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Item does not contain fulltext, Protein function can be impacted by changes in protein structure stability, but determining which change has impact is complex. Stability can be affected by a large change in the tertiary (3D) structure of the protein or due to free-energy changes caused by single amino acid substitutions. Changes in the DNA sequence can have minor or major impact on protein stability, which can lead to disease. Inherited retinal degenerations are generally caused by single mutations which are mostly located in protein-coding regions, while age-related macular degeneration (AMD) is a complex disorder that can be influenced by some genetic variants impacting proteins involved in the disease, although not all AMD risk variants lead to amino acid changes. Here, we review ways that proteins may be affected, the identification and understanding of these changes, and how to identify causal changes that can be targeted to develop treatments to alleviate retinal degenerative disease.

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Item does not contain fulltext, Age-related macular degeneration (AMD) is a common eye disease among the elderly in the Western world. AMD is a multifactorial disease, with a strong association with genetic variation in the complement system. One of the AMD-associated variants is the c.355G>A (p.Gly119Arg) variant in complement factor I (CFI), a central regulator of complement activation. Here, we report the generation of an iPSC line and its isogenic wildtype control derived from peripheral blood mononuclear cells of a female AMD-affected individual carrying the heterozygous variant c.355G>A (p.Gly119Arg). This line can be utilized to study the effects of this variant in disease-specific cell types.

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Radboud University, 26 augustus 2022, Promotores : Hollander, A.I. den, Heuvel, L.P.W.J. van den Co-promotores : Volokhina, E.B., Garanto, A., Contains fulltext : 251477.pdf (Publisher’s version ) (Open Access)

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Contains fulltext : 248812.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 245931.pdf (Publisher’s version ) (Open Access)

Item does not contain fulltext, Age-related macular degeneration (AMD) is a common eye disease among the elderly in the Western world. AMD is a multifactorial disease, with a strong association with genetic variation in the complement system. One of the AMD-associated variants is the c.355G>A (p.Gly119Arg) variant in complement factor I (CFI), a central regulator of complement activation. Here, we report the generation of an iPSC line and its isogenic wildtype control derived from peripheral blood mononuclear cells of a male AMD-affected individual carrying the heterozygous variant c.355G>A (p.Gly119Arg). The line can be utilized to study the effects of this variant in disease-specific cell types.

Contains fulltext : 251719.pdf (Publisher’s version ) (Open Access)

Radboud University, 26 augustus 2022, Promotores : Hollander, A.I. den, Heuvel, L.P.W.J. van den Co-promotores : Volokhina, E.B., Garanto, A., Contains fulltext : 251477.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 245931.pdf (Publisher’s version ) (Open Access)

Wat gebeurde er na de periode van de afdamming? Kloosters en edelen namen de ontginning ter hand. De kastelen en landgoederen zijn blijvende herinneringen aan het bruikbaar maken van dit gebied. Lees alles over deze periode en wat er nu op de kastelen en landgoederen gebeurt.

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Item does not contain fulltext, Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.

Contains fulltext : 240741.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 237835.pdf (Publisher’s version ) (Open Access), Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.

Contains fulltext : 240741.pdf (Publisher’s version ) (Open Access)

Contains fulltext : 237835.pdf (Publisher’s version ) (Open Access), Age-related macular degeneration (AMD) is the main cause of vision loss among the elderly in the Western world. While AMD is a multifactorial disease, the complement system was identified as one of the main pathways contributing to disease risk. The strong link between the complement system and AMD was demonstrated by genetic associations, and by elevated complement activation in local eye tissue and in the systemic circulation of AMD patients. Several complement inhibitors have been and are being explored in clinical trials, but thus far with limited success, leaving the majority of AMD patients without treatment options to date. This indicates that there is still a gap of knowledge regarding the functional implications of the complement system in AMD pathogenesis and how to bring these towards clinical translation. Many different experimental set-ups and disease models have been used to study complement activation in vivo and in vitro, and recently emerging patient-derived induced pluripotent stem cells and genome-editing techniques open new opportunities to study AMD disease mechanisms and test new therapeutic strategies in the future. In this review we provide an extensive overview of methods employed to understand the molecular processes of complement activation in AMD pathogenesis. We discuss the findings, advantages and challenges of each approach and conclude with an outlook on how recent, exciting developments can fill in current knowledge gaps and can aid in the development of effective complement-targeting therapeutic strategies in AMD.

