Exome sequencing identifies recurrent somatic RAC1 mutations in melanoma

We characterized the mutational landscape of melanoma, the form of skin cancer with the highest mortality rate, by sequencing the exomes of 147 melanomas. Sun-exposed melanomas had markedly more ultraviolet (UV)-like C>T somatic mutations compared to sun-shielded acral, mucosal and uveal melanomas. Among the newly identified cancer genes was PPP6C, encoding a serine/threonine phosphatase, which harbored mutations that clustered in the active site in 12% of sun-exposed melanomas, exclusively in tumors with mutations in BRAF or NRAS. Notably, we identified a recurrent UV-signature, an activating mutation in RAC1 in 9.2% of sun-exposed melanomas. This activating mutation, the third most frequent in our cohort of sun-exposed melanoma after those of BRAF and NRAS, changes Pro29 to serine (RAC1P29S) in the highly conserved switch I domain. Crystal structures, and biochemical and functional studies of RAC1P29S showed that the alteration releases the conformational restraint conferred by the conserved proline, causes an increased binding of the protein to downstream effectors, and promotes melanocyte proliferation and migration. These findings raise the possibility that pharmacological inhibition of downstream effectors of RAC1 signaling could be of therapeutic benefit.

Understanding chronic pain complicating disability: Finding meaning through focus group methodology

Over the past few decades a major paradigm shift has occurred in the conceptualisation of chronic pain as a complex multidimensional phenomenon. Yet, pain experienced by individuals with a primary disability continues to be understood largely from a traditional biomedical model, despite its inherent limitations. This is reflected in the body of literature on the topic that is primarily driven by positivist assumptions and the search for etiologic pain mechanisms. Conversely, little is known about the experiences of and meanings attributed to, disability-related pain. Thus the purpose of this paper is to discuss the use of focus group methodology in elucidating the meanings and experiences of this population. Here, a distinction is made between the method of the focus group and focus group research as methodology. Typically, the focus group is presented as a seemingly atheoretical method of research. Drawing on research undertaken on the impact of chronic pain in people with multiple sclerosis, this paper seeks to theorise the focus group in arguing the methodological congruence of focus group research and the study of pain experience. It is argued that the contributions of group interaction and shared experiences in focus group discussions produce data and insights less accessible through more structured research methods. It is concluded that a biopsychosocial perspective of chronic pain may only ever be appreciated when the person-in-context is the unit of investigation.

Formalising human recognition : a fundamental building block for security proofs

A fundamental part of many authentication protocols which authenticate a party to a human involves the human recognizing or otherwise processing a message received from the party. Examples include typical implementations of Verified by Visa in which a message, previously stored by the human at a bank, is sent by the bank to the human to authenticate the bank to the human; or the expectation that humans will recognize or verify an extended validation certificate in a HTTPS context. This paper presents general definitions and building blocks for the modelling and analysis of human recognition in authentication protocols, allowing the creation of proofs for protocols which include humans. We cover both generalized trawling and human-specific targeted attacks. As examples of the range of uses of our construction, we use the model presented in this paper to prove the security of a mutual authentication login protocol and a human-assisted device pairing protocol.

Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long–Evans rats by the α-2 adrenoreceptor antagonist yohimbine

Rationale Developing models to efficiently explore the mechanisms by which stress can mediate reinstatement of drug-seeking behavior is crucial to the development of new pharmacotherapies for alcohol use disorders. Objectives We examined the effects of multiple reinstatement sessions using the pharmacological stressor, yohimbine, in ethanol- and sucrose-seeking rats in order to develop a more efficient model of stress-induced reinstatement. Methods Long–Evans rats were trained to self-administer 10% ethanol with a sucrose-fading procedure, 20% ethanol without a sucrose-fading procedure, or 5% sucrose in 30-min operant self-administration sessions, followed by extinction training. After reaching extinction criteria, the animals were tested once per week with yohimbine vehicle and yohimbine (2 mg/kg), respectively, 30 min prior to the reinstatement sessions or blood collection. Levels of reinstatement and plasma corticosterone (CORT) were determined each week for four consecutive weeks. Results Yohimbine induced reinstatement of ethanol- and sucrose-seeking in each of the 4 weeks. Interestingly, the magnitude of the reinstatement decreased for the 10% ethanol group after the first reinstatement session but remained stable for the 20% ethanol group trained without sucrose. Plasma CORT levels in response to injection of both vehicle and yohimbine were significantly higher in the ethanol-trained animals compared to sucrose controls. Conclusions The stable reinstatement in the 20% ethanol group supports the use of this training procedure in studies using within-subject designs with multiple yohimbine reinstatement test sessions. Additionally, these results indicate that the hormonal response to stressors can be altered following extinction from self-administration of relatively modest amounts of ethanol.

