Endothelin 3 induces skin pigmentation in a keratin-driven inducible mouse model

Endothelin 3 (Edn3) is a ligand important to developing neural crest cells (NCC). Some NCC eventually migrate into the skin and give rise to the pigment-forming melanocytes found in hair follicles. Edn3's effects on NCC have been largely explored through spontaneous mutants and cell culture experiments. These studies have shown the Endothelin receptor B/Edn3 signaling pathway to be important in the proliferation/survival and differentiation of developing melanocytes. To supplement these investigations I have created doxycycline-responsive transgenic mice which conditionally over-express Edn3. These mice will help us clarify Edn3's role during the development of early embryonic melanoblasts, differentiating melanocyte precursors in the skin, and fully differentiated melanocytes in the hair follicle. The transgene mediated expression of Edn3 was predominantly confined to the roof plate of the neural tube and surface ectoderm in embryos and postnatally in the epidermal keratinocytes of the skin. Relative to littermate controls, transgenics develop increased pigmentation on most areas of the skin. My doxycycline-based temporal studies have shown that both embryonic and postnatal events are important for establishing and maintaining pigmented skin. The study of my Edn3 transgenic mice may offer some insight into the genetics behind benign dermal pigmentation and offer clues about the time periods important in establishing these conditions. This apparently abnormal development is echoed in a benign condition of human skin. Cases of dermal melanocytosis, such as common freckles, Mongolian spotting, and nevus of Ito demonstrate histological and etiological characteristics similar to those of the transgenic mice generated in this study.

Effects of Endothelin 3 on the Tumor-Angiogenic Response in a Novel Melanoma Mouse Model

Skin cancer is the most common form of cancer in the United States. Melanoma is a particular type of skin cancer, which arises from the malignant transformation of melanocytes and generally exhibits a high propensity to metastasize. Melanoma progression is dependent on angiogenesis to deliver the oxygen and nutrients required to maintain the altered metabolism of rapidly proliferating tumorigenic cells. Recent studies have implicated the growth factor Endothelin 3 (Edn3) in melanoma progression and metastasis. The aim of this study was to examine the role that Edn3 plays in the angiogenesis of melanocytic lesions. For this purpose, Dct-Grm1 transgenic mice, which spontaneously acquire melanocytic lesions through the aberrant expression of the metabotropic glutamate receptor 1 (mGluR1), were crossed with K5-Edn3 transgenic mice that overexpress Edn3. Tumors in the Dct-Grm1/K5-Edn3 experimental population were examined and compared to the control Dct-Grm1 population using immuno-fluorescent staining targeted against the vascular endothelial cell marker CD31. Proteomic arrays were also used and identified changes in the expression of specific angiogenic factors. CD31 antibody staining results revealed an increased vascular density in Dct-Grm1/K5-Edn3 tumors compared with tumors from the Dct-Grm1 controls. Analysis of the relative expression of angiogenic proteins showed an upregulation of various vascular factors in tumors from the Dct-Grm1/K5-Edn3 population, including VEGF-B, MMP-8, MMP-9, and Angiogenin. These results suggest that endothelin signaling promotes angiogenesis in melanocytic lesions. Targeting the factors upregulated by Edn3 signaling may prove effective in hindering melanoma progression.

UV-induced melanoma mouse model dependent on endothelin 3 over-expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.^

UV-Induced Melanoma Mouse Model Dependent on Endothelin 3 Over-Expression

Melanoma is one of the most aggressive types of cancer. It originates from the transformation of melanocytes present in the epidermal/dermal junction of the human skin. It is commonly accepted that melanomagenesis is influenced by the interaction of environmental factors, genetic factors, as well as tumor-host interactions. DNA photoproducts induced by UV radiation are, in normal cells, repaired by the nucleotide excision repair (NER) pathway. The prominent role of NER in cancer resistance is well exemplified by patients with Xeroderma Pigmentosum (XP). This disease results from mutations in the components of the NER pathway, such as XPA and XPC proteins. In humans, NER pathway disruption leads to the development of skin cancers, including melanoma. Similar to humans afflicted with XP, Xpa and Xpc deficient mice show high sensibility to UV light, leading to skin cancer development, except melanoma. The Endothelin 3 (Edn3) signaling pathway is essential for proliferation, survival and migration of melanocyte precursor cells. Excessive production of Edn3 leads to the accumulation of large numbers of melanocytes in the mouse skin, where they are not normally found. In humans, Edn3 signaling pathway has also been implicated in melanoma progression and its metastatic potential. The goal of this study was the development of the first UV-induced melanoma mouse model dependent on the over-expression of Edn3 in the skin. The UV-induced melanoma mouse model reported here is distinguishable from all previous published models by two features: melanocytes are not transformed a priori and melanomagenesis arises only upon neonatal UV exposure. In this model, melanomagenesis depends on the presence of Edn3 in the skin. Disruption of the NER pathway due to the lack of Xpa or Xpc proteins was not essential for melanomagenesis; however, it enhanced melanoma penetrance and decreased melanoma latency after one single neonatal erythemal UV dose. Exposure to a second dose of UV at six weeks of age did not change time of appearance or penetrance of melanomas in this mouse model. Thus, a combination of neonatal UV exposure with excessive Edn3 in the tumor microenvironment is sufficient for melanomagenesis in mice; furthermore, NER deficiency exacerbates this process.

