Loss of Let-7 Up-Regulates EZH2 in Prostate Cancer Consistent with the Acquisition of Cancer Stem Cell Signatures That Are Attenuated by BR-DIM

The emergence of castrate-resistant prostate cancer (CRPC) contributes to the high mortality of patients diagnosed with prostate cancer (PCa), which in part could be attributed to the existence and the emergence of cancer stem cells (CSCs). Recent studies have shown that deregulated expression of microRNAs (miRNAs) contributes to the initiation and progression of PCa. Among several known miRNAs, let-7 family appears to play a key role in the recurrence and progression of PCa by regulating CSCs; however, the mechanism by which let-7 family contributes to PCa aggressiveness is unclear. Enhancer of Zeste homolog 2 (EZH2), a putative target of let-7 family, was demonstrated to control stem cell function. In this study, we found loss of let-7 family with corresponding over-expression of EZH2 in human PCa tissue specimens, especially in higher Gleason grade tumors. Overexpression of let-7 by transfection of let-7 precursors decreased EZH2 expression and repressed clonogenic ability and sphere-forming capacity of PCa cells, which was consistent with inhibition of EZH2 3′UTR luciferase activity. We also found that the treatment of PCa cells with BR-DIM (formulated DIM: 3,3′-diindolylmethane by Bio Response, Boulder, CO, abbreviated as BR-DIM) up-regulated let-7 and down-regulated EZH2 expression, consistent with inhibition of self-renewal and clonogenic capacity. Moreover, BR-DIM intervention in our on-going phase II clinical trial in patients prior to radical prostatectomy showed upregulation of let-7 consistent with down-regulation of EZH2 expression in PCa tissue specimens after BR-DIM intervention. These results suggest that the loss of let-7 mediated increased expression of EZH2 contributes to PCa aggressiveness, which could be attenuated by BR-DIM treatment, and thus BR-DIM is likely to have clinical impact

Genome of the Asian Longhorned Beetle (\u3cem\u3eAnoplophora glabripennis\u3c/em\u3e), a Globally Significant Invasive Species, Reveals Key Functional and Evolutionary Innovations at the Beetle-Plant Interface

Background: Relatively little is known about the genomic basis and evolution of wood-feeding in beetles. We undertook genome sequencing and annotation, gene expression assays, studies of plant cell wall degrading enzymes, and other functional and comparative studies of the Asian longhorned beetle, Anoplophora glabripennis, a globally significant invasive species capable of inflicting severe feeding damage on many important tree species. Complementary studies of genes encoding enzymes involved in digestion of woody plant tissues or detoxification of plant allelochemicals were undertaken with the genomes of 14 additional insects, including the newly sequenced emerald ash borer and bull-headed dung beetle. Results: The Asian longhorned beetle genome encodes a uniquely diverse arsenal of enzymes that can degrade the main polysaccharide networks in plant cell walls, detoxify plant allelochemicals, and otherwise facilitate feeding on woody plants. It has the metabolic plasticity needed to feed on diverse plant species, contributing to its highly invasive nature. Large expansions of chemosensory genes involved in the reception of pheromones and plant kairomones are consistent with the complexity of chemical cues it uses to find host plants and mates. Conclusions: Amplification and functional divergence of genes associated with specialized feeding on plants, including genes originally obtained via horizontal gene transfer from fungi and bacteria, contributed to the addition, expansion, and enhancement of the metabolic repertoire of the Asian longhorned beetle, certain other phytophagous beetles, and to a lesser degree, other phytophagous insects. Our results thus begin to establish a genomic basis for the evolutionary success of beetles on plants

Speech Acts, commitment and multi-agent communication

The principle aim of this paper is to reconsider the suitability of Austin and Searle’s Speech Act theory as a basis for agent communication languages. Two distinct computational interpretations of speech acts are considered: the standard “mentalistic” approach associated with the work of Cohen and Levesque which involves attributing beliefs and intentions to artificial agents, and the “social semantics” approach originating (in the context of MAS) with Singh which aims to model commitments that agents undertake as a consequence of communicative actions. Modifications and extensions are proposed to current commitment-based analyses, drawing on recent philosophical studies by Brandom, Habermas and Heath. A case is made for adopting Brandom’s framework of normative pragmatics, modelling dialogue states as deontic scoreboards which keep track of commitments and entitlements that speakers acknowledge and hearers attribute to other interlocutors. The paper concludes by outlining an update semantics and protocol for selected locutions

Radar and photometric observations and shape modeling of contact binary near-Earth Asteroid (8567) 1996 HW1

We observed near-Earth Asteroid (8567) 1996 HW1 at the Arecibo Observatory on six dates in September 2008, obtaining radar images and spectra. By combining these data with an extensive set of new lightcurves taken during 2008-2009 and with previously published lightcurves from 2005, we were able to reconstruct the object's shape and spin state. 1996 HW1 is an elongated, bifurcated object with maximum diameters of 3.8 × 1.6 × 1.5 km and a contact-binary shape. It is the most bifurcated near-Earth asteroid yet studied and one of the most elongated as well. The sidereal rotation period is 8.76243 ± 0.00004 h and the pole direction is within 5° of ecliptic longitude and latitude (281°, -31°). Radar astrometry has reduced the orbital element uncertainties by 27% relative to the a priori orbit solution that was based on a half-century of optical data. Simple dynamical arguments are used to demonstrate that this asteroid could have originated as a binary system that tidally decayed and merged