Publicly verifiable ciphertexts

In many applications, where encrypted traffic flows from an open (public) domain to a protected (private) domain, there exists a gateway that bridges the two domains and faithfully forwards the incoming traffic to the receiver. We observe that indistinguishability against (adaptive) chosen-ciphertext attacks (IND-CCA), which is a mandatory goal in face of active attacks in a public domain, can be essentially relaxed to indistinguishability against chosen-plaintext attacks (IND-CPA) for ciphertexts once they pass the gateway that acts as an IND-CCA/CPA filter by first checking the validity of an incoming IND-CCA ciphertext, then transforming it (if valid) into an IND-CPA ciphertext, and forwarding the latter to the recipient in the private domain. “Non-trivial filtering'' can result in reduced decryption costs on the receivers' side. We identify a class of encryption schemes with publicly verifiable ciphertexts that admit generic constructions of (non-trivial) IND-CCA/CPA filters. These schemes are characterized by existence of public algorithms that can distinguish between valid and invalid ciphertexts. To this end, we formally define (non-trivial) public verifiability of ciphertexts for general encryption schemes, key encapsulation mechanisms, and hybrid encryption schemes, encompassing public-key, identity-based, and tag-based encryption flavours. We further analyze the security impact of public verifiability and discuss generic transformations and concrete constructions that enjoy this property.

Advance transit oriented development typology : case study in Brisbane, Australia

Internationally, transit oriented development (TOD) is characterised by moderate to high density development with diverse land use patterns and well connected street networks centred around high frequency transit stops (bus and rail). Although different TOD typologies have been developed in different contexts, they are based on subjective evaluation criteria derived from the context in which they are built and typically lack a validation measure. Arguably there exist sets of TOD characteristics that perform better in certain contexts, and being able to optimise TOD effectiveness would facilitate planning and supporting policy development. This research utilises data from census collection districts (CCDs) in Brisbane with different sets of TOD attributes measured across six objectively quantified built environmental indicators: net employment density, net residential density, land use diversity, intersection density, cul-de-sac density, and public transport accessibility. Using these measures, a Two Step Cluster Analysis was conducted to identify natural groupings of the CCDs with similar profiles, resulting in four unique TOD clusters: (a) residential TODs, (b) activity centre TODs, (c) potential TODs, and; (d) TOD non-suitability. The typologies are validated by estimating a multinomial logistic regression model in order to understand the mode choice behaviour of 10,013 individuals living in these areas. Results indicate that in comparison to people living in areas classified as residential TODs, people who reside in non-TOD clusters were significantly less likely to use public transport (PT) (1.4 times), and active transport (4 times) compared to the car. People living in areas classified as potential TODs were 1.3 times less likely to use PT, and 2.5 times less likely to use active transport compared to using the car. Only a little difference in mode choice behaviour was evident between people living in areas classified as residential TODs and activity centre TODs. The results suggest that: (a) two types of TODs may be suitable for classification and effect mode choice in Brisbane; (b) TOD typology should be developed based on their TOD profile and performance matrices; (c) both bus stop and train station based TODs are suitable for development in Brisbane.

