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.     

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.     

Kinetic and immunohistochemical characteristics of mitogen-induced cutaneous hypersensitivity in chickens selected for antibody responsiveness

Mitogen-induced cutaneous hypersensitivity was evaluated in chickens selected for high and low antibody responses to SRBC, and in a random bred control line. Wing web swelling responses were found after subcutaneous administration of phytohemagglutinin (PHA), concanavalin A (Con A), pokeweed mitogen (PWM), and Escherichia coli lipopolysaccharide (LPS), respectively, in all three lines. All mitogens induced significant acute 4 h wing web swelling responses, followed by a significant (classical) late 24 h wing web swelling response. The 4 h responses were significantly lower in the L line, whereas a tendency for lower responses at 24 h in the L line was found as well. Immunohistochemical evaluation of the early and late wing web swelling responses revealed extravascular localisation of leukocytes at 24 h after sensitization with mitogens, which consisted of CD4+ cells, CD8+ cells, TCR-1+ cells, and heterophils, but no B cells, whereas the 4 h swelling response was primarily characterized by oedema. Cutaneous hypersensitivity either initiated by T-cell mitogens as well as B-cell mitogens may depend for an important part on the rapid induction of local homing of lymphocytes towards the sensitizing agent, which may be mediated by an acute local expression of molecules with chemo-attractive capacities. Interpretation of cellular immunity responses in vivo such as delayed-type hypersensitivity should therefore incorporate oedema-initiating characteristics of sensitizing agents. The relationship between the magnitude of cutaneous hypersensitivity to mitogens and selection for antibody responsiveness is discussed.     

Low molecular weight Cooperia oncophora antigens. Potential to discriminate between susceptible and resistant calves after infection

The recognition of low molecular weight proteins by sera obtained during a single oral (primary) infection with 100,000 3rd-stage Cooperia oncophora larvae was studied in calves. Three groups of 6 or 7 calves were selected based on different egg excretion patterns. SDS-gel electrophoresis of adult Cooperia antigen under reducing conditions, followed by Western blotting, revealed that resistance of individual calves to C. oncophora might be related with antibody responses (42 days post infection) against at least 2 protein fragments (14-16 kDa and 27 kDa). The 14-16-kDa protein complex was bound, to some extent, by individual sera from all calves. The intensity of staining was negatively correlated with egg excretion on Day 42 p.i. Calves with high egg counts on Day 21 p.i. either did not or only weakly recognized the 27-kDa band. It has to be established whether the 14-16 kDa (or recombinant 14.2 kDa) provides a tool for immunodiagnostics and whether the 27-kDa fragment can help further unravel immune-mediated resistance to Cooperia.     

Development of thick wall 2.25Cr-1MoNiNb steel forgings for steam generators of fast breeder reactors

The large and thick forgings made of 2.25Cr-1MoNiNb steel are required for vessel material of steam generator (SG) of the fast breeder reactor SNR 300.In order to study the feasibility of 2.25Cr-1MoNiNb steel heavy section forging, chemical composition, melting practice and ingot making, hot working and heat treatment conditions were investigated. The following recommendations were derived: (1) 0.04% C, 0.10% ΔNb, (2) application of electro-slag remelting process, (3) grain refining by hot working, (4) two-step austenitizing at 1020°C.Based on these recommendations, the actual products such as hollow cylinders with maximum 290 mm thickness, solid bars with 420 mm diameter and forged plates with maximum 185 mm thickness could be supplied for application in the helical coiled SG of the SNR 300. Statistical analysis of the products showed the sufficient and isotropic material properties, which fulfill the requirements of the basic safety rules.     

Discrimination of nylon polymers using attenuated total reflection mid-infrared spectra and multivariate statistical techniques

Nylons are an important class of synthetic polymers, from an industrial, as well as forensic, perspective. A spectroscopic method, such as Fourier transform infrared (FT-IR) spectroscopy, is necessary to determine the nylon subclasses (e. g., nylon 6 or nylon 6,6). Library searching using absolute difference and absolute derivative difference algorithms gives inconsistent results for identifying nylon subclasses. The objective of this study was to evaluate the usefulness of peak ratio analysis and multivariate statistics for the identification of nylon subclasses using attenuated total reflection (ATR) spectral data. Many nylon subclasses could not be distinguished by the peak ratio of the N-H vibrational stretch to the sp(3) C-H(2) vibrational stretch intensities. Linear discriminant analysis, however, provided a graphical visualization of differences between nylon subclasses and was able to correctly classify a set of 270 spectra from eight different subclasses with 98.5% cross-validated accuracy.