgensen, Ivan Harald Holger; Bogason, Gudmundur; Bruun, Erik

    1995-01-01

    This paper proposes a new way to estimate the flow in a micromechanical flow channel. A neural network is used to estimate the delay of random temperature fluctuations induced in a fluid. The design and implementation of a hardware efficient neural flow estimator is described. The system...... is implemented using switched-current technique and is capable of estimating flow in the μl/s range. The neural estimator is built around a multiplierless neural network, containing 96 synaptic weights which are updated using the LMS1-algorithm. An experimental chip has been designed that operates at 5 V...

  20. Neural Systems Laboratory

    Data.gov (United States)

    Federal Laboratory Consortium — As part of the Electrical and Computer Engineering Department and The Institute for System Research, the Neural Systems Laboratory studies the functionality of the...

  1. A pilot study to image the vascular network of small melanocytic choroidal tumors with speckle noise-free 1050-nm swept source optical coherence tomography (OCT choroidal angiography).

    Science.gov (United States)

    Maloca, Peter; Gyger, Cyrill; Hasler, Pascal W

    2016-06-01

    To visualize and measure the vascular network of melanocytic choroidal tumors with speckle noise-free swept source optical coherence tomography (SS-OCT choroidal angiography). Melanocytic choroidal tumors from 24 eyes were imaged with 1050-nm optical coherence tomography (Topcon DRI OCT-1 Atlantis). A semi-automated algorithm was developed to remove speckle noise and to extract and measure the volume of the choroidal vessels from the obtained OCT data. In all cases, analysis of the choroidal vessels could be performed with SS-OCT without the need for pupillary dilation. The proposed method allows speckle noise-free, structure-guided visualization and measurement of the larger choroidal vessels in three dimensions. The obtained data suggest that speckle noise-free OCT may be more effective at identifying choroidal structures than traditional OCT methods. The measured volume of the extracted choroidal vessels of Haller's layer and Sattler's layer in the examined tumorous eyes was on average 0.982463955 mm(3) /982463956 μm(3) (range of 0.209764406 mm(3) /209764405.9 μm(3)to 1.78105544 mm(3) /1781055440 μm(3)). Full thickness obstruction of the choroidal vasculature by the tumor was found in 18 cases (72 %). In seven cases (18 %), choroidal vessel architecture did not show pronounced morphological abnormalities (18 %). Speckle noise-free OCT may serve as a new illustrative imaging technology and enhance visualization of the choroidal vessels without the need for dye injection. OCT can be used to identify and evaluate the choroidal vessels of melanocytic choroidal tumors, and may represent a potentially useful tool for imaging and monitoring of choroidal nevi and melanoma.

  2. Neural Networks: Implementations and Applications

    OpenAIRE

    Vonk, E.; Veelenturf, L.P.J.; Jain, L.C.

    1996-01-01

    Artificial neural networks, also called neural networks, have been used successfully in many fields including engineering, science and business. This paper presents the implementation of several neural network simulators and their applications in character recognition and other engineering areas

  3. Critical Branching Neural Networks

    Science.gov (United States)

    Kello, Christopher T.

    2013-01-01

    It is now well-established that intrinsic variations in human neural and behavioral activity tend to exhibit scaling laws in their fluctuations and distributions. The meaning of these scaling laws is an ongoing matter of debate between isolable causes versus pervasive causes. A spiking neural network model is presented that self-tunes to critical…

  4. Consciousness and neural plasticity

    DEFF Research Database (Denmark)

    changes or to abandon the strong identity thesis altogether. Were one to pursue a theory according to which consciousness is not an epiphenomenon to brain processes, consciousness may in fact affect its own neural basis. The neural correlate of consciousness is often seen as a stable structure, that is...

  5. Fluorescence-Activated Cell Sorting of EGFP-Labeled Neural Crest Cells From Murine Embryonic Craniofacial Tissue

    Directory of Open Access Journals (Sweden)

    Saurabh Singh

    2005-01-01

    Full Text Available During the early stages of embryogenesis, pluripotent neural crest cells (NCC are known to migrate from the neural folds to populate multiple target sites in the embryo where they differentiate into various derivatives, including cartilage, bone, connective tissue, melanocytes, glia, and neurons of the peripheral nervous system. The ability to obtain pure NCC populations is essential to enable molecular analyses of neural crest induction, migration, and/or differentiation. Crossing Wnt1-Cre and Z/EG transgenic mouse lines resulted in offspring in which the Wnt1-Cre transgene activated permanent EGFP expression only in NCC. The present report demonstrates a flow cytometric method to sort and isolate populations of EGFP-labeled NCC. The identity of the sorted neural crest cells was confirmed by assaying expression of known marker genes by TaqMan Quantitative Real-Time Polymerase Chain Reaction (QRT-PCR. The molecular strategy described in this report provides a means to extract intact RNA from a pure population of NCC thus enabling analysis of gene expression in a defined population of embryonic precursor cells critical to development.

  6. Gallium-67-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide for primary and metastatic melanoma imaging.

    Science.gov (United States)

    Guo, Haixun; Yang, Jianquan; Shenoy, Nalini; Miao, Yubin

    2009-12-01

    The purpose of this study was to examine the melanoma imaging properties of a novel 67Ga-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A lactam bridge-cyclized alpha-MSH peptide, DOTA-GlyGlu-CycMSH {DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp]}, was synthesized and radiolabeled with 67Ga. The melanoma targeting and pharmacokinetic properties of 67Ga-DOTA-GlyGlu-CycMSH were determined in B16/F1 flank primary melanoma-bearing and B16/F10 pulmonary metastatic melanoma-bearing C57 mice. Flank primary melanoma and pulmonary metastatic melanoma imaging were performed by small animal single photon emission computed tomography (SPECT)/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe. 67Ga-DOTA-GlyGlu-CycMSH was readily prepared with greater than 95% radiolabeling yield. 67Ga-DOTA-GlyGlu-CycMSH exhibited substantial tumor uptake (12.93 +/- 1.63%ID/g at 2 h postinjection) and prolonged tumor retention (5.02 +/- 1.35%ID/g at 24 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<0.30%ID/g) except for the kidneys at 2, 4, and 24 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited significantly (p < 0.05) higher uptakes (1.44 +/- 0.75%ID/g at 2 h postinjection and 1.49 +/- 0.69%ID/g at 4 h postinjection) in metastatic melanoma-bearing lung than those in normal lung (0.15 +/- 0.10%ID/g and 0.17 +/- 0.11%ID/g at 2 and 4 h postinjection, respectively). Both flank primary B16/F1 melanoma and B16/F10 pulmonary melanoma metastases were clearly visualized by SPECT/CT using 67Ga-DOTA-GlyGlu-CycMSH as an imaging probe 2 h postinjection. 67Ga-DOTA-GlyGlu-CycMSH exhibited favorable melanoma targeting and imaging properties, highlighting its potential as an effective imaging probe for early detection of primary and metastatic melanoma.

  7. Reducing renal uptake of 9Y- and 177Lu-labeled alpha-melanocyte stimulating hormone peptide analogues

    International Nuclear Information System (INIS)

    Miao Yubin; Fisher, Darrell R.; Quinn, Thomas P.

    2006-01-01

    Objective: The purpose of this study was to improve the tumor-to-kidney uptake ratios of 9 Y- and 177 Lu-[1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Re-Cys 3,4,1 , D-Phe 7 , Arg 11 ]α-melanocyte stimulating hormone 3-13 {DOTA-Re(Arg 11 )CCMSH} through coupling a negatively charged glutamic acid (Glu) to the peptide sequence. Methods: A new peptide of DOTA-Re(Glu 2 , Arg 11 )CCMSH was designed, synthesized and labeled with 9 Y and 177 Lu. Pharmacokinetics of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH was determined in B16/F1 murine melanoma-bearing C57 mice. Results: 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH exhibited significantly (P 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The renal uptake values of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH were 28.16% and 28.81% of those of 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH, respectively, at 4 h postinjection. 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH displayed higher tumor-to-kidney uptake ratios than 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH at 30 min and at 2, 4 and 24 h after dose administration. The tumor-to-kidney uptake ratio of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH was 2.28 and 1.69 times of 9 Y- and 177 Lu-DOTA-Re(Arg 11 )CCMSH, respectively, at 4 h postinjection. The 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH activity accumulation was low in normal organs except for kidney. Conclusions: Coupling a negatively charged amino acid (Glu) to the CCMSH peptide sequence dramatically reduced the renal uptake values and increased the tumor-to-kidney uptake ratios of 9 Y- and 177 Lu-DOTA-Re(Glu 2 , Arg 11 )CCMSH, facilitating their potential applications as radiopharmaceuticals for targeted radionuclide therapy of melanoma

  8. 3D co-cultures of keratinocytes and melanocytes and cytoprotective effects on keratinocytes against reactive oxygen species by insect virus-derived protein microcrystals

    International Nuclear Information System (INIS)

    Shimabukuro, Junji; Yamaoka, Ayako; Murata, Ken-ichi; Kotani, Eiji; Hirano, Tomoko; Nakajima, Yumiko; Matsumoto, Goichi; Mori, Hajime

    2014-01-01

    Stable protein microcrystals called polyhedra are produced by certain insect viruses. Cytokines, such as fibroblast growth factors (FGFs), can be immobilized within polyhedra. Here, we investigated three-dimensional (3D) co-cultures of keratinocytes and melanocytes on collagen gel containing FGF-2 and FGF-7 polyhedra. Melanocytes were observed to reside at the base of the 3D cell culture and melanin was also typically observed in the lower layer. The 3D cell culture model with FGF-2 and FGF-7 polyhedra was a useful in vitro model of the epidermis due to effective melanogenesis, proliferation and differentiation of keratinocytes. FGF-7 polyhedra showed a potent cytoprotective effect when keratinocytes were treated with menadione, which is a generator of reactive oxygen species. The cytoprotective effect was activated by the inositol triphosphate kinase–Akt pathway leading to upregulation of the antioxidant enzymes superoxide dismutase and peroxiredoxin 6. - Highlights: • 3D cultures using FGF-2 and FGF-7 microcrystals as a human skin model • Cytoprotection of keratinocytes against ROS by FGF-7 microcrystals • Overexpression of SOD and Prdx6 in keratinocytes by FGF-7 microcrystals

  9. 3D co-cultures of keratinocytes and melanocytes and cytoprotective effects on keratinocytes against reactive oxygen species by insect virus-derived protein microcrystals

    Energy Technology Data Exchange (ETDEWEB)

    Shimabukuro, Junji; Yamaoka, Ayako; Murata, Ken-ichi [Department of Applied Biology, Kyoto Institute of Technology, Kyoto (Japan); Kotani, Eiji [Department of Applied Biology, Kyoto Institute of Technology, Kyoto (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Kyoto (Japan); Hirano, Tomoko [Venture Laboratory, Kyoto Institute of Technology, Kyoto (Japan); Nakajima, Yumiko [Functional Genomics Group, COMB, Tropical Biosphere Research Center, University of the Ryukyus, Okinawa (Japan); Matsumoto, Goichi [Division of Oral Surgery, Yokohama Clinical Education Center of Kanagawa Dental University, Yokohama (Japan); Mori, Hajime, E-mail: hmori@kit.ac.jp [Department of Applied Biology, Kyoto Institute of Technology, Kyoto (Japan); Insect Biomedical Research Center, Kyoto Institute of Technology, Kyoto (Japan)

    2014-09-01

    Stable protein microcrystals called polyhedra are produced by certain insect viruses. Cytokines, such as fibroblast growth factors (FGFs), can be immobilized within polyhedra. Here, we investigated three-dimensional (3D) co-cultures of keratinocytes and melanocytes on collagen gel containing FGF-2 and FGF-7 polyhedra. Melanocytes were observed to reside at the base of the 3D cell culture and melanin was also typically observed in the lower layer. The 3D cell culture model with FGF-2 and FGF-7 polyhedra was a useful in vitro model of the epidermis due to effective melanogenesis, proliferation and differentiation of keratinocytes. FGF-7 polyhedra showed a potent cytoprotective effect when keratinocytes were treated with menadione, which is a generator of reactive oxygen species. The cytoprotective effect was activated by the inositol triphosphate kinase–Akt pathway leading to upregulation of the antioxidant enzymes superoxide dismutase and peroxiredoxin 6. - Highlights: • 3D cultures using FGF-2 and FGF-7 microcrystals as a human skin model • Cytoprotection of keratinocytes against ROS by FGF-7 microcrystals • Overexpression of SOD and Prdx6 in keratinocytes by FGF-7 microcrystals.

  10. Interleukins 1alpha and 1beta secreted by some melanoma cell lines strongly reduce expression of MITF-M and melanocyte differentiation antigens.

    Science.gov (United States)

    Kholmanskikh, Olga; van Baren, Nicolas; Brasseur, Francis; Ottaviani, Sabrina; Vanacker, Julie; Arts, Nathalie; van der Bruggen, Pierre; Coulie, Pierre; De Plaen, Etienne

    2010-10-01

    We report that melanoma cell lines expressing the interleukin-1 receptor exhibit 4- to 10-fold lower levels of mRNA of microphthalmia-associated transcription factor (MITF-M) when treated with interleukin-1beta. This effect is NF-kappaB and JNK-dependent. MITF-M regulates the expression of melanocyte differentiation genes such as MLANA, tyrosinase and gp100, which encode antigens recognized on melanoma cells by autologous cytolytic T lymphocytes. Accordingly, treating some melanoma cells with IL-1beta reduced by 40-100% their ability to activate such antimelanoma cytolytic T lymphocytes. Finally, we observed large amounts of biologically active IL-1alpha or IL-1beta secreted by two melanoma cell lines that did not express MITF-M, suggesting an autocrine MITF-M downregulation. We estimate that approximately 13% of melanoma cell lines are MITF-M-negative and secrete IL-1 cytokines. These results indicate that the repression of melanocyte-differentiation genes by IL-1 produced by stromal cells or by tumor cells themselves may represent an additional mechanism of melanoma immune escape.

  11. Dynamics of neural cryptography.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-05-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

  12. Dynamics of neural cryptography

    International Nuclear Information System (INIS)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-01-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible

  13. Dynamics of neural cryptography

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Kanter, Ido

    2007-05-01

    Synchronization of neural networks has been used for public channel protocols in cryptography. In the case of tree parity machines the dynamics of both bidirectional synchronization and unidirectional learning is driven by attractive and repulsive stochastic forces. Thus it can be described well by a random walk model for the overlap between participating neural networks. For that purpose transition probabilities and scaling laws for the step sizes are derived analytically. Both these calculations as well as numerical simulations show that bidirectional interaction leads to full synchronization on average. In contrast, successful learning is only possible by means of fluctuations. Consequently, synchronization is much faster than learning, which is essential for the security of the neural key-exchange protocol. However, this qualitative difference between bidirectional and unidirectional interaction vanishes if tree parity machines with more than three hidden units are used, so that those neural networks are not suitable for neural cryptography. In addition, the effective number of keys which can be generated by the neural key-exchange protocol is calculated using the entropy of the weight distribution. As this quantity increases exponentially with the system size, brute-force attacks on neural cryptography can easily be made unfeasible.

  14. ANT Advanced Neural Tool

    Energy Technology Data Exchange (ETDEWEB)

    Labrador, I.; Carrasco, R.; Martinez, L.

    1996-07-01

    This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs.

  15. ANT Advanced Neural Tool

    International Nuclear Information System (INIS)

    Labrador, I.; Carrasco, R.; Martinez, L.

    1996-01-01

    This paper describes a practical introduction to the use of Artificial Neural Networks. Artificial Neural Nets are often used as an alternative to the traditional symbolic manipulation and first order logic used in Artificial Intelligence, due the high degree of difficulty to solve problems that can not be handled by programmers using algorithmic strategies. As a particular case of Neural Net a Multilayer Perception developed by programming in C language on OS9 real time operating system is presented. A detailed description about the program structure and practical use are included. Finally, several application examples that have been treated with the tool are presented, and some suggestions about hardware implementations. (Author) 15 refs

  16. Hidden neural networks

    DEFF Research Database (Denmark)

    Krogh, Anders Stærmose; Riis, Søren Kamaric

    1999-01-01

    A general framework for hybrids of hidden Markov models (HMMs) and neural networks (NNs) called hidden neural networks (HNNs) is described. The article begins by reviewing standard HMMs and estimation by conditional maximum likelihood, which is used by the HNN. In the HNN, the usual HMM probability...... parameters are replaced by the outputs of state-specific neural networks. As opposed to many other hybrids, the HNN is normalized globally and therefore has a valid probabilistic interpretation. All parameters in the HNN are estimated simultaneously according to the discriminative conditional maximum...... likelihood criterion. The HNN can be viewed as an undirected probabilistic independence network (a graphical model), where the neural networks provide a compact representation of the clique functions. An evaluation of the HNN on the task of recognizing broad phoneme classes in the TIMIT database shows clear...

  17. Neural networks for aircraft control

    Science.gov (United States)

    Linse, Dennis

    1990-01-01

    Current research in Artificial Neural Networks indicates that networks offer some potential advantages in adaptation and fault tolerance. This research is directed at determining the possible applicability of neural networks to aircraft control. The first application will be to aircraft trim. Neural network node characteristics, network topology and operation, neural network learning and example histories using neighboring optimal control with a neural net are discussed.

  18. Active Neural Localization

    OpenAIRE

    Chaplot, Devendra Singh; Parisotto, Emilio; Salakhutdinov, Ruslan

    2018-01-01

    Localization is the problem of estimating the location of an autonomous agent from an observation and a map of the environment. Traditional methods of localization, which filter the belief based on the observations, are sub-optimal in the number of steps required, as they do not decide the actions taken by the agent. We propose "Active Neural Localizer", a fully differentiable neural network that learns to localize accurately and efficiently. The proposed model incorporates ideas of tradition...

  19. Neural cryptography with feedback.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Shacham, Lanir; Kanter, Ido

    2004-04-01

    Neural cryptography is based on a competition between attractive and repulsive stochastic forces. A feedback mechanism is added to neural cryptography which increases the repulsive forces. Using numerical simulations and an analytic approach, the probability of a successful attack is calculated for different model parameters. Scaling laws are derived which show that feedback improves the security of the system. In addition, a network with feedback generates a pseudorandom bit sequence which can be used to encrypt and decrypt a secret message.

  20. Evaluation of a novel Arg-Gly-Asp-conjugated α-melanocyte stimulating hormone hybrid peptide for potential melanoma therapy.

    Science.gov (United States)

    Yang, Jianquan; Guo, Haixun; Gallazzi, Fabio; Berwick, Marianne; Padilla, R Steven; Miao, Yubin

    2009-08-19

    The purpose of this study was to determine whether Arg-Gly-Asp (RGD)-conjugated α-melanocyte stimulating hormone (α-MSH) hybrid peptide could be employed to target melanocortin-1 (MC1) receptor for potential melanoma therapy. The RGD motif {cyclic(Arg-Gly-Asp-DTyr-Asp)} was coupled to [Cys(3,4,10), DPhe(7), Arg(11)]α-MSH(3-13) {(Arg(11))CCMSH} to generate RGD-Lys-(Arg(11))CCMSH hybrid peptide. The MC1 receptor binding affinity of RGD-Lys-(Arg(11))CCMSH was determined in B16/F1 melanoma cells. The internalization and efflux, melanoma targeting and pharmacokinetic properties and single photon emission computed tomography/CT (SPECT/CT) imaging of (99m)Tc-RGD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma cells and melanoma-bearing C57 mice. Clonogenic cytotoxic effect of RGD-Lys-(Arg(11))CCMSH was examined in B16/F1 melanoma cells. RGD-Lys-(Arg(11))CCMSH displayed 2.1 nM MC1 receptor binding affinity. (99m)Tc-RGD-Lys-(Arg(11))CCMSH showed rapid internalization and extended retention in B16/F1 cells. The cellular uptake of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was MC1 receptor-mediated. (99m)Tc-RGD-Lys-(Arg(11))CCMSH exhibited high tumor uptake (14.83 ± 2.94% ID/g 2 h postinjection) and prolonged tumor retention (7.59 ± 2.04% ID/g 24 h postinjection) in B16/F1 melanoma-bearing mice. Nontarget organ uptakes were generally low except for the kidneys. Whole-body clearance of (99m)Tc-RGD-Lys-(Arg(11))CCMSH was rapid, with approximately 62% of the injected radioactivity cleared through the urinary system by 2 h postinjection. Flank melanoma tumors were clearly imaged by small animal SPECT/CT using (99m)Tc-RGD-Lys-(Arg(11))CCMSH as an imaging probe 2 h postinjection. Single treatment (3 h incubation) with 100 nM of RGD-Lys-(Arg(11))CCMSH significantly (p < 0.05) decreased the clonogenic survival of B16/F1 cells by 65% compared to the untreated control cells. Favorable melanoma targeting property of (99m)Tc-RGD-Lys-(Arg(11))CCMSH and remarkable cytotoxic effect of RGD

  1. Receptor-Mediated Melanoma Targeting with Radiolabeled α-Melanocyte-Stimulating Hormone: Relevance of the Net Charge of the Ligand

    Directory of Open Access Journals (Sweden)

    Alex N. Eberle

    2017-04-01

    Full Text Available A majority of melanotic and amelanotic melanomas overexpress melanocortin type 1 receptors (MC1Rs for α-melanocyte-stimulating hormone. Radiolabeled linear or cyclic analogs of α-MSH have a great potential as diagnostic or therapeutic tools for the management of malignant melanoma. Compounds such as [111In]DOTA-NAP-amide exhibit high affinity for the MC1R in vitro, good tumor uptake in vivo, but they may suffer from relatively high kidney uptake and retention in vivo. We have shown previously that the introduction of negative charges into radiolabeled DOTA-NAP-amide peptide analogs may enhance their excretion and reduce kidney retention. To address the question of where to place negative charges within the ligand, we have extended these studies by designing two novel peptides, Ac-Nle-Asp-His-d-Phe-Arg-Trp-Gly-Lys(DOTA-d-Asp-d-Asp-OH (DOTA-NAP-d-Asp-d-Asp with three negative charges at the C-terminal end (overall net charge of the molecule −2 and DOTA-Gly-Tyr(P-Nle-Asp-His-d-Phe-Arg-Trp-NH2 (DOTA-Phospho-MSH2-9 with two negative charges in the N-terminal region (net charge −1. The former peptide showed markedly reduced receptor affinity and biological activity by >10-fold compared to DOTA-NAP-amide as reference compound, and the latter peptide displayed similar bioactivity and receptor affinity as the reference compound. The uptake by melanoma tumor tissue of [111In]DOTA-Phospho-MSH2-9 was 7.33 ± 0.47 %ID/g 4 h after injection, i.e., almost equally high as with [111In]DOTA-NAP-amide. The kidney retention was 2.68 ± 0.18 %ID/g 4 h after injection and hence 44% lower than that of [111In]DOTA-NAP-amide. Over an observation period from 4 to 48 h, the tumor-to-kidney ratio of [111In]DOTA-Phospho-MSH2-9 was 35% more favorable than that of the reference compound. In a comparison of DOTA-NAP-d-Asp-d-Asp, DOTA-Phospho-MSH2-9 and DOTA-NAP-amide with five previously published analogs of DOTA-NAP-amide that altogether cover a range

  2. Pro-opiomelanocortin-derived peptides in the pig pituitary: alpha- and gamma 1-melanocyte-stimulating hormones and their glycine-extended forms

    DEFF Research Database (Denmark)

    Fenger, M

    1988-01-01

    Pro-opiomelanocortin (POMC)-related peptides in extracts of anterior and neurointermediate pituitary lobes from pigs were characterized by gel chromatography, reversed-phase chromatography and radioimmunoassays. The peptide content was ca. 3-fold greater in the anterior lobe compared...... to the neurointermediate lobe (19.8 nmol POMC/anterior lobe vs 7.0 nmol/neurointermediate lobe). In the neurointermediate lobe 93% of POMC was processed to alpha-melanocyte-stimulating hormone (alpha-MSH) and analogs exclusively of low molecular weight. Most of the remaining adrenocorticotropic hormone (ACTH...... as alpha-MSH and analogs (94%). However, more than 95% of these peptides were of high molecular weight. In the anterior lobe 2.3% of N-POMC was processed and 94% was amidated gamma-MSH of only high molecular weight. These results show that gamma-MSH and alpha-MSH are amidated to the same extent...

  3. In vivo assessment of optical properties of melanocytic skin lesions and differentiation of melanoma from non-malignant lesions by high-definition optical coherence tomography

    DEFF Research Database (Denmark)

    Boone, M A L M; Suppa, M; Dhaenens, F.

    2016-01-01

    One of the most challenging problems in clinical dermatology is the early detection of melanoma. Reflectance confocal microscopy (RCM) is an added tool to dermoscopy improving considerably diagnostic accuracy. However, diagnosis strongly depends on the experience of physicians. High-definition op......One of the most challenging problems in clinical dermatology is the early detection of melanoma. Reflectance confocal microscopy (RCM) is an added tool to dermoscopy improving considerably diagnostic accuracy. However, diagnosis strongly depends on the experience of physicians. High......-definition optical coherence tomography (HD-OCT) appears to offer additional structural and cellular information on melanocytic lesions complementary to that of RCM. However, the diagnostic potential of HD-OCT seems to be not high enough for ruling out the diagnosis of melanoma if based on morphology analysis...

  4. Successful repigmentation of vitiligo after allogeneic bone marrow transplantation for Hodgkin′s lymphoma by autologous noncultured melanocyte-keratinocyte transplantation

    Directory of Open Access Journals (Sweden)

    Huijuan Tang

    2015-01-01

    Full Text Available The treatment of vitiligo is derisory since the pathogenesis of vitiligo is not clear at present. Most conservative treatments are difficult to approach satisfactory therapy. So transplantation is the only way left when the disease becomes insensitive to those conservative treatments. Here we describe an 18-year-old patient who developed vitiligo, which was triggered by graft-versus-host disease after a allogeneic bone marrow transplantation for the treatment of Hodgkin′s lymphoma from his sister. In the following treatment to vitiligo, the patient successfully performed the transplantation of autologous uncultured melanocyte on the premise of poor reaction to other conservative methods. We infer that transplantation can be a treatment of the vitiligo after allogeneic bone marrow transplantation.

