iPSC-Cardiomyocyte Models of Brugada Syndrome—Achievements,Challenges and Future Perspectives

Brugada syndrome (BrS) is an inherited cardiac arrhythmia that predisposes to ventricular fibrillation and sudden cardiac death. It originates from oligogenic alterations that affect cardiac ion channels or their accessory proteins. The main hurdle for the study of the functional effects of those variants is the need for a specific model that mimics the complex environment of human cardiomyocytes. Traditionally, animal models or transient heterologous expression systems are applied for electrophysiological investigations, each of these models having their limitations. The ability to create induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs), providing a source of human patient-specific cells, offers new opportunities in the field of cardiac disease modelling. Contemporary iPSC-CMs constitute the best possible in vitro model to study complex cardiac arrhythmia syndromes such as BrS. To date, thirteen reports on iPSC-CM models for BrS have been published and with this review we provide an overview of the current findings, with a focus on the electrophysiological parameters. We also discuss the methods that are used for cell derivation and data acquisition. In the end, we critically evaluate the knowledge gained by the use of these iPSC-CM models and discuss challenges and future perspectives for iPSC-CMs in the study of BrS and other arrhythmias.     

Vehicle routing concepts in the closed-loop container network of ARN—a case study

In this paper we discuss a real-life case study to optimize the logistics network for the collection of containers from end-of-life vehicle dismantlers in the Netherlands. Advanced planning concepts, such as dynamic assignment of dismantlers to logistic service providers, are analyzed using a simulation model. Based on this model, we periodically solve a vehicle routing problem to gain insight into the long-term performance of the system. The vehicle routing problem considered is a multi-depot pickup and delivery problem with alternative delivery locations. A special characteristic of the problem is the limited vehicle capacity of two containers. We solve this problem with a heuristic based on route generation and set partitioning.     

Tapping into past design experiences: knowledge sharing and creation during novice–expert design consultations

Designing is a knowledge-intensive activity. For novice design engineers, an important means of acquiring knowledge is to consult experienced colleagues. We observed novice?Cexpert consultations as part of three engineering projects in a large aerospace company. Seven meetings were analysed in detail regarding the design activity, the content, and the form of interaction. Although the meetings were initiated for the purpose of information seeking, this process amounted to only 8% of the time compared to knowledge creation between novices and experts (47% of meeting time), and contextual information sharing (45% of meeting time). Both experts and novices were found to contribute equally and interactively to the discussion and analysis of solutions. The analysis showed how the processes alternated in the meetings. We identified tentative patterns on how these consultation processes change over the course of the design process phases. The micro-level analysis of the design activities and form of interaction provided a deeper understanding of how the consultation processes are discursively produced by the experts and novices. Finally, implications for design engineering practitioners are derived and suggestions for further research are provided.     

Stability of size-based scheduling disciplines in resource-sharing networks

Size-based scheduling strategies such as Shortest Remaining Processing Time first (SRPT) and Least Attained Service first (LAS) provide popular mechanisms for improving the overall delay performance by favoring smaller service requests over larger ones. The performance gains from these disciplines have been thoroughly investigated for single-server systems, and have also been experimentally demonstrated in web servers for example. In the present paper we explore the fundamental stability properties of size-based scheduling strategies in multi-resource systems, such as bandwidth-sharing networks, where users require service from several shared resources simultaneously. In particular, we establish the exact stability conditions for the SRPT and LAS disciplines in various limiting regimes. The results indicate that size-based scheduling strategies may fail to use the available resources efficiently, and in fact cause instability effects, even at arbitrarily low traffic loads, and will therefore not yield optimal delay performance. The qualitative findings confirm the tendency for users with long routes and large service requirements to experience severe performance degradation.     

Evaluating knowledge and capacity development in the water sector: challenges and progress

As knowledge and capacity development (KCD) is increasingly acknowledged as crucial for development, the need to evaluate its impact increases, too. However, evaluating KCD in practice remains a challenge. This article aims to synthesize the current wisdom on the topic of KCD evaluation in the water sector. We discuss two leading approaches to KCD (positivist and complex adaptive systems) and their associated evaluation paradigms, the major methodological challenges facing KCD evaluation, and progress made in that respect. The article provides insights for KCD practitioners and policy makers in the water sector that can help them improve their KCD evaluation practice.     

