Antiproliferative and phenotype-transforming antitumor agents derived from cysteine

Selective destruction of malignant tumor cells without damaging normal cells is an important goal for cancer chemotherapy in the 21st century. Differentiating agents that transform cancer cells to either a nonproliferating or normal phenotype could potentially be tissue-specific and avoid side effects of current drugs. However, most compounds that are presently known to differentiate cancer cells are histone deacetylase inhibitors that are of low potency or suffer from low bioavailability, rapid metabolism, reversible differentiation, and nonselectivity for cancer cells over normal cells. Here we describe 36 nonpeptidic compounds derived from a simple cysteine scaffold, fused at the C-terminus to benzylamine, at the N-terminus to a small library of carboxylic acids, and at the S-terminus to 4-butanoyl hydroxamate. Six compounds were cytotoxic at nanomolar concentrations against a particularly aggressive human melanoma cell line (MM96L), four compounds showed selectivities of greater than or equal to5:1 for human melanoma over normal human cells (NFF), and four of the most potent compounds were further tested and found to be cytotoxic for six other human cancer cell lines (melanomas SK-MEL-28, DO4; prostate DU145; breast MCF-7; ovarian JAM, CI80-13S). The most active compounds typically caused hyperacetylation of histones, induced p21 expression, and reverted phenotype of surviving tumor cells to a normal morphology. Only one compound was given orally at 5 mg/kg to healthy rats to look for bioavailaiblity, and it showed reasonably high levels in plasma (C-max 6 mug/mL, T-max 15 min) for at least 4 h. Results are sufficiently promising to support further work on refining this and related classes of compounds to an orally active, more tumor-selective, antitumor drug.

Normative influence and rational conflict decisions: Group norms and cost-benefit analyses for intergroup behavior

The present paper articulates a model in which ingroup and outgroup norms inform 'rational' decision-making (cost-benefit analysis) for conflict behaviors. Norms influence perceptions of the consequences of the behavior, and individuals may thus strategically conform to or violate norms in order to acquire benefits and avoid costs. Two studies demonstrate these processes in the context of conflict in Quebec. In the first study, Anglophones' perceptions of Francophone and Anglophone norms for pro-English behaviors predicted evaluations of the benefits and costs of the behaviors, and these cost-benefit evaluations in turn mediated the norm-intention links for both group norms. In the second study, a manipulated focus on supportive versus hostile ingroup and outgroup norms also predicted cost-benefit evaluations, which mediated the norm-intention relationships. The studies support a model of strategic conflict choices in which group norms inform, rather than suppress, rational expectancy value processes. Implications for theories of decision-making and normative influence are discussed.

Personality and goal orientation as predictors of performance in a learning context

The current study aimed to investigate and provide furthering evidence of individual differences as determinants of task performance. This research focused on the effects of the personality traits Openness to Experience and Neuroticism, and two goal orientation traits. Learning Orientation and Avoid Orientation, on task performance. The hypotheses addressed the predictability of the traits, the differential effects of personality and goal orientation traits, and the mediating effects of goal orientation on the relationship between personality and performance. The results were based on questionnaire responses completed by a sample of 103 students. Scores on a computerised Air Traffic Control (ATC) decision-making task were used as a measure of task performance. Learning Orientation was found to be a significant predictor of performance, whilst the effect of Neuroticism was 'approaching' significance. Results indicated strong support for the differential relationship between personality traits and corresponding goal orientation traits. The mediating relationship between Openness to Experience, Learning Orientation and performance was also found to be 'approaching' significance. Results were indicative of the influences of personality and goal orientation on consequent performance outcomes. Implications were discussed, as well as suggestions for possible future directions in research assessing the predictabilit)' of individual differences in learning contexts.

The influence of high contrast acuity and normalised low contrast acuity upon self-reported situation avoidance and driving crashes

The aim of this study was to determine the cues used to signal avoidance of difficult driving situations and to test the hypothesis that drivers with relatively poor high contrast visual acuity (HCVA) have fewer crashes than drivers with relatively poor normalised low contrast visual acuity (NLCVA). This is because those with poorer HCVA are well aware of their difficulties and avoid dangerous driving situations while those poorer NLCVA are often unaware of the extent of their problem. Age, self-reported situation avoidance and HCVA were collected during a practice based study of 690 drivers. Screening was also carried out on 7254 drivers at various venues, mainly motorway sites, throughout the UK. Age, self-reported situation avoidance and prior crash involvement were recorded and Titmus vision screeners were used to measure HCVA and NLCVA. Situation avoidance increased in reduced visibility conditions and was influenced by age and HCVA. Only half of the drivers used visual cues to signal situation avoidance and most of these drivers used high rather than low contrast cues. A statistical model designed to remove confounding interrelationships between variables showed, for drivers that did not report situation avoidance, that crash involvement decreased for drivers with below average HCVA and increased for those with below average NLCVA. These relationships accounted for less than 1% of the crash variance, so the hypothesis was not strongly supported. © 2002 The College of Optometrists.

