Search

Traditional genome-editing reagents such as CRISPR-Cas9 achieve targeted DNA modification by introducing double-strand breaks (DSBs), thereby stimulating localized DNA repair by endogenous cellular repair factors. While highly effective at generating heterogenous knockout mutations, this approach suffers from undesirable byproducts and an inability to control product purity. Here we develop a system in human cells for programmable, DSB-free DNA integration using Type I CRISPR-associated transposons (CASTs). To adapt our previously described CAST systems, we optimized DNA targeting by the QCascade complex through a comprehensive assessment of protein design, and we developed potent transcriptional activators by exploiting the multi-valent recruitment of the AAA+ ATPase, TnsC, to genomic sites targeted by QCascade. After initial detection of plasmid-based transposition, we screened 15 homologous CAST systems from a wide range of bacterial hosts, identified a CAST homolog fromPseudoalteromonasthat exhibited improved activity, and increased integration efficiencies through parameter optimization. We further discovered that bacterial ClpX enhances genomic integration by multiple orders of magnitude, and we propose that this critical accessory factor functions to drive active disassembly of the post-transposition CAST complex, akin to its demonstrated role in Mu transposition. Our work highlights the ability to functionally reconstitute complex, multi-component machineries in human cells, and establishes a strong foundation to realize the full potential of CRISPR-associated transposons for human genome engineering.

The role of the epicardial vasculature in supraventricular and ventricular arrhythmias was described in clinical studies as well as its treatment by intravascular point ablation or alcohol injection. We report on a case series of patients with different arrhythmias linked to an epicardial site of origin with evidence supporting transmural extensions that were targeted for ablation with successful outcomes.The records of patients who has catheter ablation for Supraventricular or Ventricular arrhythmias between 2015 and 2020 was searched for patients with (1) arrhythmias linked to the epicardial vasculature and (2) findings to support an endocardial connection to the epicardial vasculature by activation mapping, pace mapping, or differential pacing, and (3) were successfully ablated via an endocardial approach only.From the data searched, we identified five patients with the following arrhythmias left ventricular summit ectopy, peri-mitral atrial flutter, preexcitation with inducible atrioventricular reentry tachycardia (AVRT), and a concealed left side accessory pathway with inducible AVRT that were linked to the following vessels: Great Cardiac vein, persistent left superior vena cava, left coronary cusp, and left ventricular outflow tract. Endocardial connections were supported by a combination of electro anatomical activation mapping, pace-mapping, and differential pacing. Endocardial ablations performed in all patients were successful without complications.This report highlights a subset of patients with arrhythmias linked to the greater cardiac vascular system that can be safely and effectively ablated endocardially, given the limitations and possible complications of epicardial ablation within or in the proximity of the epicardial vasculature.

This paper examines the ethical behaviour of new lawyers from two contrasting points of view. First, we review the prevalence and type of ethical misconduct by lawyers in the Australian state of Vi...

Because of its complex root canal morphology, dens invaginatus (DI) is a developmental anomaly that represents an endodontic challenge to complete cleaning, shaping, and disinfecting the root canal system. The present case report describes the use of antimicrobial photodynamic therapy as an adjunctive treatment in the successful management of nonsurgical complex type II DI in a left maxillary lateral incisor with thin and fragile dentin walls associated with periradicular lesion.

