Phosphorylation of the androgen receptor is associated with reduced survival in hormonerefractory prostate cancer patients

Cell line studies demonstrate that the PI3K/Akt pathway is upregulated in hormone-refractory prostate cancer (HRPC) and can result in phosphorylation of the androgen receptor (AR). The current study therefore aims to establish if this has relevance to the development of clinical HRPC. Immunohistochemistry was employed to investigate the expression and phosphorylation status of Akt and AR in matched hormone-sensitive and -refractory prostate cancer tumours from 68 patients. In the hormone-refractory tissue, only phosphorylated AR (pAR) was associated with shorter time to death from relapse (<i>P</i>=0.003). However, when an increase in expression in the transition from hormone-sensitive to -refractory prostate cancer was investigated, an increase in expression of PI3K was associated with decreased time to biochemical relapse (<i>P</i>=0.014), and an increase in expression of pAkt<sup>473</sup> and pAR<sup>210</sup> were associated with decreased disease-specific survival (<i>P</i>=0.0019 and 0.0015, respectively). Protein expression of pAkt<sup>473</sup> and pAR<sup>210</sup> also strongly correlated (<i>P</i><0.001, c.c.=0.711) in the hormone-refractory prostate tumours. These results provide evidence using clinical specimens, that upregulation of the PI3K/Akt pathway is associated with phosphorylation of the AR during development of HRPC, suggesting that this pathway could be a potential therapeutic target

Could the compact remnant of SN 1987A be a quark star?

The standard model for Type II supernovae explosions, confirmed by the detection of neutrinos emitted during the supernova explosion, predicts the formation of a compact object, usually assumed to be a neutron star. However, the lack of detection of a neutron star or pulsar formed in the SN 1987A still remains an unsolved mystery. In this paper, we suggest that the newly formed neutron star at the center of SN 1987A may undergo a phase transition after the neutrino trapping timescale (∼10 s). Consequently the compact remnant of SN 1987A may be a strange quark star, which has a softer equation of state than that of neutron star matter. Such a phase transition can induce stellar collapse and result in large amplitude stellar oscillations.We use a three-dimensional Newtonian hydrodynamic code to study the time evolution of the temperature and density at the neutrinosphere. Extremely intense pulsating neutrino fluxes, with submillisecond period and with neutrino energy (greater than 30 MeV), can be emitted because the oscillations of the temperature and density are out of phase almost 180◦. If this is true we predict that the current X-ray emission from the compact remnant of SN 1987A will be lower than 1034 erg s−1, and it should be a thermal bremsstrahlung spectrum for a bare strange star with a surface temperature of around ∼107 K.published_or_final_versio

Fibril polymorphism affects immobilized non-amyloid flanking domains of huntingtin exon1 rather than its polyglutamine core

Polyglutamine expansion in the huntingtin protein is the primary genetic cause of Huntington's disease (HD). Fragments coinciding with mutant huntingtin exon1 aggregate in vivo and induce HD-like pathology in mouse models. The resulting aggregates can have different structures that affect their biochemical behaviour and cytotoxic activity. Here we report our studies of the structure and functional characteristics of multiple mutant htt exon1 fibrils by complementary techniques, including infrared and solid-state NMR spectroscopies. Magic-angle-spinning NMR reveals that fibrillar exon1 has a partly mobile α-helix in its aggregation-accelerating N terminus, and semi-rigid polyproline II helices in the proline-rich flanking domain (PRD). The polyglutamine-proximal portions of these domains are immobilized and clustered, limiting access to aggregation-modulating antibodies. The polymorphic fibrils differ in their flanking domains rather than the polyglutamine amyloid structure. They are effective at seeding polyglutamine aggregation and exhibit cytotoxic effects when applied to neuronal cells