Knowledge:politics and knowledge

Knowledge is of crucial, and growing importance in social, political and economic relations in modern society. The range and variety of available knowledge dramatically enlarges the available options of social action. This five volume collection brings together a broad array of contributions from a variety of disciplines. Featuring essays from philosophers who have investigated the foundations of knowledge, and addressing different forms of knowledge in society such as common sense and practical knowledge, this collection also discusses the role of knowledge in economic process and gives attention to the role of expert knowledge in political decision making. Including a collection of articles from the sociology of knowledge and science, the set also provides a new introduction by the editors, making it a unique and invaluable research resource for both student and scholar.

Political discourse, media and translation

This volume addresses the role played by translation in international political communication and news reporting and brings to light the usually invisible link between politics, media, and translation. The contributors explore the interrelationship between media in the widest sense and translation, with a focus on politics texts, institutional contexts, and translation policies. These topics are explored from a Translation Studies perspective, thus bringing a new disciplinary view to the investigation of political discourse and the language of the media. The first part of the volume focuses on textual analysis, investigating transformations that occur in translation processes, and the second part examines institutional contexts and institutional policies and their effects on translation production and reception.

Development and trialling of a behavioural intervention for patients with atrial fibrillation initiating oral anticoagulation:the 'treat' study

Purpose: Atrial fibrillation (AF) is the most common heart arrhythmia and is associated with an increased risk of stroke. Stroke risk is commonly treated with oral anticoagulation (OAC) with a narrow therapeutic range (INR 2.0 to 3.0); which is poorly controlled in practice. Barriers to adherence include poor knowledge, and inaccurate perceptions surrounding illness and medications. Trial registration: ISRCTN93952605. Systematic review: Seven trials of educational, self-monitoring and decision aid interventions were included in a systematic review. Pooled analysis suggested education OR, 95% CI 7.89 (5.54-10.24) and self monitoring OR (95% CI) 5.47(2.55-8.39) significantly improve TTR; whereas decision aids are no more effective in reducing decision conflict than usual care, OR (95% CI) -0.10 (-0.17 to -0.02). Intervention development: The intervention was theoretically-driven (utilising the common sense and beliefs about medication models) and developed with expert patient feedback. Described using behavioural change techniques, the one-off group session included an educational booklet, ‘expert-patient’ focussed DVD, and worksheet. Methods: Ninety seven warfarin-naïve AF patients were randomised to receive the intervention (n=43), or usual care (n=54). The primary endpoint was time within therapeutic range (TTR), secondary endpoints included knowledge, quality of life (AF-QoL-18), beliefs about medication (BMQ), illness perceptions (IPQ-B), and anxiety and depression (HADS). Results: Intervention group had significantly higher TTR than usual care (78.5% vs. 66.7%; p=0.01). Knowledge changed significantly across time (F (3, 47) = 6.4; p<0.01), but not between groups (F (1, 47) = 3.3; p = 0.07). At six months knowledge predicted TTR (r=0.245; p=0.04). Illness concern negatively correlated with TTR (r= - 0.199; p=0.05). General Harm scores at one month predicted TTR (F (1, 72) = 4.08; p=0.048). There were significant differences in emotional representations (F (3, 49) = 3.3 (3, 49); p= 0.03), anxiety (F (3, 46) = 25.2; p<0.01) and depression (F (3, 46) = 37.7; p<0.01) across time. Conclusion: A theory-driven educational intervention can improve TTR in AF patients and potentially reduce the risk of adverse clinical outcomes. Improving education provision for AF patients is essential to ensure efficacious treatment.