Simultaneous multithreading (SMT) enables enhanced computing capacity by allowing multiple tasks to execute concurrently on the same computing core. Despite its benefits, its use has been largely eschewed in work on real-time systems due to concerns that tasks running on the same core may adversely interfere with each other. In this paper, the safety of using SMT in a mixed-criticality multicore context is considered in detail. To this end, a prior open-source framework called MC2 (mixedcriticality on multicore), which provides features for mitigating cache and memory interference, was re-implemented to support SMT on an SMT-capable multicore platform. The creation of this new, configurable $\mathrm{M}\mathrm{C}^{2}$ variant entailed producing the first operating-system implementations of several recently proposed real-time SMT schedulers and tying them together within a mixed-criticality context. These schedulers introduce new spatialisolation challenges, which required introducing isolation at both the L2 and L3 cache levels. The efficacy of the resulting $\mathrm{M}\mathrm{C}^{2}$ variant is demonstrated via three experimental efforts. The first involved obtaining execution data using a wide range of benchmark suites, including TACLeBench, DIS, SD-VBS, and synthetic microbenchmarks. The second involved conducting a large-scale overhead-aware schedulability study, parameterized by the collected benchmark data, to elucidate schedulability tradeoffs. The third involved experiments involving case-study task systems. In the schedulability study, the use of SMT proved capable of increasing platform capacity by an average factor of 1.32. In the case-study experiments, deadline misses of highly critical tasks were never observed.

Translocation renal cell carcinoma (tRCC) is an aggressive and poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 tRCC patients identified across multiple genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to many targeted therapies. Consistently, we find that outcomes for tRCC patients treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Multiparametric immunofluorescence confirmed the presence of CD8 + tumor-infiltrating T cells compatible with a clinical benefit from ICI and revealed an exhaustion immunophenotype distinct from clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

SCHED_DEADLINE (DL for short) is an Earliest-Deadline-First (EDF) scheduler included in the Linux kernel. A question motivated by DL is how EDF should be implemented in the presence of CPU affinities to maintain optimal bounded tardiness guarantees. Recent works have shown that under arbitrary affinities, DL does not maintain such guarantees. Such works have also shown that repairing DL to maintain these guarantees would likely require an impractical overhaul of the existing code. In this work, we show that for the special case where affinities are semi-partitioned, DL can be modified to maintain tardiness guarantees with minor changes. We also draw attention to the fact that admission control is already broken in several respects in the existing DL implementation.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings build on prior work and shed light on the molecular drivers of aggressivity and responsiveness to ICI of S/R RCC., Sarcomatoid and rhabdoid tumours are highly aggressive forms of renal cell carcinoma that are also responsive to immunotherapy. In this study, the authors perform a comprehensive molecular characterization of these tumours discovering an enrichment of specific alterations and an inflamed phenotype.

A gap exists between the theory of EDF scheduling on identical multiprocessors with arbitrary processor affinities (APA) and practical EDF scheduling as embodied by the SCHED_DEADLINE (SD) scheduler in Linux. This is because the EDF variant proposed in theory for APA, called Strong APA EDF, introduces affinity-related complexities that are not applicable under global EDF, the original target of SD. SD instead treats affinities as a secondary concern. It is shown herein that this treatment comes at the price of causing SD to be fundamentally broken with regard to soft real-time (SRT)-optimality with APA. This result resolves a longstanding open question regarding this matter. It also suggests that Strong APA EDF, which has been proven to be SRT-optimal, is necessary for practical EDF scheduling with APA. However, non-preemptive sections are typically required in practice, and prior work on Strong APA EDF is limited to fully preemptive systems. In this paper, this prior work is extended for the first time to deal with non-preemptivity, which introduces non-trivial nuances with APA. As a byproduct of considering non-preemptivity, it is shown that the SRT-optimality of EDF in this context carries over to a significantly expanded class of schedulers.

The combination of the Internet of Things (IoT) with Serious Games is an academic domain of research increasing in popularity. Combining Serious Games with the interconnected hardware and middleware driven ecosystem of IoT develops data-driven games that source data from the local or extended physical environment to progress in the virtual environment of gaming, better-informing players through the game experience. The following paper presents the evaluation of a software framework defined for combining Serious Games and IoT, achieved using a semester-long experiment with a randomised control trial. The study aimed to produce an effective method of measuring student engagement using sensor-based information and a game environment but not improve the level of student engagement with their related academic programme. The results of the empirical experiment provide perceived evidences in the measure of engagement when compared to academic performance. The experiment results are not statistically significant due to the small sample size and the empirical nature of the work. The findings of this paper validate the effectiveness of a software framework for combining Serious Games and IoT and encourages new real-world applications of Smart Serious Games that include healthcare, education, simulation and others.

