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.     

The fate of nitrogen in agroecosystems: An illustration using Canadian estimates

Agroecosystems rely on inputs of nitrogen (N) to sustain productivity. But added N can leak into adjacent environments, affecting the health of other ecosystems and their inhabitants. Worries about global warming have cast further attention on the N cycle in farmlands because farms are a main source of N₂O, and because carbon sequestration, proposed to help reduce CO₂ loads, requires a build-up of N. Our objective was to estimate, as an illustrative example, the net N balance of Canadian agroecosystems in 1996 and then infer some hypotheses about the routes of N loss, their magnitude, and ways of reducing them. We defined agroecosystems as all agricultural lands in Canada including soil to 1 m depth and all biota, except humans. Only net flows of N across those boundaries were counted in our balance – all others represent internal cycling. Based on our estimates, about 2.35 Tg N entered Canadian agroecosystems from biological fixation, fertilizers, and atmospheric deposition (excluding re-deposited NH₃). In the same year, about 1.03 Tg N were exported in crop products and 0.19 Tg were exported in animals and animal products. Consequently, N inputs exceed exports in products by about 1.13 Tg, a surplus that is either accumulating in agroecosystems or lost to the environment. Because potential soil organic matter gains can account for only a small part of the surplus N, most is probably lost to air or groundwater. Our finding, that N losses amount to almost half of N added, concurs with field experiments that show crop recovery of added N in a given year is often not more than 60%. Better management may reduce the fraction lost somewhat but, because N in ecosystems eventually cycles back to N₂, substantive gains in efficiency may not come easily. As well as trying to reduce losses, research might also focus on steering losses directly to N₂, away from more harmful intermediates. If some of the `missing N' can be assimilated into organic matter, agricultural soils in Canada may need little added N to achieve C sequestration targets.     

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.     

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.