  5. MuSIC report III: tumour microcirculation patterns and development of metastasis in long-term follow-up of melanocytic uveal tumours.

    Science.gov (United States)

    Klingenstein, Annemarie; Schaumberger, Markus M; Freeman, William R; Folberg, Robert; Mueller, Arthur J; Schaller, Ulrich C

    2016-03-01

    To statistically determine differences in microcirculation patterns between nevi and uveal melanomas and the influence of these patterns on metastatic potential in the long-term follow-up of 112 patients with melanocytic uveal tumours. In vivo markers indicating malignancy and metastatic potential have implications for treatment decision. Primary diagnosis and work-up included clinical examination, fundus photography, standardized A and B scan echography as well as evaluation of tumour microcirculation patterns via confocal fluorescein and indocyanine green angiography (ICGA). Patient data were collected from the patient files, the tumour registry or personal contact. Statistical analysis was performed with spss 22.0 using chi-square, Fisher's exact test and Kaplan-Meier survival analysis. Forty-three uveal melanocytic lesions remained untreated and were retrospectively classified as benign nevi, whereas 69 lesions were malignant melanomas (T1: 32, T2: 28, T3: 6 and T4: 3). 'Silent' and 'arcs without branching' were found significantly more often in nevi (p = 0.001 and p = 0.010), whereas 'parallel with cross-linking' and 'networks' were significantly more frequent in melanomas (p = 0.022 and p = 0.029). The microcirculation pattern 'parallel with cross-linking' proved significantly more frequent in patients who developed metastases (p = 0.001). Certain microcirculation patterns may guide us in differentiating uveal nevi from malignant melanomas. A non-invasive prognostic marker can be of great value for borderline lesions in which cytology is less likely taken. 'Parallel with cross-linking' did not only indicate malignancy, but it was also associated with later tumour metastasis. © 2015 Acta Ophthalmologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

  6. Parallel consensual neural networks.

    Science.gov (United States)

    Benediktsson, J A; Sveinsson, J R; Ersoy, O K; Swain, P H

    1997-01-01

    A new type of a neural-network architecture, the parallel consensual neural network (PCNN), is introduced and applied in classification/data fusion of multisource remote sensing and geographic data. The PCNN architecture is based on statistical consensus theory and involves using stage neural networks with transformed input data. The input data are transformed several times and the different transformed data are used as if they were independent inputs. The independent inputs are first classified using the stage neural networks. The output responses from the stage networks are then weighted and combined to make a consensual decision. In this paper, optimization methods are used in order to weight the outputs from the stage networks. Two approaches are proposed to compute the data transforms for the PCNN, one for binary data and another for analog data. The analog approach uses wavelet packets. The experimental results obtained with the proposed approach show that the PCNN outperforms both a conjugate-gradient backpropagation neural network and conventional statistical methods in terms of overall classification accuracy of test data.

  7. Neural Architectures for Control

    Science.gov (United States)

    Peterson, James K.

    1991-01-01

    The cerebellar model articulated controller (CMAC) neural architectures are shown to be viable for the purposes of real-time learning and control. Software tools for the exploration of CMAC performance are developed for three hardware platforms, the MacIntosh, the IBM PC, and the SUN workstation. All algorithm development was done using the C programming language. These software tools were then used to implement an adaptive critic neuro-control design that learns in real-time how to back up a trailer truck. The truck backer-upper experiment is a standard performance measure in the neural network literature, but previously the training of the controllers was done off-line. With the CMAC neural architectures, it was possible to train the neuro-controllers on-line in real-time on a MS-DOS PC 386. CMAC neural architectures are also used in conjunction with a hierarchical planning approach to find collision-free paths over 2-D analog valued obstacle fields. The method constructs a coarse resolution version of the original problem and then finds the corresponding coarse optimal path using multipass dynamic programming. CMAC artificial neural architectures are used to estimate the analog transition costs that dynamic programming requires. The CMAC architectures are trained in real-time for each obstacle field presented. The coarse optimal path is then used as a baseline for the construction of a fine scale optimal path through the original obstacle array. These results are a very good indication of the potential power of the neural architectures in control design. In order to reach as wide an audience as possible, we have run a seminar on neuro-control that has met once per week since 20 May 1991. This seminar has thoroughly discussed the CMAC architecture, relevant portions of classical control, back propagation through time, and adaptive critic designs.

  8. Sacred or Neural?

    DEFF Research Database (Denmark)

    Runehov, Anne Leona Cesarine

    Are religious spiritual experiences merely the product of the human nervous system? Anne L.C. Runehov investigates the potential of contemporary neuroscience to explain religious experiences. Following the footsteps of Michael Persinger, Andrew Newberg and Eugene d'Aquili she defines...... the terminological bounderies of "religious experiences" and explores the relevant criteria for the proper evaluation of scientific research, with a particular focus on the validity of reductionist models. Runehov's theis is that the perspectives looked at do not necessarily exclude each other but can be merged....... The question "sacred or neural?" becomes a statement "sacred and neural". The synergies thus produced provide manifold opportunities for interdisciplinary dialogue and research....

  9. Deconvolution using a neural network

    Energy Technology Data Exchange (ETDEWEB)

    Lehman, S.K.

    1990-11-15

    Viewing one dimensional deconvolution as a matrix inversion problem, we compare a neural network backpropagation matrix inverse with LMS, and pseudo-inverse. This is a largely an exercise in understanding how our neural network code works. 1 ref.

  10. Introduction to Artificial Neural Networks

    DEFF Research Database (Denmark)

    Larsen, Jan

    1999-01-01

    The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks.......The note addresses introduction to signal analysis and classification based on artificial feed-forward neural networks....

  11. Neural Network Ensembles

    DEFF Research Database (Denmark)

    Hansen, Lars Kai; Salamon, Peter

    1990-01-01

    We propose several means for improving the performance an training of neural networks for classification. We use crossvalidation as a tool for optimizing network parameters and architecture. We show further that the remaining generalization error can be reduced by invoking ensembles of similar...... networks....

  12. Neural correlates of consciousness

    African Journals Online (AJOL)

    neural cells.1 Under this approach, consciousness is believed to be a product of the ... possible only when the 40 Hz electrical hum is sustained among the brain circuits, ... expect the brain stem ascending reticular activating system. (ARAS) and the ... related synchrony of cortical neurons.11 Indeed, stimulation of brainstem ...

  13. Neural Networks and Micromechanics

    Science.gov (United States)

    Kussul, Ernst; Baidyk, Tatiana; Wunsch, Donald C.

    The title of the book, "Neural Networks and Micromechanics," seems artificial. However, the scientific and technological developments in recent decades demonstrate a very close connection between the two different areas of neural networks and micromechanics. The purpose of this book is to demonstrate this connection. Some artificial intelligence (AI) methods, including neural networks, could be used to improve automation system performance in manufacturing processes. However, the implementation of these AI methods within industry is rather slow because of the high cost of conducting experiments using conventional manufacturing and AI systems. To lower the cost, we have developed special micromechanical equipment that is similar to conventional mechanical equipment but of much smaller size and therefore of lower cost. This equipment could be used to evaluate different AI methods in an easy and inexpensive way. The proved methods could be transferred to industry through appropriate scaling. In this book, we describe the prototypes of low cost microequipment for manufacturing processes and the implementation of some AI methods to increase precision, such as computer vision systems based on neural networks for microdevice assembly and genetic algorithms for microequipment characterization and the increase of microequipment precision.

  14. Introduction to neural networks

    International Nuclear Information System (INIS)

    Pavlopoulos, P.

    1996-01-01

    This lecture is a presentation of today's research in neural computation. Neural computation is inspired by knowledge from neuro-science. It draws its methods in large degree from statistical physics and its potential applications lie mainly in computer science and engineering. Neural networks models are algorithms for cognitive tasks, such as learning and optimization, which are based on concepts derived from research into the nature of the brain. The lecture first gives an historical presentation of neural networks development and interest in performing complex tasks. Then, an exhaustive overview of data management and networks computation methods is given: the supervised learning and the associative memory problem, the capacity of networks, the Perceptron networks, the functional link networks, the Madaline (Multiple Adalines) networks, the back-propagation networks, the reduced coulomb energy (RCE) networks, the unsupervised learning and the competitive learning and vector quantization. An example of application in high energy physics is given with the trigger systems and track recognition system (track parametrization, event selection and particle identification) developed for the CPLEAR experiment detectors from the LEAR at CERN. (J.S.). 56 refs., 20 figs., 1 tab., 1 appendix

  15. Learning from neural control.

    Science.gov (United States)

    Wang, Cong; Hill, David J

    2006-01-01

    One of the amazing successes of biological systems is their ability to "learn by doing" and so adapt to their environment. In this paper, first, a deterministic learning mechanism is presented, by which an appropriately designed adaptive neural controller is capable of learning closed-loop system dynamics during tracking control to a periodic reference orbit. Among various neural network (NN) architectures, the localized radial basis function (RBF) network is employed. A property of persistence of excitation (PE) for RBF networks is established, and a partial PE condition of closed-loop signals, i.e., the PE condition of a regression subvector constructed out of the RBFs along a periodic state trajectory, is proven to be satisfied. Accurate NN approximation for closed-loop system dynamics is achieved in a local region along the periodic state trajectory, and a learning ability is implemented during a closed-loop feedback control process. Second, based on the deterministic learning mechanism, a neural learning control scheme is proposed which can effectively recall and reuse the learned knowledge to achieve closed-loop stability and improved control performance. The significance of this paper is that the presented deterministic learning mechanism and the neural learning control scheme provide elementary components toward the development of a biologically-plausible learning and control methodology. Simulation studies are included to demonstrate the effectiveness of the approach.

  16. Neural systems for control

    National Research Council Canada - National Science Library

    Omidvar, Omid; Elliott, David L

    1997-01-01

    ... is reprinted with permission from A. Barto, "Reinforcement Learning," Handbook of Brain Theory and Neural Networks, M.A. Arbib, ed.. The MIT Press, Cambridge, MA, pp. 804-809, 1995. Chapter 4, Figures 4-5 and 7-9 and Tables 2-5, are reprinted with permission, from S. Cho, "Map Formation in Proprioceptive Cortex," International Jour...

  17. Neural underpinnings of music

    DEFF Research Database (Denmark)

    Vuust, Peter; Gebauer, Line K; Witek, Maria A G

    2014-01-01

    . According to this theory, perception and learning is manifested through the brain’s Bayesian minimization of the error between the input to the brain and the brain’s prior expectations. Fourth, empirical studies of neural and behavioral effects of syncopation, polyrhythm and groove will be reported, and we...

  18. Estudo de distribuição e morfologia dos melanócitos em pele com e sem exposição solar Melanocytes distribution and morphology analysis in skin with and without sun exposure

    Directory of Open Access Journals (Sweden)

    Daniela Mayumi Takano

    2010-02-01

    Full Text Available INTRODUÇÃO E OBJETIVOS: Acredita-se que a exposição solar possa alterar número, distribuição e morfologia dos melanócitos na pele humana, muitas vezes dificultando a interpretação de biópsias de pele, principalmente para o diagnóstico de lesões melanocíticas iniciais e para a avaliação precisa de margens de ressecção. O objetivo deste trabalho foi avaliar os melanócitos da pele humana em área exposta e não exposta ao sol. MÉTODOS: Realizada análise histológica de 60 fragmentos de biópsias de pele obtidas do antebraço (área fotoexposta e região glútea (área coberta de cadáveres do Serviço de Verificação de Óbitos de Recife-PE. A estatística foi realizada com o SPSS Windows versão 12.0. RESULTADOS: Observou-se um número bastante variável de melanócitos nos fragmentos de pele, com maior concentração destes na região do antebraço (área de maior fotoexposição (p INTRODUCTION AND OBJECTIVES: It is believed that sun exposure can change the number, distribution and morphology of melanocytes in human skin, which often hinders the interpretation of skin biopsies, mainly as to diagnosis of initial melanocytic lesions and accurate assessment of resection margins. Our objective was to evaluate melanocytes in sun-exposed and non-exposed skin. METHODS: It was conducted the histological analysis of 60 skin biopsy samples resected from cadaver forearm (sun-exposed skin and cadaver buttock (non-exposed skin from the Death Verification Service (Serviço de Verificação de Óbitos of Recife, state of Pernambuco. The statistical analysis was performed with SPSS Windows version 12.0. RESULTS: There was considerable variability in melanocyte density, with a higher concentration of these cells in sun-exposed areas (p < 0.001. There was also an irregular distribution of melanocytes along the epidermal basal layer, occasionally with cells arranged side by side. This confluence was identified with a higher frequency in sun

  19. Bioprinting for Neural Tissue Engineering.

    Science.gov (United States)

    Knowlton, Stephanie; Anand, Shivesh; Shah, Twisha; Tasoglu, Savas

    2018-01-01

    Bioprinting is a method by which a cell-encapsulating bioink is patterned to create complex tissue architectures. Given the potential impact of this technology on neural research, we review the current state-of-the-art approaches for bioprinting neural tissues. While 2D neural cultures are ubiquitous for studying neural cells, 3D cultures can more accurately replicate the microenvironment of neural tissues. By bioprinting neuronal constructs, one can precisely control the microenvironment by specifically formulating the bioink for neural tissues, and by spatially patterning cell types and scaffold properties in three dimensions. We review a range of bioprinted neural tissue models and discuss how they can be used to observe how neurons behave, understand disease processes, develop new therapies and, ultimately, design replacement tissues. Copyright © 2017 Elsevier Ltd. All rights reserved.

  20. Analysis of neural data

    CERN Document Server

    Kass, Robert E; Brown, Emery N

    2014-01-01

    Continual improvements in data collection and processing have had a huge impact on brain research, producing data sets that are often large and complicated. By emphasizing a few fundamental principles, and a handful of ubiquitous techniques, Analysis of Neural Data provides a unified treatment of analytical methods that have become essential for contemporary researchers. Throughout the book ideas are illustrated with more than 100 examples drawn from the literature, ranging from electrophysiology, to neuroimaging, to behavior. By demonstrating the commonality among various statistical approaches the authors provide the crucial tools for gaining knowledge from diverse types of data. Aimed at experimentalists with only high-school level mathematics, as well as computationally-oriented neuroscientists who have limited familiarity with statistics, Analysis of Neural Data serves as both a self-contained introduction and a reference work.

  1. Deep Neural Yodelling

    OpenAIRE

    Pfäffli, Daniel (Autor/in)

    2018-01-01

    Yodel music differs from most other genres by exercising the transition from chest voice to falsetto with an audible glottal stop which is recognised even by laymen. Yodel often consists of a yodeller with a choir accompaniment. In Switzerland, it is differentiated between the natural yodel and yodel songs. Today's approaches to music generation with machine learning algorithms are based on neural networks, which are best described by stacked layers of neurons which are connected with neurons...

  2. Neural networks for triggering

    International Nuclear Information System (INIS)

    Denby, B.; Campbell, M.; Bedeschi, F.; Chriss, N.; Bowers, C.; Nesti, F.

    1990-01-01

    Two types of neural network beauty trigger architectures, based on identification of electrons in jets and recognition of secondary vertices, have been simulated in the environment of the Fermilab CDF experiment. The efficiencies for B's and rejection of background obtained are encouraging. If hardware tests are successful, the electron identification architecture will be tested in the 1991 run of CDF. 10 refs., 5 figs., 1 tab

  3. Artificial neural network modelling

    CERN Document Server

    Samarasinghe, Sandhya

    2016-01-01

    This book covers theoretical aspects as well as recent innovative applications of Artificial Neural networks (ANNs) in natural, environmental, biological, social, industrial and automated systems. It presents recent results of ANNs in modelling small, large and complex systems under three categories, namely, 1) Networks, Structure Optimisation, Robustness and Stochasticity 2) Advances in Modelling Biological and Environmental Systems and 3) Advances in Modelling Social and Economic Systems. The book aims at serving undergraduates, postgraduates and researchers in ANN computational modelling. .

  4. Rotation Invariance Neural Network

    OpenAIRE

    Li, Shiyuan

    2017-01-01

    Rotation invariance and translation invariance have great values in image recognition tasks. In this paper, we bring a new architecture in convolutional neural network (CNN) named cyclic convolutional layer to achieve rotation invariance in 2-D symbol recognition. We can also get the position and orientation of the 2-D symbol by the network to achieve detection purpose for multiple non-overlap target. Last but not least, this architecture can achieve one-shot learning in some cases using thos...

  5. Neural Mechanisms of Foraging

    OpenAIRE

    Kolling, Nils; Behrens, Timothy EJ; Mars, Rogier B; Rushworth, Matthew FS

    2012-01-01

    Behavioural economic studies, involving limited numbers of choices, have provided key insights into neural decision-making mechanisms. By contrast, animals’ foraging choices arise in the context of sequences of encounters with prey/food. On each encounter the animal chooses to engage or whether the environment is sufficiently rich that searching elsewhere is merited. The cost of foraging is also critical. We demonstrate humans can alternate between two modes of choice, comparative decision-ma...

  6. Neural Based Orthogonal Data Fitting The EXIN Neural Networks

    CERN Document Server

    Cirrincione, Giansalvo

    2008-01-01

    Written by three leaders in the field of neural based algorithms, Neural Based Orthogonal Data Fitting proposes several neural networks, all endowed with a complete theory which not only explains their behavior, but also compares them with the existing neural and traditional algorithms. The algorithms are studied from different points of view, including: as a differential geometry problem, as a dynamic problem, as a stochastic problem, and as a numerical problem. All algorithms have also been analyzed on real time problems (large dimensional data matrices) and have shown accurate solutions. Wh

  7. Human phenylalanine hydroxylase is activated by H2O2: a novel mechanism for increasing the L-tyrosine supply for melanogenesis in melanocytes

    International Nuclear Information System (INIS)

    Schallreuter, Karin U.; Wazir, Umar; Kothari, Sonal; Gibbons, Nicholas C.J.; Moore, Jeremy; Wood, John M.

    2004-01-01

    Epidermal phenylalanine hydroxylase (PAH) produces L-tyrosine from the essential amino acid L-phenylalanine supporting melanogenesis in human melanocytes. Those PAH activities increase linearly in the different skin phototypes I-VI (Fitzpatrick classification) and also increase up to 24 h after UVB light with only one minimal erythemal dose. Since UVB generates also H 2 O 2 , we here asked the question whether this reactive oxygen species could influence the activity of pure recombinant human PAH. Under saturating conditions with the substrate L-phenylalanine (1 x 10 -3 M), the V max for enzyme activity increased 4-fold by H 2 O 2 (>2.0 x 10 -3 M). Lineweaver-Burk analysis identified a mixed activation mechanism involving both the regulatory and catalytic domains of PAH. Hyperchem molecular modelling and Deep View analysis support oxidation of the single Trp 120 residue to 5-OH-Trp 120 by H 2 O 2 causing a conformational change in the regulatory domain. PAH was still activated by H 2 O 2 in the presence of the electron donor/cofactor 6(R)-L-erythro-5,6,7,8-tetrahydrobiopterin despite slow oxidation of this cofactor. In vivo FT-Raman spectroscopy confirmed decreased epidermal phenylalanine in association with increased tyrosine after UVB exposure. Hence, generation of H 2 O 2 by UVB can activate epidermal PAH leading to an increased L-tyrosine pool for melanogenesis

  8. α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways

    Science.gov (United States)

    Ru, Yusha; Huang, Yue; Liu, Huijuan; Du, Juan; Meng, Zhu; Dou, Zexia; Liu, Xun; Wei, Rui Hua; Zhang, Yan; Zhao, Shaozhen

    2015-01-01

    Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10−4 μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH’s protective effects, suggesting that both pathways are necessary for α-MSH’s protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED. PMID:26685899

  9. A Macrocyclic Agouti-Related Protein/[Nle4,DPhe7]α-Melanocyte Stimulating Hormone Chimeric Scaffold Produces Subnanomolar Melanocortin Receptor Ligands.

    Science.gov (United States)

    Ericson, Mark D; Freeman, Katie T; Schnell, Sathya M; Haskell-Luevano, Carrie

    2017-01-26

    The melanocortin system consists of five receptor subtypes, endogenous agonists, and naturally occurring antagonists. These receptors and ligands have been implicated in numerous biological pathways including processes linked to obesity and food intake. Herein, a truncation structure-activity relationship study of chimeric agouti-related protein (AGRP)/[Nle4,DPhe7]α-melanocyte stimulating hormone (NDP-MSH) ligands is reported. The tetrapeptide His-DPhe-Arg-Trp or tripeptide DPhe-Arg-Trp replaced the Arg-Phe-Phe sequence in the AGRP active loop derivative c[Pro-Arg-Phe-Phe-Xxx-Ala-Phe-DPro], where Xxx was the native Asn of AGRP or a diaminopropionic (Dap) acid residue previously shown to increase antagonist potency at the mMC4R. The Phe, Ala, and Dap/Asn residues were successively removed to generate a 14-member library that was assayed for agonist activity at the mouse MC1R, MC3R, MC4R, and MC5R. Two compounds possessed nanomolar agonist potency at the mMC4R, c[Pro-His-DPhe-Arg-Trp-Asn-Ala-Phe-DPro] and c[Pro-His-DPhe-Arg-Trp-Dap-Ala-DPro], and may be further developed to generate novel melanocortin probes and ligands for understanding and treating obesity.

  10. α-Melanocyte-stimulating hormone ameliorates ocular surface dysfunctions and lesions in a scopolamine-induced dry eye model via PKA-CREB and MEK-Erk pathways.

    Science.gov (United States)

    Ru, Yusha; Huang, Yue; Liu, Huijuan; Du, Juan; Meng, Zhu; Dou, Zexia; Liu, Xun; Wei, Rui Hua; Zhang, Yan; Zhao, Shaozhen

    2015-12-21

    Dry eye is a highly prevalent, chronic, and multifactorial disease that compromises quality of life and generates socioeconomic burdens. The pathogenic factors of dry eye disease (DED) include tear secretion abnormalities, tear film instability, and ocular surface inflammation. An effective intervention targeting the pathogenic factors is needed to control this disease. Here we applied α-Melanocyte-stimulating hormone (α-MSH) twice a day to the ocular surface of a scopolamine-induced dry eye rat model. The results showed that α-MSH at different doses ameliorated tear secretion, tear film stability, and corneal integrity, and corrected overexpression of proinflammatory factors, TNF-α, IL-1β, and IFN-γ, in ocular surface of the dry eye rats. Moreover, α-MSH, at 10(-4) μg/μl, maintained corneal morphology, inhibited apoptosis, and restored the number and size of conjunctival goblet cells in the dry eye rats. Mechanistically, α-MSH activated both PKA-CREB and MEK-Erk pathways in the dry eye corneas and conjunctivas; pharmacological blockade of either pathway abolished α-MSH's protective effects, suggesting that both pathways are necessary for α-MSH's protection under dry eye condition. The peliotropic protective functions and explicit signaling mechanism of α-MSH warrant translation of the α-MSH-containing eye drop into a novel and effective intervention to DED.

  11. Melanoma cell-derived exosomes promote epithelial-mesenchymal transition in primary melanocytes through paracrine/autocrine signaling in the tumor microenvironment

    Science.gov (United States)

    Xiao, Deyi; Barry, Samantha; Kmetz, Daniel; Egger, Michael; Pan, Jianmin; Rai, Shesh N; Qu, Jifu; McMasters, Kelly M.; Hao, Hongying

    2016-01-01

    The tumor microenvironment is abundant with exosomes that are secreted by the cancer cells themselves. Exosomes are nanosized, organelle-like membranous structures that are increasingly being recognized as major contributors in the progression of malignant neoplasms. A critical element in melanoma progression is its propensity to metastasize, but little is known about how melanoma cell-derived exosomes modulate the microenvironment to optimize conditions for tumor progression and metastasis. Here, we provide evidence that melanoma cell-derived exosomes promote phenotype switching in primary melanocytes through paracrine/autocrine signaling. We found that the mitogen-activated protein kinase (MAPK) signaling pathway was activated during the exosome-mediated epithelial-to-mesenchymal transition (EMT)-resembling process, which promotes metastasis. Let-7i, an miRNA modulator of EMT, was also involved in this process. We further defined two other miRNA modulators of EMT (miR-191 and let-7a) in serum exosomes for differentiating stage I melanoma patients from non-melanoma subjects. These results provide the first strong molecular evidence that melanoma cell-derived exosomes promote the EMT-resembling process in the tumor microenvironment. Thus, novel strategies targeting EMT and modulating the tumor microenvironment may emerge as important approaches for the treatment of metastatic melanoma. PMID:27063098

  12. Clinicohistopathological correlations in juvenile localized scleroderma: studies on a subset of children with hypopigmented juvenile localized scleroderma due to loss of epidermal melanocytes.

    Science.gov (United States)

    Sung, Joanne J; Chen, Tina S; Gilliam, Anita C; McCalmont, Timothy H; Gilliam, Amy E

    2011-08-01

    Localized scleroderma or morphea is a connective tissue disorder characterized by fibrosis of the skin and subcutaneous tissue. Excessive accumulation of collagen underlies the fibrosis, yet the pathogenesis is unknown. A subset of localized scleroderma/morphea, juvenile localized scleroderma (JLS), affects children and adolescents. The clinical and microscopic features of JLS have not been fully characterized. The goal is to better characterize the microscopic features of JLS. We collected a distinctive data set of 35 children with JLS, 19 (54%) of whom presented with hypopigmented lesions, and performed a retrospective chart and pathology review. We had adequate tissue for immunostaining studies on 8 of these individuals. We found that: (1) CD34 and factor XIIIa immunostaining, reported previously in adult morphea and scleroderma, when used with clinical information, is valuable for confirming a diagnosis of JLS; and (2) presence of hypopigmented lesions in JLS correlates with immunostaining studies. Decreased numbers of MelanA(+) melanocytes were present at the dermoepidermal junction in lesional skin in two of 3 children with hypopigmented JLS and in two of 4 children with nonhypopigmented JLS. The number of cases is small, a function of the small number of children who have biopsy specimens with material sufficient for multiple immunostaining procedures. These results provide a useful immunostaining method for confirmation of the diagnosis of JLS. They suggest a complex autoimmune phenotype in some children with JLS. Copyright © 2010 American Academy of Dermatology, Inc. Published by Mosby, Inc. All rights reserved.