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through the re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR-Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates the recruitment of AR to genomic target sites and the inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. In addition, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

Androgen receptor (AR) signaling is the central driver of prostate cancer across disease states. While androgen deprivation therapy (ADT) is effective in the initial treatment of prostate cancer, resistance to ADT or to next-generation androgen pathway inhibitors invariably arises, most commonly through re-activation of the AR axis. Thus, orthogonal approaches to inhibit AR signaling in advanced prostate cancer are essential. Here, via genome-scale CRISPR/Cas9 screening, we identify protein arginine methyltransferase 1 (PRMT1) as a critical mediator of AR expression and signaling. PRMT1 regulates recruitment of AR to genomic target sites and inhibition of PRMT1 impairs AR binding at lineage-specific enhancers, leading to decreased expression of key oncogenes, including AR itself. Additionally, AR-driven prostate cancer cells are uniquely susceptible to combined AR and PRMT1 inhibition. Our findings implicate PRMT1 as a key regulator of AR output and provide a preclinical framework for co-targeting of AR and PRMT1 in advanced prostate cancer.

Sarcomatoid and rhabdoid (S/R) renal cell carcinoma (RCC) are highly aggressive tumors with limited molecular and clinical characterization. Emerging evidence suggests immune checkpoint inhibitors (ICI) are particularly effective for these tumors1–3, although the biological basis for this property is largely unknown. Here, we evaluate multiple clinical trial and real-world cohorts of S/R RCC to characterize their molecular features, clinical outcomes, and immunologic characteristics. We find that S/R RCC tumors harbor distinctive molecular features that may account for their aggressive behavior, including BAP1 mutations, CDKN2A deletions, and increased expression of MYC transcriptional programs. We show that these tumors are highly responsive to ICI and that they exhibit an immune-inflamed phenotype characterized by immune activation, increased cytotoxic immune infiltration, upregulation of antigen presentation machinery genes, and PD-L1 expression. Our findings shed light on the molecular drivers of aggressivity and responsiveness to immune checkpoint inhibitors of S/R RCC tumors.

Translocation renal cell carcinoma (tRCC) is a poorly-characterized subtype of kidney cancer driven by MiT/TFE gene fusions. Here, we define the landmarks of tRCC through an integrative analysis of 152 patients with tRCC identified across genomic, clinical trial, and retrospective cohorts. Most tRCCs harbor few somatic alterations apart from MiT/TFE fusions and homozygous deletions at chromosome 9p21.3 (19.2% of cases). Transcriptionally, tRCCs display a heightened NRF2-driven antioxidant response that is associated with resistance to targeted therapies. Consistently, we find that outcomes for patients with tRCC treated with vascular endothelial growth factor receptor inhibitors (VEGFR-TKI) are worse than those treated with immune checkpoint inhibition (ICI). Using multiparametric immunofluorescence, we find that the tumors are infiltrated with CD8(+) T cells, though the T cells harbor an exhaustion immunophenotype distinct from that of clear cell RCC. Our findings comprehensively define the clinical and molecular features of tRCC and may inspire new therapeutic hypotheses.

Social Internet-of-Things (SIoT) environment comprises not only smart devices but also the humans who interact with these IoT devices. The benefits of such system are overshadowed due to the cyber security issues. A novel approach is required to understand the security implication under such a dynamic environment while taking both the social and technical aspects into consideration. This paper addressed such challenges and proposed a 3-D security modeling platform that can capture and model the security requirements in the SIoT environment. The modeling process is graphical notation based and works as a security extension to the Business Process Model and Notation. Still, it utilizes the latest 3-D game technology; thus, the security extensions are generated through the third dimension. Consequently, the introduction of security extensions will not increase the complexity of the original SIoT scenario, while keeping all the key information on the same platform. Together with the proposed security ontology, these comprehensive security notations created a unique platform that aims at addressing the ever complicated security issues in the SIoT environment.

