Rhetoric in the language of real estate marketing

“Des. Res.”, “rarely available”, “viewing essential” – these are all part of the peculiar parlance of housing advertisements which contain a heady mix of euphemism, hyperbole and superlative. Of interest is whether the selling agent’s penchant for rhetoric is spatially uniform or whether there are variations across the urban system. We are also interested in how the use of superlatives varies over the market cycle and over the selling season. For example, are estate agents more inclined to use hyperbole when the market is buoyant or when it is flat, and does it matter whether a house is marketed in the summer or winter? This paper attempts to answer these questions by applying textual analysis to a unique dataset of 49,926 records of real estate transactions in the Strathclyde conurbation over the period 1999 to 2006. The analysis opens up a new avenue of research into the use of real estate rhetoric and its interaction with agency behaviour and market dynamics

Design, Synthesis, and Biological Activity of 5\u27-Phenyl-1,2,5,6-tetrahydro-3,3\u27-bipyridine Analogues as Potential Antagonists of Nicotinic Acetylcholine Receptors

Starting from a known non-specific agonist (1) of nicotinic acetylcholine receptors (nAChRs), rationally guided structural-based design resulted in the discovery of a small series of 5′-phenyl-1,2,5,6-tetrahydro-3,3′-bipyridines (3a – 3e) incorporating a phenyl ring off the pyridine core of 1. The compounds were synthesized via successive Suzuki couplings on a suitably functionalized pyridine starting monomer 4 to append phenyl and pyridyl substituents off the 3- and 5-positions, respectively, and then make subsequent modifications on the flanking pyridyl ring to provide target compounds. Compound 3a is a novel antagonist which is highly selective for α3β4 nAChR (Ki = 123 nM) over the α4β2, and α7 receptors

Human iPSC-derived neurons and cerebral organoids establish differential effects of germline NF1 gene mutations

Neurofibromatosis type 1 (NF1) is a common neurodevelopmental disorder caused by a spectrum of distinct germline NF1 gene mutations, traditionally viewed as equivalent loss-of-function alleles. To specifically address the issue of mutational equivalency in a disease with considerable clinical heterogeneity, we engineered seven isogenic human induced pluripotent stem cell lines, each with a different NF1 patient NF1 mutation, to identify potential differential effects of NF1 mutations on human central nervous system cells and tissues. Although all mutations increased proliferation and RAS activity in 2D neural progenitor cells (NPCs) and astrocytes, we observed striking differences between NF1 mutations on 2D NPC dopamine levels, and 3D NPC proliferation, apoptosis, and neuronal differentiation in developing cerebral organoids. Together, these findings demonstrate differential effects of NF1 gene mutations at the cellular and tissue levels, suggesting that the germline NF1 gene mutation is one factor that underlies clinical variability

Generalized model for dynamic percolation

We study the dynamics of a carrier, which performs a biased motion under the influence of an external field E, in an environment which is modeled by dynamic percolation and created by hard-core particles. The particles move randomly on a simple cubic lattice, constrained by hard-core exclusion, and they spontaneously annihilate and re-appear at some prescribed rates. Using decoupling of the third-order correlation functions into the product of the pairwise carrier-particle correlations we determine the density profiles of the "environment" particles, as seen from the stationary moving carrier, and calculate its terminal velocity, V_c, as the function of the applied field and other system parameters. We find that for sufficiently small driving forces the force exerted on the carrier by the "environment" particles shows a viscous-like behavior. An analog Stokes formula for such dynamic percolative environments and the corresponding friction coefficient are derived. We show that the density profile of the environment particles is strongly inhomogeneous: In front of the stationary moving carrier the density is higher than the average density, $\rho_s$, and approaches the average value as an exponential function of the distance from the carrier. Past the carrier the local density is lower than $\rho_s$ and the relaxation towards $\rho_s$ may proceed differently depending on whether the particles number is or is not explicitly conserved.Comment: Latex, 32 pages, 4 ps-figures, submitted to PR

The key project managers’ competences for different types of projects

This paper describes a quantitative research approach for identifying key project managers’ competences for different types of projects. By identifying the perceived most valuable project manager competences, as having the most potential for increased contribution to project management (PM) performance, practitioners and organizations can select their priorities when developing their PM practices. The 46 competences (technical, behavioural and contextual) provided by IPMA (International Project Management Association) were surveyed through an online questionnaire. Three dimensions to distinguish project types were used: application area, innovation and complexity. Completed questionnaires were received from 96 project managers from Portugal. The results showed that 13 key competences (20%) were common to the majority of the projects. Most of these are behavioural competences, such as: ethics, reliability, engagement, openness, and leadership. It was also observed a clear correlation between technical competences and project complexity