  13. Phorbol 12-myristate 13-acetate enhances nm23 gene expression in murine melanocytes but not in syngeneic B16-BL6 melanoma variants.

    Science.gov (United States)

    Huijzer, J C; McFarland, M; Niles, R M; Meadows, G G

    1996-03-01

    The nm23 gene has been described as a potential metastasis suppressor gene in certain rodent and human tumors. We previously demonstrated that tyrosine and phenylalanine restriction suppresses metastatic heterogeneity of B16-BL6 murine melanoma and selects for tumor variants with decreased metastatic potential. In this study, we investigated nm23 expression in the highly metastatic B16-BL6 (ND) melanoma, its nutritionally derived poorly metastatic (LT) variant, and the syngeneic non-tumorigenic Mel-ab melanocytes. No differences in nm23 expression were observed between ND and LT cells, and nm23 expression varied between different isolates. Previously, we showed that metastatic potential of 1-ND cells decreases and is not altered in 1-LT cells after prolonged in vitro cell passage; however, nm23 expression is equivalently increased by 2-fold. In 2-ND and 2-LT cells, expression of nm23 is not different at higher in vitro cell passage. Expression of nm23 decreased about 2-fold when phorbol 12-myristate 13-acetate (PMA) was removed from Mel-ab cells, which induces these cells to become quiescent. Although membrane-associated protein kinase C (PKC) activity decreased after prolonged PMA treatment in all cells, neither nm23 expression nor proliferation of ND and LT cells was affected by PMA. These data indicate that nm23 expression is related to proliferative activity rather than to the suppression of metastatic potential.

  14. Induction of autocrine factor inhibiting cell motility from murine B16-BL6 melanoma cells by alpha-melanocyte stimulating hormone.

    Science.gov (United States)

    Murata, J; Ayukawa, K; Ogasawara, M; Watanabe, H; Saiki, I

    1999-03-15

    We have previously reported that neuropeptide alpha-melanocyte stimulating hormone (alpha-MSH) successfully inhibited Matrigel invasion and haptotactic migration of B16-BL6 melanoma cells towards both fibronectin and laminin without affecting their growth. In the present study, we investigated the inhibitory mechanism of tumor cell motility by alpha-MSH. Alpha-MSH significantly blocked the autocrine motility factor (AMF)-enhanced cell motility. However, alpha-MSH did neither prevent the secretion of AMF from B16-BL6 cells nor alter the expression level of AMF receptor (gp78). On the other hand, alpha-MSH induced the secretion of the motility inhibitory factor(s) from B16-BL6 cells in a concentration- and time-dependent manner. The induction of the motility inhibitor(s) was proportional to increasing levels of intracellular cAMP induced by alpha-MSH as well as forskolin, and the activity was abolished by an adenylate cyclase inhibitor, 2',5'-dideoxyadenosine (DDA). The motility-inhibiting activity in conditioned medium (CM) from alpha-MSH-treated B16-BL6 cells was found to have a m.w. below 3 kDa after fractionation. This activity was abolished by boiling but insensitive to trypsin. The treatment of tumor cells with cycloheximide reduced the activity in alpha-MSH-stimulated CM. Our results suggest that alpha-MSH inhibited the motility of B16-BL6 cells through induction of autocrine factor(s).

  15. Mef2c-F10N enhancer driven β-galactosidase (LacZ) and Cre recombinase mice facilitate analyses of gene function and lineage fate in neural crest cells.

    Science.gov (United States)

    Aoto, Kazushi; Sandell, Lisa L; Butler Tjaden, Naomi E; Yuen, Kobe C; Watt, Kristin E Noack; Black, Brian L; Durnin, Michael; Trainor, Paul A

    2015-06-01

    Neural crest cells (NCC) comprise a multipotent, migratory stem cell and progenitor population that gives rise to numerous cell and tissue types within a developing embryo, including craniofacial bone and cartilage, neurons and glia of the peripheral nervous system, and melanocytes within the skin. Here we describe two novel stable transgenic mouse lines suitable for lineage tracing and analysis of gene function in NCC. Firstly, using the F10N enhancer of the Mef2c gene (Mef2c-F10N) linked to LacZ, we generated transgenic mice (Mef2c-F10N-LacZ) that express LacZ in the majority, if not all migrating NCC that delaminate from the neural tube. Mef2c-F10N-LacZ then continues to be expressed primarily in neurogenic, gliogenic and melanocytic NCC and their derivatives, but not in ectomesenchymal derivatives. Secondly, we used the same Mef2c-F10N enhancer together with Cre recombinase to generate transgenic mice (Mef2c-F10N-Cre) that can be used to indelibly label, or alter gene function in, migrating NCC and their derivatives. At early stages of development, Mef2c-F10N-LacZ and Mef2c-F10N-Cre label NCC in a pattern similar to Wnt1-Cre mice, with the exception that Mef2c-F10N-LacZ and Mef2c-F10N-Cre specifically label NCC that have delaminated from the neural plate, while premigratory NCC are not labeled. Thus, our Mef2c-F10N-LacZ and Mef2c-F10N-Cre transgenic mice provide new resources for tracing migratory NCC and analyzing gene function in migrating and differentiating NCC independently of NCC formation. Copyright © 2015 Elsevier Inc. All rights reserved.

  16. Trimaran Resistance Artificial Neural Network

    Science.gov (United States)

    2011-01-01

    11th International Conference on Fast Sea Transportation FAST 2011, Honolulu, Hawaii, USA, September 2011 Trimaran Resistance Artificial Neural Network Richard...Trimaran Resistance Artificial Neural Network 5a. CONTRACT NUMBER 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) 5d. PROJECT NUMBER 5e... Artificial Neural Network and is restricted to the center and side-hull configurations tested. The value in the parametric model is that it is able to

  17. Optics in neural computation

    Science.gov (United States)

    Levene, Michael John

    In all attempts to emulate the considerable powers of the brain, one is struck by both its immense size, parallelism, and complexity. While the fields of neural networks, artificial intelligence, and neuromorphic engineering have all attempted oversimplifications on the considerable complexity, all three can benefit from the inherent scalability and parallelism of optics. This thesis looks at specific aspects of three modes in which optics, and particularly volume holography, can play a part in neural computation. First, holography serves as the basis of highly-parallel correlators, which are the foundation of optical neural networks. The huge input capability of optical neural networks make them most useful for image processing and image recognition and tracking. These tasks benefit from the shift invariance of optical correlators. In this thesis, I analyze the capacity of correlators, and then present several techniques for controlling the amount of shift invariance. Of particular interest is the Fresnel correlator, in which the hologram is displaced from the Fourier plane. In this case, the amount of shift invariance is limited not just by the thickness of the hologram, but by the distance of the hologram from the Fourier plane. Second, volume holography can provide the huge storage capacity and high speed, parallel read-out necessary to support large artificial intelligence systems. However, previous methods for storing data in volume holograms have relied on awkward beam-steering or on as-yet non- existent cheap, wide-bandwidth, tunable laser sources. This thesis presents a new technique, shift multiplexing, which is capable of very high densities, but which has the advantage of a very simple implementation. In shift multiplexing, the reference wave consists of a focused spot a few millimeters in front of the hologram. Multiplexing is achieved by simply translating the hologram a few tens of microns or less. This thesis describes the theory for how shift

  18. Analysis of neural networks

    CERN Document Server

    Heiden, Uwe

    1980-01-01

    The purpose of this work is a unified and general treatment of activity in neural networks from a mathematical pOint of view. Possible applications of the theory presented are indica­ ted throughout the text. However, they are not explored in de­ tail for two reasons : first, the universal character of n- ral activity in nearly all animals requires some type of a general approach~ secondly, the mathematical perspicuity would suffer if too many experimental details and empirical peculiarities were interspersed among the mathematical investigation. A guide to many applications is supplied by the references concerning a variety of specific issues. Of course the theory does not aim at covering all individual problems. Moreover there are other approaches to neural network theory (see e.g. Poggio-Torre, 1978) based on the different lev­ els at which the nervous system may be viewed. The theory is a deterministic one reflecting the average be­ havior of neurons or neuron pools. In this respect the essay is writt...

  19. Neural Synchronization and Cryptography

    Science.gov (United States)

    Ruttor, Andreas

    2007-11-01

    Neural networks can synchronize by learning from each other. In the case of discrete weights full synchronization is achieved in a finite number of steps. Additional networks can be trained by using the inputs and outputs generated during this process as examples. Several learning rules for both tasks are presented and analyzed. In the case of Tree Parity Machines synchronization is much faster than learning. Scaling laws for the number of steps needed for full synchronization and successful learning are derived using analytical models. They indicate that the difference between both processes can be controlled by changing the synaptic depth. In the case of bidirectional interaction the synchronization time increases proportional to the square of this parameter, but it grows exponentially, if information is transmitted in one direction only. Because of this effect neural synchronization can be used to construct a cryptographic key-exchange protocol. Here the partners benefit from mutual interaction, so that a passive attacker is usually unable to learn the generated key in time. The success probabilities of different attack methods are determined by numerical simulations and scaling laws are derived from the data. They show that the partners can reach any desired level of security by just increasing the synaptic depth. Then the complexity of a successful attack grows exponentially, but there is only a polynomial increase of the effort needed to generate a key. Further improvements of security are possible by replacing the random inputs with queries generated by the partners.

  20. Neural Networks for Optimal Control

    DEFF Research Database (Denmark)

    Sørensen, O.

    1995-01-01

    Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process.......Two neural networks are trained to act as an observer and a controller, respectively, to control a non-linear, multi-variable process....

  1. Neural networks at the Tevatron

    International Nuclear Information System (INIS)

    Badgett, W.; Burkett, K.; Campbell, M.K.; Wu, D.Y.; Bianchin, S.; DeNardi, M.; Pauletta, G.; Santi, L.; Caner, A.; Denby, B.; Haggerty, H.; Lindsey, C.S.; Wainer, N.; Dall'Agata, M.; Johns, K.; Dickson, M.; Stanco, L.; Wyss, J.L.

    1992-10-01

    This paper summarizes neural network applications at the Fermilab Tevatron, including the first online hardware application in high energy physics (muon tracking): the CDF and DO neural network triggers; offline quark/gluon discrimination at CDF; ND a new tool for top to multijets recognition at CDF

  2. Neural Networks for the Beginner.

    Science.gov (United States)

    Snyder, Robin M.

    Motivated by the brain, neural networks are a right-brained approach to artificial intelligence that is used to recognize patterns based on previous training. In practice, one would not program an expert system to recognize a pattern and one would not train a neural network to make decisions from rules; but one could combine the best features of…

  3. Neural fields theory and applications

    CERN Document Server

    Graben, Peter; Potthast, Roland; Wright, James

    2014-01-01

    With this book, the editors present the first comprehensive collection in neural field studies, authored by leading scientists in the field - among them are two of the founding-fathers of neural field theory. Up to now, research results in the field have been disseminated across a number of distinct journals from mathematics, computational neuroscience, biophysics, cognitive science and others. Starting with a tutorial for novices in neural field studies, the book comprises chapters on emergent patterns, their phase transitions and evolution, on stochastic approaches, cortical development, cognition, robotics and computation, large-scale numerical simulations, the coupling of neural fields to the electroencephalogram and phase transitions in anesthesia. The intended readership are students and scientists in applied mathematics, theoretical physics, theoretical biology, and computational neuroscience. Neural field theory and its applications have a long-standing tradition in the mathematical and computational ...

  4. Artificial neural networks in NDT

    International Nuclear Information System (INIS)

    Abdul Aziz Mohamed

    2001-01-01

    Artificial neural networks, simply known as neural networks, have attracted considerable interest in recent years largely because of a growing recognition of the potential of these computational paradigms as powerful alternative models to conventional pattern recognition or function approximation techniques. The neural networks approach is having a profound effect on almost all fields, and has been utilised in fields Where experimental inter-disciplinary work is being carried out. Being a multidisciplinary subject with a broad knowledge base, Nondestructive Testing (NDT) or Nondestructive Evaluation (NDE) is no exception. This paper explains typical applications of neural networks in NDT/NDE. Three promising types of neural networks are highlighted, namely, back-propagation, binary Hopfield and Kohonen's self-organising maps. (Author)

  5. Effects of amino acids on melanoma targeting and clearance properties of Tc-99m-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone peptides.

    Science.gov (United States)

    Flook, Adam M; Yang, Jianquan; Miao, Yubin

    2013-11-14

    The purpose of this study was to examine the effects of amino acids on melanoma targeting and clearance properties of new (99m)Tc-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RSD-Lys-(Arg(11))CCMSH {c[Arg-Ser-Asp-DTyr-Asp]-Lys-Cys-Cys-Glu-His-dPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2}, RNleD-Lys-(Arg(11))CCMSH, RPheD-Lys-(Arg(11))CCMSH, and RdPheD-Lys-(Arg(11))CCMSH peptides were synthesized and evaluated for their melanocortin-1 (MC1) receptor binding affinities in B16/F1 melanoma cells. The biodistribution of (99m)Tc-RSD-Lys-(Arg(11))CCMSH, (99m)Tc-RFD-Lys-(Arg(11))CCMSH, and (99m)Tc-RfD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The substitution of Gly with Ser, Phe, and dPhe increased the MC1 receptor binding affinities of the peptides, whereas the substitution of Gly with Nle decreased the MC1 receptor binding affinity of the peptide. (99m)Tc-RSD-Lys-(Arg(11))CCMSH exhibited the highest melanoma uptake (18.01 ± 4.22% ID/g) and the lowest kidney and liver uptake among these (99m)Tc-peptides. The B16/F1 melanoma lesions could be clearly visualized by SPECT/CT using (99m)Tc-RSD-Lys-(Arg(11))CCMSH as an imaging probe. It is desirable to reduce the renal uptake of (99m)Tc-RSD-Lys-(Arg(11))CCMSH to facilitate its potential therapeutic application.

  6. Genetic and biochemical evidence that haploinsufficiency of the Nf1 tumor suppressor gene modulates melanocyte and mast cell fates in vivo.

    Science.gov (United States)

    Ingram, D A; Yang, F C; Travers, J B; Wenning, M J; Hiatt, K; New, S; Hood, A; Shannon, K; Williams, D A; Clapp, D W

    2000-01-03

    Neurofibromatosis type 1 (NF1) is a common autosomal-dominant disorder characterized by cutaneous neurofibromas infiltrated with large numbers of mast cells, melanocyte hyperplasia, and a predisposition to develop malignant neoplasms. NF1 encodes a GTPase activating protein (GAP) for Ras. Consistent with Knudson's "two hit" model of tumor suppressor genes, leukemias and malignant solid tumors in NF1 patients frequently demonstrate somatic loss of the normal NF1 allele. However, the phenotypic and biochemical consequences of heterozygous inactivation of Nf1 are largely unknown. Recently neurofibromin, the protein encoded by NF1, was shown to negatively regulate Ras activity in Nf1-/- murine myeloid hematopoietic cells in vitro through the c-kit receptor tyrosine kinase (dominant white spotting, W). Since the W and Nf1 locus appear to function along a common developmental pathway, we generated mice with mutations at both loci to examine potential interactions in vivo. Here, we show that haploinsufficiency at Nf1 perturbs cell fates in mast cells in vivo, and partially rescues coat color and mast cell defects in W(41) mice. Haploinsufficiency at Nf1 also increased mast cell proliferation, survival, and colony formation in response to Steel factor, the ligand for c-kit. Furthermore, haploinsufficiency was associated with enhanced Ras-mitogen-activated protein kinase activity, a major downstream effector of Ras, via wild-type and mutant (W(41)) c-kit receptors. These observations identify a novel interaction between c-kit and neurofibromin in vivo, and offer experimental evidence that haploinsufficiency of Nf1 alters both cellular and biochemical phenotypes in two cell lineages that are affected in individuals with NF1. Collectively, these data support the emerging concept that heterozygous inactivation of tumor suppressor genes may have profound biological effects in multiple cell types.

  7. Chronic delivery of α-melanocyte-stimulating hormone in rat hypothalamus using albumin-alginate microparticles: effects on food intake and body weight.

    Science.gov (United States)

    Lucas, N; Legrand, R; Breton, J; Déchelotte, P; Edwards-Lévy, F; Fetissov, S O

    2015-04-02

    Chronic delivery of neuropeptides in the brain is a useful experimental approach to study their long-term effects on various biological parameters. In this work, we tested albumin-alginate microparticles, as a potential delivery system, to study if continuous release in the hypothalamus of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide, may result in a long-term decrease in food intake and body weight. The 2-week release of α-MSH from peptide-loaded particles was confirmed by an in vitro assay. Then, daily food intake and body weight were studied for 18 days in rats injected bilaterally into the paraventricular hypothalamic nucleus with particles loaded or not with α-MSH. A decrease in body weight gain, persisting throughout the study, was found in rats injected with α-MSH-charged particles as compared with rats receiving non-charged particles and with rats injected with the same dose of α-MSH in solution. Food intake was significantly decreased for 3 days in rats receiving α-MSH-loaded particles and it was not followed by the feeding rebound effect which appears after food restriction. The presence of α-MSH-loaded particles in the hypothalamus was confirmed by immunohistochemistry. In conclusion, our study validates albumin-alginate microparticles as a new carrier system for long-term delivery of neuropeptides in the brain and demonstrates that chronic delivery of α-MSH in the hypothalamus results in a prolonged suppression of food intake and a decrease of body weight gain in rats. Copyright © 2015 IBRO. Published by Elsevier Ltd. All rights reserved.

  8. Systemic photoprotection in solar urticaria with α-melanocyte-stimulating hormone analogue [Nle4-D-Phe7]-α-MSH.

    Science.gov (United States)

    Haylett, A K; Nie, Z; Brownrigg, M; Taylor, R; Rhodes, L E

    2011-02-01

    Solar urticaria is a rare photosensitivity disorder demonstrating a range of action spectra, which can inflict a very large impact on life quality despite available treatments. Melanin broadly reduces skin penetration by ultraviolet-visible wavelengths, thus increased melanization may protect in solar urticaria. To examine quantitatively for impact of the potent α-melanocyte stimulating hormone analogue afamelanotide ([Nle(4)-D-Phe(7)]-α-MSH, Scenesse(®); Clinuvel Pharmaceuticals Ltd, Melbourne, Vic., Australia) on the solar urticaria response and skin melanization. Five patients with solar urticaria received a single dose of 16 mg subcutaneous afamelanotide implant in winter time. Melanin density was assessed spectrophotometrically from day 0 to day 60. Detailed monochromated light testing to geometric dose series (increment ) of wavelengths 300-600 nm was performed at 0, 30 and 60 days, with assessment of weal and flare area and minimum urticarial dose (MUD). Data were analysed by repeated-measures anova. Mean melanin density increased by day 7, peaked at day 15 and remained elevated at day 60 (P=0·03, 0·01, 0·02 vs. baseline, respectively). Baseline phototesting revealed action spectra of 320-400 (n=1), 320-500 (n=2), 300-600 (n=1) and 370-500 nm (n=1), and on afamelanotide mean rises in MUD of 1-12 and 1-3 dose increments were seen at the individual wavelengths tested, at 30 and 60 days, respectively. A significant fall in weal area occurred across responding wavelengths from 300 to 600 nm at 60 days postimplant (P=0·049 vs. baseline), accompanied by greater than twofold overall increase in MUD (P=0·058 vs. baseline). Melanization following afamelanotide is accompanied by reduction in solar urticaria response across a broad spectrum of wavelengths. Further study is warranted to assess clinical benefit under ambient conditions in summer. © 2011 The Authors. BJD © 2011 British Association of Dermatologists.

  9. Culture media-based selection of endothelial cells, pericytes, and perivascular-resident macrophage-like melanocytes from the young mouse vestibular system.

    Science.gov (United States)

    Zhang, Jinhui; Chen, Songlin; Cai, Jing; Hou, Zhiqiang; Wang, Xiaohan; Kachelmeier, Allan; Shi, Xiaorui

    2017-03-01

    The vestibular blood-labyrinth barrier (BLB) is comprised of perivascular-resident macrophage-like melanocytes (PVM/Ms) and pericytes (PCs), in addition to endothelial cells (ECs) and basement membrane (BM), and bears strong resemblance to the cochlear BLB in the stria vascularis. Over the past few decades, in vitro cell-based models have been widely used in blood-brain barrier (BBB) and blood-retina barrier (BRB) research, and have proved to be powerful tools for studying cell-cell interactions in their respective organs. Study of both the vestibular and strial BLB has been limited by the unavailability of primary culture cells from these barriers. To better understand how barrier component cells interact in the vestibular system to control BLB function, we developed a novel culture medium-based method for obtaining EC, PC, and PVM/M primary cells from tiny explants of the semicircular canal, sacculus, utriculus, and ampullae tissue of young mouse ears at post-natal age 8-12 d. Each phenotype is grown in a specific culture medium which selectively supports the phenotype in a mixed population of vestibular cell types. The unwanted phenotypes do not survive passaging. The protocol does not require additional equipment or special enzyme treatment. The harvesting process takes less than 2 h. Primary cell types are generated within 7-10 d. The primary culture ECs, PCs, and PVM/M shave consistent phenotypes more than 90% pure after two passages (∼ 3 weeks). The highly purified primary cell lines can be used for studying cell-cell interactions, barrier permeability, and angiogenesis. Copyright © 2017 Elsevier B.V. All rights reserved.

  10. A spontaneous and novel Pax3 mutant mouse that models Waardenburg syndrome and neural tube defects.

    Science.gov (United States)

    Ohnishi, Tetsuo; Miura, Ikuo; Ohba, Hisako; Shimamoto, Chie; Iwayama, Yoshimi; Wakana, Shigeharu; Yoshikawa, Takeo

    2017-04-05

    Genes responsible for reduced pigmentation phenotypes in rodents are associated with human developmental defects, such as Waardenburg syndrome, where patients display congenital deafness along with various abnormalities mostly related to neural crest development deficiency. In this study, we identified a spontaneous mutant mouse line Rwa, which displays variable white spots on mouse bellies and white digits and tail, on a C57BL/6N genetic background. Curly tail and spina bifida were also observed, although at a lower penetrance. These phenotypes were dominantly inherited by offspring. We searched for the genetic mechanism of the observed phenotypes. We harnessed a rapid mouse gene mapping system newly developed in our laboratories to identify a responsible gene. We detected a region within chromosome 1 as a probable locus for the causal mutation. Dense mapping using interval markers narrowed the locus down to a 670-kbp region, containing four genes including Pax3, a gene known to be implicated in the types I and III Waardenburg syndrome. Extensive mutation screening of Pax3 detected an 841-bp deletion, spanning the promoter region and intron 1 of the gene. The defective allele of Pax3, named Pax3 Rwa , lacked the first coding exon and co-segregated perfectly with the phenotypes, confirming its causal nature. The genetic background of Rwa mice is almost identical to that of inbred C57BL/6N. These results highlight Pax3 Rwa mice as a beneficial tool for analyzing biological processes involving Pax3, in particular the development and migration of neural crest cells and melanocytes. Copyright © 2017 Elsevier B.V. All rights reserved.

  11. Interacting neural networks

    Science.gov (United States)

    Metzler, R.; Kinzel, W.; Kanter, I.

    2000-08-01

    Several scenarios of interacting neural networks which are trained either in an identical or in a competitive way are solved analytically. In the case of identical training each perceptron receives the output of its neighbor. The symmetry of the stationary state as well as the sensitivity to the used training algorithm are investigated. Two competitive perceptrons trained on mutually exclusive learning aims and a perceptron which is trained on the opposite of its own output are examined analytically. An ensemble of competitive perceptrons is used as decision-making algorithms in a model of a closed market (El Farol Bar problem or the Minority Game. In this game, a set of agents who have to make a binary decision is considered.); each network is trained on the history of minority decisions. This ensemble of perceptrons relaxes to a stationary state whose performance can be better than random.

  12. Neural circuitry and immunity

    Science.gov (United States)

    Pavlov, Valentin A.; Tracey, Kevin J.

    2015-01-01

    Research during the last decade has significantly advanced our understanding of the molecular mechanisms at the interface between the nervous system and the immune system. Insight into bidirectional neuroimmune communication has characterized the nervous system as an important partner of the immune system in the regulation of inflammation. Neuronal pathways, including the vagus nerve-based inflammatory reflex are physiological regulators of immune function and inflammation. In parallel, neuronal function is altered in conditions characterized by immune dysregulation and inflammation. Here, we review these regulatory mechanisms and describe the neural circuitry modulating immunity. Understanding these mechanisms reveals possibilities to use targeted neuromodulation as a therapeutic approach for inflammatory and autoimmune disorders. These findings and current clinical exploration of neuromodulation in the treatment of inflammatory diseases defines the emerging field of Bioelectronic Medicine. PMID:26512000

  13. Neural Darwinism and consciousness.

    Science.gov (United States)

    Seth, Anil K; Baars, Bernard J

    2005-03-01

    Neural Darwinism (ND) is a large scale selectionist theory of brain development and function that has been hypothesized to relate to consciousness. According to ND, consciousness is entailed by reentrant interactions among neuronal populations in the thalamocortical system (the 'dynamic core'). These interactions, which permit high-order discriminations among possible core states, confer selective advantages on organisms possessing them by linking current perceptual events to a past history of value-dependent learning. Here, we assess the consistency of ND with 16 widely recognized properties of consciousness, both physiological (for example, consciousness is associated with widespread, relatively fast, low amplitude interactions in the thalamocortical system), and phenomenal (for example, consciousness involves the existence of a private flow of events available only to the experiencing subject). While no theory accounts fully for all of these properties at present, we find that ND and its recent extensions fare well.

  14. N-terminal fatty acylated His-dPhe-Arg-Trp-NH(2) tetrapeptides: influence of fatty acid chain length on potency and selectivity at the mouse melanocortin receptors and human melanocytes.