Efforts towards hosting safety-critical, real-time applications on multicore platforms have been stymied by a problem dubbed the “one-out-of-m” problem: due to excessive analysis pessimism, the overall capacity of an m-core platform can easily be reduced to roughly just one core. The predominant approach for addressing this problem introduces hardware-isolation techniques that ameliorate contention experienced by tasks when accessing shared hardware components, such as DRAM memory or caches. Unfortunately, in work on such techniques, the operating system (OS), which is a key source of potential interference, has been largely ignored. Most real-time OSs do facilitate the use of a coarse-grained partitioning strategy to separate the OS from user-level tasks. However, such a strategy by itself fails to address any data sharing between the OS and tasks, such as when OS services are required for interprocess communication (IPC) or I/O. This paper presents techniques for lessening the impacts of such sharing, specifically in the context of $${\textsf {MC}}^{\textsf {2}}$$ , a hardware-isolation framework designed for mixed-criticality systems. Additionally, it presents the results from micro-benchmark experiments and a large-scale schedulability study conducted to evaluate the efficacy of the proposed techniques and also to elucidate sharing vs. isolation tradeoffs involving the OS. This is the first paper to systematically consider such tradeoffs and consequent impacts of OS-induced sharing on the one-out-of-m problem.

Accurate recognition and effective monitoring of physical activities (PA) in daily life is a goal of many healthcare fields. Existing PA recognition approaches are mostly designed for specific scenarios and often lack extensibility for application in other areas, thereby limiting their usefulness. In this paper, we present a hybrid hierarchical framework that successfully combines two of the main specific-sensor-based PA methods into an effective hybrid solution for general weight exercise applications. The fusion solution separates free weight and non-free weight activities and then further classifies free weight exercises, whilst measuring quantities of repetitions and sets, thus providing a measure of intensity. By fusing accelerometer and electrocardiogram (ECG) data, a One Class Support Vector Machine (OC-SVM) and a Hidden Markov Model (HMM) are applied for exercise recognition and we use semantic inference for determining the intensity of the exercise. The results are based on data from 10 healthy subjects (age: 30 ± 5; BMI: 25 ± 5.5 kg/m^2; body fat: 20.5 ± 5.4), which shows good accuracy in exercise recognition and intensity measurement. This framework can be extended to support additional types of PA recognition in complex applications.

Serious Games and the Internet of Things are research topics of high interest. The integration of these two domains has the potential for innovative new applications. This paper presents a framework for the combination of Serious Games and the Internet of Things. In addition, we present the system architecture for a Smart Serious Game ( SSG ) developed for measuring student engagement, and define the difference between an event driven game and an SSG. This paper also includes the updated data algorithms for representing student engagement as game points, based on further consideration on our previous publication.

Security requirements is the fundamental component in designing and defending IT systems against cyber attacks. Still in reality they are every so often to be overlooked due to the lack of expertise and technical approach to capture and model these requirements in an effective way. It is not helped by the fact that many companies, especially SMEs, tend to focus on the functionality of their business processes first, before considering security as an afterthought. New extensions for modelling cyber security requirements in Business Process Model and Notation (BPMN) have been proposed in the past to address this issue. In this chapter, we analyse existing extensions and identify the notational issues present within each of them. We discuss how there is yet no single extension which represents a comprehensive range of cyber security concepts. Consequently, a new framework is proposed that can be used to extend, visualise and verify cyber security requirements in not only BPMN, but any other existing modelling language. We investigate a new approach to modelling security and propose a solution that overcomes current issues whilst still providing functionality to include all concepts potentially modellable in BPMN related to cyber security. The framework utilises a “what you see is what you get” approach to allow intuitive modelling of rather complicated security concepts. It increases human understanding of the security requirements whilst minimising the cognitive load. We detail how we implemented our solution along with the novel approach our application takes to current challenges.

