Fulvestrant-Induced Cell Death and Proteasomal Degradation of Estrogen Receptor α Protein in MCF-7 Cells Require the CSK c-Src Tyrosine Kinase

Fulvestrant is a representative pure antiestrogen and a Selective Estrogen Receptor Down-regulator (SERD). In contrast to the Selective Estrogen Receptor Modulators (SERMs) such as 4-hydroxytamoxifen that bind to estrogen receptor α (ERα) as antagonists or partial agonists, fulvestrant causes proteasomal degradation of ERα protein, shutting down the estrogen signaling to induce proliferation arrest and apoptosis of estrogen-dependent breast cancer cells. We performed genome-wide RNAi knockdown screenings for protein kinases required for fulvestrant-induced apoptosis of the MCF-7 estrogen-dependent human breast caner cells and identified the c-Src tyrosine kinase (CSK), a negative regulator of the oncoprotein c-Src and related protein tyrosine kinases, as one of the necessary molecules. Whereas RNAi knockdown of CSK in MCF-7 cells by shRNA-expressing lentiviruses strongly suppressed fulvestrant-induced cell death, CSK knockdown did not affect cytocidal actions of 4-hydroxytamoxifen or paclitaxel, a chemotherapeutic agent. In the absence of CSK, fulvestrant-induced proteasomal degradation of ERα protein was suppressed in both MCF-7 and T47D estrogen-dependent breast cancer cells whereas the TP53-mutated T47D cells were resistant to the cytocidal action of fulvestrant in the presence or absence of CSK. MCF-7 cell sensitivities to fulvestrant-induced cell death or ERα protein degradation was not affected by small-molecular-weight inhibitors of the tyrosine kinase activity of c-Src, suggesting possible involvement of other signaling molecules in CSK-dependent MCF-7 cell death induced by fulvestrant. Our observations suggest the importance of CSK in the determination of cellular sensitivity to the cytocidal action of fulvestrant

Data-Driven Analysis of Pareto Set Topology

When and why can evolutionary multi-objective optimization (EMO) algorithms cover the entire Pareto set? That is a major concern for EMO researchers and practitioners. A recent theoretical study revealed that (roughly speaking) if the Pareto set forms a topological simplex (a curved line, a curved triangle, a curved tetrahedron, etc.), then decomposition-based EMO algorithms can cover the entire Pareto set. Usually, we cannot know the true Pareto set and have to estimate its topology by using the population of EMO algorithms during or after the runtime. This paper presents a data-driven approach to analyze the topology of the Pareto set. We give a theory of how to recognize the topology of the Pareto set from data and implement an algorithm to judge whether the true Pareto set may form a topological simplex or not. Numerical experiments show that the proposed method correctly recognizes the topology of high-dimensional Pareto sets within reasonable population size.Comment: 8 pages, accepted at GECCO'18 as a full pape

Produção de sementes de coentro em função dos tipos de adubação.

O objetivo deste trabalho foi avaliar a influência de tipos de adubo na produção de sementes de coentro (Coriandrum sativum L.) nas condições de Botucatu-SP. Utilizou-se sementes Aglofora S.A, cv. Português

Liouville Integrability of Classical Calogero-Moser Models

Liouville integrability of classical Calogero-Moser models is proved for models based on any root systems, including the non-crystallographic ones. It applies to all types of elliptic potentials, i.e. untwisted and twisted together with their degenerations (hyperbolic, trigonometric and rational), except for the rational potential models confined by a harmonic force.Comment: 8 pages, LaTeX2e, no figure

Elliptic Calabi-Yau Threefolds with Z_3 x Z_3 Wilson Lines

A torus fibered Calabi-Yau threefold with first homotopy group Z_3 x Z_3 is constructed as a free quotient of a fiber product of two dP_9 surfaces. Calabi-Yau threefolds of this type admit Z_3 x Z_3 Wilson lines. In conjunction with SU(4) holomorphic vector bundles, such vacua lead to anomaly free, three generation models of particle physics with a right handed neutrino and a U(1)_{B-L} gauge factor, in addition to the SU(3)_C x SU(2)_L x U(1)_Y standard model gauge group. This factor helps to naturally suppress nucleon decay. The moduli space and Dolbeault cohomology of the threefold is also discussed.Comment: 51 pages, 13 figures; v2: references adde

Dose-Related Estrogen Effects on Gene Expression in Fetal Mouse Prostate Mesenchymal Cells

Developmental exposure of mouse fetuses to estrogens results in dose-dependent permanent effects on prostate morphology and function. Fetal prostatic mesenchyme cells express estrogen receptor alpha (ERα) and androgen receptors and convert stimuli from circulating estrogens and androgens into paracrine signaling to regulate epithelial cell proliferation and differentiation. To obtain mechanistic insight into the role of different doses of estradiol (E2) in regulating mesenchymal cells, we examined E2-induced transcriptomal changes in primary cultures of fetal mouse prostate mesenchymal cells. Urogenital sinus mesenchyme cells were obtained from male mouse fetuses at gestation day 17 and exposed to 10 pM, 100 pM or 100 nM E2 in the presence of a physiological concentration of dihydrotestosterone (0.69 nM) for four days. Gene ontology studies suggested that low doses of E2 (10 pM and 100 pM) induce genes involved in morphological tissue development and sterol biosynthesis but suppress genes involved in growth factor signaling. Genes involved in cell adhesion were enriched among both up-regulated and down-regulated genes. Genes showing inverted-U-shape dose responses (enhanced by E2 at 10 pM E2 but suppressed at 100 pM) were enriched in the glycolytic pathway. At the highest dose (100 nM), E2 induced genes enriched for cell adhesion, steroid hormone signaling and metabolism, cytokines and their receptors, cell-to-cell communication, Wnt signaling, and TGF- β signaling. These results suggest that prostate mesenchymal cells may regulate epithelial cells through direct cell contacts when estrogen level is low whereas secreted growth factors and cytokines might play significant roles when estrogen level is high

Expanding homogeneous culture of human primordial germ cell-like cells maintaining germline features without serum or feeder layers.