    Science.gov (United States)

    Todorovic, Aleksandar; Holder, Jerry Ryan; Bauzo, Rayna M; Scott, Joseph Walker; Kavanagh, Renny; Abdel-Malek, Zalfa; Haskell-Luevano, Carrie

    2005-05-05

    The melanocortin system is involved in the regulation of a diverse number of physiologically important pathways including pigmentation, feeding behavior, weight and energy homeostasis, inflammation, and sexual function. All the endogenous melanocortin agonist ligands possess the conserved His-Phe-Arg-Trp tetrapeptide sequence that is postulated to be important for melanocortin receptor molecular recognition and stimulation. Previous studies by our laboratory resulted in the discovery that increasing alkyl chain length at the N-terminal "capping" region of the His-dPhe-Arg-Trp-NH(2) tetrapeptide resulted in a 100-fold increased melanocortin receptor agonist potency. This study was undertaken to systematically evaluate the pharmacological effects of increasing N-capping alkyl chain length of the CH(3)(CH(2))(n)CO-His-dPhe-Arg-Trp-NH(2) (n = 6-16) tetrapeptide template. Twelve analogues were synthesized and pharmacologically characterized at the mouse melanocortin receptors MC1R and MC3R-MC5R and human melanocytes known to express the MC1R. These peptides demonstrated melanocortin receptor selectivity profiles different from those of previously published tetrapeptides. The most notable results of enhanced ligand potency (20- to 200-fold) and receptor selectivity were observed at the MC1R. Tetrapeptides that possessed greater than nine alkyl groups were superior to alpha-MSH in terms of the stimulation of human melanocyte tyrosinase activity. Additionally, the n-pentadecanoyl derivative had a residual effect on tyrosinase activity that existed for at least 4 days after the peptide was removed from the human melanocyte culture medium. These data demonstrate the utility, potency, and residual effect of melanocortin tetrapeptides by adding N-terminal fatty acid moieties.

  15. Program Helps Simulate Neural Networks

    Science.gov (United States)

    Villarreal, James; Mcintire, Gary

    1993-01-01

    Neural Network Environment on Transputer System (NNETS) computer program provides users high degree of flexibility in creating and manipulating wide variety of neural-network topologies at processing speeds not found in conventional computing environments. Supports back-propagation and back-propagation-related algorithms. Back-propagation algorithm used is implementation of Rumelhart's generalized delta rule. NNETS developed on INMOS Transputer(R). Predefines back-propagation network, Jordan network, and reinforcement network to assist users in learning and defining own networks. Also enables users to configure other neural-network paradigms from NNETS basic architecture. Small portion of software written in OCCAM(R) language.

  16. Artificial Neural Network Analysis System

    Science.gov (United States)

    2001-02-27

    Contract No. DASG60-00-M-0201 Purchase request no.: Foot in the Door-01 Title Name: Artificial Neural Network Analysis System Company: Atlantic... Artificial Neural Network Analysis System 5b. GRANT NUMBER 5c. PROGRAM ELEMENT NUMBER 6. AUTHOR(S) Powell, Bruce C 5d. PROJECT NUMBER 5e. TASK NUMBER...34) 27-02-2001 Report Type N/A Dates Covered (from... to) ("DD MON YYYY") 28-10-2000 27-02-2001 Title and Subtitle Artificial Neural Network Analysis

  17. Cooperating attackers in neural cryptography.

    Science.gov (United States)

    Shacham, Lanir N; Klein, Einat; Mislovaty, Rachel; Kanter, Ido; Kinzel, Wolfgang

    2004-06-01

    A successful attack strategy in neural cryptography is presented. The neural cryptosystem, based on synchronization of neural networks by mutual learning, has been recently shown to be secure under different attack strategies. The success of the advanced attacker presented here, called the "majority-flipping attacker," does not decay with the parameters of the model. This attacker's outstanding success is due to its using a group of attackers which cooperate throughout the synchronization process, unlike any other attack strategy known. An analytical description of this attack is also presented, and fits the results of simulations.

  18. Creative-Dynamics Approach To Neural Intelligence

    Science.gov (United States)

    Zak, Michail A.

    1992-01-01

    Paper discusses approach to mathematical modeling of artificial neural networks exhibiting complicated behaviors reminiscent of creativity and intelligence of biological neural networks. Neural network treated as non-Lipschitzian dynamical system - as described in "Non-Lipschitzian Dynamics For Modeling Neural Networks" (NPO-17814). System serves as tool for modeling of temporal-pattern memories and recognition of complicated spatial patterns.

  19. Neural components of altruistic punishment

    Directory of Open Access Journals (Sweden)

    Emily eDu

    2015-02-01

    Full Text Available Altruistic punishment, which occurs when an individual incurs a cost to punish in response to unfairness or a norm violation, may play a role in perpetuating cooperation. The neural correlates underlying costly punishment have only recently begun to be explored. Here we review the current state of research on the neural basis of altruism from the perspectives of costly punishment, emphasizing the importance of characterizing elementary neural processes underlying a decision to punish. In particular, we emphasize three cognitive processes that contribute to the decision to altruistically punish in most scenarios: inequity aversion, cost-benefit calculation, and social reference frame to distinguish self from others. Overall, we argue for the importance of understanding the neural correlates of altruistic punishment with respect to the core computations necessary to achieve a decision to punish.

  20. Neural complexity, dissociation, and schizophrenia

    Czech Academy of Sciences Publication Activity Database

    Bob, P.; Šusta, M.; Chládek, Jan; Glaslová, K.; Fedor-Ferybergh, P.

    2007-01-01

    Roč. 13, č. 10 (2007), HY1-5 ISSN 1234-1010 Institutional research plan: CEZ:AV0Z20650511 Keywords : neural complexity * dissociation * schizophrenia Subject RIV: FH - Neurology Impact factor: 1.607, year: 2007

  1. Neural Networks in Control Applications

    DEFF Research Database (Denmark)

    Sørensen, O.

    The intention of this report is to make a systematic examination of the possibilities of applying neural networks in those technical areas, which are familiar to a control engineer. In other words, the potential of neural networks in control applications is given higher priority than a detailed...... study of the networks themselves. With this end in view the following restrictions have been made: - Amongst numerous neural network structures, only the Multi Layer Perceptron (a feed-forward network) is applied. - Amongst numerous training algorithms, only four algorithms are examined, all...... in a recursive form (sample updating). The simplest is the Back Probagation Error Algorithm, and the most complex is the recursive Prediction Error Method using a Gauss-Newton search direction. - Over-fitting is often considered to be a serious problem when training neural networks. This problem is specifically...

  2. Complex-Valued Neural Networks

    CERN Document Server

    Hirose, Akira

    2012-01-01

    This book is the second enlarged and revised edition of the first successful monograph on complex-valued neural networks (CVNNs) published in 2006, which lends itself to graduate and undergraduate courses in electrical engineering, informatics, control engineering, mechanics, robotics, bioengineering, and other relevant fields. In the second edition the recent trends in CVNNs research are included, resulting in e.g. almost a doubled number of references. The parametron invented in 1954 is also referred to with discussion on analogy and disparity. Also various additional arguments on the advantages of the complex-valued neural networks enhancing the difference to real-valued neural networks are given in various sections. The book is useful for those beginning their studies, for instance, in adaptive signal processing for highly functional sensing and imaging, control in unknown and changing environment, robotics inspired by human neural systems, and brain-like information processing, as well as interdisciplina...

  3. Artificial intelligence: Deep neural reasoning

    Science.gov (United States)

    Jaeger, Herbert

    2016-10-01

    The human brain can solve highly abstract reasoning problems using a neural network that is entirely physical. The underlying mechanisms are only partially understood, but an artificial network provides valuable insight. See Article p.471

  4. Optical Neural Network Classifier Architectures

    National Research Council Canada - National Science Library

    Getbehead, Mark

    1998-01-01

    We present an adaptive opto-electronic neural network hardware architecture capable of exploiting parallel optics to realize real-time processing and classification of high-dimensional data for Air...

  5. Memristor-based neural networks

    International Nuclear Information System (INIS)

    Thomas, Andy

    2013-01-01

    The synapse is a crucial element in biological neural networks, but a simple electronic equivalent has been absent. This complicates the development of hardware that imitates biological architectures in the nervous system. Now, the recent progress in the experimental realization of memristive devices has renewed interest in artificial neural networks. The resistance of a memristive system depends on its past states and exactly this functionality can be used to mimic the synaptic connections in a (human) brain. After a short introduction to memristors, we present and explain the relevant mechanisms in a biological neural network, such as long-term potentiation and spike time-dependent plasticity, and determine the minimal requirements for an artificial neural network. We review the implementations of these processes using basic electric circuits and more complex mechanisms that either imitate biological systems or could act as a model system for them. (topical review)

  6. Spinal cord self-repair during tail regeneration in Polypedates maculatus and putative role of FGF1 as a neurotrophic factor.

    Science.gov (United States)

    Hota, Jutshina; Pati, Sushri Sangita; Mahapatra, Pravati Kumari

    2018-03-01

    Spinal cord injury could be fatal in man and often results in irreversible medical conditions affecting mobility. However, anuran amphibians win over such pathological condition by the virtue of regeneration abilities. The tail of anuran tadpoles therefore allures researchers to study spinal cord injury and self- repair process. In the present study, we inflicted injury to the spinal cord by means of surgical transection of the tail and investigated the self-repair activity in the tadpoles of the Indian tree frog Polypedates maculatus. We also demonstrate for the first time by immunofluorescence localization the expression pattern of Fibroblast Growth Factor1 (FGF1) during spinal cord regeneration which has not been documented earlier in anurans. FGF1, bearer of the mitogenic and neurotrophic properties seems to be expressed by progenitor cells that facilitate regeneration. Spinal cord during tail regeneration in P. maculatus attains functional recovery within a span of 2 weeks thus enabling the organism to survive in an aquatic medium till metamorphosis. Moreover, during the course of spinal cord regeneration in the regenerating tail, melanocytes showed an interesting behaviour as these neural crest derivatives were missing near the early regenerates until their reappearance where they were positioned in close proximity with the regenerated spinal cord as in the normal tail. Copyright © 2017 Elsevier B.V. All rights reserved.

  7. Sequential neural models with stochastic layers

    DEFF Research Database (Denmark)

    Fraccaro, Marco; Sønderby, Søren Kaae; Paquet, Ulrich

    2016-01-01

    How can we efficiently propagate uncertainty in a latent state representation with recurrent neural networks? This paper introduces stochastic recurrent neural networks which glue a deterministic recurrent neural network and a state space model together to form a stochastic and sequential neural...... generative model. The clear separation of deterministic and stochastic layers allows a structured variational inference network to track the factorization of the model's posterior distribution. By retaining both the nonlinear recursive structure of a recurrent neural network and averaging over...

  8. Implantable Neural Interfaces for Sharks

    Science.gov (United States)

    2007-05-01

    technology for recording and stimulating from the auditory and olfactory sensory nervous systems of the awake, swimming nurse shark , G. cirratum (Figures...overlay of the central nervous system of the nurse shark on a horizontal MR image. Implantable Neural Interfaces for Sharks ...Neural Interfaces for Characterizing Population Responses to Odorants and Electrical Stimuli in the Nurse Shark , Ginglymostoma cirratum.” AChemS Abs

  9. What are artificial neural networks?

    DEFF Research Database (Denmark)

    Krogh, Anders

    2008-01-01

    Artificial neural networks have been applied to problems ranging from speech recognition to prediction of protein secondary structure, classification of cancers and gene prediction. How do they work and what might they be good for? Udgivelsesdato: 2008-Feb......Artificial neural networks have been applied to problems ranging from speech recognition to prediction of protein secondary structure, classification of cancers and gene prediction. How do they work and what might they be good for? Udgivelsesdato: 2008-Feb...

  10. Evaluation of new Tc-99m-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone peptides for melanoma imaging.

    Science.gov (United States)

    Flook, Adam M; Yang, Jianquan; Miao, Yubin

    2013-09-03

    The purpose of this study was to examine the melanoma targeting and imaging properties of two new (99m)Tc-labeled Arg-X-Asp-conjugated α-melanocyte stimulating hormone (α-MSH) peptides. RTD-Lys-(Arg(11))CCMSH {c[Asp-Arg-Thr-Asp-DTyr]-Lys-Cys-Cys-Glu-His-DPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2} and RVD-Lys-(Arg(11))CCMSH peptides were synthesized, and their melanocortin-1 (MC1) receptor binding affinities were determined in B16/F1 melanoma cells. The biodistribution and melanoma imaging properties of (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The IC50 values of RTD-Lys-(Arg(11))CCMSH and RVD-Lys-(Arg(11))CCMSH were 0.7 ± 0.07 and 1.0 ± 0.3 nM in B16/F1 melanoma cells. Both (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH displayed high melanoma uptake. (99m)Tc-RTD-Lys-(Arg(11))CCMSH exhibited the highest tumor uptake of 18.77 ± 5.13% ID/g at 2 h postinjection, whereas (99m)Tc-RVD-Lys-(Arg(11))CCMSH reached the highest tumor uptake of 19.63 ± 4.68% ID/g at 4 h postinjection. Both (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH showed low accumulation in normal organs (<1.7% ID/g) except for the kidneys at 2 h postinjection. The renal uptake of (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH was 135.14 ± 23.62 and 94.01 ± 18.31% ID/g at 2 h postinjection, respectively. The melanoma lesions were clearly visualized by single-photon emission computed tomography (SPECT)/CT using either (99m)Tc-RTD-Lys-(Arg(11))CCMSH or (99m)Tc-RVD-Lys-(Arg(11))CCMSH as an imaging probe at 2 h postinjection. Overall, the introduction of Thr or Val residue retained high melanoma uptake of (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH. However, high renal uptake of (99m)Tc-RTD-Lys-(Arg(11))CCMSH and (99m)Tc-RVD-Lys-(Arg(11))CCMSH need to be reduced to facilitate their future applications.

  11. Melanoma targeting with alpha-melanocyte stimulating hormone analogs labeled with fac-[99mTc(CO)3]+: effect of cyclization on tumor-seeking properties.

    Science.gov (United States)

    Raposinho, Paula D; Xavier, Catarina; Correia, João D G; Falcão, Soraia; Gomes, Paula; Santos, Isabel

    2008-03-01

    Early detection of primary melanoma tumors is essential because there is no effective treatment for metastatic melanoma. Several linear and cyclic radiolabeled alpha-melanocyte stimulating hormone (alpha-MSH) analogs have been proposed to target the melanocortin type 1 receptor (MC1R) overexpressed in melanoma. The compact structure of a rhenium-cyclized alpha-MSH analog (Re-CCMSH) significantly enhanced its in vivo tumor uptake and retention. Melanotan II (MT-II), a cyclic lactam analog of alpha-MSH (Ac-Nle-cyclo[Asp-His-DPhe-Arg-Trp-Lys]-NH2]), is a very potent and stable agonist peptide largely used in the characterization of melanocortin receptors. Taking advantage of the superior biological features associated with the MT-II cyclic peptide, we assessed the effect of lactam-based cyclization on the tumor-seeking properties of alpha-MSH analogs by comparing the pharmacokinetics profile of the 99mTc-labeled cyclic peptide betaAla-Nle-cyclo[Asp-His-D-Phe-Arg-Trp-Lys]-NH2 with that of the linear analog betaAla-Nle-Asp-His-DPhe-Arg-Trp-Lys-NH2 in melanoma-bearing mice. We have synthesized and coupled the linear and cyclic peptides to a bifunctional chelator containing a pyrazolyl-diamine backbone (pz) through the amino group of betaAla, and the resulting pz-peptide conjugates were reacted with the fac-[99mTc(CO)3]+ moiety. The 99mTc(CO)3-labeled conjugates were obtained in high yield, high specific activity, and high radiochemical purity. The cyclic 99mTc(CO)3-labeled conjugate presents a remarkable internalization (87.1% of receptor-bound tracer and 50.5% of total applied activity, after 6 h at 37 degrees C) and cellular retention (only 24.7% released from the cells after 5 h) in murine melanoma B16F1 cells. A significant tumor uptake and retention was obtained in melanoma-bearing C57BL6 mice for the cyclic radioconjugate [9.26 +/- 0.83 and 11.31 +/- 1.83% ID/g at 1 and 4 h after injection, respectively]. The linear 99mTc(CO)3-pz-peptide presented lower values for

  12. Effect of DOTA position on melanoma targeting and pharmacokinetic properties of 111In-labeled lactam bridge-cyclized alpha-melanocyte stimulating hormone peptide.

    Science.gov (United States)

    Guo, Haixun; Yang, Jianquan; Gallazzi, Fabio; Prossnitz, Eric R; Sklar, Larry A; Miao, Yubin

    2009-11-01

    The purpose of this study was to examine the effect of DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) position on melanoma targeting and pharmacokinetics of radiolabeled lactam bridge-cyclized alpha-melanocyte stimulating hormone (alpha-MSH) peptide. A novel lactam bridge-cyclized alpha-MSH peptide, Ac-GluGlu-CycMSH[DOTA] {Ac-Glu-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Lys(DOTA)]}, was synthesized using standard 9-fluorenylmethyloxycarbonyl (Fmoc) chemistry. DOTA was directly attached to the alpha-amino group of Lys in the cyclic ring, while the N-terminus of the peptide was acetylated to generate Ac-GluGlu-CycMSH[DOTA]. The MC1 receptor binding affinity of Ac-GluGlu-CycMSH[DOTA] was determined in B16/F1 melanoma cells. Melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In were determined in B16/F1 melanoma-bearing C57 mice and compared to that of 111In-DOTA-Gly-Glu-c[Lys-Nle-Glu-His-DPhe-Arg-Trp-Gly-Arg-Pro-Val-Asp] (111In-DOTA-GlyGlu-CycMSH; DOTA was coupled to the N-terminus of the peptide). Ac-GluGlu-CycMSH[DOTA] displayed 0.6 nM MC1 receptor binding affinity in B16/F1 cells. Ac-GluGlu-CycMSH[DOTA]-111In was readily prepared with greater than 95% radiolabeling yield. Ac-GluGlu-CycMSH[DOTA]-111In exhibited high tumor uptake (11.42 +/- 2.20% ID/g 2 h postinjection) and prolonged tumor retention (9.42 +/- 2.41% ID/g 4 h postinjection) in B16/F1 melanoma-bearing C57 mice. The uptake values for nontarget organs were generally low (<1.3% ID/g) except for the kidneys 2, 4, and 24 h postinjection. DOTA position exhibited profound effect on melanoma targeting and pharmacokinetic properties of Ac-GluGlu-CycMSH[DOTA]-111In, providing a new insight into the design of lactam bridge-cyclized peptide for melanoma imaging and therapy.

  13. Complex microcirculation patterns detected by confocal indocyanine green angiography predict time to growth of small choroidal melanocytic tumors: MuSIC Report II.

    Science.gov (United States)

    Mueller, Arthur J; Freeman, William R; Schaller, Ulrich C; Kampik, Anselm; Folberg, Robert

    2002-12-01

    Multiple independent laboratories have confirmed the histologic observation that some tumor microcirculation patterns (MCPs) in uveal melanomas are associated strongly with death resulting from metastatic disease. Because these patterns are imageable with confocal indocyanine green angiography (ICG), we designed a prospective study to evaluate whether these angiographically detectable MCPs predict time to tumor growth. Observational case series, prospective, non-randomized. Ninety-eight patients with unilateral, small, choroidal melanocytic tumors. The following information and tumor characteristics were recorded for each patient: demographic parameters, best-corrected visual acuity, intraocular pressure, related visual symptoms, location and dimension of tumor, pigmentation, orange pigment, drusen, tumor-associated hemorrhage, subretinal fluid, and confocal ICG angiographically determined microcirculation patterns-silent (avascularity), normal (preexisting normal choroidal vessels within the tumor), straight vessels, parallel without and with cross-linking, arcs without and with branching, loops, and networks. Time to growth of the tumor, with growth defined as an increase in the maximal apical tumor height of 0.5 mm measured by standardized A-scan ultrasonography, photographic documentation of an increase of the largest basal diameter of at least 1.5 mm, advancement of one tumor border of at least 0.75 mm, or a combination thereof. Twenty-eight of the 98 tumors in this study (29%) met the predetermined criteria for tumor growth. The median time to growth was 127 days (range, 51-625 days). The following tumor characteristics were significantly associated with time to tumor growth: flashes (P = 0.0224), orange pigment (P = 0.012), subretinal fluid (P < 0.001), maximum basal tumor diameter at initial examination (P = 0.015), maximum apical tumor height (P < 0.001), parallel with cross-linking MCP (P < 0.001), arcs with branching MCP (P = 0.006), loops (P < 0

  14. The modulatory role of alpha-melanocyte stimulating hormone administered spinally in the regulation of blood glucose level in d-glucose-fed and restraint stress mouse models.

    Science.gov (United States)

    Sim, Yun-Beom; Park, Soo-Hyun; Kim, Sung-Su; Lim, Su-Min; Jung, Jun-Sub; Suh, Hong-Won

    2014-08-01

    Alpha-melanocyte stimulating hormone (α-MSH) is known as a regulator of the blood glucose homeostasis and food intake. In the present study, the possible roles of α-MSH located in the spinal cord in the regulation of the blood glucose level were investigated in d-glucose-fed and immobilization stress (IMO) mouse models. We found in the present study that intrathecal (i.t.) injection with α-MSH alone did not affect the blood glucose level. However, i.t. administration with α-MSH reduced the blood glucose level in d-glucose-fed model. The plasma insulin level was increased in d-glucose-fed model and was further increased by α-MSH, whereas α-MSH did not affect plasma corticosterone level in d-glucose-fed model. In addition, i.t. administration with glucagon alone enhanced blood glucose level and, i.t. injection with glucagon also increased the blood glucose level in d-glucose-fed model. In contrasted to results observed in d-glucose-fed model, i.t. treatment with α-MSH caused enhancement of the blood glucose level in IMO model. The plasma insulin level was increased in IMO model. The increased plasma insulin level by IMO was reduced by i.t. treatment with α-MSH, whereas i.t. pretreatment with α-MSH did not affect plasma corticosterone level in IMO model. Taken together, although spinally located α-MSH itself does not alter the blood glucose level, our results suggest that the activation of α-MSH system located in the spinal cord play important modulatory roles for the reduction of the blood glucose level in d-glucose fed model whereas α-MSH is responsible for the up-regulation of the blood glucose level in IMO model. The enhancement of insulin release may be responsible for modulatory action of α-MSH in down-regulation of the blood glucose in d-glucose fed model whereas reduction of insulin release may be responsible for modulatory action of α-MSH in up-regulation of the blood glucose in IMO model. Copyright © 2014 Elsevier Ltd. All rights reserved.

  15. Melanoma targeting with [99mTc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analogs: Effects of cyclization on the radiopharmaceutical properties

    International Nuclear Information System (INIS)

    Carta, Davide; Salvarese, Nicola; Morellato, Nicolò; Gao, Feng; Sihver, Wiebke; Pietzsch, Hans Jurgen; Biondi, Barbara; Ruzza, Paolo; Refosco, Fiorenzo; Carpanese, Debora; Rosato, Antonio; Bolzati, Cristina

    2016-01-01

    The purpose of this study was to evaluate the effect of cyclization on the biological profile of a [ 99m Tc(N)(PNP3)]-labeled α-melanocyte stimulating hormone peptide analog. A lactam bridge-cyclized H-Cys-Ahx-βAla 3 -c[Lys 4 -Glu-His-D-Phe-Arg-Trp-Glu 10 ]-Arg 11 -Pro-Val-NH 2 (NAP―NS2) and the corresponding linear H-Cys-Ahx-βAla-Nle-Asp-His-D-Phe-Arg-Trp-Gly-NH 2 (NAP―NS1) peptide were synthetized, characterized by ESI-MS spectroscopy and their melanocortin-1 receptor (MC1R) binding affinity was determined in B16/F10 melanoma cells. The consistent [ 99m Tc(N)(PNP3)]-labeled compounds were readily obtained in high specific activity and their stability and biological properties were assessed. As an example, the chemical identity of [ 99m Tc(N)(NAP–NS1)(PNP3)] + was confirmed by carrier added experiments supported by radio/UV HPLC analysis combined with ESI(+)-MS. Compared with the linear peptide, cyclization negatively affected the biological properties of NAP–NS2 peptide by reducing its binding affinity for MC1R and by decreasing the overall excretion rate of the corresponding [ 99m Tc(N)(PNP3)]-labeled peptide from the body as well as its in vivo stability. [ 99m Tc(N)(NAP–NS1)(PNP3)] + was evaluated for its potential as melanoma imaging probe in murine melanoma model. Data from in vitro and in vivo studies on B16/F10 melanoma model of [ 99m Tc(N)(NAP–NS1)(PNP3)] + clearly evidenced that the radiolabeled linear peptide keeps its biological properties up on the conjugation to the [ 99m Tc(N)(PNP3)]-building block. The progressive increase of the tumor-to-nontarget ratios over the time indicates a quite stable interaction between the radio-complex and the MC1R.

  16. Alpha-Melanocyte-Stimulating Hormone and Agouti-Related Protein: Do They Play a Role in Appetite Regulation in Childhood Obesity?

    Science.gov (United States)

    Vehapoğlu, Aysel; Türkmen, Serdar; Terzioğlu, Şule

    2016-03-05

    The hypothalamus plays a crucial role in the regulation of feeding behavior. The anorexigenic neuropeptide alpha-melanocyte-stimulating hormone (α-MSH) and the orexigenic neuropeptide agouti-related protein (AgRP) are among the major peptides produced in the hypothalamus. This study investigated the plasma concentrations of α-MSH and AgRP in underweight and obese children and their healthy peers. The associations between α-MSH and AgRP levels and anthropometric and nutritional markers of malnutrition and obesity were also assessed. Healthy sex-matched subjects aged 2 to 12 years were divided into 3 groups, as underweight (n=57), obese (n=61), and of normal weight (n=57). Plasma fasting concentrations of α-MSH and AgRP were measured by enzyme-linked immunosorbent assay. The differences between the three groups as to the relationships between plasma concentrations of α-MSH and AgRP and anthropometric data, serum biochemical parameters and homeostatic model assessment of insulin resistance were evaluated. Obese children had significantly lower α-MSH levels than underweight (1194±865 vs. 1904±1312 ng/mL, p=0.006) and normal weight (1194±865 vs. 1762±1463 ng/mL, p=0.036) children; there were no significant differences in the α-MSH levels between the underweight and normal weight children (p=0.811). Also, no significant differences were observed between the underweight and obese children regarding the AgRP levels (742±352 vs. 828±417 ng/mL, p=0.125). We found a significant positive correlation between plasma α-MSH and AgRP levels across the entire sample. This study is the first to demonstrate body weight-related differences in α-MSH and AgRP levels in children. Circulating plasma α-MSH levels in obese children were markedly lower than those of underweight and normal-weight children. This suggests that α-MSH could play a role in appetite regulation.