Small Hairy Black Holes in Global AdS Spacetime

We study small charged black holes in global AdS spacetime in the presence of a charged massless minimally coupled scalar field. In a certain parameter range these black holes suffer from well known superradiant instabilities. We demonstrate that the end point of the resultant tachyon condensation process is a hairy black hole which we construct analytically in a perturbative expansion in the black hole radius. At leading order our solution is a small undeformed RNAdS black hole immersed into a charged scalar condensate that fills the AdS `box'. These hairy black hole solutions appear in a two parameter family labelled by their mass and charge. Their mass is bounded from below by a function of their charge; at the lower bound a hairy black hole reduces to a regular horizon free soliton which can also be thought of as a nonlinear Bose condensate. We compute the microcanonical phase diagram of our system at small mass, and demonstrate that it exhibits a second order `phase transition' between the RNAdS black hole and the hairy black hole phases.Comment: 68+1 pages, 18 figures, JHEP format. v2 : small typos corrected and a reference adde

Synthesis of an anion receptor for acetate based on the frame of ferrocene

An anion receptor was synthesized with ferrocene as binding frame. Anion recognition can be monitored by anion complexation-induced changes in UV-vis absorption spectra. Interaction between the receptor and acetate was described on the basis of 1H NMR experiments

From nodal liquid to nodal Mottness in a frustrated Hubbard model

We investigate the physics of frustrated 3-leg Hubbard ladders in the band limit, when hopping across the ladder's rungs (t$_{\perp}$) is of the same order as hopping along them (t) much greater than the onsite Coulomb repulsion (U). We show that this model exhibits a striking electron-hole asymmetry close to half-filling: the hole-doped system at low temperatures develops a Resonating Valence Bond (RVB)-like d-wave gap (pseudogap close to ($\pi$,0)) coinciding with gapless nodal excitations (nodal liquid); in contrast, the electron-doped system is seen to develop a Mott gap at the nodes, whilst retaining a metallic character of its majority Fermi surface. At lower temperatures in the electron-doped case, d-wave superconducting correlations -- here, coexisting with gapped nodal excitations -- are already seen to arise. Upon further doping the hole-doped case, the RVB-like state yields to d-wave superconductivity. Such physics is reminiscent of that exhibited by the high temperature cuprate superconductors--notably electron-hole asymmetry as noted by Angle Resolved PhotoEmission Spectroscopy (ARPES) and the resistivity exponents observed. This toy model also reinforces the importance of a more thorough experimental investigation of the known 3-leg ladder cuprate systems, and may have some bearing on low dimensional organic superconductors.Comment: 26 pages, 16 figure

Cytoplasmic PML promotes TGF-β-associated epithelial–mesenchymal transition and invasion in prostate cancer

Epithelial–mesenchymal transition (EMT) is a key event that is involved in the invasion and dissemination of cancer cells. Although typically considered as having tumour-suppressive properties, transforming growth factor (TGF)-β signalling is altered during cancer and has been associated with the invasion of cancer cells and metastasis. In this study, we report a previously unknown role for the cytoplasmic promyelocytic leukaemia (cPML) tumour suppressor in TGF-β signalling-induced regulation of prostate cancer-associated EMT and invasion. We demonstrate that cPML promotes a mesenchymal phenotype and increases the invasiveness of prostate cancer cells. This event is associated with activation of TGF-β canonical signalling pathway through the induction of Sma and Mad related family 2 and 3 (SMAD2 and SMAD3) phosphorylation. Furthermore, the cytoplasmic localization of promyelocytic leukaemia (PML) is mediated by its nuclear export in a chromosomal maintenance 1 (CRM1)-dependent manner. This was clinically tested in prostate cancer tissue and shown that cytoplasmic PML and CRM1 co-expression correlates with reduced disease-specific survival. In summary, we provide evidence of dysfunctional TGF-β signalling occurring at an early stage in prostate cancer. We show that this disease pathway is mediated by cPML and CRM1 and results in a more aggressive cancer cell phenotype. We propose that the targeting of this pathway could be therapeutically exploited for clinical benefit

Extracellular Matrix Aggregates from Differentiating Embryoid Bodies as a Scaffold to Support ESC Proliferation and Differentiation