Design and designing:a critical introduction

Design and Designing provides a broad and critical understanding of what is essentially a practical subject. Designing today is less a craft and more a part of the knowledge economy. It's all about knowing how to acquire knowledge and how to apply it creatively. Design and Designing covers the design process, modelling and drawing, working with clients, production and consumption, sustainability, professional practice and design futures. Chapters are written by expert teachers and practitioners from around the globe, each presenting an accessible and engaging overview of their field of design. Every chapter is highly illustrated with a combination of images and information boxes, which extend or highlight key material. Each section concludes with a design project, a hands-on activity for the reader. Design and Designing covers the full spectrum of design types, from graphic communication to product design, from fashion to games design, setting every type in its aesthetic, ethical and social contexts. With this essential book, readers will learn from today's best practice and best thinking in design, they will develop a critical sense, and become the designers of tomorrow.

Beyond cultural values? Cultural leadership ideals and entrepreneurship

This paper offers a fresh perspective on national culture and entrepreneurship research. It explores the role of Culturally-endorsed implicit Leadership Theories (CLTs) – i.e., the cultural expectations about outstanding, ideal leadership – on individual entrepreneurship. Developing arguments based on culture-entrepreneurship fit, we predict that charismatic and self-protective CLTs positively affect entrepreneurship. They provide a context that enables entrepreneurs to be co-operative in order to initiate change but also to be self-protective and competitive so as to safeguard their venture and avoid being exploited. We further theorize that CLTs are more proximal drivers of cross-country differences in entrepreneurship as compared with distal cultural values. We find support for our propositions in a multi-level study of 42 countries. Cultural values (of uncertainty avoidance and collectivism) influence entrepreneurship mainly indirectly, via charismatic and self-protective CLTs. We do not find a similar indirect effect for cultural practices.

Four essays of environmental risk-mitigation

Expected damages of environmental risks depend both on their intensities and probabilities. There is very little control over probabilities of climate related disasters such as hurricanes. Therefore, researchers of social science are interested identifying preparation and mitigation measures that build human resilience to disasters and avoid serious loss. Conversely, environmental degradation, which is a process through which the natural environment is compromised in some way, has been accelerated by human activities. As scientists are finding effective ways on how to prevent and reduce pollution, the society often fails to adopt these effective preventive methods. Researchers of psychological and contextual characterization offer specific lessons for policy interventions that encourage human efforts to reduce pollution. This dissertation addresses four discussions of effective policy regimes encouraging pro-environmental preference in consumption and production, and promoting risk mitigation behavior in the face of natural hazards. The first essay describes how the speed of adoption of environment friendly technologies is driven largely by consumers' preferences and their learning dynamics rather than producers' choice. The second essay is an empirical analysis of a choice experiment to understand preferences for energy efficient investments. The empirical analysis suggests that subjects tend to increase energy efficient investment when they pay a pollution tax proportional to the total expenditure on energy consumption. However, investments in energy efficiency seem to be crowded out when subjects have the option to buy health insurance to cover pollution related health risks. In context of hurricane risk mitigation and in evidence of recently adopted My Safe Florida Home (MSFH) program by the State of Florida, the third essay shows that households with home insurance, prior experience with damages, and with a higher sense of vulnerability to be affected by hurricanes are more likely to allow home inspection to seek mitigation information. The fourth essay evaluates the impact of utility disruption on household well being based on the responses of a household-level phone survey in the wake of hurricane Wilma. Findings highlight the need for significant investment to enhance the capacity of rapid utility restoration after a hurricane event in the context of South Florida.

Subfornical organ neurons integrate cardiovascular and metabolic signals

The subfornical organ (SFO) is a critical circumventricular organ involved in the control of cardiovascular and metabolic homeostasis. Despite the abundant literature clearly demonstrating the ability of SFO neurons to sense and respond to a plethora of circulating signals that influence various physiological systems, investigation of how simultaneously sensed signals interact and are integrated in the SFO is lacking. In this study, we use patch clamp techniques to investigate how the traditionally classified ‘cardiovascular’ hormone angiotensin II (ANG), ‘metabolic’ hormone cholecystokinin (CCK) and ‘metabolic’ signal glucose interact and are integrated in the SFO. Sequential bath-application of CCK (10nM) and ANG (10nM) onto dissociated SFO neurons revealed that: 63% of responsive SFO neurons depolarized to both CCK & ANG; 25% depolarized to ANG only; and 12% hyperpolarized to CCK only. We next investigated the effects of glucose by incubating and recording neurons in either hypo-, normo- or hyperglycemic conditions for a minimum of 24 hours and comparing the proportions of responses to ANG (n=55) or CCK (n=83) application in each condition. A hyperglycemic environment was associated with a larger proportion of depolarizing responses to ANG (X2, p<0.05), and a smaller proportion of depolarizing responses along with a larger proportion of hyperpolarizing responses to CCK (X2, p<0.01). These data demonstrate that SFO neurons excited by CCK are also excited by ANG, suggesting that CCK may influence fluid intake or blood pressure via the SFO, complementary to the well-understood actions of ANG at this site. Additionally, the demonstration that glucose environment affects the responsiveness of neurons to both these hormones highlights the ability of SFO neurons to integrate multiple metabolic and cardiovascular signals to affect transmission of information from the circulation to the brain, which has important implications for this structure’s critical role regulation of autonomic function.

