Naturalized Metaphysics and Scientific Constraint: A Model-Building Approach

A problem with recent work about the relationship between metaphysics and science, especially in the theorizing of those who identify as “naturalized metaphysicians”, is the spotty, metaphorical characterization of what it means for science to “constrain” metaphysics. The most robust account of scientific constraint on metaphysical theorizing is advanced by James Ladyman and Don Ross in their 2007 book Every Thing Must Go. Ladyman & Ross claim that the only legitimate metaphysical hypotheses are those that unify two previously disparate scientific explanations. I will critique Ladyman & Ross’ account of naturalized metaphysics (and, by extension, their view of science’s constraint on metaphysics), and offer an alternative view of naturalized metaphysics as a practice of constructing physically possible models of reality. This account yields a different view of science’s constraint on metaphysics, specifically, that models must be physically possible in order to be of methodological and heuristic use to scientists

Properties of high-density matter in neutron stars

This short review aims at giving a brief overview of various states of matter that have been suggested to exist in the ultra-dense centers of neutron stars. Particular emphasis is put on the role of quark deconfinement in neutron stars and on the possible existence of compact stars made of absolutely stable strange quark matter (strange stars). Astrophysical phenomena, which distinguish neutron stars from quark stars, are discussed and the question of whether or not quark deconfinement may occur in neutron stars is investigated. Combined with observed astrophysical data, such studies are invaluable to delineate the complex structure of compressed baryonic matter and to put firm constraints on the largely unknown equation of state of such matter.Fil: Weber, Fridolin. San Diego State University; Estados Unidos. University of California; Estados UnidosFil: Contrera, Gustavo Aníbal Gabriel. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto de Física La Plata. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Instituto de Física La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Área Física Teórica; Argentina. San Diego State University; Estados UnidosFil: Orsaria, Milva Gabriela. Universidad Nacional de La Plata. Facultad de Ciencias Astronómicas y Geofísicas. Área Física Teórica; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. San Diego State University; Estados UnidosFil: Spinella, William. San Diego State University. Computational Sciences Research Center; Estados UnidosFil: Zubairi, Omair. San Diego State University. Computational Sciences Research Center; Estados Unido

The endothelin A receptor and epidermal growth factor receptor signaling converge on β-catenin to promote ovarian cancer metastasis

Aims: Endothelin A receptor (ETAR) and epidermal growth factor receptor (EGFR) cross-talk enhances the metastatic potential of epithelial ovarian cancer (EOC) cells activating different pathways, including β-catenin signalling. Here, we evaluated β-catenin as one of ETAR/EGFR downstream pathway in the invasive behaviour of EOC cells and their therapeutic potential to co-target ETAR and EGFR. Main methods: The phosphorylation status and interactions of different proteins were analysed by immunoblotting and immunoprecipitation. Reporter activity and RT-PCR was used for evaluation of β-catenin transcriptional activity and gene expression. Functional effects were evaluated by gelatin zymography and cell invasion assays. An orthotopic model of metastatic human EOC in mice was used for in vivo studies. Key findings: In EOC cell lines, ET-1 induced Src-dependent EGFR transactivation, causing tyrosine (Y) phosphorylation of β-catenin at the residue Y654, its dissociation from E-cadherin complexes and the accumulation as an active form. This pool of Tyr-β-catenin relocalised to the nucleus promoting its transcriptional activity, and the expression of its target genes, such as MMP-2. At functional level, ET-1 and EGFR circuits enhanced protease activity and cell invasion. All these effects were significantly inhibited by the ETAR antagonist, zibotentan, or EGFR inhibitor, gefitinib, and are completely blocked by co-addition of both drugs. In vivo, zibotentan treatment significantly inhibited metastases, associated with reduced expression and activation of MMPs and active β-catenin, especially when combined with gefitinib. Significance: Altogether these findings provide additional support to the potential use of ETAR and EGFR blockade as a new therapeutic opportunity for EOC treatment. © 2012 Elsevier Inc