International trade and domestic competition: Evidence from Belgium

We investigate the effect of domestic market competition on firm-level export intensity. We employ a comprehensive dataset of Belgian firms from 2005–2008, when the fall in the number of firms engaged in trade was accompanied by a growing amount of transactions. The resulting increase in the domestic concentration of Belgian firms has sparked numerous debates, since the direction of causality between domestic market structure and export performance is unclear. We apply the fractional logit estimator and control for both self-selection and simultaneity bias. We find that a positive linkage exists between the level of competition and export intensity

Concurrent Inhibition of IGF1R and ERK Increases Pancreatic Cancer Sensitivity to Autophagy Inhibitors

The aggressive nature of pancreatic ductal adenocarcinoma (PDAC) mandates the development of improved therapies. As KRAS mutations are found in 95% of PDAC and are critical for tumor maintenance, one promising strategy involves exploiting KRAS-dependent metabolic perturbations. The macrometabolic process of autophagy is upregulated in KRAS-mutant PDAC, and PDAC growth is reliant on autophagy. However, inhibition of autophagy as monotherapy using the lysosomal inhibitor hydroxychloroquine (HCQ) has shown limited clinical efficacy. To identify strategies that can improve PDAC sensitivity to HCQ, we applied a CRISPR-Cas9 loss-of-function screen and found that a top sensitizer was the receptor tyrosine kinase (RTK) insulin-like growth factor 1 receptor (IGF1R). Additionally, reverse phase protein array pathway activation mapping profiled the signaling pathways altered by chloroquine (CQ) treatment. Activating phosphorylation of RTKs, including IGF1R, was a common compensatory increase in response to CQ. Inhibition of IGF1R increased autophagic flux and sensitivity to CQ-mediated growth suppression both in vitro and in vivo. Cotargeting both IGF1R and pathways that antagonize autophagy, such as ERK-MAPK axis, was strongly synergistic. IGF1R and ERK inhibition converged on suppression of glycolysis, leading to enhanced dependence on autophagy. Accordingly, concurrent inhibition of IGF1R, ERK, and autophagy induced cytotoxicity in PDAC cell lines and decreased viability in human PDAC organoids. In conclusion, targeting IGF1R together with ERK enhances the effectiveness of autophagy inhibitors in PDAC. Significance: Compensatory upregulation of IGF1R and ERK- MAPK signaling limits the efficacy of autophagy inhibitors chloroquine and hydroxychloroquine, and their concurrent inhibition synergistically increases autophagy dependence and chloroquine sensitivity in pancreatic ductal adenocarcinoma.Peer reviewe

The analgesic-like properties of the alpha7 nAChR silent agonist NS6740 is associated with non-conducting conformations of the receptor

The alpha 7 nicotinic acetylcholine receptor (nAChR) is a promising drug target for a number of neurological disorders including chronic pain and inflammatory diseases. Since alpha 7 can function as a ligand-gated ion channel, drug development initially focused on ligands that were selective activators of the alpha 7 ion channel. However, the best alpha 7 drugs for chronic pain and inflammation indications may not be ion channel activators but rather "silent agonists", which bind to the receptor but preferentially induce non-conducting states that modulate signal transduction in non-neuronal cells. One such compound is NS6740. We show that NS6740 selectively induces prolonged desensitization of alpha 7 nAChRs. There are two forms of alpha 7 desensitization that can be distinguished by their sensitivity to the positive allosteric modulators (PAMs). At high concentrations, NS6740 preferentially induces PAM-insensitive desensitization, which over the course of several minutes reverts to the sensitive form. NS6740 was tested in several pain models after in vivo administration in the mouse. Although it had no effects in acute thermal pain, NS6740 induced significant dose- and time-dependent antinociceptive activity in formalin- and acetic acid-induced nociceptive behaviors as well as in the chronic constrictive nerve injury (CCI) model for neuropathic pain. The antinociceptive activity of NS6740 in these models was alpha 7-dependent. In addition, NS6740 administration reversed pain-induced aversion, an important affective component of pain. The time and concentration dependence of the effects were consistent with NS6740 induction of PAM-insensitive non-conducting states, suggesting that signal transduction required for analgesia is accomplished by alpha 7 receptors in that conformation.VCU Massey Cancer Center (A-35337)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (DA032246)United States Department of Health & Human Services National Institutes of Health (NIH) - USA (GM57481)United States Department of Health & Human Services National Institutes of Health (NIH) - USA (DA027113)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute of General Medical Sciences (NIGMS) (R01GM057481)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA032246)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R01DA012610)United States Department of Health & Human Services National Institutes of Health (NIH) - USA NIH National Institute on Drug Abuse (NIDA) European Commission (R03DA027113