Embryonic stem cells (ESCs) have emerged as potential cell sources for tissue engineering and regeneration owing to its virtually unlimited replicative capacity and the potential to differentiate into a variety of cell types. Current differentiation strategies primarily involve various growth factor/inducer/repressor concoctions with less emphasis on the substrate. Developing biomaterials to promote stem cell proliferation and differentiation could aid in the realization of this goal. Extracellular matrix (ECM) components are important physiological regulators, and can provide cues to direct ESC expansion and differentiation. ECM undergoes constant remodeling with surrounding cells to accommodate specific developmental event. In this study, using ESC derived aggregates called embryoid bodies (EB) as a model, we characterized the biological nature of ECM in EB after exposure to different treatments: spontaneously differentiated and retinoic acid treated (denoted as SPT and RA, respectively). Next, we extracted this treatment-specific ECM by detergent decellularization methods (Triton X-100, DOC and SDS are compared). The resulting EB ECM scaffolds were seeded with undifferentiated ESCs using a novel cell seeding strategy, and the behavior of ESCs was studied. Our results showed that the optimized protocol efficiently removes cells while retaining crucial ECM and biochemical components. Decellularized ECM from SPT EB gave rise to a more favorable microenvironment for promoting ESC attachment, proliferation, and early differentiation, compared to native EB and decellularized ECM from RA EB. These findings suggest that various treatment conditions allow the formulation of unique ESC-ECM derived scaffolds to enhance ESC bioactivities, including proliferation and differentiation for tissue regeneration applications. © 2013 Goh et al

Emotional Fuzzy Sliding-Mode Control for Unknown Nonlinear Systems

[[abstract]]The brain emotional learning model can be implemented with a simple hardware and processor; however, the learning model cannot model the qualitative aspects of human knowledge. To solve this problem, a fuzzy-based emotional learning model (FELM) with structure and parameter learning is proposed. The membership functions and fuzzy rules can be learned through the derived learning scheme. Further, an emotional fuzzy sliding-mode control (EFSMC) system, which does not need the plant model, is proposed for unknown nonlinear systems. The EFSMC system is applied to an inverted pendulum and a chaotic synchronization. The simulation results with the use of EFSMC system demonstrate the feasibility of FELM learning procedure. The main contributions of this paper are (1) the FELM varies its structure dynamically with a simple computation; (2) the parameter learning imitates the role of emotions in mammalians brain; (3) by combining the advantage of nonsingular terminal sliding-mode control, the EFSMC system provides very high precision and finite-time control performance; (4) the system analysis is given in the sense of the gradient descent method.[[notice]]補正完

MRI of the lung (3/3)-current applications and future perspectives

BACKGROUND: MRI of the lung is recommended in a number of clinical indications. Having a non-radiation alternative is particularly attractive in children and young subjects, or pregnant women. METHODS: Provided there is sufficient expertise, magnetic resonance imaging (MRI) may be considered as the preferential modality in specific clinical conditions such as cystic fibrosis and acute pulmonary embolism, since additional functional information on respiratory mechanics and regional lung perfusion is provided. In other cases, such as tumours and pneumonia in children, lung MRI may be considered an alternative or adjunct to other modalities with at least similar diagnostic value. RESULTS: In interstitial lung disease, the clinical utility of MRI remains to be proven, but it could provide additional information that will be beneficial in research, or at some stage in clinical practice. Customised protocols for chest imaging combine fast breath-hold acquisitions from a "buffet" of sequences. Having introduced details of imaging protocols in previous articles, the aim of this manuscript is to discuss the advantages and limitations of lung MRI in current clinical practice. CONCLUSION: New developments and future perspectives such as motion-compensated imaging with self-navigated sequences or fast Fourier decomposition MRI for non-contrast enhanced ventilation- and perfusion-weighted imaging of the lung are discussed. Main Messages • MRI evolves as a third lung imaging modality, combining morphological and functional information. • It may be considered first choice in cystic fibrosis and pulmonary embolism of young and pregnant patients. • In other cases (tumours, pneumonia in children), it is an alternative or adjunct to X-ray and CT. • In interstitial lung disease, it serves for research, but the clinical value remains to be proven. • New users are advised to make themselves familiar with the particular advantages and limitations