Debris flows are mixtures of water and sediment that flow rapidly down a slope due to gravity force (Iverson, 1997; Takahashi, 2014). They are destructive to property and often fatal, a single event potentially killing thousands of people (Iverson, 1997 and 2011; Haas and Woerkom, 2016). The catastrophe is worsened when the volume of debris flow increases by bed entrainment caused by the interaction between flowing particles and bed particles (Takahashi, 1981; Pierson et al., 1990; Haas and Woerkom, 2016). Bed entrainment may result from impact forces and basal-shear forces and are mainly driven by the debris flow composition. However, it has long been unclear whether impact or basal-shear forces bear more responsibility in the erosion process, or it is a combination of both forces. This study shows that impact forces play a critical role in the occurrence of debris flows, and thereby in the erosion of bed material. Geophone capable of quantifying impact forces, and load cell capable of measuring flow weight in dry granular flows (representing debris flows) were used on laboratory-scale simulations. Impact forces were strongly controlled by debris flow composition (i.e. grain-size distribution) and moderately by flow properties (i.e. flow depth, flow weight, flow velocity). Thus, impact forces significantly affect debris-flow erosion, mainly by progressive scour rather than mass failure. Impact forces possibly result in bed entrainment, which is related to increasing debris-flow volume. A better understanding of how the debris-flow volume increases will help minimise the negative impacts of debris flows as well as strengthen hazard mitigation strategies.

Contains fulltext : 225117.pdf (Publisher’s version ) (Open Access), Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.

Contains fulltext : 225117.pdf (Publisher’s version ) (Open Access), Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.

Contains fulltext : 225117.pdf (Publisher’s version ) (Open Access), Factor I (FI) is one of the main inhibitors of complement activity, and numerous rare coding variants have been reported in patients with age-related macular degeneration, atypical hemolytic uremic syndrome and C3 glomerulopathy. Since many of these variants are of unknown clinical significance, this study aimed to determine the effect of rare coding variants in the complement factor I (CFI) gene on FI expression. We measured FI levels in plasma samples of carriers of rare coding variants and in vitro in the supernatants of epithelial cells expressing recombinant FI. FI levels were measured in 177 plasma samples of 155 individuals, carrying 24 different rare coding variants in CFI. In carriers of the variants p.Gly119Arg, p.Leu131Arg, p.Gly188Ala and c.772G>A (r.685_773del), significantly reduced FI plasma levels were detected. Furthermore, recombinant FI expression levels were determined for 126 rare coding variants. Of these variants 68 (54%) resulted in significantly reduced FI expression in supernatant compared to wildtype (WT). The recombinant protein expression levels correlated significantly with the FI level in plasma of carriers of CFI variants. In this study, we performed the most comprehensive FI expression level analysis of rare coding variants in CFI to date. More than half of CFI variants lead to reduced FI expression, which might impair complement regulation in vivo. Our study will aid the interpretation of rare coding CFI variants identified in clinical practice, which is in particular important in light of patient inclusion in ongoing clinical trials for CFI gene supplementation in AMD.

Debris flows are mixtures of water and sediment that flow rapidly down a slope due to gravity force (Iverson, 1997; Takahashi, 2014). They are destructive to property and often fatal, a single event potentially killing thousands of people (Iverson, 1997 and 2011; Haas and Woerkom, 2016). The catastrophe is worsened when the volume of debris flow increases by bed entrainment caused by the interaction between flowing particles and bed particles (Takahashi, 1981; Pierson et al., 1990; Haas and Woerkom, 2016). Bed entrainment may result from impact forces and basal-shear forces and are mainly driven by the debris flow composition. However, it has long been unclear whether impact or basal-shear forces bear more responsibility in the erosion process, or it is a combination of both forces. This study shows that impact forces play a critical role in the occurrence of debris flows, and thereby in the erosion of bed material. Geophone capable of quantifying impact forces, and load cell capable of measuring flow weight in dry granular flows (representing debris flows) were used on laboratory-scale simulations. Impact forces were strongly controlled by debris flow composition (i.e. grain-size distribution) and moderately by flow properties (i.e. flow depth, flow weight, flow velocity). Thus, impact forces significantly affect debris-flow erosion, mainly by progressive scour rather than mass failure. Impact forces possibly result in bed entrainment, which is related to increasing debris-flow volume. A better understanding of how the debris-flow volume increases will help minimise the negative impacts of debris flows as well as strengthen hazard mitigation strategies.

