Waartoe wetenschap?

Sinds de Verlichting hebben volkeren met moderne wetenschap grotere overlevingskansen dan volkeren zonder, zodat in korte tijd vrijwel alle volkeren over de hele wereld zich bedienen van wetenschappelijk onderwijs en onderzoek. Zo spreken we thans niet alleen van een kenniseconomie, maar ook van een kennissamenleving. Waar het ook en vooral om zou moeten gaan, is dat het creatieeve moment in de wetenschap, dat nieuwe inzichten in natuur en cultuur bijdragen tot onze veerkracht, tot duurzame ontwikkeling, tot overleven. In Waartoe Wetenschap? onderzoekt Frans W. Saris de wetenschap in evolutionair perspectief en hij bepleit een radical enlightenment in een dertiental essays en een toneeltekst waarin zulke uiteenlopende wetenschappers verschijnen als Francis Bacon, Kamerlingh Onnes, Albert Einstein, Charles Darwin, Spinoza en Niko Tinbergen, maar ook de schrijvers Franz Kafka, Michael Frayn en Harry Mulisch

Prorenin accumulation and activation in human endothelial cells: importance of mannose 6-phosphate receptors

ACE inhibitors improve endothelial dysfunction, possibly by blocking endothelial angiotensin production. Prorenin, through its binding and activation by endothelial mannose 6-phosphate (M6P) receptors, may contribute to this production. Here, we investigated this possibility as well as prorenin activation kinetics, the nature of the prorenin-activating enzyme, and M6P receptor-independent prorenin binding. Human umbilical vein endothelial cells (HUVECs) were incubated with wild-type prorenin, K/A-2 prorenin (in which Lys42 is mutated to Ala, thereby preventing cleavage by known proteases), M6P-free prorenin, and nonglycosylated prorenin, with or without M6P, protease inhibitors, or angiotensinogen. HUVECs bound only M6P-containing prorenin (K(d) 0.9+/-0.1 nmol/L, maximum number of binding sites [B(max)] 1010+/-50 receptors/cell). At 37 degrees C, because of M6P receptor recycling, the amount of prorenin internalized via M6P receptors was >25 times B(max). Inside the cells, wild-type and K/A-2 prorenin were proteolytically activated to renin. Renin was subsequently degraded. Protease inhibitors interfered with the latter but not with prorenin activation, thereby indicating that the activating enzyme is different from any of the known prorenin-activating enzymes. Incubation with angiotensinogen did not lead to endothelial angiotensin generation, inasmuch as HUVECs were unable to internalize angiotensinogen. Most likely, therefore, in the absence of angiotensinogen synthesis or endocytosis, M6P receptor-mediated prorenin internalization by endothelial cells represents prorenin clearance

Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal disorders : evidence from SNP arrays

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD.Peer reviewe

Segmental and total uniparental isodisomy (UPiD) as a disease mechanism in autosomal recessive lysosomal

Analyses in our diagnostic DNA laboratory include genes involved in autosomal recessive (AR) lysosomal storage disorders such as glycogenosis type II (Pompe disease) and mucopolysaccharidosis type I (MPSI, Hurler disease). We encountered 4 cases with apparent homozygosity for a disease-causing sequence variant that could be traced to one parent only. In addition, in a young child with cardiomyopathy, in the absence of other symptoms, a diagnosis of Pompe disease was considered. Remarkably, he presented with different enzymatic and genotypic features between leukocytes and skin fibroblasts. All cases were examined with microsatellite markers and SNP genotyping arrays. We identified one case of total uniparental disomy (UPD) of chromosome 17 leading to Pompe disease and three cases of segmental uniparental isodisomy (UPiD) causing Hurler-(4p) or Pompe disease (17q). One Pompe patient with unusual combinations of features was shown to have a mosaic segmental UPiD of chromosome 17q. The chromosome 17 UPD cases amount to 11% of our diagnostic cohort of homozygous Pompe patients (plus one case of pseudoheterozygosity) where segregation analysis was possible. We conclude that inclusion of parental DNA is mandatory for reliable DNA diagnostics. Mild or unusual phenotypes of AR diseases should alert physicians to the possibility of mosaic segmental UPiD. SNP genotyping arrays are used in diagnostic workup of patients with developmental delay. Our results show that even small Regions of Homozygosity that include telomeric areas are worth reporting, regardless of the imprinting status of the chromosome, as they might indicate segmental UPiD