Plaintext awareness in identity-based key encapsulation

The notion of plaintext awareness ( PA ) has many applications in public key cryptography: it offers unique, stand-alone security guarantees for public key encryption schemes, has been used as a sufficient condition for proving indistinguishability against adaptive chosen-ciphertext attacks ( IND-CCA ), and can be used to construct privacy-preserving protocols such as deniable authentication. Unlike many other security notions, plaintext awareness is very fragile when it comes to differences between the random oracle and standard models; for example, many implications involving PA in the random oracle model are not valid in the standard model and vice versa. Similarly, strategies for proving PA of schemes in one model cannot be adapted to the other model. Existing research addresses PA in detail only in the public key setting. This paper gives the first formal exploration of plaintext awareness in the identity-based setting and, as initial work, proceeds in the random oracle model. The focus is laid mainly on identity-based key encapsulation mechanisms (IB-KEMs), for which the paper presents the first definitions of plaintext awareness, highlights the role of PA in proof strategies of IND-CCA security, and explores relationships between PA and other security properties. On the practical side, our work offers the first, highly efficient, general approach for building IB-KEMs that are simultaneously plaintext-aware and IND-CCA -secure. Our construction is inspired by the Fujisaki-Okamoto (FO) transform, but demands weaker and more natural properties of its building blocks. This result comes from a new look at the notion of γ -uniformity that was inherent in the original FO transform. We show that for IB-KEMs (and PK-KEMs), this assumption can be replaced with a weaker computational notion, which is in fact implied by one-wayness. Finally, we give the first concrete IB-KEM scheme that is PA and IND-CCA -secure by applying our construction to a popular IB-KEM and optimizing it for better performance.

Legal Reasoning in Environmental Law : a Study of Structure, Form and Language

This book analyses the structure, form and language of a selected number of international and national legal instruments and reviews how an illustrative range of international and national judicial institutions have responded to the issues before them and the processes of legal reasoning engaged by them in reaching their decisions. This involves a very detailed discussion of these primary sources of international and national environmental law with a view to determining their jurisprudential architecture and the processes of reasoning expected of those responsible for implementing these architectural arrangements. This book is concerned not with the effectiveness or the quality of an environmental legal system but only with its jurisprudential characteristics and their associated processes of legal reasoning.

Predicting crack initiation due to ratchetting in rail heads using critical element analysis

This paper presents a strategy to predict the lifetime of rails subjected to large rolling contact loads that induce ratchetting strains in the rail head. A critical element concept is used to calculate the number of loading cycles needed for crack initiation to occur in the rail head surface. In this technique the finite element method (FEM) is used to determine the maximum equivalent ratchetting strain per load cycle, which is calculated by combining longitudinal and shear stains in the critical element. This technique builds on a previously developed critical plane concept that has been used to calculate the number of cycles to crack initiation in rolling contact fatigue under ratchetting failure conditions. The critical element concept simplifies the analytical difficulties of critical plane analysis. Finite element analysis (FEA) is used to identify the critical element in the mesh, and then the strain values of the critical element are used to calculate the ratchetting rate analytically. Finally, a ratchetting criterion is used to calculate the number of cycles to crack initiation from the ratchetting rate calculated.

Neoliberalism and Spatial Adaptation

Human spatial environments must adapt to climate change. Spatial planning is central to climate change adaptation and potentially well suited to the task, however neoliberal influences and trends threaten this capacity. This paper explores the significance of neoliberal influences on urban planning to climate change adaptation. The potential form of spatial adaptation within the context of a planning environment influenced by neoliberal principles is evaluated. This influence relates to spatial scale, temporal scale, responsibility for action, strategies and mechanisms, accrual of benefits, negotiation of priorities and approach to uncertainty. This paper presents a conceptual framework of the influence of neoliberalism on spatial adaptation. It identifies the potential characteristics, challenges and opportunities of spatial adaptation under a neoliberal frame. The neoliberal frame does not entirely preclude spatial adaptation but significantly influence its form. Neoliberal approaches involve individual action in response to private incentives and near term impacts while collective action, regulatory mechanisms and long term planning is approached cautiously. Challenges concern the degree to which collective action and a long term orientation are necessary, how individual adaptation relates to collective vulnerability and the prioritisation of adaptation by markets. Opportunities might involve the operability of individual and local adaptation, the existence of private incentives to adapt and the potential to align adaptation with entrepreneurial projects.