Item does not contain fulltext

Soil moisture is a small component, but essential variable in the hydrological cycle. Over the past years remote sensing techniques developed substantially. VanderSat developed a downscaling technique to deliver satellite soil moisture sampled at 100 m resolution, daily and worldwide. The aim of this study is to do a quality control on this product by comparing with in-situ soil moisture sensor data and volumetric soil moisture measurements collected in the field. In June 2017, 5 locations were selected in Bago, Myanmar to monitor in-situ soil moisture content in the unsaturated zone. In-situ soil moisture is measured with Decagon GS1 ruggedized soil moisture sensors. At each location 5 sensors are present: one at surface level, two at 10cm and two at 20cm depth. The sensors are connected to an EM50 analogue data logger. Since installation of the sensors a measurement is collected every half an hour. This yields in a time series of over one year. Every location has different soil and vegetation conditions. During an 8-week fieldwork in June and July 2018, 342 volumetric soil moisture measurements were collected. Volumetric soil moisture measurements are sampled at every sensor location on the same depth with the use of Kopecky rings. After quality control on dry bulk density, 329 samples were used for validation with in-situ soil moisture sensor data at the same date and time. The best correlation between volumetric soil moisture measurements and in-situ soil moisture sensor data is found at nest 1 and the worst at nest 2. This is because at nest 2 the soil is saturated and at nest 1 the soil is very suitable to collect reliable volumetric soil moisture samples. Root mean square errors range between 0.01 and 0.29 m3/m3. From the 25 sensors, 10 exceed the threshold value of 0.05 m3/m3 used for validation of SMAP satellites (Colliander et al., 2017). Time series of over one year in-situ soil moisture sensor data from every nest are validated with VanderSat soil moistu

Every year the Dutch agricultural businesses submit all sorts of agricultural data like crop type and parcel geometry to RVO.nl in accordance with CAP (the Common Agricultural Policy). This annual declaration is an enormous burden for the agricultural entrepreneur. To lessen this burden, RVO.nl searched for manners in which the declaration can be simplified. The prediction of crop types cultivated in the next year based on historical declaration information was one of the efforts. Crop type is very detailed information, in 2017 364 individual crop types could be declared in the Netherlands. Former research performed by RVO.nl in 2016 tried to predict crop types by using information about crop rotation schemas which was extracted out of historical declaration information, however, only very few rotation schemas were found. A reason for finding very few rotation schemas was the change in crop type codification during the research period. Therefore this research focused on identifying the length of crop rotation schemas in the declaration information and assessed whether this information improved crop type prediction for the declaration year of 2017. All the declared crop type information was gathered for the research period of 2008 till 2017 and combined with additional variable data: farm type, soil type, groundwater level, climate data, user identifier and organic farming. Sixty crop types were adjusted for the change in crop type codification, corresponding crop type codes from 2017 were used instead. Furthermore, a study area with a variety of crop rotation schemas was selected. Then search patterns were used to find repetitive patterns in the crop sequences derived from the historical declaration information in order to identify the length of crop rotation schemas. This information was stored as a new variable for predicting crop types. All the input variables contained nominal values. As a target variable was present (crop types of 2016), supervised modeling was

Item does not contain fulltext

Soil moisture is a small component, but essential variable in the hydrological cycle. Over the past years remote sensing techniques developed substantially. VanderSat developed a downscaling technique to deliver satellite soil moisture sampled at 100 m resolution, daily and worldwide. The aim of this study is to do a quality control on this product by comparing with in-situ soil moisture sensor data and volumetric soil moisture measurements collected in the field. In June 2017, 5 locations were selected in Bago, Myanmar to monitor in-situ soil moisture content in the unsaturated zone. In-situ soil moisture is measured with Decagon GS1 ruggedized soil moisture sensors. At each location 5 sensors are present: one at surface level, two at 10cm and two at 20cm depth. The sensors are connected to an EM50 analogue data logger. Since installation of the sensors a measurement is collected every half an hour. This yields in a time series of over one year. Every location has different soil and vegetation conditions. During an 8-week fieldwork in June and July 2018, 342 volumetric soil moisture measurements were collected. Volumetric soil moisture measurements are sampled at every sensor location on the same depth with the use of Kopecky rings. After quality control on dry bulk density, 329 samples were used for validation with in-situ soil moisture sensor data at the same date and time. The best correlation between volumetric soil moisture measurements and in-situ soil moisture sensor data is found at nest 1 and the worst at nest 2. This is because at nest 2 the soil is saturated and at nest 1 the soil is very suitable to collect reliable volumetric soil moisture samples. Root mean square errors range between 0.01 and 0.29 m3/m3. From the 25 sensors, 10 exceed the threshold value of 0.05 m3/m3 used for validation of SMAP satellites (Colliander et al., 2017). Time series of over one year in-situ soil moisture sensor data from every nest are validated with VanderSat soil moistu

