ROCK2/rasHa cooperation induce malignant conversion via p53 loss, elevated NF-κβ and tenascin C-associated rigidity but p21 inhibits ROCK2/NF-κβ-mediated progression

To study ROCK2 activation in carcinogenesis, mice expressing 4-hydroxytamoxifen (4HT)- activated ROCK2 [K14.ROCKer] were crossed to mice expressing epidermal activated ras Ha [HK1.ras1205]. At 8 weeks, 4HT-treated K14.ROCKer-HK1.ras1205 cohorts exhibited papillomas similar to HK1.ras1205 controls; however, K14.ROCKer-HK1.ras1205 histotypes comprised a mixed papilloma/well-differentiated squamous cell carcinoma [wdSCC], exhibiting p53 loss, increased proliferation, and novel NF-κβ expression. By 12 weeks, K14.ROCKer-HK1.ras1205 wdSCCs exhibited increased NF-κβ and novel tenascin C, indicative of elevated rigidity; yet despite continued ROCK2 activities /p-Mypt1 inactivation, progression to SCC required loss of compensatory p21 expression. K14.ROCKer -HK1.ras1205 papillomatogenesis also required a wound-promotion stimulus, confirmed by breeding K14.ROCKer into promotion-insensitive HK1.ras1276 mice, suggesting a permissive K14.ROCKer-HK1.ras1205 papilloma context [wound-promoted/NF-κβ+ve/p53-ve/p21+ve] preceded K14.ROCKer-mediated [p-Mypt1/tenascin C/rigidity] malignant conversion. Malignancy depended on ROCKer/p-Mypt1 expression, as cessation of 4HT-treatment induced disorganised tissue architecture and p21-associated differentiation in wdSCCs; yet tenascin C retention in connective tissue ECM suggests the rigidity laid down for conversion persists. Novel papilloma outgrowths appeared expressing intense, basal-layer p21 which confined endogenous ROCK2/p-Mypt1/NF-κβ to supra-basal layers, and was paralleled by restored basal-layer p53. In later SCCs, 4HT-cessation became irrelevant as endogenous ROCK2 expression increased, driving progression via p21 loss, elevated NF-κβ expression and tenascin C-associated rigidity; with p-Mypt1 inactivation/actinomyosin-mediated contractility to facilitate invasion. However, p21-associated inhibition of early-stage malignant progression and the intense expression in papilloma outgrowths, identifies a novel, significant antagonism between p21 and ras Ha/ROCK2/NF-κβ signalling in skin 3 carcinogenesis. Collectively these data show that ROCK2 activation induces malignancy in rasHa-initiated/promoted papillomas in the context of p53 loss and novel NF-κβ expression;whilst increased tissue rigidity and cell motility/contractility help mediate tumour progression

Detecting child grooming behaviour patterns on social media

Online paedophile activity in social media has become a major concern in society as Internet access is easily available to a broader younger population. One common form of online child exploitation is child grooming, where adults and minors exchange sexual text and media via social media platforms. Such behaviour involves a number of stages performed by a predator (adult) with the final goal of approaching a victim (minor) in person. This paper presents a study of such online grooming stages from a machine learning perspective. We propose to characterise such stages by a series of features covering sentiment polarity, content, and psycho-linguistic and discourse patterns. Our experiments with online chatroom conversations show good results in automatically classifying chatlines into various grooming stages. Such a deeper understanding and tracking of predatory behaviour is vital for building robust systems for detecting grooming conversations and potential predators on social media

Targeting Conservation Investments in Heterogeneous Landscapes: A distance function approach and application to watershed management

To achieve a given level of an environmental amenity at least cost, decision-makers must integrate information about spatially variable biophysical and economic conditions. Although the biophysical attributes that contribute to supplying an environmental amenity are often known, the way in which these attributes interact to produce the amenity is often unknown. Given the difficulty in converting multiple attributes into a unidimensional physical measure of an environmental amenity (e.g., habitat quality), analyses in the academic literature tend to use a single biophysical attribute as a proxy for the environmental amenity (e.g., species richness). A narrow focus on a single attribute, however, fails to consider the full range of biophysical attributes that are critical to the supply of an environmental amenity. Drawing on the production efficiency literature, we introduce an alternative conservation targeting approach that relies on distance functions to cost-efficiently allocate conservation funds across a spatially heterogeneous landscape. An approach based on distance functions has the advantage of not requiring a parametric specification of the amenity function (or cost function), but rather only requiring that the decision-maker identify important biophysical and economic attributes. We apply the distance-function approach empirically to an increasingly common, but little studied, conservation initiative: conservation contracting for water quality objectives. The contract portfolios derived from the distance-function application have many desirable properties, including intuitive appeal, robust performance across plausible parametric amenity measures, and the generation of ranking measures that can be easily used by field practitioners in complex decision-making environments that cannot be completely modeled. Working Paper # 2002-01

Transverse Phase Locking for Vortex Motion in Square and Triangular Pinning Arrays

We analyze transverse phase locking for vortex motion in a superconductor with a longitudinal DC drive and a transverse AC drive. For both square and triangular arrays we observe a variety of fractional phase locking steps in the velocity versus DC drive which correspond to stable vortex orbits. The locking steps are more pronounced for the triangular arrays which is due to the fact that the vortex motion has a periodic transverse velocity component even for zero transverse AC drive. All the steps increase monotonically in width with AC amplitude. We confirm that the width of some fractional steps in the square arrays scales as the square of the AC driving amplitude. In addition we demonstrate scaling in the velocity versus applied DC driving curves at depinning and on the main step, similar to that seen for phase locking in charge-density wave systems. The phase locking steps are most prominent for commensurate vortex fillings where the interstitial vortices form symmetrical ground states. For increasing temperature, the fractional steps are washed out very quickly, while the main step gains a linear component and disappears at melting. For triangular pinning arrays we again observe transverse phase locking, with the main and several of the fractional step widths scaling linearly with AC amplitude.Comment: 10 pages, 14 postscript figure

Stability of persistent currents in a Bose-Einstein condensate confined in a toroidal trap

Motivated by recent experiments in Bose-Einstein condensed atoms that have been confined in toroidal traps, we examine the stability of persistent currents in such systems. We investigate the extent that the stability of these currents may be tunable, and the possible difficulties in their creation and detection.Comment: 6 pages, 5 figure

Rho GTPase function in flies: insights from a developmental and organismal perspective.

Morphogenesis is a key event in the development of a multicellular organism and is reliant on coordinated transcriptional and signal transduction events. To establish the segmented body plan that underlies much of metazoan development, individual cells and groups of cells must respond to exogenous signals with complex movements and shape changes. One class of proteins that plays a pivotal role in the interpretation of extracellular cues into cellular behavior is the Rho family of small GTPases. These molecular switches are essential components of a growing number of signaling pathways, many of which regulate actin cytoskeletal remodeling. Much of our understanding of Rho biology has come from work done in cell culture. More recently, the fruit fly Drosophila melanogaster has emerged as an excellent genetic system for the study of these proteins in a developmental and organismal context. Studies in flies have greatly enhanced our understanding of pathways involving Rho GTPases and their roles in development

Fine-Scale Mapping of the 5q11.2 Breast Cancer Locus Reveals at Least Three Independent Risk Variants Regulating MAP3K1

Peer reviewe