Doing adaptation differently? Does neoliberalism influence adaptation planning in Queensland?

Australian cities are particularly vulnerable to climate change. Adapting to climate change is a critical task for contemporary spatial planning, one that is widely recognised by the planning profession and beginning to receive substantive attention in planning policy. However adaptation takes place within the context of established spatial governance regimes and planning cultures, and examples of effective adaptation are often grounded in progressive contexts markedly different than Australia. In Australia, planning is subject to strong neoliberal reform agendas (Gleeson & Low, 2000a, 2000b) and national adaptation policies align with neoliberal views (Granberg & Glover, 2011). Planning in Queensland has been subject to deregulation (Buxton et al., 2012) and the continued influence of neoliberalism (Wright & Cleary, 2012). The influence of neoliberalism on climate change adaptation has received little consideration in research and literature. This paper reviews a case study of adaptation planning through the lens of the recent and contemporary influences of neoliberalism. It examines spatial/land-use planning for climate change adaptation in Queensland, identifying the underlying rationales, priorities and strategies. A justification for such an investigation is advanced based on the challenges to planning facilitating adaptation and identified links to neoliberalism. A preliminary analysis of interviews with planners is then used to identify and discuss the ideological influences practitioners perceive in current approaches to adaptation in Queensland and the implications of such.

What factors influence nurses’ assessment practices? Development of the Barriers to Nurses’ use of Physical Assessment Scale

Aim To develop and psychometrically test the Barriers to Nurses’ use of Physical Assessment Scale. Background There is growing evidence of failure to recognise hospitalised patients at risk of clinical deterioration, in part due to inadequate physical assessment by nurses. Yet, little is known about the barriers to nurses’ use of physical assessment in the acute hospital setting and no validated scales have been published. Design Instrument development study. Method Scale development was based on a comprehensive literature review, focus groups, expert review and psychometric evaluation. The scale was administered to 434 acute care registered nurses working at a large Australian teaching hospital between June and July 2013. Psychometric analysis included factor analysis, model fit statistics and reliability testing. Results The final scale was reduced to 38 items representing seven factors, together accounting for 57.7% of the variance: (1) reliance on others and technology, (2) lack of time and interruptions, (3) ward culture, (4) lack of confidence, (5) lack of nursing role models, (6) lack of influence on patient care, and; (7) specialty area. Internal reliability ranged from .70 to .86. Conclusion Findings provide initial evidence for the validity and reliability of the Barriers to Nurses’ use of Physical Assessment Scale and point to the importance of understanding the organisational determinants of nurses’ assessment practices. The new scale has potential clinical and research applications to support nursing assessment in acute care settings.

Reasons for non-urgent presentations to the emergency department in Saudi Arabia

Background The majority of patients who attend emergency departments (EDs) in Saudi Arabia have non-urgent problems, resulting in overcrowding, excessive waiting times and delayed care for more acutely ill patients. The purpose of this research was to examine the reasons for non-urgent visits to a Saudi ED and factors associated with patient perceptions of urgency. Methods We administered a survey to 350 consecutively presenting Canadian Triage and Acuity Scale (CTAS) IV or V adult patients at a large tertiary ED in Riyadh region, Saudi Arabia, during 25 days of data collection in March 2013. Results Over half of the sample usually visited the ED to access healthcare. The most common reasons for attending the ED were not having a regular healthcare provider (63%), being able to receive care on the same day (62%), and the convenience of and access to medical care 24/7 (62%). Approximately two-thirds of CTAS V patients and one-third of CTAS IV patients believed their condition was more urgent than their triage nurse rating. Conclusion Multiple factors influence non-urgent visits to the ED in the Saudi context including insufficient community awareness of the role of the ED and perceived lack of access to primary healthcare services.