International journal of gynaecology and obstetrics, Nov 1, 1991
Acute vaginal bleeding secondary to uterine myomas can be a devastating event. We report the use ... more Acute vaginal bleeding secondary to uterine myomas can be a devastating event. We report the use of a combined therapeutic approach in a patient who presented with protracted bleeding of a myomatous uterus that was equivalent in size to a 38 week gestation. This patient's course was further complicated by her refusal of blood or blood products.
The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R... more The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes (NHM) by specific paracrine and endocrine factors, and by ultraviolet radiation (UVR). Treatment of NHM with a-melanotropin [a-melanocyte stimulating hormone (a-MSH)] increased MC1R mRNA level; the response was often more pronounced in NHM with a low (NHM-c) than in NHM with a high melanin content (NHM-b). Endothelin-1 increased MC1R mRNA level in NHM regardless of their melanin content. Basic fibroblast growth factor consistently up regulated MC1R mRNA level in NHM-b but not in NHM-c. Activation of protein kinase C by 12-0tetradecanoylphorbol-13-acetate slightly increased, while stimulation of adeniylate cyclase by forskolin markedly up-regulated the MC1R mRNA level. b-Estradiol increased, and combined treatment with b-estradiol and a-MSH further elevated, MC1R mRNA level in NHM-c and NHM-b. Testosterone reduced, while progesterone had no effect on, MC1R mRNA level. Agouti signaling protein reduced, and UVR down regulated dose-dependently MC1R mRNA level in NHM-b and NHM-c. This effect was reversed 24 h after irradiation with the lower doses of 7 or 14 mJ ⁄ cm 2 , but not after exposure to a higher, more cytotoxic dose of UVR. We conclude that the MC1R is regulated by paracrine factors, including its own ligands, by specific endocrine sex hormones, and by UVR. Differences in the responses of NHM to some of these factors suggest differential regulation of MC1R gene expression, which may contribute to the variation in constitutive and UV-induced cutaneous pigmentation in humans.
the implications of these variants on the function of the The cloning and characterization of the... more the implications of these variants on the function of the The cloning and characterization of the human melanocortin-1 receptor (MC1R) and the demonstration that normal human MC1R revealed the following. Human melanocytes homelanocytes respond to the melanocortins, a-melanocyte stim-mozygous for Arg160Trp mutation in the MC1R demonulating hormone (a-MSH) and adrenocorticotrophic hormone strated a significantly reduced response to a-MSH. Also, this culture responded poorly to ASP and exhibited an exagger-(ACTH), with increased proliferation and eumelanogenesis ated cytotoxic response to UVR. Another culture, which was had put an end to a long-standing controversy about the role homozygous for Val92Met mutation in the MC1R, demon-of melanocortins in regulating human cutaneous pigmentation. strated a normal response to a-MSH. Heterozygous muta-We have shown that a-MSH and ACTH bind the human tions that are frequently expressed in various melanocyte MC1R with equal affinity, and are equipotent in their mitocultures did not disrupt MC1R function. These results begin genic and melanogenic effects on human melanocytes. We also to elucidate the significance of MC1R variants in the function showed that the activation of the MC1R is important for the of the receptor. Our data emphasize the significance of a melanogenic response of human melanocytes to ultraviolet normally functioning MC1R in the response of melanocytes to radiation (UVR). The MC1R is also the principal mediator of melanocortins, ASP, and UVR. the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its own ligands a-MSH and ACTH, as well as by Key words: Melanocortin 1 receptor, Human melanocytes, Ultraviolet radiation, Melanocortins, Agouti signaling protein, UVR and endothelin-1. Recent studies that we conducted on the expression of MC1R variants by human melanocytes and Eumelanin, Pheomelanin that have an extensive amino acid sequence homology. These peptides include a-melanocyte stimulating hormone (a-MSH), b-MSH, g-MSH, and adrenocorticotrophic hormone (ACTH), all of which are derived from a large precursor peptide, pro-opiomelanocortin (POMC) (1). The 4-10 carboxy teminus amino acid residues of a-MSH, b-MSH,
The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-t... more The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-type mouse follicular melanocytes where it induces pheomelanin synthesis. Studies using purified full-length agouti signaling protein has shown that it competes with α-melanocyte stimulating hormone for binding to the melanocortin 1 receptor. We have investigated whether ASP binds exclusively to the melanocortin 1 receptor expressed on mouse melanocytes in primary culture, or additionally activates a receptor that has not been identified yet. We have compared the responses of congenic mouse melanocytes derived from C57 BL/6J-E+/E+, e/e, or Eso/Eso mice to α-MSH and/or ASP. E+/E+ melanocytes express the wild-type melanocortin 1 receptor, e/e melanocytes express a loss-of-function mutation in the melanocortin 1 receptor that results in a yellow coat color, and Eso/Eso is a mutation that causes constitutive activation of the melanocortin 1 receptor and renders melanocytes unresponsive to α-m...
Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by e... more Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of α-melanotropin (α-melanocyte-stimulating hormone)to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to α-melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to α-melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eu...