The case for strategic international alliances to harness nutritional genomics for public and personal health

Nutrigenomics is the study of how constituents of the diet interact with genes, and their products, to alter phenotype and, conversely, how genes and their products metabolise these constituents into nutrients, antinutrients, and bioactive compounds. Results from molecular and genetic epidemiological studies indicate that dietary unbalance can alter gene-nutrient interactions in ways that increase the risk of developing chronic disease. The interplay of human genetic variation and environmental factors will make identifying causative genes and nutrients a formidable, but not intractable, challenge. We provide specific recommendations for how to best meet this challenge and discuss the need for new methodologies and the use of comprehensive analyses of nutrient-genotype interactions involving large and diverse populations. The objective of the present paper is to stimulate discourse and collaboration among nutrigenomic researchers and stakeholders, a process that will lead to an increase in global health and wellness by reducing health disparities in developed and developing countrie

Waartoe wetenschap?

Sinds de Verlichting hebben volkeren met moderne wetenschap grotere overlevingskansen dan volkeren zonder, zodat in korte tijd vrijwel alle volkeren over de hele wereld zich bedienen van wetenschappelijk onderwijs en onderzoek. Zo spreken we thans niet alleen van een kenniseconomie, maar ook van een kennissamenleving. Waar het ook en vooral om zou moeten gaan, is dat het creatieeve moment in de wetenschap, dat nieuwe inzichten in natuur en cultuur bijdragen tot onze veerkracht, tot duurzame ontwikkeling, tot overleven. In Waartoe Wetenschap? onderzoekt Frans W. Saris de wetenschap in evolutionair perspectief en hij bepleit een radical enlightenment in een dertiental essays en een toneeltekst waarin zulke uiteenlopende wetenschappers verschijnen als Francis Bacon, Kamerlingh Onnes, Albert Einstein, Charles Darwin, Spinoza en Niko Tinbergen, maar ook de schrijvers Franz Kafka, Michael Frayn en Harry Mulisch

Carbon Neutral Aviation

The aviation industry can become carbon neutral by CO2 recycling into synthetic kerosene using renewable energy. As an example we take CO2 emissions from Tata Steel in the Netherlands as well as Schiphol Airport’s kerosene consumption

Improved device performance by multistep or carbon co-implants

High-energy ion implantation is used for forming the collector in vertical bipolar transistors in a BiCMOS process. Secondary defects, remaining after annealing the implant damage, give rise to an increased leakage current and to collector-emitter shorts. These shorts reduce the transistor yield. The use of multiple step implants or the introduction of a C gettering layer are demonstrated to avoid dislocation formation. Experimental results show that these schemes subsequently lower the leakage current and dramatically increase device yield. The presence of C can cause increased collector/substrate leakage, indicating that the C profile needs to be optimized with respect to the doping profile

Neonatal screening for profound biotinidase deficiency in the Netherlands:consequences and considerations

Biotinidase deficiency is a rare inherited metabolic disorder that can cause severe neurological symptoms. To prevent severe clinical presentations, it was included in the Dutch neonatal screening programme in 2007. Since then the number of cases detected has been high. This study set out to describe the incidence of the disease, the clinical and demographic characteristics of the neonates identified and the type of mutations found. In the south-western Netherlands, 304 982 neonates were screened between 2007 and 2012; and 92 were identified for further testing. Confirmatory testing revealed 6 (7%) with a profound biotinidase deficiency (o10% enzyme activity), 44 (48%) with a partial deficiency (10-30%) and 42 (46%) with normal activity (> 30%). All six patients whose profound deficiency was confirmed had enzyme activities below 15% on neonatal screening. Mutation analysis was performed in 61 neonates: 5 'profound', 35 'partial' and 21 'normal'. All five 'profound' cases had two severe mutations. Comparison with the northern Netherlands showed that the frequency and types of mutation were representative for the Netherlands as a whole. The most common mutation detected was c.[1330G > C] (p.(Asp444His); 34%), which is considered to be mild, followed by three severe mutations c.[1368A > C], c.[1595C > T] and c.[1330G > C; 511G > A]. Seven new mutations were identified. We conclude that neonatal screening for profound biotinidase produces a high number of false positives. Biotinidase deficiency was profound in less than 10% of cases identified. As biotinidase activity lay below 15% on neonatal screening in all such cases, the screening threshold might be reduced to 15%