When hosting real-time applications on multicore platforms, interference from shared hardware resources can significantly increase task execution times. Most proposed approaches for lessening interference rely on mechanisms for providing hardware isolation to tasks. However, one limitation of most prior work on such mechanisms is that only static task systems have been considered that never change at runtime. In reality, safety-critical applications often transition among different functional modes, each defined by a distinct set of running tasks. In a given mode, only tasks from that mode execute, yet tasks from all modes consume memory space, and this creates additional constraints affecting hardware-isolation techniques. This paper shows how to address such constraints in the context of an existing real-time resource-allocation framework called MC2 (mixed-criticality on multicore). In MC2, hardware-isolation techniques are employed in conjunction with criticality-aware task-provisioning assumptions that enable hardware resources to be utilized more efficiently.

Physical activity (PA) measurement is a crucial task in healthcare technology aimed at monitoring the progression and treatment of many chronic diseases. Traditional lifelogging PA measures require relatively high cost and can only be conducted in controlled or semi-controlled environments, though they exhibit remarkable precision of PA monitoring outcomes. Recent advancement of commercial wearable devices and smartphones for recording one’s lifelogging PA has popularized data capture in uncontrolled environments. However, due to diverse life patterns and heterogeneity of connected devices as well as the PA recognition accuracy, lifelogging PA data measured by wearable devices and mobile phones contains much uncertainty thereby limiting their adoption for healthcare studies. To improve the feasibility of PA tracking datasets from commercial wearable/mobile devices, this paper proposes a lifelogging PA intensity pattern decision making approach for lifelong PA measures. The method is to firstly remove some irregular uncertainties (IU) via an Ellipse fitting model, and then construct a series of monthly based hour-day density map images for representing PA intensity patterns with regular uncertainties (RU) on each month. Finally it explores Dempster-Shafer theory of evidence fusing information from these density map images for generating a decision making model of a final personal lifelogging PA intensity pattern. The approach has significantly reduced the uncertainties and incompleteness of datasets from third party devices. Two case studies on a mobile personalized healthcare platform MHA [1] connecting the mobile app Moves are carried out. The results indicate that the proposed approach can improve effectiveness of PA tracking devices or apps for various types of people who frequently use them as a healthcare indicator.

Background Preoperative brain injury is common in neonates with complex congenital heart disease. Increasing evidence suggests a complex interaction of prenatal and postnatal risk factors for development of brain white matter injury, called periventricular leukomalacia (PVL), in neonates with complex congenital heart disease. To date, there remains a limited understanding of the risk factors contributing to preoperative PVL in hypoplastic left heart syndrome (HLHS). Methods Neonates with HLHS or HLHS variants from 3 prospective magnetic resonance imaging studies (2003-2010) were selected for this cohort. Preoperative brain magnetic resonance imaging was performed the morning of the surgery. Stepwise multilogistic regression of patient characteristics, mode of delivery (cesarean section vs vaginal), time of diagnosis (prenatal vs postnatal), HLHS subtypes, brain total maturation score, time to surgery, individual averaged daily preoperative blood gases, and complete blood cell count values was used to determine significant associations. Results A total of 57 neonates with HLHS were born at 38.7 ± 2.3 weeks; 86% (49/57) had a prenatal diagnosis, with 31% (18/57) delivered by cesarean section. HLHS with aortic atresia (AA) was common in this cohort, 71% (41/57). Preoperative PVL was identified in 19% (11/57). Male patients with AA ( P = .004) were at higher risk for PVL. Lower total brain maturation score was also identified as a strong predictor for preoperative PVL ( P = .005). Conclusions In neonates with HLHS, nonmodifiable patient-related factors, including male sex with AA (lack of antegrade blood flow) and lower total brain maturation score, placed neonates at the greatest risk for preoperative white matter injury.

