The new Dutch timetable: The OR revolution

In December 2006, Netherlands Railways introduced a completely new timetable. Its objective was to facilitate the growth of passenger and freight transport on a highly utilized railway network, and improve the robustness of the timetable resulting in less train delays in the operation. Further adjusting the existing timetable constructed in 1970 was not option anymore, because further growth would then require significant investments in the rail infrastructure. Constructing a railway timetable from scratch for about 5,500 daily trains was a complex problem. To support this process, we generated several timetables using sophisticated operations research techniques, and finally selected and implemented one of these timetables. Furthermore, because rolling-stock and crew costs are principal components of the cost of a passenger railway operator, we used innovative operations research tools to devise efficient schedules for these two resources. The new resource schedules and the increased number of passengers resulted in an additional annual profit of 40 million euros ($60 million) of which about 10 million euros were created by additional revenues. We expect this to increase to 70 million euros ($105 million) annually in the coming years. However, the benefits of the new timetable for the Dutch society as a whole are much greater: more trains are transporting more passengers on the same railway infrastructure, and these trains are arriving and departing on schedule more than they ever have in the past. In addition, the rail transport system will be able to handle future transportation demand growth and thus allow cities to remain accessible. Therefore, people can switch from car transport to rail transport, which will reduce the emission of greenhouse gases.

A nonsense mutation in B3GALNT2 is concordant with hydrocephalus in Friesian horses

Background: Hydrocephalus in Friesian horses is a developmental disorder that often results in stillbirth of affected foals and dystocia in dams. The occurrence is probably related to a founder effect and inbreeding in the population. The aim of our study was to find genomic associations, to investigate the mode of inheritance, to allow a DNA test for hydrocephalus in Friesian horses to be developed. In case of a monogenic inheritance we aimed to identify the causal mutation. Results: A genome-wide association study of hydrocephalus in 13 cases and 69 controls using 29,720 SNPs indicated the involvement of a region on ECA1 (P T corresponding to XP_001491595 p.Gln475* was identical to a B3GALNT2 mutation identified in a human case of muscular dystrophy-dystroglycanopathy with hydrocephalus. All 16 available cases and none of the controls were homozygous for the mutation, and all 17 obligate carriers (= dams of cases) were heterozygous. A random sample of the Friesian horse population (n = 865) was tested for the mutation in a commercial laboratory. One-hundred and forty-seven horses were carrier and 718 horses were homozygous for the normal allele; the estimated allele frequency in the Friesian horse population is 0.085. Conclusions: Hydrocephalus in Friesian horses has an autosomal recessive mode of inheritance. A nonsense mutation XM_001491545 c.1423C>T corresponding to XP_001491595 p.Gln475* in B3GALNT2 (1: 75,859,296-75,909,376) is concordant with hydrocephalus in Friesian horses. Application of a DNA test in the breeding programme will reduce the losses caused by hydrocephalus in the Friesian horse population

Dwarfism with joint laxity in Friesian horses is associated with a splice site mutation in B4GALT7