Plato on Oblivion. About Memory and Forgetfullness in the Platonic Dialogues

The aim of this paper is to tackle the role of oblivion in the Plato’s dialogues. It takes as work texts the dialogues where the anamnesis doctrine is exposed, and from these writings, but also attending to several other ones, the connexions between oblivion and other Platonic issues, as, e. g., language, memory, experience or love are explored, in order to clarify their relations of mutual dependence. In this way, we attempt to find out in the Platonic oblivion a philosophical sense, which is not disdainful in comparison with the sense and the relevance that the readers of all times have granted to anamnesis; for anamnesis and oblivion are inseparable indeed.

Multilingualism and conceptual modelling

One of the leading motivations behind the multilingual semantic web is to make resources accessible digitally in an online global multilingual context. Consequently, it is fundamental for knowledge bases to find a way to manage multilingualism and thus be equipped with those procedures for its conceptual modelling. In this context, the goal of this paper is to discuss how common-sense knowledge and cultural knowledge are modelled in a multilingual framework. More particularly, multilingualism and conceptual modelling are dealt with from the perspective of FunGramKB, a lexico-conceptual knowledge base for natural language understanding. This project argues for a clear division between the lexical and the conceptual dimensions of knowledge. Moreover, the conceptual layer is organized into three modules, which result from a strong commitment towards capturing semantic knowledge (Ontology), procedural knowledge (Cognicon) and episodic knowledge (Onomasticon). Cultural mismatches are discussed and formally represented at the three conceptual levels of FunGramKB.

Achievable rates and outage probability of cognitive radio with dynamic frequency hopping under imperfect spectrum sensing

In this study, the authors propose simple methods to evaluate the achievable rates and outage probability of a cognitive radio (CR) link that takes into account the imperfectness of spectrum sensing. In the considered system, the CR transmitter and receiver correlatively sense and dynamically exploit the spectrum pool via dynamic frequency hopping. Under imperfect spectrum sensing, false-alarm and miss-detection occur which cause impulsive interference emerged from collisions due to the simultaneous spectrum access of primary and cognitive users. That makes it very challenging to evaluate the achievable rates. By first examining the static link where the channel is assumed to be constant over time, they show that the achievable rate using a Gaussian input can be calculated accurately through a simple series representation. In the second part of this study, they extend the calculation of the achievable rate to wireless fading environments. To take into account the effect of fading, they introduce a piece-wise linear curve fitting-based method to approximate the instantaneous achievable rate curve as a combination of linear segments. It is then demonstrated that the ergodic achievable rate in fast fading and the outage probability in slow fading can be calculated to achieve any given accuracy level.

Implementing a structural continuity constraint and a halting method for the topology optimization of energy absorbers

This study investigates topology optimization of energy absorbing structures in which material damage is accounted for in the optimization process. The optimization objective is to design the lightest structures that are able to absorb the required mechanical energy. A structural continuity constraint check is introduced that is able to detect when no feasible load path remains in the finite element model, usually as a result of large scale fracture. This assures that designs do not fail when loaded under the conditions prescribed in the design requirements. This continuity constraint check is automated and requires no intervention from the analyst once the optimization process is initiated. Consequently, the optimization algorithm proceeds towards evolving an energy absorbing structure with the minimum structural mass that is not susceptible to global structural failure. A method is also introduced to determine when the optimization process should halt. The method identifies when the optimization method has plateaued and is no longer likely to provide improved designs if continued for further iterations. This provides the designer with a rational method to determine the necessary time to run the optimization and avoid wasting computational resources on unnecessary iterations. A case study is presented to demonstrate the use of this method.