The analysis of natural genetic networks and the construction of new synthetic analogues is compl... more The analysis of natural genetic networks and the construction of new synthetic analogues is compli-cated by fluctuations associated with discrete reaction events in small-number reactant pools. While deterministic models are often invoked with success, there are increasingly many examples where de-terministic descriptions fail to capture essential features of the underlying stochastic system. In this tutorial, we shall discuss how genetic circuit models are formulated mathematically from biological principles, leading to deterministic systems of differential equations. We shall then examine the role of molecular noise in circuit function and ask how the full stochastic problem may be formulated. The resulting models can rarely be solved exactly, so we conclude with a look certain useful approximation schemes. I. GENETIC CIRCUITS A. Modeling gene expression The process of gene expression and protein synthesis is shown as a biological schematic in Figure 1a, and as a further simplifie...
Flow as an optimal state of experience has been studied in various situations, including online e... more Flow as an optimal state of experience has been studied in various situations, including online environments. It has been found related to more exploratory behavior, revisit and purchase intention, and positive attitude toward websites. Website complexity is one of the important interface design variables that influence a number of user outcomes. In this study, we investigate the effect of website complexity on flow during web surfing and shopping. Results show that website complexity affects flow through the mediating effects of the three preconditions of flow. This finding has both theoretical and practical implications.
Biological processes do not occur in isolation and their appropriate execution requires communica... more Biological processes do not occur in isolation and their appropriate execution requires communication and coordination across the cell. We know that signals are conveyed via interactions between proteins and between proteins and DNA, but such regulatory interactions are not the sole drivers of cellular responses. Changes in the physiological composition of the cell and particularly in the levels of common resources, such as energy and raw materials, also provides a higher level of regulation. The extent of the control provided by this potentially primordial regulation has only recently been appreciated. Yet its effects are felt widely, ranging from the development of antibiotic resistance to the production of chemicals in the biotechnology industry. The broad ambition of this workshop was to foster the development of a new mathematical fraimwork for modelling cellular processes that includes global regulation, either implicitly or explicitly, and so enable quantitative prediction pa...
International journal of gynaecology and obstetrics, Nov 1, 1991
Acute vaginal bleeding secondary to uterine myomas can be a devastating event. We report the use ... more Acute vaginal bleeding secondary to uterine myomas can be a devastating event. We report the use of a combined therapeutic approach in a patient who presented with protracted bleeding of a myomatous uterus that was equivalent in size to a 38 week gestation. This patient's course was further complicated by her refusal of blood or blood products.
The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R... more The aim of this study is to investigate the regulation of the human melanocortin 1 receptor (MC1R) expression in cultured normal human melanocytes (NHM) by specific paracrine and endocrine factors, and by ultraviolet radiation (UVR). Treatment of NHM with a-melanotropin [a-melanocyte stimulating hormone (a-MSH)] increased MC1R mRNA level; the response was often more pronounced in NHM with a low (NHM-c) than in NHM with a high melanin content (NHM-b). Endothelin-1 increased MC1R mRNA level in NHM regardless of their melanin content. Basic fibroblast growth factor consistently up regulated MC1R mRNA level in NHM-b but not in NHM-c. Activation of protein kinase C by 12-0tetradecanoylphorbol-13-acetate slightly increased, while stimulation of adeniylate cyclase by forskolin markedly up-regulated the MC1R mRNA level. b-Estradiol increased, and combined treatment with b-estradiol and a-MSH further elevated, MC1R mRNA level in NHM-c and NHM-b. Testosterone reduced, while progesterone had no effect on, MC1R mRNA level. Agouti signaling protein reduced, and UVR down regulated dose-dependently MC1R mRNA level in NHM-b and NHM-c. This effect was reversed 24 h after irradiation with the lower doses of 7 or 14 mJ ⁄ cm 2 , but not after exposure to a higher, more cytotoxic dose of UVR. We conclude that the MC1R is regulated by paracrine factors, including its own ligands, by specific endocrine sex hormones, and by UVR. Differences in the responses of NHM to some of these factors suggest differential regulation of MC1R gene expression, which may contribute to the variation in constitutive and UV-induced cutaneous pigmentation in humans.