  17. Profiles of alpha-melanocyte-stimulating hormone in the Japanese flounder as revealed by a newly developed time-resolved fluoroimmunoassay and immunohistochemistry.

    Science.gov (United States)

    Amiya, Noriko; Amano, Masafumi; Takahashi, Akiyoshi; Yamanome, Takeshi; Yamamori, Kunio

    2007-03-01

    Profiles of alpha-melanocyte-stimulating hormone (alpha-MSH) in the Japanese flounder were examined by a newly developed time-resolved fluoroimmunoassay (TR-FIA) and immunohistochemistry. A TR-FIA for alpha-MSH was newly developed, and its levels in the pituitary gland and plasma of Japanese flounder reared in a white or black tank for 5 months were compared. A competitive assay using two antibodies was performed among secondary antibodies in the solid phase, alpha-MSH antibodies, samples, and europium-labeled Des-Ac-alpha-MSH. The sensitivity of the assay, defined as twice the standard deviation at a zero dose, was 0.98 ng/ml (49 pg/well). The intra- and interassay coefficients of variation of the assay were 8.8% (n=8) and 17.3% (n=5), respectively, at about 50% binding. Cross-reactivities of Des-Ac-alpha-MSH and Di-Ac-alpha-MSH were about 100%. Cross-reactivities of adrenocorticotropic hormone, salmon gonadotropin-releasing hormone (sGnRH), and chicken GnRH-II were less than 0.2%, and that of melanin-concentrating hormone was less than 2.0% at 50% binding. Displacement curves of serially twofold-diluted hypothalamus extract, pituitary gland extract, and plasma extract of Japanese flounder with the assay buffer were parallel to the alpha-MSH standard curve. Moreover, displacement curves of serially twofold-diluted hypothalamus and/or pituitary gland extract of masu salmon, goldfish, red seabream, Japanese eel, tiger puffer, and barfin flounder with the assay buffer were also parallel to the alpha-MSH standard. In Japanese flounder, total immunoreactive (ir)-alpha-MSH levels in the pituitary gland were lower in the black tank, whereas those in the plasma tended to be higher in the black tank, suggesting that the synthesis and release of alpha-MSH are higher in the black tank. alpha-MSH-ir cells were detected in the pars intermedia and a small part of the pars distalis of the pituitary gland. alpha-MSH-ir cell bodies were located in the basal hypothalamus and alpha

  18. Neural correlates of hate.

    Directory of Open Access Journals (Sweden)

    Semir Zeki

    Full Text Available In this work, we address an important but unexplored topic, namely the neural correlates of hate. In a block-design fMRI study, we scanned 17 normal human subjects while they viewed the face of a person they hated and also faces of acquaintances for whom they had neutral feelings. A hate score was obtained for the object of hate for each subject and this was used as a covariate in a between-subject random effects analysis. Viewing a hated face resulted in increased activity in the medial frontal gyrus, right putamen, bilaterally in premotor cortex, in the frontal pole and bilaterally in the medial insula. We also found three areas where activation correlated linearly with the declared level of hatred, the right insula, right premotor cortex and the right fronto-medial gyrus. One area of deactivation was found in the right superior frontal gyrus. The study thus shows that there is a unique pattern of activity in the brain in the context of hate. Though distinct from the pattern of activity that correlates with romantic love, this pattern nevertheless shares two areas with the latter, namely the putamen and the insula.

  19. neural control system

    International Nuclear Information System (INIS)

    Elshazly, A.A.E.

    2002-01-01

    Automatic power stabilization control is the desired objective for any reactor operation , especially, nuclear power plants. A major problem in this area is inevitable gap between a real plant ant the theory of conventional analysis and the synthesis of linear time invariant systems. in particular, the trajectory tracking control of a nonlinear plant is a class of problems in which the classical linear transfer function methods break down because no transfer function can represent the system over the entire operating region . there is a considerable amount of research on the model-inverse approach using feedback linearization technique. however, this method requires a prices plant model to implement the exact linearizing feedback, for nuclear reactor systems, this approach is not an easy task because of the uncertainty in the plant parameters and un-measurable state variables . therefore, artificial neural network (ANN) is used either in self-tuning control or in improving the conventional rule-based exper system.the main objective of this thesis is to suggest an ANN, based self-learning controller structure . this method is capable of on-line reinforcement learning and control for a nuclear reactor with a totally unknown dynamics model. previously, researches are based on back- propagation algorithm . back -propagation (BP), fast back -propagation (FBP), and levenberg-marquardt (LM), algorithms are discussed and compared for reinforcement learning. it is found that, LM algorithm is quite superior

  20. Influence of neural adaptation on dynamics and equilibrium state of neural activities in a ring neural network

    Science.gov (United States)

    Takiyama, Ken

    2017-12-01

    How neural adaptation affects neural information processing (i.e. the dynamics and equilibrium state of neural activities) is a central question in computational neuroscience. In my previous works, I analytically clarified the dynamics and equilibrium state of neural activities in a ring-type neural network model that is widely used to model the visual cortex, motor cortex, and several other brain regions. The neural dynamics and the equilibrium state in the neural network model corresponded to a Bayesian computation and statistically optimal multiple information integration, respectively, under a biologically inspired condition. These results were revealed in an analytically tractable manner; however, adaptation effects were not considered. Here, I analytically reveal how the dynamics and equilibrium state of neural activities in a ring neural network are influenced by spike-frequency adaptation (SFA). SFA is an adaptation that causes gradual inhibition of neural activity when a sustained stimulus is applied, and the strength of this inhibition depends on neural activities. I reveal that SFA plays three roles: (1) SFA amplifies the influence of external input in neural dynamics; (2) SFA allows the history of the external input to affect neural dynamics; and (3) the equilibrium state corresponds to the statistically optimal multiple information integration independent of the existence of SFA. In addition, the equilibrium state in a ring neural network model corresponds to the statistically optimal integration of multiple information sources under biologically inspired conditions, independent of the existence of SFA.

  1. Direct Genesis of Functional Rodent and Human Schwann Cells from Skin Mesenchymal Precursors

    Directory of Open Access Journals (Sweden)

    Matthew P. Krause

    2014-07-01

    Full Text Available Recent reports of directed reprogramming have raised questions about the stability of cell lineages. Here, we have addressed this issue, focusing upon skin-derived precursors (SKPs, a dermally derived precursor cell. We show by lineage tracing that murine SKPs from dorsal skin originate from mesenchymal and not neural crest-derived cells. These mesenchymally derived SKPs can, without genetic manipulation, generate functional Schwann cells, a neural crest cell type, and are highly similar at the transcriptional level to Schwann cells isolated from the peripheral nerve. This is not a mouse-specific phenomenon, since human SKPs that are highly similar at the transcriptome level can be made from neural crest-derived facial and mesodermally derived foreskin dermis and the foreskin SKPs can make myelinating Schwann cells. Thus, nonneural crest-derived mesenchymal precursors can differentiate into bona fide peripheral glia in the absence of genetic manipulation, suggesting that developmentally defined lineage boundaries are more flexible than widely thought.

  2. Mutations in MITF and PAX3 Cause “Splashed White” and Other White Spotting Phenotypes in Horses

    Science.gov (United States)

    Blatter, Marlis; Brooks, Samantha A.; Burger, Dominik; Drögemüller, Cord; Gerber, Vincent; Henke, Diana; Janda, Jozef; Jude, Rony; Magdesian, K. Gary; Matthews, Jacqueline M.; Poncet, Pierre-André; Svansson, Vilhjálmur; Tozaki, Teruaki; Wilkinson-White, Lorna; Penedo, M. Cecilia T.; Rieder, Stefan; Leeb, Tosso

    2012-01-01

    During fetal development neural-crest-derived melanoblasts migrate across the entire body surface and differentiate into melanocytes, the pigment-producing cells. Alterations in this precisely regulated process can lead to white spotting patterns. White spotting patterns in horses are a complex trait with a large phenotypic variance ranging from minimal white markings up to completely white horses. The “splashed white” pattern is primarily characterized by an extremely large blaze, often accompanied by extended white markings at the distal limbs and blue eyes. Some, but not all, splashed white horses are deaf. We analyzed a Quarter Horse family segregating for the splashed white coat color. Genome-wide linkage analysis in 31 horses gave a positive LOD score of 1.6 in a region on chromosome 6 containing the PAX3 gene. However, the linkage data were not in agreement with a monogenic inheritance of a single fully penetrant mutation. We sequenced the PAX3 gene and identified a missense mutation in some, but not all, splashed white Quarter Horses. Genome-wide association analysis indicated a potential second signal near MITF. We therefore sequenced the MITF gene and found a 10 bp insertion in the melanocyte-specific promoter. The MITF promoter variant was present in some splashed white Quarter Horses from the studied family, but also in splashed white horses from other horse breeds. Finally, we identified two additional non-synonymous mutations in the MITF gene in unrelated horses with white spotting phenotypes. Thus, several independent mutations in MITF and PAX3 together with known variants in the EDNRB and KIT genes explain a large proportion of horses with the more extreme white spotting phenotypes. PMID:22511888

  3. Fractional Hopfield Neural Networks: Fractional Dynamic Associative Recurrent Neural Networks.

    Science.gov (United States)

    Pu, Yi-Fei; Yi, Zhang; Zhou, Ji-Liu

    2017-10-01

    This paper mainly discusses a novel conceptual framework: fractional Hopfield neural networks (FHNN). As is commonly known, fractional calculus has been incorporated into artificial neural networks, mainly because of its long-term memory and nonlocality. Some researchers have made interesting attempts at fractional neural networks and gained competitive advantages over integer-order neural networks. Therefore, it is naturally makes one ponder how to generalize the first-order Hopfield neural networks to the fractional-order ones, and how to implement FHNN by means of fractional calculus. We propose to introduce a novel mathematical method: fractional calculus to implement FHNN. First, we implement fractor in the form of an analog circuit. Second, we implement FHNN by utilizing fractor and the fractional steepest descent approach, construct its Lyapunov function, and further analyze its attractors. Third, we perform experiments to analyze the stability and convergence of FHNN, and further discuss its applications to the defense against chip cloning attacks for anticounterfeiting. The main contribution of our work is to propose FHNN in the form of an analog circuit by utilizing a fractor and the fractional steepest descent approach, construct its Lyapunov function, prove its Lyapunov stability, analyze its attractors, and apply FHNN to the defense against chip cloning attacks for anticounterfeiting. A significant advantage of FHNN is that its attractors essentially relate to the neuron's fractional order. FHNN possesses the fractional-order-stability and fractional-order-sensitivity characteristics.

  4. Neural network regulation driven by autonomous neural firings

    Science.gov (United States)

    Cho, Myoung Won

    2016-07-01

    Biological neurons naturally fire spontaneously due to the existence of a noisy current. Such autonomous firings may provide a driving force for network formation because synaptic connections can be modified due to neural firings. Here, we study the effect of autonomous firings on network formation. For the temporally asymmetric Hebbian learning, bidirectional connections lose their balance easily and become unidirectional ones. Defining the difference between reciprocal connections as new variables, we could express the learning dynamics as if Ising model spins interact with each other in magnetism. We present a theoretical method to estimate the interaction between the new variables in a neural system. We apply the method to some network systems and find some tendencies of autonomous neural network regulation.

  5. Neural networks and statistical learning

    CERN Document Server

    Du, Ke-Lin

    2014-01-01

    Providing a broad but in-depth introduction to neural network and machine learning in a statistical framework, this book provides a single, comprehensive resource for study and further research. All the major popular neural network models and statistical learning approaches are covered with examples and exercises in every chapter to develop a practical working understanding of the content. Each of the twenty-five chapters includes state-of-the-art descriptions and important research results on the respective topics. The broad coverage includes the multilayer perceptron, the Hopfield network, associative memory models, clustering models and algorithms, the radial basis function network, recurrent neural networks, principal component analysis, nonnegative matrix factorization, independent component analysis, discriminant analysis, support vector machines, kernel methods, reinforcement learning, probabilistic and Bayesian networks, data fusion and ensemble learning, fuzzy sets and logic, neurofuzzy models, hardw...

  6. Neural networks in signal processing

    International Nuclear Information System (INIS)

    Govil, R.

    2000-01-01

    Nuclear Engineering has matured during the last decade. In research and design, control, supervision, maintenance and production, mathematical models and theories are used extensively. In all such applications signal processing is embedded in the process. Artificial Neural Networks (ANN), because of their nonlinear, adaptive nature are well suited to such applications where the classical assumptions of linearity and second order Gaussian noise statistics cannot be made. ANN's can be treated as nonparametric techniques, which can model an underlying process from example data. They can also adopt their model parameters to statistical change with time. Algorithms in the framework of Neural Networks in Signal processing have found new applications potentials in the field of Nuclear Engineering. This paper reviews the fundamentals of Neural Networks in signal processing and their applications in tasks such as recognition/identification and control. The topics covered include dynamic modeling, model based ANN's, statistical learning, eigen structure based processing and generalization structures. (orig.)

  7. Principles of neural information processing

    CERN Document Server

    Seelen, Werner v

    2016-01-01

    In this fundamental book the authors devise a framework that describes the working of the brain as a whole. It presents a comprehensive introduction to the principles of Neural Information Processing as well as recent and authoritative research. The books´ guiding principles are the main purpose of neural activity, namely, to organize behavior to ensure survival, as well as the understanding of the evolutionary genesis of the brain. Among the developed principles and strategies belong self-organization of neural systems, flexibility, the active interpretation of the world by means of construction and prediction as well as their embedding into the world, all of which form the framework of the presented description. Since, in brains, their partial self-organization, the lifelong adaptation and their use of various methods of processing incoming information are all interconnected, the authors have chosen not only neurobiology and evolution theory as a basis for the elaboration of such a framework, but also syst...

  8. Neural Decoder for Topological Codes

    Science.gov (United States)

    Torlai, Giacomo; Melko, Roger G.

    2017-07-01

    We present an algorithm for error correction in topological codes that exploits modern machine learning techniques. Our decoder is constructed from a stochastic neural network called a Boltzmann machine, of the type extensively used in deep learning. We provide a general prescription for the training of the network and a decoding strategy that is applicable to a wide variety of stabilizer codes with very little specialization. We demonstrate the neural decoder numerically on the well-known two-dimensional toric code with phase-flip errors.

  9. Entropy Learning in Neural Network

    Directory of Open Access Journals (Sweden)

    Geok See Ng

    2017-12-01

    Full Text Available In this paper, entropy term is used in the learning phase of a neural network.  As learning progresses, more hidden nodes get into saturation.  The early creation of such hidden nodes may impair generalisation.  Hence entropy approach is proposed to dampen the early creation of such nodes.  The entropy learning also helps to increase the importance of relevant nodes while dampening the less important nodes.  At the end of learning, the less important nodes can then be eliminated to reduce the memory requirements of the neural network.

  10. The neural cell adhesion molecule

    DEFF Research Database (Denmark)

    Berezin, V; Bock, E; Poulsen, F M

    2000-01-01

    During the past year, the understanding of the structure and function of neural cell adhesion has advanced considerably. The three-dimensional structures of several of the individual modules of the neural cell adhesion molecule (NCAM) have been determined, as well as the structure of the complex...... between two identical fragments of the NCAM. Also during the past year, a link between homophilic cell adhesion and several signal transduction pathways has been proposed, connecting the event of cell surface adhesion to cellular responses such as neurite outgrowth. Finally, the stimulation of neurite...

  11. Antenna analysis using neural networks

    Science.gov (United States)

    Smith, William T.

    1992-01-01

    Conventional computing schemes have long been used to analyze problems in electromagnetics (EM). The vast majority of EM applications require computationally intensive algorithms involving numerical integration and solutions to large systems of equations. The feasibility of using neural network computing algorithms for antenna analysis is investigated. The ultimate goal is to use a trained neural network algorithm to reduce the computational demands of existing reflector surface error compensation techniques. Neural networks are computational algorithms based on neurobiological systems. Neural nets consist of massively parallel interconnected nonlinear computational elements. They are often employed in pattern recognition and image processing problems. Recently, neural network analysis has been applied in the electromagnetics area for the design of frequency selective surfaces and beam forming networks. The backpropagation training algorithm was employed to simulate classical antenna array synthesis techniques. The Woodward-Lawson (W-L) and Dolph-Chebyshev (D-C) array pattern synthesis techniques were used to train the neural network. The inputs to the network were samples of the desired synthesis pattern. The outputs are the array element excitations required to synthesize the desired pattern. Once trained, the network is used to simulate the W-L or D-C techniques. Various sector patterns and cosecant-type patterns (27 total) generated using W-L synthesis were used to train the network. Desired pattern samples were then fed to the neural network. The outputs of the network were the simulated W-L excitations. A 20 element linear array was used. There were 41 input pattern samples with 40 output excitations (20 real parts, 20 imaginary). A comparison between the simulated and actual W-L techniques is shown for a triangular-shaped pattern. Dolph-Chebyshev is a different class of synthesis technique in that D-C is used for side lobe control as opposed to pattern

  12. Arabic Handwriting Recognition Using Neural Network Classifier

    African Journals Online (AJOL)

    pc

    2018-03-05

    Mar 5, 2018 ... an OCR using Neural Network classifier preceded by a set of preprocessing .... Artificial Neural Networks (ANNs), which we adopt in this research, consist of ... advantage and disadvantages of each technique. In [9],. Khemiri ...

  13. Neural overlap in processing music and speech.

    Science.gov (United States)

    Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L

    2015-03-19

    Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. © 2015 The Author(s) Published by the Royal Society. All rights reserved.

  14. Application of neural networks in coastal engineering

    Digital Repository Service at National Institute of Oceanography (India)

    Mandal, S.

    the neural network attractive. A neural network is an information processing system modeled on the structure of the dynamic process. It can solve the complex/nonlinear problems quickly once trained by operating on problems using an interconnected number...

  15. Ocean wave forecasting using recurrent neural networks

    Digital Repository Service at National Institute of Oceanography (India)

    Mandal, S.; Prabaharan, N.

    , merchant vessel routing, nearshore construction, etc. more efficiently and safely. This paper describes an artificial neural network, namely recurrent neural network with rprop update algorithm and is applied for wave forecasting. Measured ocean waves off...

  16. Neural overlap in processing music and speech

    Science.gov (United States)

    Peretz, Isabelle; Vuvan, Dominique; Lagrois, Marie-Élaine; Armony, Jorge L.

    2015-01-01

    Neural overlap in processing music and speech, as measured by the co-activation of brain regions in neuroimaging studies, may suggest that parts of the neural circuitries established for language may have been recycled during evolution for musicality, or vice versa that musicality served as a springboard for language emergence. Such a perspective has important implications for several topics of general interest besides evolutionary origins. For instance, neural overlap is an important premise for the possibility of music training to influence language acquisition and literacy. However, neural overlap in processing music and speech does not entail sharing neural circuitries. Neural separability between music and speech may occur in overlapping brain regions. In this paper, we review the evidence and outline the issues faced in interpreting such neural data, and argue that converging evidence from several methodologies is needed before neural overlap is taken as evidence of sharing. PMID:25646513

  17. Α-Melanocyte-Stimulating Hormone Protects Early Diabetic Retina from Blood-Retinal Barrier Breakdown and Vascular Leakage via MC4R.

    Science.gov (United States)

    Cai, Siwei; Yang, Qianhui; Hou, Mengzhu; Han, Qian; Zhang, Hanyu; Wang, Jiantao; Qi, Chen; Bo, Qiyu; Ru, Yusha; Yang, Wei; Gu, Zhongxiu; Wei, Ruihua; Cao, Yunshan; Li, Xiaorong; Zhang, Yan

    2018-01-01

    Blood-retinal barrier (BRB) breakdown and vascular leakage is the leading cause of blindness of diabetic retinopathy (DR). Hyperglycemia-induced oxidative stress and inflammation are primary pathogenic factors of this severe DR complication. An effective interventional modality against the pathogenic factors during early DR is needed to curb BRB breakdown and vascular leakage. This study sought to examine the protective effects of α-Melanocyte-stimulating hormone (α-MSH) on early diabetic retina against vascular hyperpermeability, electrophysiological dysfunction, and morphological deterioration in a rat model of diabetes and probe the mechanisms underlying the α-MSH's anti-hyperpermeability in both rodent retinas and simian retinal vascular endothelial cells (RF6A). Sprague Dawley rats were injected through tail vein with streptozotocin to induce diabetes. The rats were intravitreally injected with α-MSH or saline at Week 1 and 3 after hyperglycemia. In another 2 weeks, Evans blue assay, transmission electron microscopy, electroretinogram (ERG), and hematoxylin and eosin (H&E) staining were performed to examine the protective effects of α-MSH in diabetic retinas. The expression of pro-inflammatory factors and tight junction at mRNA and protein levels in retinas was analyzed. Finally, the α-MSH's anti-hyperpermeability was confirmed in a high glucose (HG)-treated RF6A cell monolayer transwell culture by transendothelial electrical resistance (TEER) measurement and a fluorescein isothiocyanate-Dextran assay. Universal or specific melanocortin receptor (MCR) blockers were also employed to elucidate the MCR subtype mediating α-MSH's protection. Evans blue assay showed that BRB breakdown and vascular leakage was detected, and rescued by α-MSH both qualitatively and quantitatively in early diabetic retinas; electron microscopy revealed substantially improved retinal and choroidal vessel ultrastructures in α-MSH-treated diabetic retinas; scotopic ERG suggested

  18. Evaluation of New Tc-99m-Labeled Arg-X-Asp-Conjugated Alpha-Melanocyte Stimulating Hormone Peptides for Melanoma Imaging

    Science.gov (United States)

    Flook, Adam M.; Yang, Jianquan; Miao, Yubin

    2013-01-01

    The purpose of this study was to examine the melanoma targeting and imaging properties of two new 99mTc-labeled Arg-X-Asp-conjugated alpha-melanocyte stimulating hormone (α-MSH) peptides. RTD-Lys-(Arg11)CCMSH {c[Asp-Arg-Thr-Asp-DTyr]-Lys-Cys-Cys-Glu-His-DPhe-Arg-Trp-Cys-Arg-Pro-Val-NH2} and RVD-Lys-(Arg11)CCMSH peptides were synthesized and their melanocortin-1 (MC1) receptor binding affinities were determined in B16/F1 melanoma cells. The biodistribution and melanoma imaging properties of 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH were determined in B16/F1 melanoma-bearing C57 mice. The IC50 values of RTD-Lys-(Arg11)CCMSH and RVD-Lys-(Arg11)CCMSH were 0.7 ± 0.07 and 1.0 ± 0.3 nM in B16/F1 melanoma cells. Both 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH displayed high melanoma uptake. 99mTc-RTD-Lys-(Arg11)CCMSH exhibited the peak tumor uptake of 18.77 ± 5.13% ID/g at 2 h post-injection, whereas 99mTc-RVD-Lys-(Arg11)CCMSH reached the peak tumor uptake of 19.63 ± 4.68% ID/g at 4 h post-injection. Both 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH showed low accumulation in normal organs (<1.7% ID/g) except for the kidneys at 2 h post-injection. The renal uptake of 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH was 135.14 ± 23.62 and 94.01 ± 18.31% ID/g at 2 h post-injection, respectively. The melanoma lesions were clearly visualized by SPECT/CT using either 99mTc-RTD-Lys-(Arg11)CCMSH or 99mTc-RVD-Lys-(Arg11)CCMSH as an imaging probe at 2 h post-injection. Overall, the introduction of Thr or Val residue retained high melanoma uptake of 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH. However, high renal uptake of 99mTc-RTD-Lys-(Arg11)CCMSH and 99mTc-RVD-Lys-(Arg11)CCMSH need to be reduced to facilitate their future applications. PMID:23885640

  19. Technetium-99m-labeled Arg-Gly-Asp-conjugated alpha-melanocyte stimulating hormone hybrid peptides for human melanoma imaging

    Energy Technology Data Exchange (ETDEWEB)

    Yang Jianquan; Guo Haixun [College of Pharmacy, University of New Mexico, Albuquerque, NM 87131 (United States); Miao Yubin, E-mail: ymiao@salud.unm.ed [College of Pharmacy, University of New Mexico, Albuquerque, NM 87131 (United States); Cancer Research and Treatment Center, University of New Mexico, Albuquerque, NM 87131 (United States); Department of Dermatology, University of New Mexico, Albuquerque, NM 87131 (United States)

    2010-11-15

    Introduction: The purpose of this study was to examine whether {sup 99m}Tc-labeled Arg-Gly-Asp (RGD)-conjugated alpha-melanocyte stimulating hormone ({alpha}-MSH) hybrid peptide targeting both melanocortin-1 (MC1) and {alpha}{sub v{beta}3} integrin receptors was superior in melanoma targeting to {sup 99m}Tc-labeled {alpha}-MSH or RGD peptide targeting only the MC1 or {alpha}{sub v{beta}3} integrin receptor. Methods: RGD-Lys-(Arg{sup 11})CCMSH, RAD-Lys-(Arg{sup 11})CCMSH and RGD-Lys-(Arg{sup 11})CCMSHscramble were designed to target both MC1 and {alpha}{sub v{beta}3} integrin receptors, MC1 receptor only and {alpha}{sub v{beta}3} integrin receptor only, respectively. The MC1 or {alpha}{sub v{beta}3} integrin receptor binding affinities of three peptides were determined in M21 human melanoma cells. The melanoma targeting properties of {sup 99m}Tc-labeled RGD-Lys-(Arg{sup 11})CCMSH, RAD-Lys-(Arg{sup 11})CCMSH and RGD-Lys-(Arg{sup 11})CCMSHscramble were determined in M21 human melanoma-xenografted nude mice. Meanwhile, the melanoma uptake of {sup 99m}Tc-RGD-Lys-(Arg{sup 11})CCMSH was blocked with various non-radiolabeled peptides in M21 melanoma xenografts. Results: RGD-Lys-(Arg{sup 11})CCMSH displayed 2.0 and 403 nM binding affinities to both MC1 and {alpha}{sub v{beta}3} integrin receptors, whereas RAD-Lys-(Arg{sup 11})CCMSH or RGD-Lys-(Arg{sup 11})CCMSHscramble lost their {alpha}{sub v{beta}3} integrin receptor binding affinity by greater than 248-fold or MC1 receptor binding affinity by more than 100-fold, respectively. The melanoma uptake of {sup 99m}Tc-RGD-Lys-(Arg{sup 11})CCMSH was 2.49 and 2.24 times (P < .05) the melanoma uptakes of {sup 99m}Tc-RAD-Lys-(Arg{sup 11})CCMSH and {sup 99m}Tc-RGD-Lys-(Arg{sup 11})CCMSHscramble at 2 h post-injection, respectively. Either RGD or (Arg{sup 11})CCMSH peptide co-injection could block 42% and 57% of the tumor uptake of {sup 99m}Tc-RGD-Lys-(Arg{sup 11})CCMSH, whereas the coinjection of RGD+(Arg{sup 11})CCMSH peptide mixture

  20. MEMBRAIN NEURAL NETWORK FOR VISUAL PATTERN RECOGNITION

    Directory of Open Access Journals (Sweden)

    Artur Popko

    2013-06-01

    Full Text Available Recognition of visual patterns is one of significant applications of Artificial Neural Networks, which partially emulate human thinking in the domain of artificial intelligence. In the paper, a simplified neural approach to recognition of visual patterns is portrayed and discussed. This paper is dedicated for investigators in visual patterns recognition, Artificial Neural Networking and related disciplines. The document describes also MemBrain application environment as a powerful and easy to use neural networks’ editor and simulator supporting ANN.