Background: Inbreeding and population bottlenecks in the ancestry of Friesian horses has led to health issues such as dwarfism. The limbs of dwarfs are short and the ribs are protruding inwards at the costochondral junction, while the head and back appear normal. A striking feature of the condition is the flexor tendon laxity that leads to hyperextension of the fetlock joints. The growth plates of dwarfs display disorganized and thickened chondrocyte columns. The aim of this study was to identify the gene defect that causes the recessively inherited trait in Friesian horses to understand the disease process at the molecular level. Results: We have localized the genetic cause of the dwarfism phenotype by a genome wide approach to a 3 Mb region on the p-arm of equine chromosome 14. The DNA of two dwarfs and one control Friesian horse was sequenced completely and we identified the missense mutation ECA14:g.4535550C> T that cosegregated with the phenotype in all Friesians analyzed. The mutation leads to the amino acid substitution p.(Arg17Lys) of xylosylprotein beta 1,4-galactosyltransferase 7 encoded by B4GALT7. The protein is one of the enzymes that synthesize the tetrasaccharide linker between protein and glycosaminoglycan moieties of proteoglycans of the extracellular matrix. The mutation not only affects a conserved arginine codon but also the last nucleotide of the first exon of the gene and we show that it impedes splicing of the primary transcript in cultured fibroblasts from a heterozygous horse. As a result, the level of B4GALT7 mRNA in fibroblasts from a dwarf is only 2 % compared to normal levels. Mutations in B4GALT7 in humans are associated with Ehlers-Danlos syndrome progeroid type 1 and Larsen of Reunion Island syndrome. Growth retardation and ligamentous laxity are common manifestations of these syndromes. Conclusions: We suggest that the identified mutation of equine B4GALT7 leads to the typical dwarfism phenotype in Friesian horses due to deficient splicing of transcripts of the gene. The mutated gene implicates the extracellular matrix in the regular organization of chrondrocyte columns of the growth plate. Conservation of individual amino acids may not be necessary at the protein level but instead may reflect underlying conservation of nucleotide sequence that are required for efficient splicing

Can self-reported disability assessment behaviour of insurance physicians be explained? Applying the ASE model

<p>Abstract</p> <p>Background</p> <p>Very little is known about the attitudes and views that might underlie and explain the variation in occupational disability assessment behaviour between insurance physicians. In an earlier study we presented an adjusted ASE model (Attitude, Social norm, Self-efficacy) to identify the determinants of the disability assessment behaviour among insurance physicians. The research question of this study is how Attitude, Social norm, Self-efficacy and Intention shape the behaviour that insurance physicians themselves report with regard to the process (Behaviour: process) and content of the assessment (Behaviour: assessment) while taking account of Knowledge and Barriers.</p> <p>Methods</p> <p>This study was based on 231 questionnaires filled in by insurance physicians, resulting into 48 scales and dimension scores. The number of variables was reduced by a separate estimation of each of the theoretical ASE constructs as a latent variable in a measurement model. The saved factor scores of these latent variables were treated as observed variables when we estimated a path model with Lisrel to confirm the ASE model. We estimated latent ASE constructs for most of the assigned scales and dimensions. All could be described and interpreted. We used these constructs to build a path model that showed a good fit.</p> <p>Results</p> <p>Contrary to our initial expectations, we did not find direct effects for Attitude on Intention and for Intention on self reported assessment behaviour in the model. This may well have been due to the operationalization of the concept of 'Intention'. We did, however, find that Attitude had a positive direct effect on Behaviour: process and Behaviour: Assessment and that Intention had a negative direct effect on Behaviour: process.</p> <p>Conclusion</p> <p>A path model pointed to the existence of relationships between Attitude on the one hand and self-reported behaviour by insurance physicians with regard to process and content of occupational disability assessments on the other hand. In addition, Intention was only related to the self reported behaviour with regard to the process of occupational disability assessments. These findings provide some evidence of the relevance of the ASE model in this setting. Further research is needed to determine whether the ASE variables measured for insurance physicians are related to the real practice outcomes of occupational disability assessments.</p

Combining ecosystem modeling with serious gaming in support of transboundary maritime spatial planning

The Maritime Spatial Planning (MSP) Challenge simulation platform helps planners and stakeholders understand and manage the complexity of MSP. In the interactive simulation, different data layers covering an entire sea region can be viewed to make an assessment of the current status. Users can create scenarios for future uses of the marine space over a period of several decades. Changes in energy infrastructure, shipping, and the marine environment are then simulated, and the effects are visualized using indicators and heat maps. The platform is built with advanced game technology and uses aspects of role-play to create interactive sessions; it can thus be referred to as serious gaming. To calculate and visualize the effects of planning decisions on the marine ecology, we integrated the Ecopath with Ecosim (EwE) food web modeling approach into the platform. We demonstrate how EwE was connected to MSP, considering the range of constraints imposed by running scientific software in interactive serious gaming sessions while still providing cascading ecological feedback in response to planning actions. We explored the connection by adapting two published ecological models for use in MSP sessions. We conclude with lessons learned and identify future developments of the simulation platform