Immunological Properties of Inulin-Type Fructans

Beneficial effects of inulin-type fructans are discussed in view of studies that applied the oligosaccharides in colon cancer, chronic inflammatory diseases, vaccination efficacy, and prevention of infection and allergy. In the present paper, we discuss their immunomodulating effects. It is suggested that immunomodulation is elicited through indirect and direct mechanisms. Indirect mechanisms encompass stimulation of growth and activity of lactic acid bacteria, but can also be caused by fermentation products of these bacteria, i.e., short chain fatty acids. Evidence for direct effects on the immune system generally remains to be confirmed. It is suggested that inulin-type fructans can be detected by gut dendritic cells (DCs), through receptor ligation of pathogen recognition receptors (PRRs) such as Toll-like receptors, nucleotide oligomerization domain containing proteins (NODs), C-type lectin receptors, and galectins, eventually inducing pro- and anti-inflammatory cytokines. DCs may also exert antigen presenting capacity toward effector cells, such as B cells, T cells, and natural killer cells locally, or in the spleen. Inulin-type fructans may also ligate PRRs expressed on gut epithelium, which could influence its barrier function. Inulin-type fructans are potent immunomodulating food components that hold many promises for prevention of disease. However, more studies into the mechanisms, dose-effect relations, and structure-function studies are required.     

On operator effectiveness: the role of expertise and familiarity of environment on the detection of deviant behaviour

This paper examines factors contributing to the effectiveness of camera operators in urban camera surveillance. The use of camera surveillance has taken an enormous flight in the past decades. Despite this increase, its effectiveness is strongly debated. One reason for the disputed effectiveness may be that an understanding of how to use camera surveillance, including elements contributing to the effectiveness of camera operators, has not kept track with technological developments. This paper focuses on the role of expertise and familiarity with the environment on the effectiveness of camera operators to detect offenders in video footage from Rotterdam City Surveillance in the Netherlands. Results show no effect of expertise, but do show that familiarity with the location contributes to operator effectiveness and that camera operators seem to use different criteria for detecting and selecting suspects depending on the familiarity with the location. These results contribute to our understanding of operator effectiveness and offer guidelines for the training of camera operators. Implications are discussed.     

Jasmonic Acid-Induced Changes in <Emphasis Type="BoldItalic">Brassica oleracea</Emphasis> Affect Oviposition Preference of Two Specialist Herbivores

Jasmonic acid (JA) is a key hormone involved in plant defense responses. The effect of JA treatment of cabbage plants on their acceptability for oviposition by two species of cabbage white butterflies, Pieris rapae and P. brassicae, was investigated. Both butterfly species laid fewer eggs on leaves of JA-treated plants compared to control plants. We show that this is due to processes in the plant after JA treatment rather than an effect of JA itself. The oviposition preference for control plants is adaptive, as development time from larval hatch until pupation of P. rapae caterpillars was longer on JA-treated plants. Total glucosinolate content in leaf surface extracts was similar for control and treated plants; however, two of the five glucosinolates were present in lower amounts in leaf surface extracts of JA-treated plants. When the butterflies were offered a choice between the purified glucosinolate fraction isolated from leaf surface extracts of JA-treated plants and that from control plants, they did not discriminate. Changes in leaf surface glucosinolate profile, therefore, do not seem to explain the change in oviposition preference of the butterflies after JA treatment, suggesting that as yet unknown infochemicals are involved.     

Au-Sn SLID Bonding: A Reliable HT Interconnect and Die Attach Technology

Au-Sn solid–liquid interdiffusion (SLID) bonding is an established reliable high temperature (HT) die attach and interconnect technology. This article presents the life cycle of an optimized HT Au-Sn SLID bond, from fabrication, via thermal treatment, to mechanical rupture. The layered structure of a strong and uniform virgin bond was identified by X-ray diffraction to be Au/ζ (Au_0.85Sn_0.15)/Au. During HT exposure, it was transformed to Au/β (Au_1.8Sn_0.2)/Au. After HT exposure, the die shear strength was reduced by 50 pct, from 14 Pa to 70 MPa, which is still remarkably high. Fractographic studies revealed a change in fracture mode; it was changed from a combination of adhesive Au/Ni and cohesive SiC fracture to a cohesive β-phase fracture. Design rules for high quality Au-Sn SLID bonds are given.     

Automated Legal Decision Systems in Practice: The Mirror of Reality

Automated decision systems are often used to enforce legislation.As such, they have considerable regulating effects. These systemsregulate the behaviour of users and addressees mainly throughstandardization. This research classifies these systems intocategories according to which the regulating effects can bedescribed more clearly. Furthermore, this categorization resultsin a better understanding how problems encountered with atpresent can be avoided in the future. Many problems result fromthe way the development process has been organized. It turns outthe development process can be divided according to the time thesystems are developed with regard to the legislation they aim toenforce. Present procedures lack good monitoring of thedevelopment process. To this end, legal procedures are needed toensure that a legally correct product will be made, partiesinvolved should change their tune, system developers should bemore concerned with the legal status of the system and thelegislator should be actively involved in the development of thesystem. Moreover, an ex ante-evaluation should notice thepossible regulating effects caused by the system to ensure acorrect balance of the pros and cons. It should be ensured thatthese systems are effectively put to control. Transparency isindispensable.