  1. Neural network to diagnose lining condition

    Science.gov (United States)

    Yemelyanov, V. A.; Yemelyanova, N. Y.; Nedelkin, A. A.; Zarudnaya, M. V.

    2018-03-01

    The paper presents data on the problem of diagnosing the lining condition at the iron and steel works. The authors describe the neural network structure and software that are designed and developed to determine the lining burnout zones. The simulation results of the proposed neural networks are presented. The authors note the low learning and classification errors of the proposed neural networks. To realize the proposed neural network, the specialized software has been developed.

  2. Simplified LQG Control with Neural Networks

    DEFF Research Database (Denmark)

    Sørensen, O.

    1997-01-01

    A new neural network application for non-linear state control is described. One neural network is modelled to form a Kalmann predictor and trained to act as an optimal state observer for a non-linear process. Another neural network is modelled to form a state controller and trained to produce...

  3. Analysis of neural networks through base functions

    NARCIS (Netherlands)

    van der Zwaag, B.J.; Slump, Cornelis H.; Spaanenburg, L.

    Problem statement. Despite their success-story, neural networks have one major disadvantage compared to other techniques: the inability to explain comprehensively how a trained neural network reaches its output; neural networks are not only (incorrectly) seen as a "magic tool" but possibly even more

  4. Genetic Algorithm Optimized Neural Networks Ensemble as ...

    African Journals Online (AJOL)

    NJD

    Improvements in neural network calibration models by a novel approach using neural network ensemble (NNE) for the simultaneous ... process by training a number of neural networks. .... Matlab® version 6.1 was employed for building principal component ... provide a fair simulation of calibration data set with some degree.

  5. Recycling signals in the neural crest

    OpenAIRE

    Taneyhill, Lisa A.; Bronner-Fraser, Marianne E.

    2006-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  6. Recycling signals in the neural crest.

    Science.gov (United States)

    Taneyhill, Lisa A; Bronner-Fraser, Marianne

    2005-01-01

    Vertebrate neural crest cells are multipotent and differentiate into structures that include cartilage and the bones of the face, as well as much of the peripheral nervous system. Understanding how different model vertebrates utilize signaling pathways reiteratively during various stages of neural crest formation and differentiation lends insight into human disorders associated with the neural crest.

  7. Neural chips, neural computers and application in high and superhigh energy physics experiments

    International Nuclear Information System (INIS)

    Nikityuk, N.M.; )

    2001-01-01

    Architecture peculiarity and characteristics of series of neural chips and neural computes used in scientific instruments are considered. Tendency of development and use of them in high energy and superhigh energy physics experiments are described. Comparative data which characterize the efficient use of neural chips for useful event selection, classification elementary particles, reconstruction of tracks of charged particles and for search of hypothesis Higgs particles are given. The characteristics of native neural chips and accelerated neural boards are considered [ru

  8. Medical Imaging with Neural Networks

    International Nuclear Information System (INIS)

    Pattichis, C.; Cnstantinides, A.

    1994-01-01

    The objective of this paper is to provide an overview of the recent developments in the use of artificial neural networks in medical imaging. The areas of medical imaging that are covered include : ultrasound, magnetic resonance, nuclear medicine and radiological (including computerized tomography). (authors)

  9. Optoelectronic Implementation of Neural Networks

    Indian Academy of Sciences (India)

    neural networks, such as learning, adapting and copying by means of parallel ... to provide robust recognition of hand-printed English text. Engine idle and misfiring .... and s represents the bounded activation function of a neuron. It is typically ...

  10. Aphasia Classification Using Neural Networks

    DEFF Research Database (Denmark)

    Axer, H.; Jantzen, Jan; Berks, G.

    2000-01-01

    A web-based software model (http://fuzzy.iau.dtu.dk/aphasia.nsf) was developed as an example for classification of aphasia using neural networks. Two multilayer perceptrons were used to classify the type of aphasia (Broca, Wernicke, anomic, global) according to the results in some subtests...

  11. Intelligent neural network diagnostic system

    International Nuclear Information System (INIS)

    Mohamed, A.H.

    2010-01-01

    Recently, artificial neural network (ANN) has made a significant mark in the domain of diagnostic applications. Neural networks are used to implement complex non-linear mappings (functions) using simple elementary units interrelated through connections with adaptive weights. The performance of the ANN is mainly depending on their topology structure and weights. Some systems have been developed using genetic algorithm (GA) to optimize the topology of the ANN. But, they suffer from some limitations. They are : (1) The computation time requires for training the ANN several time reaching for the average weight required, (2) Slowness of GA for optimization process and (3) Fitness noise appeared in the optimization of ANN. This research suggests new issues to overcome these limitations for finding optimal neural network architectures to learn particular problems. This proposed methodology is used to develop a diagnostic neural network system. It has been applied for a 600 MW turbo-generator as a case of real complex systems. The proposed system has proved its significant performance compared to two common methods used in the diagnostic applications.

  12. Medical Imaging with Neural Networks

    Energy Technology Data Exchange (ETDEWEB)

    Pattichis, C [Department of Computer Science, University of Cyprus, Kallipoleos 75, P.O.Box 537, Nicosia (Cyprus); Cnstantinides, A [Department of Electrical Engineering, Imperial College of Science, Technology and Medicine, London SW7 2BT (United Kingdom)

    1994-12-31

    The objective of this paper is to provide an overview of the recent developments in the use of artificial neural networks in medical imaging. The areas of medical imaging that are covered include : ultrasound, magnetic resonance, nuclear medicine and radiological (including computerized tomography). (authors). 61 refs, 4 tabs.

  13. Numerical experiments with neural networks

    International Nuclear Information System (INIS)

    Miranda, Enrique.

    1990-01-01

    Neural networks are highly idealized models which, in spite of their simplicity, reproduce some key features of the real brain. In this paper, they are introduced at a level adequate for an undergraduate computational physics course. Some relevant magnitudes are defined and evaluated numerically for the Hopfield model and a short term memory model. (Author)

  14. Serotonin, neural markers and memory

    Directory of Open Access Journals (Sweden)

    Alfredo eMeneses

    2015-07-01

    Full Text Available Diverse neuropsychiatric disorders present dysfunctional memory and no effective treatment exits for them; likely as result of the absence of neural markers associated to memory. Neurotransmitter systems and signaling pathways have been implicated in memory and dysfunctional memory; however, their role is poorly understood. Hence, neural markers and cerebral functions and dysfunctions are revised. To our knowledge no previous systematic works have been published addressing these issues. The interactions among behavioral tasks, control groups and molecular changes and/or pharmacological effects are mentioned. Neurotransmitter receptors and signaling pathways, during normal and abnormally functioning memory with an emphasis on the behavioral aspects of memory are revised. With focus on serotonin, since as it is a well characterized neurotransmitter, with multiple pharmacological tools, and well characterized downstream signaling in mammals’ species. 5-HT1A, 5-HT4, 5-HT5, 5-HT6 and 5-HT7 receptors as well as SERT (serotonin transporter seem to be useful neural markers and/or therapeutic targets. Certainly, if the mentioned evidence is replicated, then the translatability from preclinical and clinical studies to neural changes might be confirmed. Hypothesis and theories might provide appropriate limits and perspectives of evidence

  15. Neural correlates of viewing paintings

    DEFF Research Database (Denmark)

    Vartanian, Oshin; Skov, Martin

    2014-01-01

    Many studies involving functional magnetic resonance imaging (fMRI) have exposed participants to paintings under varying task demands. To isolate neural systems that are activated reliably across fMRI studies in response to viewing paintings regardless of variation in task demands, a quantitative...

  16. Neural Basis of Visual Distraction

    Science.gov (United States)

    Kim, So-Yeon; Hopfinger, Joseph B.

    2010-01-01

    The ability to maintain focus and avoid distraction by goal-irrelevant stimuli is critical for performing many tasks and may be a key deficit in attention-related problems. Recent studies have demonstrated that irrelevant stimuli that are consciously perceived may be filtered out on a neural level and not cause the distraction triggered by…

  17. Vestibular hearing and neural synchronization.

    Science.gov (United States)

    Emami, Seyede Faranak; Daneshi, Ahmad

    2012-01-01

    Objectives. Vestibular hearing as an auditory sensitivity of the saccule in the human ear is revealed by cervical vestibular evoked myogenic potentials (cVEMPs). The range of the vestibular hearing lies in the low frequency. Also, the amplitude of an auditory brainstem response component depends on the amount of synchronized neural activity, and the auditory nerve fibers' responses have the best synchronization with the low frequency. Thus, the aim of this study was to investigate correlation between vestibular hearing using cVEMPs and neural synchronization via slow wave Auditory Brainstem Responses (sABR). Study Design. This case-control survey was consisted of twenty-two dizzy patients, compared to twenty healthy controls. Methods. Intervention comprised of Pure Tone Audiometry (PTA), Impedance acoustic metry (IA), Videonystagmography (VNG), fast wave ABR (fABR), sABR, and cVEMPs. Results. The affected ears of the dizzy patients had the abnormal findings of cVEMPs (insecure vestibular hearing) and the abnormal findings of sABR (decreased neural synchronization). Comparison of the cVEMPs at affected ears versus unaffected ears and the normal persons revealed significant differences (P < 0.05). Conclusion. Safe vestibular hearing was effective in the improvement of the neural synchronization.

  18. Spin glasses and neural networks

    International Nuclear Information System (INIS)

    Parga, N.; Universidad Nacional de Cuyo, San Carlos de Bariloche

    1989-01-01

    The mean-field theory of spin glass models has been used as a prototype of systems with frustration and disorder. One of the most interesting related systems are models of associative memories. In these lectures we review the main concepts developed to solve the Sherrington-Kirkpatrick model and its application to neural networks. (orig.)

  19. Non-invasive neural stimulation

    Science.gov (United States)

    Tyler, William J.; Sanguinetti, Joseph L.; Fini, Maria; Hool, Nicholas

    2017-05-01

    Neurotechnologies for non-invasively interfacing with neural circuits have been evolving from those capable of sensing neural activity to those capable of restoring and enhancing human brain function. Generally referred to as non-invasive neural stimulation (NINS) methods, these neuromodulation approaches rely on electrical, magnetic, photonic, and acoustic or ultrasonic energy to influence nervous system activity, brain function, and behavior. Evidence that has been surmounting for decades shows that advanced neural engineering of NINS technologies will indeed transform the way humans treat diseases, interact with information, communicate, and learn. The physics underlying the ability of various NINS methods to modulate nervous system activity can be quite different from one another depending on the energy modality used as we briefly discuss. For members of commercial and defense industry sectors that have not traditionally engaged in neuroscience research and development, the science, engineering and technology required to advance NINS methods beyond the state-of-the-art presents tremendous opportunities. Within the past few years alone there have been large increases in global investments made by federal agencies, foundations, private investors and multinational corporations to develop advanced applications of NINS technologies. Driven by these efforts NINS methods and devices have recently been introduced to mass markets via the consumer electronics industry. Further, NINS continues to be explored in a growing number of defense applications focused on enhancing human dimensions. The present paper provides a brief introduction to the field of non-invasive neural stimulation by highlighting some of the more common methods in use or under current development today.

  20. Neural networks and applications tutorial

    Science.gov (United States)

    Guyon, I.

    1991-09-01

    The importance of neural networks has grown dramatically during this decade. While only a few years ago they were primarily of academic interest, now dozens of companies and many universities are investigating the potential use of these systems and products are beginning to appear. The idea of building a machine whose architecture is inspired by that of the brain has roots which go far back in history. Nowadays, technological advances of computers and the availability of custom integrated circuits, permit simulations of hundreds or even thousands of neurons. In conjunction, the growing interest in learning machines, non-linear dynamics and parallel computation spurred renewed attention in artificial neural networks. Many tentative applications have been proposed, including decision systems (associative memories, classifiers, data compressors and optimizers), or parametric models for signal processing purposes (system identification, automatic control, noise canceling, etc.). While they do not always outperform standard methods, neural network approaches are already used in some real world applications for pattern recognition and signal processing tasks. The tutorial is divided into six lectures, that where presented at the Third Graduate Summer Course on Computational Physics (September 3-7, 1990) on Parallel Architectures and Applications, organized by the European Physical Society: (1) Introduction: machine learning and biological computation. (2) Adaptive artificial neurons (perceptron, ADALINE, sigmoid units, etc.): learning rules and implementations. (3) Neural network systems: architectures, learning algorithms. (4) Applications: pattern recognition, signal processing, etc. (5) Elements of learning theory: how to build networks which generalize. (6) A case study: a neural network for on-line recognition of handwritten alphanumeric characters.

  1. Parameterization Of Solar Radiation Using Neural Network

    International Nuclear Information System (INIS)

    Jiya, J. D.; Alfa, B.

    2002-01-01

    This paper presents a neural network technique for parameterization of global solar radiation. The available data from twenty-one stations is used for training the neural network and the data from other ten stations is used to validate the neural model. The neural network utilizes latitude, longitude, altitude, sunshine duration and period number to parameterize solar radiation values. The testing data was not used in the training to demonstrate the performance of the neural network in unknown stations to parameterize solar radiation. The results indicate a good agreement between the parameterized solar radiation values and actual measured values

  2. A zebrafish model for Waardenburg syndrome type IV reveals diverse roles for Sox10 in the otic vesicle.

    Science.gov (United States)

    Dutton, Kirsten; Abbas, Leila; Spencer, Joanne; Brannon, Claire; Mowbray, Catriona; Nikaido, Masataka; Kelsh, Robert N; Whitfield, Tanya T

    2009-01-01

    In humans, mutations in the SOX10 gene are a cause of the auditory-pigmentary disorder Waardenburg syndrome type IV (WS4) and related variants. SOX10 encodes an Sry-related HMG box protein essential for the development of the neural crest; deafness in WS4 and other Waardenburg syndromes is usually attributed to loss of neural-crest-derived melanocytes in the stria vascularis of the cochlea. However, SOX10 is strongly expressed in the developing otic vesicle and so direct roles for SOX10 in the otic epithelium might also be important. Here, we examine the otic phenotype of zebrafish sox10 mutants, a model for WS4. As a cochlea is not present in the fish ear, the severe otic phenotype in these mutants cannot be attributed to effects on this tissue. In zebrafish sox10 mutants, we see abnormalities in all otic placodal derivatives. Gene expression studies indicate deregulated expression of several otic genes, including fgf8, in sox10 mutants. Using a combination of mutant and morphant data, we show that the three sox genes belonging to group E (sox9a, sox9b and sox10) provide a link between otic induction pathways and subsequent otic patterning: they act redundantly to maintain sox10 expression throughout otic tissue and to restrict fgf8 expression to anterior macula regions. Single-cell labelling experiments indicate a small and transient neural crest contribution to the zebrafish ear during normal development, but this is unlikely to account for the strong defects seen in the sox10 mutant. We discuss the implication that the deafness in WS4 patients with SOX10 mutations might reflect a haploinsufficiency for SOX10 in the otic epithelium, resulting in patterning and functional abnormalities in the inner ear.

  3. Spike Neural Models Part II: Abstract Neural Models

    Directory of Open Access Journals (Sweden)

    Johnson, Melissa G.

    2018-02-01

    Full Text Available Neurons are complex cells that require a lot of time and resources to model completely. In spiking neural networks (SNN though, not all that complexity is required. Therefore simple, abstract models are often used. These models save time, use less computer resources, and are easier to understand. This tutorial presents two such models: Izhikevich's model, which is biologically realistic in the resulting spike trains but not in the parameters, and the Leaky Integrate and Fire (LIF model which is not biologically realistic but does quickly and easily integrate input to produce spikes. Izhikevich's model is based on Hodgkin-Huxley's model but simplified such that it uses only two differentiation equations and four parameters to produce various realistic spike patterns. LIF is based on a standard electrical circuit and contains one equation. Either of these two models, or any of the many other models in literature can be used in a SNN. Choosing a neural model is an important task that depends on the goal of the research and the resources available. Once a model is chosen, network decisions such as connectivity, delay, and sparseness, need to be made. Understanding neural models and how they are incorporated into the network is the first step in creating a SNN.

  4. Optical resonators and neural networks

    Science.gov (United States)

    Anderson, Dana Z.

    1986-08-01

    It may be possible to implement neural network models using continuous field optical architectures. These devices offer the inherent parallelism of propagating waves and an information density in principle dictated by the wavelength of light and the quality of the bulk optical elements. Few components are needed to construct a relatively large equivalent network. Various associative memories based on optical resonators have been demonstrated in the literature, a ring resonator design is discussed in detail here. Information is stored in a holographic medium and recalled through a competitive processes in the gain medium supplying energy to the ring rsonator. The resonator memory is the first realized example of a neural network function implemented with this kind of architecture.

  5. Neural Network for Sparse Reconstruction

    Directory of Open Access Journals (Sweden)

    Qingfa Li

    2014-01-01

    Full Text Available We construct a neural network based on smoothing approximation techniques and projected gradient method to solve a kind of sparse reconstruction problems. Neural network can be implemented by circuits and can be seen as an important method for solving optimization problems, especially large scale problems. Smoothing approximation is an efficient technique for solving nonsmooth optimization problems. We combine these two techniques to overcome the difficulties of the choices of the step size in discrete algorithms and the item in the set-valued map of differential inclusion. In theory, the proposed network can converge to the optimal solution set of the given problem. Furthermore, some numerical experiments show the effectiveness of the proposed network in this paper.

  6. IMNN: Information Maximizing Neural Networks

    Science.gov (United States)

    Charnock, Tom; Lavaux, Guilhem; Wandelt, Benjamin D.

    2018-04-01

    This software trains artificial neural networks to find non-linear functionals of data that maximize Fisher information: information maximizing neural networks (IMNNs). As compressing large data sets vastly simplifies both frequentist and Bayesian inference, important information may be inadvertently missed. Likelihood-free inference based on automatically derived IMNN summaries produces summaries that are good approximations to sufficient statistics. IMNNs are robustly capable of automatically finding optimal, non-linear summaries of the data even in cases where linear compression fails: inferring the variance of Gaussian signal in the presence of noise, inferring cosmological parameters from mock simulations of the Lyman-α forest in quasar spectra, and inferring frequency-domain parameters from LISA-like detections of gravitational waveforms. In this final case, the IMNN summary outperforms linear data compression by avoiding the introduction of spurious likelihood maxima.

  7. Genetic attack on neural cryptography.

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Naeh, Rivka; Kanter, Ido

    2006-03-01

    Different scaling properties for the complexity of bidirectional synchronization and unidirectional learning are essential for the security of neural cryptography. Incrementing the synaptic depth of the networks increases the synchronization time only polynomially, but the success of the geometric attack is reduced exponentially and it clearly fails in the limit of infinite synaptic depth. This method is improved by adding a genetic algorithm, which selects the fittest neural networks. The probability of a successful genetic attack is calculated for different model parameters using numerical simulations. The results show that scaling laws observed in the case of other attacks hold for the improved algorithm, too. The number of networks needed for an effective attack grows exponentially with increasing synaptic depth. In addition, finite-size effects caused by Hebbian and anti-Hebbian learning are analyzed. These learning rules converge to the random walk rule if the synaptic depth is small compared to the square root of the system size.

  8. Neural Networks Methodology and Applications

    CERN Document Server

    Dreyfus, Gérard

    2005-01-01

    Neural networks represent a powerful data processing technique that has reached maturity and broad application. When clearly understood and appropriately used, they are a mandatory component in the toolbox of any engineer who wants make the best use of the available data, in order to build models, make predictions, mine data, recognize shapes or signals, etc. Ranging from theoretical foundations to real-life applications, this book is intended to provide engineers and researchers with clear methodologies for taking advantage of neural networks in industrial, financial or banking applications, many instances of which are presented in the book. For the benefit of readers wishing to gain deeper knowledge of the topics, the book features appendices that provide theoretical details for greater insight, and algorithmic details for efficient programming and implementation. The chapters have been written by experts ands seemlessly edited to present a coherent and comprehensive, yet not redundant, practically-oriented...

  9. Genetic attack on neural cryptography

    International Nuclear Information System (INIS)

    Ruttor, Andreas; Kinzel, Wolfgang; Naeh, Rivka; Kanter, Ido

    2006-01-01

    Different scaling properties for the complexity of bidirectional synchronization and unidirectional learning are essential for the security of neural cryptography. Incrementing the synaptic depth of the networks increases the synchronization time only polynomially, but the success of the geometric attack is reduced exponentially and it clearly fails in the limit of infinite synaptic depth. This method is improved by adding a genetic algorithm, which selects the fittest neural networks. The probability of a successful genetic attack is calculated for different model parameters using numerical simulations. The results show that scaling laws observed in the case of other attacks hold for the improved algorithm, too. The number of networks needed for an effective attack grows exponentially with increasing synaptic depth. In addition, finite-size effects caused by Hebbian and anti-Hebbian learning are analyzed. These learning rules converge to the random walk rule if the synaptic depth is small compared to the square root of the system size

  10. Genetic attack on neural cryptography

    Science.gov (United States)

    Ruttor, Andreas; Kinzel, Wolfgang; Naeh, Rivka; Kanter, Ido

    2006-03-01

    Different scaling properties for the complexity of bidirectional synchronization and unidirectional learning are essential for the security of neural cryptography. Incrementing the synaptic depth of the networks increases the synchronization time only polynomially, but the success of the geometric attack is reduced exponentially and it clearly fails in the limit of infinite synaptic depth. This method is improved by adding a genetic algorithm, which selects the fittest neural networks. The probability of a successful genetic attack is calculated for different model parameters using numerical simulations. The results show that scaling laws observed in the case of other attacks hold for the improved algorithm, too. The number of networks needed for an effective attack grows exponentially with increasing synaptic depth. In addition, finite-size effects caused by Hebbian and anti-Hebbian learning are analyzed. These learning rules converge to the random walk rule if the synaptic depth is small compared to the square root of the system size.

  11. Scheduling with artificial neural networks

    OpenAIRE

    Gürgün, Burçkaan

    1993-01-01

    Ankara : Department of Industrial Engineering and The Institute of Engineering and Sciences of Bilkent Univ., 1993. Thesis (Master's) -- Bilkent University, 1993. Includes bibliographical references leaves 59-65. Artificial Neural Networks (ANNs) attempt to emulate the massively parallel and distributed processing of the human brain. They are being examined for a variety of problems that have been very difficult to solve. The objective of this thesis is to review the curren...

  12. Handbook on neural information processing

    CERN Document Server

    Maggini, Marco; Jain, Lakhmi

    2013-01-01

    This handbook presents some of the most recent topics in neural information processing, covering both theoretical concepts and practical applications. The contributions include:                         Deep architectures                         Recurrent, recursive, and graph neural networks                         Cellular neural networks                         Bayesian networks                         Approximation capabilities of neural networks                         Semi-supervised learning                         Statistical relational learning                         Kernel methods for structured data                         Multiple classifier systems                         Self organisation and modal learning                         Applications to ...

  13. Deep Gate Recurrent Neural Network

    Science.gov (United States)

    2016-11-22

    and Fred Cummins. Learning to forget: Continual prediction with lstm . Neural computation, 12(10):2451–2471, 2000. Alex Graves. Generating sequences...DSGU) and Simple Gated Unit (SGU), which are structures for learning long-term dependencies. Compared to traditional Long Short-Term Memory ( LSTM ) and...Gated Recurrent Unit (GRU), both structures require fewer parameters and less computation time in sequence classification tasks. Unlike GRU and LSTM

  14. Adaptive Graph Convolutional Neural Networks

    OpenAIRE

    Li, Ruoyu; Wang, Sheng; Zhu, Feiyun; Huang, Junzhou

    2018-01-01

    Graph Convolutional Neural Networks (Graph CNNs) are generalizations of classical CNNs to handle graph data such as molecular data, point could and social networks. Current filters in graph CNNs are built for fixed and shared graph structure. However, for most real data, the graph structures varies in both size and connectivity. The paper proposes a generalized and flexible graph CNN taking data of arbitrary graph structure as input. In that way a task-driven adaptive graph is learned for eac...

  15. Adaptive Regularization of Neural Classifiers

    DEFF Research Database (Denmark)

    Andersen, Lars Nonboe; Larsen, Jan; Hansen, Lars Kai

    1997-01-01

    We present a regularization scheme which iteratively adapts the regularization parameters by minimizing the validation error. It is suggested to use the adaptive regularization scheme in conjunction with optimal brain damage pruning to optimize the architecture and to avoid overfitting. Furthermo......, we propose an improved neural classification architecture eliminating an inherent redundancy in the widely used SoftMax classification network. Numerical results demonstrate the viability of the method...