Clinical report A 78-year-old woman had a cardiac resynchronization implantable cardioverter-defibrillator implanted in January 2008 for nonischemic cardiomyopathy with New York Heart Association class III heart failure, left ventricular ejection fraction 22%, and left bundle branch block. A St Jude Medical Model 7121 Durata right ventricular lead (St Jude Medical, St Paul, MN) and a Medtronic Model D224TRK Consulta generator (Medtronic, Minneapolis, MN) were implanted. Three months later, ejection fraction improved to 47% and heart failure improved to class I. In July 2010, a combination of recent short intervals ≤140 ms and rapid, repetitive oversensing triggered the Lead Integrity Alert. Interrogation showed an inappropriate detection of ventricular tachycardia treated with antitachycardia pacing. Stored electrograms showed nonphysiological signals, some of which occurred synchronously with the cardiac cycle, timing with the T wave. Pacing threshold was 1.0 V, the R wave was stable at 10 mV, and both pacing and high-voltage impedances were within nominal ranges. However, the weekly minimum pacing impedance decreased by approximately 150 Ω (from 470 to 320 Ω) in February 2010. Differential real-time and telemetry Holter recordings isolated the nonphysiological signals to the cable to the ring electrode rather than the helix to the tip electrode (Figure 1A). Corresponding recordings from shock channels determined that simultaneous nonphysiological signals were present on the distal coil, but not the proximal coil. Additional diagnostic steps excluded other causes of oversensing. Initially, the patient declined lead replacement. But when frequent oversensing caused the percentage of biventricular pacing to decrease below 90% in late 2012, lead replacement was recommended to preserve resynchronization. Cinefluoroscopy (Figure 1B) showed no exteriorized cables or mechanical lead-lead interaction.

Every so often a paper is published presenting a new extension for modelling cyber security requirements in Business Process Model and Notation (BPMN). The frequent production of new extensions by experts belies the need for a richer and more usable representation of security requirements in BPMN processes. In this paper, we present our work considering an analysis of existing extensions and identify the notational issues present within each of them. We discuss how there is as yet no single extension which represents a comprehensive range of cyber security concepts. Consequently there is no adequate solution for accurately specifying cyber security requirements within BPMN. In order to address this, we investigate a new approach to modelling security and propose a solution which aims to overcome current issues whilst still providing functionality to include all concepts potentially modellable in BPMN related to cyber security. We explain how our solution takes a novel approach to current challenges that is both effective and with adequate coverage of the cyber security domain.

Practical experience is crucial in pharmacy education, but it can be difficult to provide pharmacy students with a sufficient level of experience during their education due to a number of challenges. Video games might provide a platform where students can gain positive learning experience in a virtual environment. Serious games have been used successfully across many industries, which suggest that a well-designed serious game can have positive learning outcomes. Increased engagement and motivation are mentioned by experts as some of the main benefits of serious games. Being able to practise skills before utilising them in real-world scenarios is another advantage identified. In this paper, we present a virtual patient simulator which is designed specifically teaching pharmacy students patient communication and administration of drugs. A pilot study and an expert review were carried out to evaluate the effectiveness of the application and its findings are presented.

(2012). Practising Professionalism: Observations from an Empirical Study of New Australian Lawyers. Legal Ethics: Vol. 15, No. 1, pp. 29-55.

Preliminary results of a pilot study of law students suggest that, during the first year of law study, students may experience changes in thinking styles, stress levels, and satisfaction with life. Although further inquiry into the cause of law student distress is necessary, the authors consider certain assumptions underlying the legal curriculum—particularly the conception of a lawyer as adversarial, emotionally detached, and competitive—to be possible sources of the negative impact on student wellbeing. It is suggested that legal educators should re-examine their curricula, particularly their conception of what it means to be a lawyer, and think creatively about ways that law schools may encourage healthier approaches to the study of law.