Large-scale production of LGR5-positive bipotential human liver stem cells

Background and Aims: The gap between patients on transplant waiting lists and available donor organs is steadily increasing. Human organoids derived from leucine‐rich repeat‐containing G protein‐coupled receptor 5 (LGR5)–positive adult stem cells represent an exciting new cell source for liver regeneration; however, culturing large numbers of organoids with current protocols is tedious and the level of hepatic differentiation is limited. Approach and Results: Here, we established a method for the expansion of large quantities of human liver organoids in spinner flasks. Due to improved oxygenation in the spinner flasks, organoids rapidly proliferated and reached an average 40‐fold cell expansion after 2 weeks, compared with 6‐fold expansion in static cultures. The organoids repopulated decellularized liver discs and formed liver‐like tissue. After differentiation in spinner flasks, mature hepatocyte markers were highly up‐regulated compared with static organoid cultures, and cytochrome p450 activity reached levels equivalent to hepatocytes. Conclusions: We established a highly efficient method for culturing large numbers of LGR5‐positive stem cells in the form of organoids, which paves the way for the application of organoids for tissue engineering and liver transplantation

Rates of agonism among female primates: a cross-taxon perspective

Agonism is common in group-living animals, shaping dominance relationships and ultimately impacting individual tness. Rates of agonism vary considerably among taxa, however, and explaining this variation has been central in ecological models of female social relationships in primates. Early iterations of these models posited a link to diet, with more frequent agonism predicted in frugivorous species due to the presumed greater contestability of fruits relative to other food types. Although some more recent studies have suggested that dietary categories may be poor predictors of contest competition among primates, to date there have been no broad, cross-taxa comparisons of rates of female–female agonism in relation to diet. This study tests whether dietary variables do indeed pre- dict rates of female agonism and further investigates the role of group size (i.e., number of competitors) and substrate use (i.e., degree of arboreality) on the frequency of agonism. Data from 44 wild, unprovisioned groups, including 3 strepsirhine species, 3 platyrrhines, 5 colobines, 10 cercopithecines, and 2 hominoids were analyzed using phylogenetically controlled and uncontrolled methods. Results indicate that diet does not predict agonistic rates, with trends actually being in the opposite direction than predicted for all taxa except cercopithecines. In contrast, agonistic rates are positively associated with group size and possibly degree of terrestriality. Competitor density and perhaps the risk of ghting, thus, appear more important than general diet in predicting agonism among female primates. We discuss the implications of these results for socio-ecological hypotheses

Targeting lipid metabolism as a new therapeutic strategy for inherited cardiomyopathies

Inherited cardiomyopathies caused by pathological genetic variants include multiple subtypes of heart disease. Advances in next-generation sequencing (NGS) techniques have allowed for the identification of numerous genetic variants as pathological variants. However, the disease penetrance varies among mutated genes. Some can be associated with more than one disease subtype, leading to a complex genotype-phenotype relationship in inherited cardiomyopathies. Previous studies have demonstrated disrupted metabolism in inherited cardiomyopathies and the importance of metabolic adaptations in disease onset and progression. In addition, genotype- and phenotype-specific metabolic alterations, especially in lipid metabolism, have been revealed. In this mini-review, we describe the metabolic changes that are associated with dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM), which account for the largest proportion of inherited cardiomyopathies. We also summarize the affected expression of genes involved in fatty acid oxidation (FAO) in DCM and HCM, highlighting the potential of PPARA-targeting drugs as FAO modulators in treating patients with inherited cardiomyopathies