  16. Central neural pathways for thermoregulation

    Science.gov (United States)

    Morrison, Shaun F.; Nakamura, Kazuhiro

    2010-01-01

    Central neural circuits orchestrate a homeostatic repertoire to maintain body temperature during environmental temperature challenges and to alter body temperature during the inflammatory response. This review summarizes the functional organization of the neural pathways through which cutaneous thermal receptors alter thermoregulatory effectors: the cutaneous circulation for heat loss, the brown adipose tissue, skeletal muscle and heart for thermogenesis and species-dependent mechanisms (sweating, panting and saliva spreading) for evaporative heat loss. These effectors are regulated by parallel but distinct, effector-specific neural pathways that share a common peripheral thermal sensory input. The thermal afferent circuits include cutaneous thermal receptors, spinal dorsal horn neurons and lateral parabrachial nucleus neurons projecting to the preoptic area to influence warm-sensitive, inhibitory output neurons which control thermogenesis-promoting neurons in the dorsomedial hypothalamus that project to premotor neurons in the rostral ventromedial medulla, including the raphe pallidus, that descend to provide the excitation necessary to drive thermogenic thermal effectors. A distinct population of warm-sensitive preoptic neurons controls heat loss through an inhibitory input to raphe pallidus neurons controlling cutaneous vasoconstriction. PMID:21196160

  17. Adaptive competitive learning neural networks

    Directory of Open Access Journals (Sweden)

    Ahmed R. Abas

    2013-11-01

    Full Text Available In this paper, the adaptive competitive learning (ACL neural network algorithm is proposed. This neural network not only groups similar input feature vectors together but also determines the appropriate number of groups of these vectors. This algorithm uses a new proposed criterion referred to as the ACL criterion. This criterion evaluates different clustering structures produced by the ACL neural network for an input data set. Then, it selects the best clustering structure and the corresponding network architecture for this data set. The selected structure is composed of the minimum number of clusters that are compact and balanced in their sizes. The selected network architecture is efficient, in terms of its complexity, as it contains the minimum number of neurons. Synaptic weight vectors of these neurons represent well-separated, compact and balanced clusters in the input data set. The performance of the ACL algorithm is evaluated and compared with the performance of a recently proposed algorithm in the literature in clustering an input data set and determining its number of clusters. Results show that the ACL algorithm is more accurate and robust in both determining the number of clusters and allocating input feature vectors into these clusters than the other algorithm especially with data sets that are sparsely distributed.

  18. Neural mechanisms of social dominance

    Science.gov (United States)

    Watanabe, Noriya; Yamamoto, Miyuki

    2015-01-01

    In a group setting, individuals' perceptions of their own level of dominance or of the dominance level of others, and the ability to adequately control their behavior based on these perceptions are crucial for living within a social environment. Recent advances in neural imaging and molecular technology have enabled researchers to investigate the neural substrates that support the perception of social dominance and the formation of a social hierarchy in humans. At the systems' level, recent studies showed that dominance perception is represented in broad brain regions which include the amygdala, hippocampus, striatum, and various cortical networks such as the prefrontal, and parietal cortices. Additionally, neurotransmitter systems such as the dopaminergic and serotonergic systems, modulate and are modulated by the formation of the social hierarchy in a group. While these monoamine systems have a wide distribution and multiple functions, it was recently found that the Neuropeptide B/W contributes to the perception of dominance and is present in neurons that have a limited projection primarily to the amygdala. The present review discusses the specific roles of these neural regions and neurotransmitter systems in the perception of dominance and in hierarchy formation. PMID:26136644

  19. Neural mechanisms of social dominance

    Directory of Open Access Journals (Sweden)

    Noriya eWatanabe

    2015-06-01

    Full Text Available In a group setting, individuals’ perceptions of their own level of dominance or of the dominance level of others, and the ability to adequately control their behavior based on these perceptions are crucial for living within a social environment. Recent advances in neural imaging and molecular technology have enabled researchers to investigate the neural substrates that support the perception of social dominance and the formation of a social hierarchy in humans. At the systems’ level, recent studies showed that dominance perception is represented in broad brain regions which include the amygdala, hippocampus, striatum, and various cortical networks such as the prefrontal, and parietal cortices. Additionally, neurotransmitter systems such as the dopaminergic and serotonergic systems, modulate and are modulated by the formation of the social hierarchy in a group. While these monoamine systems have a wide distribution and multiple functions, it was recently found that the Neuropeptide B/W contributes to the perception of dominance and is present in neurons that have a limited projection primarily to the amygdala. The present review discusses the specific roles of these neural regions and neurotransmitter systems in the perception of dominance and in hierarchy formation.

  20. Neural Representations of Physics Concepts.

    Science.gov (United States)

    Mason, Robert A; Just, Marcel Adam

    2016-06-01

    We used functional MRI (fMRI) to assess neural representations of physics concepts (momentum, energy, etc.) in juniors, seniors, and graduate students majoring in physics or engineering. Our goal was to identify the underlying neural dimensions of these representations. Using factor analysis to reduce the number of dimensions of activation, we obtained four physics-related factors that were mapped to sets of voxels. The four factors were interpretable as causal motion visualization, periodicity, algebraic form, and energy flow. The individual concepts were identifiable from their fMRI signatures with a mean rank accuracy of .75 using a machine-learning (multivoxel) classifier. Furthermore, there was commonality in participants' neural representation of physics; a classifier trained on data from all but one participant identified the concepts in the left-out participant (mean accuracy = .71 across all nine participant samples). The findings indicate that abstract scientific concepts acquired in an educational setting evoke activation patterns that are identifiable and common, indicating that science education builds abstract knowledge using inherent, repurposed brain systems. © The Author(s) 2016.

  1. Photon spectrometry utilizing neural networks

    International Nuclear Information System (INIS)

    Silveira, R.; Benevides, C.; Lima, F.; Vilela, E.

    2015-01-01

    Having in mind the time spent on the uneventful work of characterization of the radiation beams used in a ionizing radiation metrology laboratory, the Metrology Service of the Centro Regional de Ciencias Nucleares do Nordeste - CRCN-NE verified the applicability of artificial intelligence (artificial neural networks) to perform the spectrometry in photon fields. For this, was developed a multilayer neural network, as an application for the classification of patterns in energy, associated with a thermoluminescent dosimetric system (TLD-700 and TLD-600). A set of dosimeters was initially exposed to various well known medium energies, between 40 keV and 1.2 MeV, coinciding with the beams determined by ISO 4037 standard, for the dose of 10 mSv in the quantity Hp(10), on a chest phantom (ISO slab phantom) with the purpose of generating a set of training data for the neural network. Subsequently, a new set of dosimeters irradiated in unknown energies was presented to the network with the purpose to test the method. The methodology used in this work was suitable for application in the classification of energy beams, having obtained 100% of the classification performed. (authors)

  2. Neural plasticity of development and learning.

    Science.gov (United States)

    Galván, Adriana

    2010-06-01

    Development and learning are powerful agents of change across the lifespan that induce robust structural and functional plasticity in neural systems. An unresolved question in developmental cognitive neuroscience is whether development and learning share the same neural mechanisms associated with experience-related neural plasticity. In this article, I outline the conceptual and practical challenges of this question, review insights gleaned from adult studies, and describe recent strides toward examining this topic across development using neuroimaging methods. I suggest that development and learning are not two completely separate constructs and instead, that they exist on a continuum. While progressive and regressive changes are central to both, the behavioral consequences associated with these changes are closely tied to the existing neural architecture of maturity of the system. Eventually, a deeper, more mechanistic understanding of neural plasticity will shed light on behavioral changes across development and, more broadly, about the underlying neural basis of cognition. (c) 2010 Wiley-Liss, Inc.

  3. Neurosecurity: security and privacy for neural devices.

    Science.gov (United States)

    Denning, Tamara; Matsuoka, Yoky; Kohno, Tadayoshi

    2009-07-01

    An increasing number of neural implantable devices will become available in the near future due to advances in neural engineering. This discipline holds the potential to improve many patients' lives dramatically by offering improved-and in some cases entirely new-forms of rehabilitation for conditions ranging from missing limbs to degenerative cognitive diseases. The use of standard engineering practices, medical trials, and neuroethical evaluations during the design process can create systems that are safe and that follow ethical guidelines; unfortunately, none of these disciplines currently ensure that neural devices are robust against adversarial entities trying to exploit these devices to alter, block, or eavesdrop on neural signals. The authors define "neurosecurity"-a version of computer science security principles and methods applied to neural engineering-and discuss why neurosecurity should be a critical consideration in the design of future neural devices.

  4. The Neural Border: Induction, Specification and Maturation of the territory that generates Neural Crest cells.

    Science.gov (United States)

    Pla, Patrick; Monsoro-Burq, Anne H

    2018-05-28

    The neural crest is induced at the edge between the neural plate and the nonneural ectoderm, in an area called the neural (plate) border, during gastrulation and neurulation. In recent years, many studies have explored how this domain is patterned, and how the neural crest is induced within this territory, that also participates to the prospective dorsal neural tube, the dorsalmost nonneural ectoderm, as well as placode derivatives in the anterior area. This review highlights the tissue interactions, the cell-cell signaling and the molecular mechanisms involved in this dynamic spatiotemporal patterning, resulting in the induction of the premigratory neural crest. Collectively, these studies allow building a complex neural border and early neural crest gene regulatory network, mostly composed by transcriptional regulations but also, more recently, including novel signaling interactions. Copyright © 2018. Published by Elsevier Inc.

  5. Direct adaptive control using feedforward neural networks

    OpenAIRE

    Cajueiro, Daniel Oliveira; Hemerly, Elder Moreira

    2003-01-01

    ABSTRACT: This paper proposes a new scheme for direct neural adaptive control that works efficiently employing only one neural network, used for simultaneously identifying and controlling the plant. The idea behind this structure of adaptive control is to compensate the control input obtained by a conventional feedback controller. The neural network training process is carried out by using two different techniques: backpropagation and extended Kalman filter algorithm. Additionally, the conver...

  6. Introduction to Concepts in Artificial Neural Networks

    Science.gov (United States)

    Niebur, Dagmar

    1995-01-01

    This introduction to artificial neural networks summarizes some basic concepts of computational neuroscience and the resulting models of artificial neurons. The terminology of biological and artificial neurons, biological and machine learning and neural processing is introduced. The concepts of supervised and unsupervised learning are explained with examples from the power system area. Finally, a taxonomy of different types of neurons and different classes of artificial neural networks is presented.

  7. Mode Choice Modeling Using Artificial Neural Networks

    OpenAIRE

    Edara, Praveen Kumar

    2003-01-01

    Artificial intelligence techniques have produced excellent results in many diverse fields of engineering. Techniques such as neural networks and fuzzy systems have found their way into transportation engineering. In recent years, neural networks are being used instead of regression techniques for travel demand forecasting purposes. The basic reason lies in the fact that neural networks are able to capture complex relationships and learn from examples and also able to adapt when new data becom...

  8. Dynamic training algorithm for dynamic neural networks

    International Nuclear Information System (INIS)

    Tan, Y.; Van Cauwenberghe, A.; Liu, Z.

    1996-01-01

    The widely used backpropagation algorithm for training neural networks based on the gradient descent has a significant drawback of slow convergence. A Gauss-Newton method based recursive least squares (RLS) type algorithm with dynamic error backpropagation is presented to speed-up the learning procedure of neural networks with local recurrent terms. Finally, simulation examples concerning the applications of the RLS type algorithm to identification of nonlinear processes using a local recurrent neural network are also included in this paper

  9. Adaptive optimization and control using neural networks

    Energy Technology Data Exchange (ETDEWEB)

    Mead, W.C.; Brown, S.K.; Jones, R.D.; Bowling, P.S.; Barnes, C.W.

    1993-10-22

    Recent work has demonstrated the ability of neural-network-based controllers to optimize and control machines with complex, non-linear, relatively unknown control spaces. We present a brief overview of neural networks via a taxonomy illustrating some capabilities of different kinds of neural networks. We present some successful control examples, particularly the optimization and control of a small-angle negative ion source.

  10. The quest for a Quantum Neural Network

    OpenAIRE

    Schuld, M.; Sinayskiy, I.; Petruccione, F.

    2014-01-01

    With the overwhelming success in the field of quantum information in the last decades, the "quest" for a Quantum Neural Network (QNN) model began in order to combine quantum computing with the striking properties of neural computing. This article presents a systematic approach to QNN research, which so far consists of a conglomeration of ideas and proposals. It outlines the challenge of combining the nonlinear, dissipative dynamics of neural computing and the linear, unitary dynamics of quant...

  11. NeuroMEMS: Neural Probe Microtechnologies

    Directory of Open Access Journals (Sweden)

    Sam Musallam

    2008-10-01

    Full Text Available Neural probe technologies have already had a significant positive effect on our understanding of the brain by revealing the functioning of networks of biological neurons. Probes are implanted in different areas of the brain to record and/or stimulate specific sites in the brain. Neural probes are currently used in many clinical settings for diagnosis of brain diseases such as seizers, epilepsy, migraine, Alzheimer’s, and dementia. We find these devices assisting paralyzed patients by allowing them to operate computers or robots using their neural activity. In recent years, probe technologies were assisted by rapid advancements in microfabrication and microelectronic technologies and thus are enabling highly functional and robust neural probes which are opening new and exciting avenues in neural sciences and brain machine interfaces. With a wide variety of probes that have been designed, fabricated, and tested to date, this review aims to provide an overview of the advances and recent progress in the microfabrication techniques of neural probes. In addition, we aim to highlight the challenges faced in developing and implementing ultralong multi-site recording probes that are needed to monitor neural activity from deeper regions in the brain. Finally, we review techniques that can improve the biocompatibility of the neural probes to minimize the immune response and encourage neural growth around the electrodes for long term implantation studies.

  12. Fuzzy neural network theory and application

    CERN Document Server

    Liu, Puyin

    2004-01-01

    This book systematically synthesizes research achievements in the field of fuzzy neural networks in recent years. It also provides a comprehensive presentation of the developments in fuzzy neural networks, with regard to theory as well as their application to system modeling and image restoration. Special emphasis is placed on the fundamental concepts and architecture analysis of fuzzy neural networks. The book is unique in treating all kinds of fuzzy neural networks and their learning algorithms and universal approximations, and employing simulation examples which are carefully designed to he

  13. Practical neural network recipies in C++

    CERN Document Server

    Masters

    2014-01-01

    This text serves as a cookbook for neural network solutions to practical problems using C++. It will enable those with moderate programming experience to select a neural network model appropriate to solving a particular problem, and to produce a working program implementing that network. The book provides guidance along the entire problem-solving path, including designing the training set, preprocessing variables, training and validating the network, and evaluating its performance. Though the book is not intended as a general course in neural networks, no background in neural works is assum

  14. Boolean Factor Analysis by Attractor Neural Network

    Czech Academy of Sciences Publication Activity Database

    Frolov, A. A.; Húsek, Dušan; Muraviev, I. P.; Polyakov, P.Y.

    2007-01-01

    Roč. 18, č. 3 (2007), s. 698-707 ISSN 1045-9227 R&D Projects: GA AV ČR 1ET100300419; GA ČR GA201/05/0079 Institutional research plan: CEZ:AV0Z10300504 Keywords : recurrent neural network * Hopfield-like neural network * associative memory * unsupervised learning * neural network architecture * neural network application * statistics * Boolean factor analysis * dimensionality reduction * features clustering * concepts search * information retrieval Subject RIV: BB - Applied Statistics, Operational Research Impact factor: 2.769, year: 2007

  15. Premalignant quiescent melanocytic nevi do not express the MHC class I chain-related protein A Los nevos melanocíticos premalignos quiescentes no expresan la molécula MHC class I chain-related protein A

    Directory of Open Access Journals (Sweden)

    Mercedes B. Fuertes

    2011-08-01

    Full Text Available The MHC class I chain-related protein A (MICA is an inducible molecule almost not expressed by normal cells but strongly up-regulated in tumor cells. MICA-expressing cells are recognized by natural killer (NK cells, CD8+ aßTCR and ?dTCR T lymphocytes through the NKG2D receptor. Engagement of NKG2D by MICA triggers IFN-? secretion and cytotoxicity against malignant cells. Although most solid tumors express MICA and this molecule is a target during immune surveillance against tumors, it has been observed that high grade tumors from different histotypes express low amounts of cell surface MICA due to a metalloprotease- induced shedding. Also, melanomas develop after a complex process of neotransformation of normal melanocytes. However, the expression of MICA in premalignant stages (primary human quiescent melanocytic nevi remains unknown. Here, we assessed expression of MICA by flow cytometry using cell suspensions from 15 primary nevi isolated from 11 patients. When collected material was abundant, cell lysates were prepared and MICA expression was also analyzed by Western blot. We observed that MICA was undetectable in the 15 primary nevi (intradermic, junction, mixed, lentigo and congenital samples as well as in normal skin, benign lesions (seborrheic keratosis, premalignant lesions (actinic keratosis and benign basocellular cancer. Conversely, a primary recently diagnosed melanoma showed intense cell surface MICA. We conclude that the onset of MICA expression is a tightly regulated process that occurs after melanocytes trespass the stage of malignant transformation. Thus, analysis of MICA expression in tissue sections of skin samples may constitute a useful marker to differentiate between benign and malignant nevi.MHC class I chain-related protein A (MICA es una molécula casi ausente en células normales pero sobre-expresada por células tumorales, que promueve el reconocimiento por células citotóxicas naturales (natural killer o NK y por

  16. Association of giant congenital melanocytic nevus, halo nevus and vitiligo in a 75-year-old patient Associação de nevo melanocítico congênito gigante, nevo halo e vitiligo. Relato de caso em paciente de 75 anos

    Directory of Open Access Journals (Sweden)

    Marina Leite da Silveira

    2012-04-01

    Full Text Available A giant congenital melanocytic nevus represents a rare condition. The halo phenomenon may be seen in congenital or acquired melanocytic nevi. In the literature, association of halo nevus and giant congenital melanocytic nevus is rare and the association of both with vitiligo even more rare. A 75-yearold woman at first consultation complained of a hyperchromic bluish-brown hairy macula on the lower back, buttocks and thighs present since birth and an achromic halo of onset three years ago. The histological features were consistent with congenital melanocytic nevus and halo nevus, respectively. After two years the patient developed achromic areas in normal skin, histologically consistent with vitiligo. The authors emphasize the rarity of this triple combination, the patient's age and the absence of malignant degeneration to date.Nevo melanocitico congênito gigante constitui uma condição rara. O fenômeno halo pode ser observado em nevos melanocíticos congênitos ou adquiridos. Na literatura a associação nevo halo e nevo melanocítico congênito gigante é rara e a associação de ambos com vitiligo ainda mais rara. Mulher de 75 anos que à primeira consulta apresentava mácula hipercrômica castanho-azulada pilosa na região lombar, nádegas e coxas desde o nascimento e halo acrômico de aparecimento há 3 anos. Os histológicos foram compatíveis com nevo melanocítico congênito e nevo halo respectivamente. Após dois anos evoluiu com áreas de acromia à distância, com histológico de vitiligo. Os autores ressaltam a raridade desta tripla associação; a idade da paciente e a ausência de degeneração maligna até o presente momento.

  17. Evolutionary loss of melanogenesis in the tunicate Molgula occulta

    Directory of Open Access Journals (Sweden)

    Claudia Racioppi

    2017-07-01

    Full Text Available Abstract Background Analyzing close species with diverse developmental modes is instrumental for investigating the evolutionary significance of physiological, anatomical and behavioral features at a molecular level. Many examples of trait loss are known in metazoan populations living in dark environments. Tunicates are the closest living relatives of vertebrates and typically present a lifecycle with distinct motile larval and sessile adult stages. The nervous system of the motile larva contains melanized cells associated with geotactic and light-sensing organs. It has been suggested that these are homologous to vertebrate neural crest-derived melanocytes. Probably due to ecological adaptation to distinct habitats, several species of tunicates in the Molgulidae family have tailless (anural larvae that fail to develop sensory organ-associated melanocytes. Here we studied the evolution of Tyrosinase family genes, indispensible for melanogenesis, in the anural, unpigmented Molgula occulta and in the tailed, pigmented Molgula oculata by using phylogenetic, developmental and molecular approaches. Results We performed an evolutionary reconstruction of the tunicate Tyrosinase gene family: in particular, we found that M. oculata possesses genes predicted to encode one Tyrosinase (Tyr and three Tyrosinase-related proteins (Tyrps while M. occulta has only Tyr and Tyrp.a pseudogenes that are not likely to encode functional proteins. Analysis of Tyr sequences from various M. occulta individuals indicates that different alleles independently acquired frameshifting short indels and/or larger mobile genetic element insertions, resulting in pseudogenization of the Tyr locus. In M. oculata, Tyr is expressed in presumptive pigment cell precursors as in the model tunicate Ciona robusta. Furthermore, a M. oculata Tyr reporter gene construct was active in the pigment cell precursors of C. robusta embryos, hinting at conservation of the regulatory network underlying

  18. The LILARTI neural network system

    Energy Technology Data Exchange (ETDEWEB)

    Allen, J.D. Jr.; Schell, F.M.; Dodd, C.V.

    1992-10-01

    The material of this Technical Memorandum is intended to provide the reader with conceptual and technical background information on the LILARTI neural network system of detail sufficient to confer an understanding of the LILARTI method as it is presently allied and to facilitate application of the method to problems beyond the scope of this document. Of particular importance in this regard are the descriptive sections and the Appendices which include operating instructions, partial listings of program output and data files, and network construction information.

  19. Finite connectivity attractor neural networks

    International Nuclear Information System (INIS)

    Wemmenhove, B; Coolen, A C C

    2003-01-01

    We study a family of diluted attractor neural networks with a finite average number of (symmetric) connections per neuron. As in finite connectivity spin glasses, their equilibrium properties are described by order parameter functions, for which we derive an integral equation in replica symmetric approximation. A bifurcation analysis of this equation reveals the locations of the paramagnetic to recall and paramagnetic to spin-glass transition lines in the phase diagram. The line separating the retrieval phase from the spin-glass phase is calculated at zero temperature. All phase transitions are found to be continuous

  20. Aplicación de terapia de vacío en el tratamiento de nevus pigmentario gigante en la infancia Negative pressure therapy in the treatment of a giant melanocytic nevus in chilhood

    Directory of Open Access Journals (Sweden)

    J. Fregenal

    2011-12-01

    Full Text Available Los nevus melanocíticos gigantes congénitos son muy infrecuentes. Su incidencia de malignización varía según las series clínicas entre el 2 y el 45%. Este riesgo de malignización y los problemas de adaptación psicosocial que suelen acarrear hacen recomendable el inicio del tratamiento quirúrgico de este tipo de lesiones antes de la edad escolar. Presentamos el caso de un niño de 7 años de edad con nevus melanocítico congénito gigante que afectaba a la espalda y al flanco derecho, de 30 x 19 cm de diámetro. Desarrollamos un protocolo terapéutico mediante programación de intervenciones quirúrgicas seriadas de mínima morbilidad, con postoperatorio simple y poco doloroso. En un primer tiempo realizamos extirpación de la lesión con bisturí ultrasónico y cobertura temporal del defecto creado con dermis artificial. En un segundo tiempo intentamos cobertura definitiva con piel cultivada autóloga, siendo necesario un tercer tiempo de cobertura con autoinjerto de espesor ultrafino. En este caso, el sistema de terapia de presión negativa VAC® mostró su eficacia para inmovilizar los apósitos de forma segura, indolora y en régimen ambulatorio.Giant congenital melanocytic nevi are very uncommon. Malignization incidence varies according to clinical series between 2 and 45%. This risk of malignization and psychosocial adaptation problems make necessary to begin the surgical treatment before school age. We present a 7-year-old child with a giant melanocytic nevus in the back and right flank, 30 x 19 cm in size. A therapeutic protocol using serial surgical interventions with minimal morbidity and an easy and painless postoperative care were developed. In the first surgery we removed the nevus with ultrasonic scalpel and used artificial dermis as a temporary coverage. In the second time we tried to complete the definitive coverage with autologous cultured skin, but we needed a third time to apply definitive ultrathin skin autograft. In

  1. Nevus melanocítico intradérmico congénito gigante. "El niño tortuga (testudines": Caso clínico Giant congenital melanocytic nevus. "Turtle boy": Case report

    Directory of Open Access Journals (Sweden)

    J.F. Arango Ospina

    2009-09-01

    Full Text Available Presentamos el caso de un paciente de 2 años de edad, conocido en su pueblo, como "el niño tortuga (testudines" debido a la gran similitud con dicho reptil. Desde su nacimiento presentó nevus melanocítico gigante localizado en región torácica posterior, región lumbosacra y lesiones satélites en extremidades y abdomen, de 50 por 40cm de diámetro y color café oscuro; la piel en las zonas afectadas es gruesa con grandes surcos de aspecto corrugado (cerebriforme. El nombre dado al niño se basa en la similitud de sus lesiones con la morfología de una tortuga, ya que el caparazón cubre la zona superior, inferior y lateral del cuerpo de este animal, de la misma forma que el nevus gigante lo hacía en el caso de nuestro paciente. Este caparazón está formado por placas óseas revestidas de placas corneas, que se asemejan a los surcos de aspecto corrugado que conforman el nevus melanocítico gigante. Los estudios clínicos practicados revelaron compromiso cardiovascular, hepático y esplénico, así como una desfavorable evolución y pronostico del cuadro clínico, por lo que esta patología, específicamente para este niño y de acuerdo a la junta Médico-Quirúrgica y valoraciones, fue considerada inoperable.We present the case of a 2 years-old patient, known in his town as "turtle boy"(testudines due to his great simility with this reptile because of his giant congenital melanocytic nevus, located in the posterior and lateral aspect of the chest and in smaller proportion in abdomen and extremities, of 50 by 40cm and dark brown colour. The skin in this zone is thick with great furrows and corrugated aspect. He was called "turtle boy" based on the morphology of the turtle, its shell covers the superior, inferior and lateral zone like in our patient's case. It is formed by bone layers covered by cornea layers, which resemble the furrows and corrugated aspect of the giant congenital melanocytic nevus. Medical investigation reveals

  2. Neural Network Based Load Frequency Control for Restructuring ...

    African Journals Online (AJOL)

    Neural Network Based Load Frequency Control for Restructuring Power Industry. ... an artificial neural network (ANN) application of load frequency control (LFC) of a Multi-Area power system by using a neural network controller is presented.