One of the advantages of farmed salmon is the consistent nature of the product and its availability. Because of the remote locations of salmon farms in British Columbia (BC), Canada, providing the freshest salmon products on a daily basis and in a cost-effective manner requires regular transport of live, market-sized adult fish at very high densities from farm sites to processing plants. Live-hauling also occurs annually when salmon smolts are moved to the farms from freshwater hatcheries and when fish are moved among farms. This article has two parts. The first part considers recent published works assessing Atlantic salmon, Salmo salar, welfare during live-haul transport between commercial aquaculture sites in BC, Canada, trips that can last for 2-12 h. These assessments involved novel methodologies, which are highlighted here. The results show that while juvenile and adult Atlantic salmon are stressed during loading into a live-haul vessel, open-hold transport in a state-of-the-art vessel promotes fish recovery, thereby alleviating some of the concerns regarding fish welfare during high-density transport. The second part of the article presents novel unpublished data on the effects on the flesh quality of Atlantic salmon of high carbon dioxide concentrations, levels that simulate those that might be encountered during closed-hold transport.

Many applications optimistically claim the title of virtual campus tour nowadays with a small minority deserving it. Throughout this paper various virtual campus tours are explored and analysed along with the problems of interior navigation. The technologies that support development of virtual worlds for computer games are studied and a solution to interior navigation and virtual campus tour derived from this technology is proposed.

Visual impairments define a wide spectrum of disabilities that vary in severity, from the need to wear glasses, to permanent loss of vision or blindness. This paper discusses the process undertaken in creating two simulators, one which emulates partially-sighted visual impairment and another focused on full -blindness. In order to create the simulators, extensive research was conducted surrounding the effects of partially-sightedness and blindness, highlighting existing software and games that promote awareness for visual impairments. This paper underlines the necessity of raising awareness for visual impairments and the effectiveness of applying serious games for this very goal. After developing the simulators, experiments were conducted to evaluate the effectiveness of it. Findings from the experiments were analysed and documented.

Travel can be an enjoyable experience but it can also be stressful when one is unable to get to the destination in timely manner. Satellite navigation systems (satnav) such as the ubiquitous Global Positioning System (GPS) provide an aid to locating unfamiliar places without hassle. However, the effectiveness of satnav stops at the doorstep of the building due to its requirement for line of sight with orbiting satellites. Within a large complex building, navigation typically relies on building signage, information from kiosks and getting assistance from information desks. The advancement of mobile devices and wireless technology offer an interesting proposition for the development of indoor positioning systems. In this paper, we propose a passive indoor positioning system to provide navigational aid and discuss findings from our pilot experiment using NFC technology.

Every so often a paper is published presenting a new extension for modelling cyber security requirements in Business Process Model and Notation (BPMN). The frequent production of new extensions by experts belies the need for a richer and more expressive representation of security requirements in BPMN processes. One reason for this is that current extensions focus on only specific areas and so fail to provide adequate coverage of the cyber security domain. In this paper, we present our work considering an analysis of existing extensions and identify the security concepts used within each of them. We discuss how there is as yet no single extension which covers a comprehensive range of cyber security concepts. Consequently there is no adequate solution for accurately specifying cyber security requirements within BPMN. In order to address this, we propose a new comprehensive ontology which includes all concepts potentially modellable in BPMN related to cyber security. We explain how this ontology can be used as the basis for developing future BPMN-security extensions, and explore the challenges that must be overcome in order to develop a representation that is both effective and with adequate coverage of security requirements.

Play has been an informal approach to teach young ones the skills of survival for centuries. With advancements in computing technology, many researchers believe that computer games1 can be used as a viable teaching and learning tool to enhance a student’s learning. It is important that the educational content of these games is well designed with meaningful game-play based on pedagogically sound theories to ensure constructive learning. This chapter features theoretical aspects of game design from a pedagogical perspective. It serves as a useful guide for educational game designers to design better educational games for use in game-based learning. The chapter provides a brief overview of educational games and game-based learning before highlighting theories of learning that are relevant to educational games. Selected theories of learning are then integrated into conventional game design practices to produce a set of guidelines for educational games design.