Surface wind stress modeled for the Panama Seaway with the Community Climate System Model 3

The early Pliocene warm phase was characterized by high sea surface temperatures and a deep thermocline in the eastern equatorial Pacific. A new hypothesis suggests that the progressive closure of the Panamanian seaway contributed substantially to the termination of this zonally symmetric state in the equatorial Pacific. According to this hypothesis, intensification of the Atlantic meridional overturning circulation (AMOC) - induced by the closure of the gateway - was the principal cause of equatorial Pacific thermocline shoaling during the Pliocene. In this study, twelve Panama seaway sensitivity experiments from eight ocean/climate models of different complexity are analyzed to examine the effect of an open gateway on AMOC strength and thermocline depth. All models show an eastward Panamanian net throughflow, leading to a reduction in AMOC strength compared to the corresponding closed-Panama case. In those models that do not include a dynamic atmosphere, deepening of the equatorial Pacific thermocline appears to scale almost linearly with the throughflow-induced reduction in AMOC strength. Models with dynamic atmosphere do not follow this simple relation. There are indications that in four out of five models equatorial wind-stress anomalies amplify the tropical Pacific thermocline deepening. In summary, the models provide strong support for the hypothesized relationship between Panama closure and equatorial Pacific thermocline shoaling.

Purine catabolic pathway revealed by transcriptomics in the model marine bacteriumRuegeria pomeroyiDSS-3

Purines are nitrogen-rich compounds that are widely distributed in the marine environment and are an important component of the dissolved organic nitrogen (DON) pool. Even though purines have been shown to be degraded by bacterioplankton, the identities of marine bacteria capable of purine degradation and their underlying catabolic mechanisms are currently unknown. This study shows that Ruegeria pomeroyi, a model marine bacterium and Marine Roseobacter Clade (MRC) representative, utilizes xanthine as a source of carbon and nitrogen. The R. pomeroyi genome contains putative genes that encode xanthine dehydrogenase (XDH), which is expressed during growth with xanthine. RNAseq-based analysis of the R. pomeroyi transcriptome revealed that the transcription of an XDH-initiated catabolic pathway is up-regulated during growth with xanthine, with transcription greatest when xanthine was the only available carbon source. The RNAseq-deduced pathway indicates that glyoxylate and ammonia are the key intermediates from xanthine degradation. Utilising a laboratory model, this study has identified the potential genes and catabolic pathway active during xanthine degradation. The ability of R. pomeroyi to utilize xanthine provides novel insights into the capabilities of the MRC that may contribute to their success in marine ecosystems and the potential biogeochemical importance of the group in processing DON.

Purine catabolic pathway revealed by transcriptomics in the model marine bacteriumRuegeria pomeroyiDSS-3

Purines are nitrogen-rich compounds that are widely distributed in the marine environment and are an important component of the dissolved organic nitrogen (DON) pool. Even though purines have been shown to be degraded by bacterioplankton, the identities of marine bacteria capable of purine degradation and their underlying catabolic mechanisms are currently unknown. This study shows that Ruegeria pomeroyi, a model marine bacterium and Marine Roseobacter Clade (MRC) representative, utilizes xanthine as a source of carbon and nitrogen. The R. pomeroyi genome contains putative genes that encode xanthine dehydrogenase (XDH), which is expressed during growth with xanthine. RNAseq-based analysis of the R. pomeroyi transcriptome revealed that the transcription of an XDH-initiated catabolic pathway is up-regulated during growth with xanthine, with transcription greatest when xanthine was the only available carbon source. The RNAseq-deduced pathway indicates that glyoxylate and ammonia are the key intermediates from xanthine degradation. Utilising a laboratory model, this study has identified the potential genes and catabolic pathway active during xanthine degradation. The ability of R. pomeroyi to utilize xanthine provides novel insights into the capabilities of the MRC that may contribute to their success in marine ecosystems and the potential biogeochemical importance of the group in processing DON.

Transient simulations for present and last interglacials using a comprehensive coupled climate model CCSM3 (Community Climate System Model 3.0), links to model result files in NetCDF format

Transient simulations are widely used in studying the past climate as they provide better comparison with any exisiting proxy data. However, multi-millennial transient simulations using coupled climate models are usually computationally very expensive. As a result several acceleration techniques are implemented when using numerical simulations to recreate past climate. In this study, we compare the results from transient simulations of the present and the last interglacial with and without acceleration of the orbital forcing, using the comprehensive coupled climate model CCSM3 (Community Climate System Model 3). Our study shows that in low-latitude regions, the simulation of long-term variations in interglacial surface climate is not significantly affected by the use of the acceleration technique (with an acceleration factor of 10) and hence, large-scale model-data comparison of surface variables is not hampered. However, in high-latitude regions where the surface climate has a direct connection to the deep ocean, e.g. in the Southern Ocean or the Nordic Seas, acceleration-induced biases in sea-surface temperature evolution may occur with potential influence on the dynamics of the overlying atmosphere. The data provided here are from both accelerated and non-accelerated runs as decadal mean values.

A functional specification and validation model for networks on chip in the ACL2 logic

International audience

Definition of Model-based diagnosis problems with Altarica

International audience

Survival, differentiation, and neuroprotective mechanisms of human stem cells complexed with neurotrophin-3-releasing pharmacologically active microcarriers in an ex vivo model of Parkinson's disease

International audience

Signatures of doubly charged Higgs in the SU(3)(L) circle times U(1)(N) model at the CERN LHC

The scalar sector of the simplest version of the 3-3-1 electroweak model is constructed with three Higgs triplets only. We show that a relation involving two of the constants of the model, two vacuum expectation values of the neutral scalars, and the mass of the doubly charged Higgs boson leads to important information concerning the signals of this scalar particle.