  3. In-vitro differentiation induction of neural stem cells

    NARCIS (Netherlands)

    Balasubramaniyan, Veerakumar

    2006-01-01

    Neurale stamcellen maken de drie belangrijkste celtypes van ons zenuwstelsel aan. Veerakumar Balasubramaniyan onderzocht hoe neurale stamcellen kunnen worden aangezet tot het aanmaken van specifieke neurale celtypes. Met behulp van genetische technieken lukte het hem oligodendrocyten te verkrijgen:

  4. Molecular Pathogenesis of Pheochromocytomas and Paragangliomash

    NARCIS (Netherlands)

    H. Dannenberg (Hilde)

    2005-01-01

    textabstractGeneral aspectsParaganglia are small neuroendocrine organs, that usually manifest as anatomically discrete bodies, the parenchymal cells of which are neural crest-derived, and produce catecholamines and various peptides. One group of paraganglia is aligned to the sympathoadrenal and

  5. MEIS homeobox genes in neuroblastoma

    NARCIS (Netherlands)

    Geerts, Dirk; Revet, Ingrid; Jorritsma, Gerda; Schilderink, Nathalie; Versteeg, Rogier

    2005-01-01

    The common pediatric tumor neuroblastoma originates from primitive neural crest-derived precursor cells of the peripheral nervous system. Neuroblastoma especially affects very young children, and can already be present at birth. Its early onset and cellular origin predict the involvement of

  6. Neural network modeling of emotion

    Science.gov (United States)

    Levine, Daniel S.

    2007-03-01

    This article reviews the history and development of computational neural network modeling of cognitive and behavioral processes that involve emotion. The exposition starts with models of classical conditioning dating from the early 1970s. Then it proceeds toward models of interactions between emotion and attention. Then models of emotional influences on decision making are reviewed, including some speculative (not and not yet simulated) models of the evolution of decision rules. Through the late 1980s, the neural networks developed to model emotional processes were mainly embodiments of significant functional principles motivated by psychological data. In the last two decades, network models of these processes have become much more detailed in their incorporation of known physiological properties of specific brain regions, while preserving many of the psychological principles from the earlier models. Most network models of emotional processes so far have dealt with positive and negative emotion in general, rather than specific emotions such as fear, joy, sadness, and anger. But a later section of this article reviews a few models relevant to specific emotions: one family of models of auditory fear conditioning in rats, and one model of induced pleasure enhancing creativity in humans. Then models of emotional disorders are reviewed. The article concludes with philosophical statements about the essential contributions of emotion to intelligent behavior and the importance of quantitative theories and models to the interdisciplinary enterprise of understanding the interactions of emotion, cognition, and behavior.

  7. Imaging Posture Veils Neural Signals

    Directory of Open Access Journals (Sweden)

    Robert T Thibault

    2016-10-01

    Full Text Available Whereas modern brain imaging often demands holding body positions incongruent with everyday life, posture governs both neural activity and cognitive performance. Humans commonly perform while upright; yet, many neuroimaging methodologies require participants to remain motionless and adhere to non-ecological comportments within a confined space. This inconsistency between ecological postures and imaging constraints undermines the transferability and generalizability of many a neuroimaging assay.Here we highlight the influence of posture on brain function and behavior. Specifically, we challenge the tacit assumption that brain processes and cognitive performance are comparable across a spectrum of positions. We provide an integrative synthesis regarding the increasingly prominent influence of imaging postures on autonomic function, mental capacity, sensory thresholds, and neural activity. Arguing that neuroimagers and cognitive scientists could benefit from considering the influence posture wields on both general functioning and brain activity, we examine existing imaging technologies and the potential of portable and versatile imaging devices (e.g., functional near infrared spectroscopy. Finally, we discuss ways that accounting for posture may help unveil the complex brain processes of everyday cognition.

  8. Learning in Artificial Neural Systems

    Science.gov (United States)

    Matheus, Christopher J.; Hohensee, William E.

    1987-01-01

    This paper presents an overview and analysis of learning in Artificial Neural Systems (ANS's). It begins with a general introduction to neural networks and connectionist approaches to information processing. The basis for learning in ANS's is then described, and compared with classical Machine learning. While similar in some ways, ANS learning deviates from tradition in its dependence on the modification of individual weights to bring about changes in a knowledge representation distributed across connections in a network. This unique form of learning is analyzed from two aspects: the selection of an appropriate network architecture for representing the problem, and the choice of a suitable learning rule capable of reproducing the desired function within the given network. The various network architectures are classified, and then identified with explicit restrictions on the types of functions they are capable of representing. The learning rules, i.e., algorithms that specify how the network weights are modified, are similarly taxonomized, and where possible, the limitations inherent to specific classes of rules are outlined.

  9. Neural dynamics in reconfigurable silicon.

    Science.gov (United States)

    Basu, A; Ramakrishnan, S; Petre, C; Koziol, S; Brink, S; Hasler, P E

    2010-10-01

    A neuromorphic analog chip is presented that is capable of implementing massively parallel neural computations while retaining the programmability of digital systems. We show measurements from neurons with Hopf bifurcations and integrate and fire neurons, excitatory and inhibitory synapses, passive dendrite cables, coupled spiking neurons, and central pattern generators implemented on the chip. This chip provides a platform for not only simulating detailed neuron dynamics but also uses the same to interface with actual cells in applications such as a dynamic clamp. There are 28 computational analog blocks (CAB), each consisting of ion channels with tunable parameters, synapses, winner-take-all elements, current sources, transconductance amplifiers, and capacitors. There are four other CABs which have programmable bias generators. The programmability is achieved using floating gate transistors with on-chip programming control. The switch matrix for interconnecting the components in CABs also consists of floating-gate transistors. Emphasis is placed on replicating the detailed dynamics of computational neural models. Massive computational area efficiency is obtained by using the reconfigurable interconnect as synaptic weights, resulting in more than 50 000 possible 9-b accurate synapses in 9 mm(2).

  10. Chimera States in Neural Oscillators

    Science.gov (United States)

    Bahar, Sonya; Glaze, Tera

    2014-03-01

    Chimera states have recently been explored both theoretically and experimentally, in various coupled nonlinear oscillators, ranging from phase-oscillator models to coupled chemical reactions. In a chimera state, both coherent and incoherent (or synchronized and desynchronized) states occur simultaneously in populations of identical oscillators. We investigate chimera behavior in a population of neural oscillators using the Huber-Braun model, a Hodgkin-Huxley-like model originally developed to characterize the temperature-dependent bursting behavior of mammalian cold receptors. One population of neurons is allowed to synchronize, with each neuron receiving input from all the others in its group (global within-group coupling). Subsequently, a second population of identical neurons is placed under an identical global within-group coupling, and the two populations are also coupled to each other (between-group coupling). For certain values of the coupling constants, the neurons in the two populations exhibit radically different synchronization behavior. We will discuss the range of chimera activity in the model, and discuss its implications for actual neural activity, such as unihemispheric sleep.

  11. Improved transformer protection using probabilistic neural network ...

    African Journals Online (AJOL)

    user

    secure and dependable protection for power transformers. Owing to its superior learning and generalization capabilities Artificial. Neural Network (ANN) can considerably enhance the scope of WI method. ANN approach is faster, robust and easier to implement than the conventional waveform approach. The use of neural ...

  12. Neural network signal understanding for instrumentation

    DEFF Research Database (Denmark)

    Pau, L. F.; Johansen, F. S.

    1990-01-01

    understanding research is surveyed, and the selected implementation and its performance in terms of correct classification rates and robustness to noise are described. Formal results on neural net training time and sensitivity to weights are given. A theory for neural control using functional link nets is given...

  13. A Chip for an Implantable Neural Stimulator

    DEFF Research Database (Denmark)

    Gudnason, Gunnar; Bruun, Erik; Haugland, Morten

    2000-01-01

    This paper describes a chip for a multichannel neural stimulator for functional electrical stimulation (FES). The purpose of FES is to restore muscular control in disabled patients. The chip performs all the signal processing required in an implanted neural stimulator. The power and digital data...

  14. Hidden neural networks: application to speech recognition

    DEFF Research Database (Denmark)

    Riis, Søren Kamaric

    1998-01-01

    We evaluate the hidden neural network HMM/NN hybrid on two speech recognition benchmark tasks; (1) task independent isolated word recognition on the Phonebook database, and (2) recognition of broad phoneme classes in continuous speech from the TIMIT database. It is shown how hidden neural networks...

  15. Neural Network Classifier Based on Growing Hyperspheres

    Czech Academy of Sciences Publication Activity Database

    Jiřina Jr., Marcel; Jiřina, Marcel

    2000-01-01

    Roč. 10, č. 3 (2000), s. 417-428 ISSN 1210-0552. [Neural Network World 2000. Prague, 09.07.2000-12.07.2000] Grant - others:MŠMT ČR(CZ) VS96047; MPO(CZ) RP-4210 Institutional research plan: AV0Z1030915 Keywords : neural network * classifier * hyperspheres * big -dimensional data Subject RIV: BA - General Mathematics

  16. A high-speed analog neural processor

    NARCIS (Netherlands)

    Masa, P.; Masa, Peter; Hoen, Klaas; Hoen, Klaas; Wallinga, Hans

    1994-01-01

    Targeted at high-energy physics research applications, our special-purpose analog neural processor can classify up to 70 dimensional vectors within 50 nanoseconds. The decision-making process of the implemented feedforward neural network enables this type of computation to tolerate weight

  17. Neurophysiology and neural engineering: a review.

    Science.gov (United States)

    Prochazka, Arthur

    2017-08-01

    Neurophysiology is the branch of physiology concerned with understanding the function of neural systems. Neural engineering (also known as neuroengineering) is a discipline within biomedical engineering that uses engineering techniques to understand, repair, replace, enhance, or otherwise exploit the properties and functions of neural systems. In most cases neural engineering involves the development of an interface between electronic devices and living neural tissue. This review describes the origins of neural engineering, the explosive development of methods and devices commencing in the late 1950s, and the present-day devices that have resulted. The barriers to interfacing electronic devices with living neural tissues are many and varied, and consequently there have been numerous stops and starts along the way. Representative examples are discussed. None of this could have happened without a basic understanding of the relevant neurophysiology. I also consider examples of how neural engineering is repaying the debt to basic neurophysiology with new knowledge and insight. Copyright © 2017 the American Physiological Society.

  18. Neural Networks for Non-linear Control

    DEFF Research Database (Denmark)

    Sørensen, O.

    1994-01-01

    This paper describes how a neural network, structured as a Multi Layer Perceptron, is trained to predict, simulate and control a non-linear process.......This paper describes how a neural network, structured as a Multi Layer Perceptron, is trained to predict, simulate and control a non-linear process....

  19. Interpretable neural networks with BP-SOM

    NARCIS (Netherlands)

    Weijters, A.J.M.M.; Bosch, van den A.P.J.; Pobil, del A.P.; Mira, J.; Ali, M.

    1998-01-01

    Artificial Neural Networks (ANNS) are used successfully in industry and commerce. This is not surprising since neural networks are especially competitive for complex tasks for which insufficient domain-specific knowledge is available. However, interpretation of models induced by ANNS is often

  20. Deciphering the Cognitive and Neural Mechanisms Underlying ...

    International Development Research Centre (IDRC) Digital Library (Canada)

    Deciphering the Cognitive and Neural Mechanisms Underlying Auditory Learning. This project seeks to understand the brain mechanisms necessary for people to learn to perceive sounds. Neural circuits and learning. The research team will test people with and without musical training to evaluate their capacity to learn ...

  1. The neural network approach to parton fitting

    International Nuclear Information System (INIS)

    Rojo, Joan; Latorre, Jose I.; Del Debbio, Luigi; Forte, Stefano; Piccione, Andrea

    2005-01-01

    We introduce the neural network approach to global fits of parton distribution functions. First we review previous work on unbiased parametrizations of deep-inelastic structure functions with faithful estimation of their uncertainties, and then we summarize the current status of neural network parton distribution fits

  2. NEURAL METHODS FOR THE FINANCIAL PREDICTION

    OpenAIRE

    Jerzy Balicki; Piotr Dryja; Waldemar Korłub; Piotr Przybyłek; Maciej Tyszka; Marcin Zadroga; Marcin Zakidalski

    2016-01-01

    Artificial neural networks can be used to predict share investment on the stock market, assess the reliability of credit client or predicting banking crises. Moreover, this paper discusses the principles of cooperation neural network algorithms with evolutionary method, and support vector machines. In addition, a reference is made to other methods of artificial intelligence, which are used in finance prediction.

  3. NEURAL METHODS FOR THE FINANCIAL PREDICTION

    Directory of Open Access Journals (Sweden)

    Jerzy Balicki

    2016-06-01

    Full Text Available Artificial neural networks can be used to predict share investment on the stock market, assess the reliability of credit client or predicting banking crises. Moreover, this paper discusses the principles of cooperation neural network algorithms with evolutionary method, and support vector machines. In addition, a reference is made to other methods of artificial intelligence, which are used in finance prediction.

  4. Neural Network to Solve Concave Games

    OpenAIRE

    Liu, Zixin; Wang, Nengfa

    2014-01-01

    The issue on neural network method to solve concave games is concerned. Combined with variational inequality, Ky Fan inequality, and projection equation, concave games are transformed into a neural network model. On the basis of the Lyapunov stable theory, some stability results are also given. Finally, two classic games’ simulation results are given to illustrate the theoretical results.

  5. Neural Network Algorithm for Particle Loading

    International Nuclear Information System (INIS)

    Lewandowski, J.L.V.

    2003-01-01

    An artificial neural network algorithm for continuous minimization is developed and applied to the case of numerical particle loading. It is shown that higher-order moments of the probability distribution function can be efficiently renormalized using this technique. A general neural network for the renormalization of an arbitrary number of moments is given

  6. Neural constructivism or self-organization?

    NARCIS (Netherlands)

    van der Maas, H.L.J.; Molenaar, P.C.M.

    2000-01-01

    Comments on the article by S. R. Quartz et al (see record 1998-00749-001) which discussed the constructivist perspective of interaction between cognition and neural processes during development and consequences for theories of learning. Three arguments are given to show that neural constructivism

  7. Memory in Neural Networks and Glasses

    NARCIS (Netherlands)

    Heerema, M.

    2000-01-01

    The thesis tries and models a neural network in a way which, at essential points, is biologically realistic. In a biological context, the changes of the synapses of the neural network are most often described by what is called `Hebb's learning rule'. On careful analysis it is, in fact, nothing but a

  8. Windowed active sampling for reliable neural learning

    NARCIS (Netherlands)

    Barakova, E.I; Spaanenburg, L

    The composition of the example set has a major impact on the quality of neural learning. The popular approach is focused on extensive pre-processing to bridge the representation gap between process measurement and neural presentation. In contrast, windowed active sampling attempts to solve these

  9. Neural Control of the Immune System

    Science.gov (United States)

    Sundman, Eva; Olofsson, Peder S.

    2014-01-01

    Neural reflexes support homeostasis by modulating the function of organ systems. Recent advances in neuroscience and immunology have revealed that neural reflexes also regulate the immune system. Activation of the vagus nerve modulates leukocyte cytokine production and alleviates experimental shock and autoimmune disease, and recent data have…

  10. A new perspective on behavioral inconsistency and neural noise in aging: Compensatory speeding of neural communication

    Directory of Open Access Journals (Sweden)

    S. Lee Hong

    2012-09-01

    Full Text Available This paper seeks to present a new perspective on the aging brain. Here, we make connections between two key phenomena of brain aging: 1 increased neural noise or random background activity; and 2 slowing of brain activity. Our perspective proposes the possibility that the slowing of neural processing due to decreasing nerve conduction velocities leads to a compensatory speeding of neuron firing rates. These increased firing rates lead to a broader distribution of power in the frequency spectrum of neural oscillations, which we propose, can just as easily be interpreted as neural noise. Compensatory speeding of neural activity, as we present, is constrained by the: A availability of metabolic energy sources; and B competition for frequency bandwidth needed for neural communication. We propose that these constraints lead to the eventual inability to compensate for age-related declines in neural function that are manifested clinically as deficits in cognition, affect, and motor behavior.

  11. 22nd Italian Workshop on Neural Nets

    CERN Document Server

    Bassis, Simone; Esposito, Anna; Morabito, Francesco

    2013-01-01

    This volume collects a selection of contributions which has been presented at the 22nd Italian Workshop on Neural Networks, the yearly meeting of the Italian Society for Neural Networks (SIREN). The conference was held in Italy, Vietri sul Mare (Salerno), during May 17-19, 2012. The annual meeting of SIREN is sponsored by International Neural Network Society (INNS), European Neural Network Society (ENNS) and IEEE Computational Intelligence Society (CIS). The book – as well as the workshop-  is organized in three main components, two special sessions and a group of regular sessions featuring different aspects and point of views of artificial neural networks and natural intelligence, also including applications of present compelling interest.

  12. Dynamic decomposition of spatiotemporal neural signals.

    Directory of Open Access Journals (Sweden)

    Luca Ambrogioni

    2017-05-01

    Full Text Available Neural signals are characterized by rich temporal and spatiotemporal dynamics that reflect the organization of cortical networks. Theoretical research has shown how neural networks can operate at different dynamic ranges that correspond to specific types of information processing. Here we present a data analysis framework that uses a linearized model of these dynamic states in order to decompose the measured neural signal into a series of components that capture both rhythmic and non-rhythmic neural activity. The method is based on stochastic differential equations and Gaussian process regression. Through computer simulations and analysis of magnetoencephalographic data, we demonstrate the efficacy of the method in identifying meaningful modulations of oscillatory signals corrupted by structured temporal and spatiotemporal noise. These results suggest that the method is particularly suitable for the analysis and interpretation of complex temporal and spatiotemporal neural signals.

  13. Signal Processing and Neural Network Simulator

    Science.gov (United States)

    Tebbe, Dennis L.; Billhartz, Thomas J.; Doner, John R.; Kraft, Timothy T.

    1995-04-01

    The signal processing and neural network simulator (SPANNS) is a digital signal processing simulator with the capability to invoke neural networks into signal processing chains. This is a generic tool which will greatly facilitate the design and simulation of systems with embedded neural networks. The SPANNS is based on the Signal Processing WorkSystemTM (SPWTM), a commercial-off-the-shelf signal processing simulator. SPW provides a block diagram approach to constructing signal processing simulations. Neural network paradigms implemented in the SPANNS include Backpropagation, Kohonen Feature Map, Outstar, Fully Recurrent, Adaptive Resonance Theory 1, 2, & 3, and Brain State in a Box. The SPANNS was developed by integrating SAIC's Industrial Strength Neural Networks (ISNN) Software into SPW.

  14. Neural networks with discontinuous/impact activations

    CERN Document Server

    Akhmet, Marat

    2014-01-01

    This book presents as its main subject new models in mathematical neuroscience. A wide range of neural networks models with discontinuities are discussed, including impulsive differential equations, differential equations with piecewise constant arguments, and models of mixed type. These models involve discontinuities, which are natural because huge velocities and short distances are usually observed in devices modeling the networks. A discussion of the models, appropriate for the proposed applications, is also provided. This book also: Explores questions related to the biological underpinning for models of neural networks\\ Considers neural networks modeling using differential equations with impulsive and piecewise constant argument discontinuities Provides all necessary mathematical basics for application to the theory of neural networks Neural Networks with Discontinuous/Impact Activations is an ideal book for researchers and professionals in the field of engineering mathematics that have an interest in app...

  15. International Conference on Artificial Neural Networks (ICANN)

    CERN Document Server

    Mladenov, Valeri; Kasabov, Nikola; Artificial Neural Networks : Methods and Applications in Bio-/Neuroinformatics

    2015-01-01

    The book reports on the latest theories on artificial neural networks, with a special emphasis on bio-neuroinformatics methods. It includes twenty-three papers selected from among the best contributions on bio-neuroinformatics-related issues, which were presented at the International Conference on Artificial Neural Networks, held in Sofia, Bulgaria, on September 10-13, 2013 (ICANN 2013). The book covers a broad range of topics concerning the theory and applications of artificial neural networks, including recurrent neural networks, super-Turing computation and reservoir computing, double-layer vector perceptrons, nonnegative matrix factorization, bio-inspired models of cell communities, Gestalt laws, embodied theory of language understanding, saccadic gaze shifts and memory formation, and new training algorithms for Deep Boltzmann Machines, as well as dynamic neural networks and kernel machines. It also reports on new approaches to reinforcement learning, optimal control of discrete time-delay systems, new al...

  16. Decentralized neural control application to robotics

    CERN Document Server

    Garcia-Hernandez, Ramon; Sanchez, Edgar N; Alanis, Alma y; Ruz-Hernandez, Jose A

    2017-01-01

    This book provides a decentralized approach for the identification and control of robotics systems. It also presents recent research in decentralized neural control and includes applications to robotics. Decentralized control is free from difficulties due to complexity in design, debugging, data gathering and storage requirements, making it preferable for interconnected systems. Furthermore, as opposed to the centralized approach, it can be implemented with parallel processors. This approach deals with four decentralized control schemes, which are able to identify the robot dynamics. The training of each neural network is performed on-line using an extended Kalman filter (EKF). The first indirect decentralized control scheme applies the discrete-time block control approach, to formulate a nonlinear sliding manifold. The second direct decentralized neural control scheme is based on the backstepping technique, approximated by a high order neural network. The third control scheme applies a decentralized neural i...

  17. Neural neworks in a management information systems

    Directory of Open Access Journals (Sweden)

    Jana Weinlichová

    2009-01-01

    Full Text Available For having retrospection for all over the data which are used, analyzed, evaluated and for a future incident predictions are used Management Information Systems and Business Intelligence. In case of not to be able to apply standard methods of data processing there can be with benefit applied an Artificial Intelligence. In this article will be referred to proofed abilities of Neural Networks. The Neural Networks is supported by many software products related to provide effective solution of manager issues. Those products are given as primary support for manager issues solving. We were tried to find reciprocally between products using Neural Networks and between Management Information Systems for finding a real possibility of applying Neural Networks as a direct part of Management Information Systems (MIS. In the article are presented possibilities to apply Neural Networks on different types of tasks in MIS.

  18. Noradrenergic modulation of neural erotic stimulus perception.

    Science.gov (United States)

    Graf, Heiko; Wiegers, Maike; Metzger, Coraline Danielle; Walter, Martin; Grön, Georg; Abler, Birgit

    2017-09-01

    We recently investigated neuromodulatory effects of the noradrenergic agent reboxetine and the dopamine receptor affine amisulpride in healthy subjects on dynamic erotic stimulus processing. Whereas amisulpride left sexual functions and neural activations unimpaired, we observed detrimental activations under reboxetine within the caudate nucleus corresponding to motivational components of sexual behavior. However, broadly impaired subjective sexual functioning under reboxetine suggested effects on further neural components. We now investigated the same sample under these two agents with static erotic picture stimulation as alternative stimulus presentation mode to potentially observe further neural treatment effects of reboxetine. 19 healthy males were investigated under reboxetine, amisulpride and placebo for 7 days each within a double-blind cross-over design. During fMRI static erotic picture were presented with preceding anticipation periods. Subjective sexual functions were assessed by a self-reported questionnaire. Neural activations were attenuated within the caudate nucleus, putamen, ventral striatum, the pregenual and anterior midcingulate cortex and in the orbitofrontal cortex under reboxetine. Subjective diminished sexual arousal under reboxetine was correlated with attenuated neural reactivity within the posterior insula. Again, amisulpride left neural activations along with subjective sexual functioning unimpaired. Neither reboxetine nor amisulpride altered differential neural activations during anticipation of erotic stimuli. Our results verified detrimental effects of noradrenergic agents on neural motivational but also emotional and autonomic components of sexual behavior. Considering the overlap of neural network alterations with those evoked by serotonergic agents, our results suggest similar neuromodulatory effects of serotonergic and noradrenergic agents on common neural pathways relevant for sexual behavior. Copyright © 2017 Elsevier B.V. and

  19. Localization of amylin-like immunoreactivity in melanocyte-stimulating hormone-containing cells of the pars intermedia but not those of the pars distalis in the axolotl (Ambystoma mexicanum) pituitary.

    Science.gov (United States)

    Suzuki, Hirohumi; Yamamoto, Toshiharu

    2016-04-01

    Immunohistochemical techniques were employed to investigate the distribution of amylin-like immunoreactivity in the axolotl (Ambystoma mexicanum) pituitary. Amylin-immunoreactive cells were observed in the pars intermedia, and these cells were found to be immunoreactive for α-melanocyte-stimulating hormone (αMSH) as well. In contrast, αMSH-immunoreactive cells in the pars distalis were immuno-negaitive for amylin. These light microscopic findings were confirmed by immunoelectron microscopy. Amylin-immunoreactive signals were located on the haloes of presumable secretory granules in association with αMSH-immunoreactive signals in the amylin-positive cells. However, in the pars distalis, the αMSH-positive cells did not contain amylin-immunoreactive secretory granules. Western blot analysis of axolotl pituitary extracts revealed the labeling of a protein band at approximately 10.5-kDa by the anti-rat amylin serum, which was not labeled by the anti-αMSH antibody. These findings indicate that amylin secreted from MSH-producing cells in the pars intermedia may modulate MSH secretion in an autocrine fashion and may participate in MSH functions such as fatty homeostasis together with MSH. Copyright © 2016 Elsevier GmbH. All rights reserved.

  20. Neural Networks in Control Applications

    DEFF Research Database (Denmark)

    Sørensen, O.

    are examined. The models are separated into three groups representing input/output descriptions as well as state space descriptions: - Models, where all in- and outputs are measurable (static networks). - Models, where some inputs are non-measurable (recurrent networks). - Models, where some in- and some...... outputs are non-measurable (recurrent networks with incomplete state information). The three groups are ordered in increasing complexity, and for each group it is shown how to solve the problems concerning training and application of the specific model type. Of particular interest are the model types...... Kalmann filter) representing state space description. The potentials of neural networks for control of non-linear processes are also examined, focusing on three different groups of control concepts, all considered as generalizations of known linear control concepts to handle also non-linear processes...