To understand the role of Ras-MAPK (mitogen-activated protein kinase) in trophic factor withdrawal- and oxidative stress-induced apoptotic cell death processes, undifferentiated rat pheochromocytoma PC12 cells and a PC12 variant cell line stably expressing the Ras dominant-negative mutant (M-M17-26) were subjected to serum withdrawal in the absence or presence of H2O2 treatment. The extent of cell death was analyzed by lactate dehydrogenase release, internucleosomal DNA fragmentation, and caspase-3 assays. Both serum with-drawal and H2O2 treatment induced apoptotic cell death in PC12 cells, and the extent of cell death was greatly enhanced in M-M17-26 cells. DNA fragmentation induced by serum withdrawal or H2O2 treatment was blocked completely by a general caspase inhibitor, Z-VAD-FMK. A selective MAPK kinase inhibitor, U0126, blocked the H2O2-induced phosphorylation of Erk1/2 (extracellular signal-regulated kinase) in PC12 cells and increased the levels of active caspase-3 in M-M17-26 under serum withdrawal or H2O2 treatment. In addition, the short-term H2O2 treatment (5–30 min) was sufficient to cause DNA fragmentation in M-M17-26 cells even though H2O2 was removed and cells were incubated in regular growth medium with complete serum for 24 h. However, similar, short-term H2O2 treatment of PC12 cells did not induce DNA fragmentation 24 h later. These results suggest that the Ras-Erk pathway is critical in mediating protection against apoptotic cell death induced by either trophic factor withdrawal or increased oxidative stress.

Surveys of students in the Australian National University’s Legal Workshop Professional Legal Education (PLE) programme showed that students began and ended a core course with low levels of psychological distress. In contrast to other studies, we found no evidence of elevated symptoms of depressive symptoms and no signs that this PLE programme may impair wellbeing. While small increases in average stress symptoms were observed, this was associated with a more positive course experience. Self-perceptions of professional identity and concurrent legal employment predicted lower distress, suggesting that wellbeing is enhanced by building meaningful connections between legal education and students’ wider identities.

The cervical mucus penetration tests aid research and determine the clinical importance of positive sperm antibody tests. Limited availability and variability of human cervical mucus have instigated the search for mucus substitutes for these tests. This study compares sperm migration in cervical mucus with that in artificial media including hyaluronate solution, egg white and albumin Tyrode solution. Results were quantified by measuring the migration distance (the maximum distance of capillary migration from a semen reservoir by spermatozoa after 1 h) and the sperm concentration at half the migration distance. The mean of both measures for cervical mucus and hyaluronate solution were equivalent [4.4 +/- 1.1 (SD) versus 4.3 +/- 1.0 cm and 118 +/- 51 versus 111 +/- 44x10(3)/ml], and higher than in egg white and albumin Tyrode solution. Antisperm antibodies impaired sperm penetration in cervical mucus and hyaluronate solution in a similar manner (r = 0.92). These results suggest that hyaluronate solution sufficiently resembles human cervical mucus in terms of penetrability that it may be used as a substitute for mucus in capillary tube tests of sperm function. The higher penetrability of cervical mucus and hyaluronate solution is probably related to a channelling effect due to their polymeric structure.

Computer games is a form of real-time interactive software wrapped in creatively crafted media that offers game-players engaging, goal-directed play. Designing computer games requires adequate experience and great attention to detail to describe the rules, play and aesthetics that compose the interactive experience. For inexperienced game designers, formalised methods such as game design languages and game meta-models can provide a guide and language to produce a game design specification correct by design. This paper introduces a new game content model that can aid game designers document specification of game design.

Computer games, predominantly a form of interactive entertainment, have been repurposed for game-based learning in recent years. Many studies have presented the educational value that computer games possess with evidence that supports the positive experiences of game-based learning. Game-based learning could be an invaluable learning approach for the 21st century, but is currently hindered by the lack of availability of serious games to support this innovative approach. Developments in software engineering that enable automatic generation of software artefacts through modelling promises new hope for game-based learning adopters, especially those with little or no technical knowledge, to produce their own serious games for use in game-based learning. This paper presents a new framework based on a model-driven approach designed to aid non-technical domain experts in the production of serious games.