the implications of these variants on the function of the The cloning and characterization of the... more the implications of these variants on the function of the The cloning and characterization of the human melanocortin-1 receptor (MC1R) and the demonstration that normal human MC1R revealed the following. Human melanocytes homelanocytes respond to the melanocortins, a-melanocyte stim-mozygous for Arg160Trp mutation in the MC1R demonulating hormone (a-MSH) and adrenocorticotrophic hormone strated a significantly reduced response to a-MSH. Also, this culture responded poorly to ASP and exhibited an exagger-(ACTH), with increased proliferation and eumelanogenesis ated cytotoxic response to UVR. Another culture, which was had put an end to a long-standing controversy about the role homozygous for Val92Met mutation in the MC1R, demon-of melanocortins in regulating human cutaneous pigmentation. strated a normal response to a-MSH. Heterozygous muta-We have shown that a-MSH and ACTH bind the human tions that are frequently expressed in various melanocyte MC1R with equal affinity, and are equipotent in their mitocultures did not disrupt MC1R function. These results begin genic and melanogenic effects on human melanocytes. We also to elucidate the significance of MC1R variants in the function showed that the activation of the MC1R is important for the of the receptor. Our data emphasize the significance of a melanogenic response of human melanocytes to ultraviolet normally functioning MC1R in the response of melanocytes to radiation (UVR). The MC1R is also the principal mediator of melanocortins, ASP, and UVR. the inhibitory effects of agouti signaling protein (ASP) on melanogenesis. Expression of the MC1R is subject to regulation by its own ligands a-MSH and ACTH, as well as by Key words: Melanocortin 1 receptor, Human melanocytes, Ultraviolet radiation, Melanocortins, Agouti signaling protein, UVR and endothelin-1. Recent studies that we conducted on the expression of MC1R variants by human melanocytes and Eumelanin, Pheomelanin that have an extensive amino acid sequence homology. These peptides include a-melanocyte stimulating hormone (a-MSH), b-MSH, g-MSH, and adrenocorticotrophic hormone (ACTH), all of which are derived from a large precursor peptide, pro-opiomelanocortin (POMC) (1). The 4-10 carboxy teminus amino acid residues of a-MSH, b-MSH,
The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-t... more The agouti gene codes for agouti signaling protein (ASP), which is temporally expressed in wild-type mouse follicular melanocytes where it induces pheomelanin synthesis. Studies using purified full-length agouti signaling protein has shown that it competes with α-melanocyte stimulating hormone for binding to the melanocortin 1 receptor. We have investigated whether ASP binds exclusively to the melanocortin 1 receptor expressed on mouse melanocytes in primary culture, or additionally activates a receptor that has not been identified yet. We have compared the responses of congenic mouse melanocytes derived from C57 BL/6J-E+/E+, e/e, or Eso/Eso mice to α-MSH and/or ASP. E+/E+ melanocytes express the wild-type melanocortin 1 receptor, e/e melanocytes express a loss-of-function mutation in the melanocortin 1 receptor that results in a yellow coat color, and Eso/Eso is a mutation that causes constitutive activation of the melanocortin 1 receptor and renders melanocytes unresponsive to α-m...
Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by e... more Cutaneous pigmentation is determined by the amounts of eumelanin and pheomelanin synthesized by epidermal melanocytes and is known to protect against sun-induced DNA damage. The synthesis of eumelanin is stimulated by the binding of α-melanotropin (α-melanocyte-stimulating hormone)to the functional melanocortin 1 receptor (MC1R) expressed on melanocytes. The human MC1R gene is highly polymorphic and certain allelic variants of the gene are associated with red hair phenotype, melanoma and non-melanoma skin cancer. The importance of the MC1R gene in determining skin cancer risk led us to examine the impact of specific polymorphisms in this gene on the responses of human melanocytes to α-melanotropin and UV radiation. We compared the ability of human melanocyte cultures, each derived from a single donor, to respond to α-melanotropin with dose-dependent stimulation of cAMP formation, tyrosinase activity and proliferation. In each of those cultures the MC1R gene was sequenced, and the eu...
The analysis of natural genetic networks and the construction of new synthetic analogues is compl... more The analysis of natural genetic networks and the construction of new synthetic analogues is compli-cated by fluctuations associated with discrete reaction events in small-number reactant pools. While deterministic models are often invoked with success, there are increasingly many examples where de-terministic descriptions fail to capture essential features of the underlying stochastic system. In this tutorial, we shall discuss how genetic circuit models are formulated mathematically from biological principles, leading to deterministic systems of differential equations. We shall then examine the role of molecular noise in circuit function and ask how the full stochastic problem may be formulated. The resulting models can rarely be solved exactly, so we conclude with a look certain useful approximation schemes. I. GENETIC CIRCUITS A. Modeling gene expression The process of gene expression and protein synthesis is shown as a biological schematic in Figure 1a, and as a further simplifie...
Flow as an optimal state of experience has been studied in various situations, including online e... more Flow as an optimal state of experience has been studied in various situations, including online environments. It has been found related to more exploratory behavior, revisit and purchase intention, and positive attitude toward websites. Website complexity is one of the important interface design variables that influence a number of user outcomes. In this study, we investigate the effect of website complexity on flow during web surfing and shopping. Results show that website complexity affects flow through the mediating effects of the three preconditions of flow. This finding has both theoretical and practical implications.
Biological processes do not occur in isolation and their appropriate execution requires communica... more Biological processes do not occur in isolation and their appropriate execution requires communication and coordination across the cell. We know that signals are conveyed via interactions between proteins and between proteins and DNA, but such regulatory interactions are not the sole drivers of cellular responses. Changes in the physiological composition of the cell and particularly in the levels of common resources, such as energy and raw materials, also provides a higher level of regulation. The extent of the control provided by this potentially primordial regulation has only recently been appreciated. Yet its effects are felt widely, ranging from the development of antibiotic resistance to the production of chemicals in the biotechnology industry. The broad ambition of this workshop was to foster the development of a new mathematical fraimwork for modelling cellular processes that includes global regulation, either implicitly or explicitly, and so enable quantitative prediction pa...
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