In vitro expansion of human primordial germ cell-like cells (hPGCLCs), a pluripotent stem cell-derived PGC model, has proved challenging due to rapid loss of primordial germ cell (PGC)-like identity and limited cell survival/proliferation. Here, we describe long-term culture hPGCLCs (LTC-hPGCLCs), which actively proliferate in a serum-free, feeder-free condition without apparent limit as highly homogeneous diploid cell populations maintaining transcriptomic and epigenomic characteristics of hPGCLCs. Histone proteomics confirmed reduced H3K9me2 and increased H3K27me3 marks in LTC-hPGCLCs compared with induced pluripotent stem cells (iPSCs). LTC-hPGCLCs established from multiple human iPSC clones of both sexes were telomerase positive, senescence-free cells readily passaged with minimal cell death or deviation from the PGC-like identity. LTC-hPGCLCs are capable of differentiating to DAZL-positive M-spermatogonia-like cells in the xenogeneic reconstituted testis (xrTestis) organ culture milieu as well as efficiently producing fully pluripotent embryonic germ cell-like cells in the presence of stem cell factor and fibroblast growth factor 2. Thus, LTC-hPGCLCs provide convenient access to unlimited amounts of high-quality and homogeneous hPGCLCs

Ferromagnetism in Mn doped GaAs due to substitutional-interstitial complexes

While most calculations on the properties of the ferromagnetic semiconductor GaAs:Mn have focussed on isolated Mn substituting the Ga site (Mn$_{Ga}$), we investigate here whether alternate lattice sites are favored and what the magnetic consequences of this might be. Under As-rich (Ga-poor) conditions prevalent at growth, we find that the formation energies are lower for Mn$_{Ga}$ over interstitial Mn (Mn$_i$).As the Fermi energy is shifted towards the valence band maximum via external $p$-doping, the formation energy of Mn$_i$ is reduced relative to Mn$_{Ga}$. Furthermore, under epitaxial growth conditions, the solubility of both substitutional and interstitial Mn are strongly enhanced over what is possible under bulk growth conditions. The high concentration of Mn attained under epitaxial growth of p-type material opens the possibility of Mn atoms forming small clusters. We consider various types of clusters, including the Coulomb-stabilized clusters involving two Mn$_{Ga}$ and one Mn$_i$. While isolated Mn$_i$ are hole killers (donors), and therefore destroy ferromagnetism,complexes such as Mn$_{Ga}$-Mn$_i$-Mn$_{Ga}$) are found to be more stable than complexes involving Mn$_{Ga}$-Mn$_{Ga}$-Mn$_{Ga}$. The former complexes exhibit partial or total quenching of holes, yet Mn$_i$ in these complexes provide a channel for a ferromagnetic arrangement of the spins on the two Mn$_{Ga}$ within the complex. This suggests that ferromagnetism in Mn doped GaAs arises both from holes due to isolated Mn$_{Ga}$ as well as from strongly Coulomb stabilized Mn$_{Ga}$-Mn$_i$-Mn$_{Ga}$ clusters.Comment: 7 figure

F-Theory and the Mordell-Weil Group of Elliptically-Fibered Calabi-Yau Threefolds

The Mordell-Weil group of an elliptically fibered Calabi-Yau threefold X contains information about the abelian sector of the six-dimensional theory obtained by compactifying F-theory on X. After examining features of the abelian anomaly coefficient matrix and U(1) charge quantization conditions of general F-theory vacua, we study Calabi-Yau threefolds with Mordell-Weil rank-one as a first step towards understanding the features of the Mordell-Weil group of threefolds in more detail. In particular, we generate an interesting class of F-theory models with U(1) gauge symmetry that have matter with both charges 1 and 2. The anomaly equations --- which relate the Neron-Tate height of a section to intersection numbers between the section and fibral rational curves of the manifold --- serve as an important tool in our analysis.Comment: 29 pages + appendices, 5 figures; v2: minor correction

Quantum states and linear response in dc and electromagnetic fields for charge current and spin polarization of electrons at Bi/Si interface with giant spin-orbit coupling

An expansion of the nearly free-electron model constructed by Frantzeskakis, Pons and Grioni [Phys. Rev. B {\bf 82}, 085440 (2010)] describing quantum states at Bi/Si(111) interface with giant spin-orbit coupling is developed and applied for the band structure and spin polarization calculation, as well as for the linear response analysis for charge current and induced spin caused by dc field and by electromagnetic radiation. It is found that the large spin-orbit coupling in this system may allow resolving the spin-dependent properties even at room temperature and at realistic collision rate. The geometry of the atomic lattice combined with spin-orbit coupling leads to an anisotropic response both for current and spin components related to the orientation of the external field. The in-plane dc electric field produces only the in-plane components of spin in the sample while both the in-plane and out-of-plane spin components can be excited by normally propagating electromagnetic wave with different polarizations.Comment: 10 pages, 9 figure