Every year the Dutch agricultural businesses submit all sorts of agricultural data like crop type and parcel geometry to RVO.nl in accordance with CAP (the Common Agricultural Policy). This annual declaration is an enormous burden for the agricultural entrepreneur. To lessen this burden, RVO.nl searched for manners in which the declaration can be simplified. The prediction of crop types cultivated in the next year based on historical declaration information was one of the efforts. Crop type is very detailed information, in 2017 364 individual crop types could be declared in the Netherlands. Former research performed by RVO.nl in 2016 tried to predict crop types by using information about crop rotation schemas which was extracted out of historical declaration information, however, only very few rotation schemas were found. A reason for finding very few rotation schemas was the change in crop type codification during the research period. Therefore this research focused on identifying the length of crop rotation schemas in the declaration information and assessed whether this information improved crop type prediction for the declaration year of 2017. All the declared crop type information was gathered for the research period of 2008 till 2017 and combined with additional variable data: farm type, soil type, groundwater level, climate data, user identifier and organic farming. Sixty crop types were adjusted for the change in crop type codification, corresponding crop type codes from 2017 were used instead. Furthermore, a study area with a variety of crop rotation schemas was selected. Then search patterns were used to find repetitive patterns in the crop sequences derived from the historical declaration information in order to identify the length of crop rotation schemas. This information was stored as a new variable for predicting crop types. All the input variables contained nominal values. As a target variable was present (crop types of 2016), supervised modeling was

Een dierenarts krijgt leptospirose (ziekte van Weil) na contact met een zieke pup van een hondenfokker. Met inspanning en geluk wordt een zeer waarschijnlijke match vastgesteld. Het gaat om het Leptospira interrogans s.s. Wat is in zo’n situatie het volksgezondheidsrisico? Het is belangrijk dat zowel artsen als dierenartsen de risico’s van zoönosen onderkennen. Hygiënemaatregelen en preventie, door het vaccineren van honden, kunnen het risico op overdracht beperken. One-health-projecten of projecten over zoönosen&huisdieren kunnen hieraan bijdragen.

Normaliter is het verbruik van drinkwater nauwelijks afhankelijk van de druk in het leidingnet. Wanneer de druk daalt, bijvoorbeeld tijdens calamiteiten, wordt het verbruik wel drukafhankelijk. In dit onderzoek is het verbruik bij lagere drukken gesimuleerd voor verschillende soorten gebouwen – vrijstaande woningen, rijtjeswoningen, appartementencomplexen – en tot op het niveau van individuele kranen. De simulaties (met SIMDEUM) tonen dat drukafhankelijkheid van het waterverbruik afhangt van het gebouwtype en de mate van de drukverlaging. De simulaties waarin de druk-verbruik relatie was aangepast, gaven een reëler beeld van het drinkwaterverbruik bij lage drukken en kwamen goed overeen met de werkelijk opgetreden drukken en volumestromen.

Na de ontdekking van het Groningen aardgasveld in 1959, het grootste gasveld in West-Europa, is Nederland meer dan een halve eeuw zelfvoorzienend geweest met deze energiebron. Het keerpunt kwam door de aardbeving in Huizinge in de provincie Groningen in augustus 2012 met een kracht van 3,6 op de schaal van Richter die gebeurtenis heeft geleid tot een palfond voor de jaarlijkse productie van 21,6 miljard kubieke meter, ruim de helft minder dan in de jaren voor 2014.

In deze interdisciplinaire thesis onderzoeken wij vanuit de disciplines Algemene Sociale Wetenschappen, Religiewetenschappen en Wijsbegeerte wat voor veranderingen van levensbeschouwelijke bronnen van zingeving er plaatsvinden in de hedendaagse Nederlandse samenleving en waar deze ontwikkelingen hun oorsprong in vinden. Wij concluderen dat het post-seculiere veld zich qua heterogeniteit uitbreidt en dat de factoren die van invloed zijn op de uitbreiding van het veld (secularisering, individualisering, rationalisering en irrationaliteit) zelf echter ook een limiterende functie in zich dragen en grens stellen aan de variatie binnen het veld

The aim of this exploratory qualitative study was to examine the relation between religious identity and solidarity with refugees among orthodox-protestants in the Netherlands. Until now no European studies exist which explore the relationship between identification with a denomination and solidarity towards immigrants. The results of the semi-structured interviews show that the attitude of orthodox-protestants to refugees is ambiguous. This ambiguity finds its source in the multidimensionality of their religious identity. While drive to show solidarity is related to their horizontal identity in broad sense, i.e. their relationship towards fellow human beings, the participants struggle to find a balance between the care they want to provide immigrants from this identity, and the concerns they have what consequences a possible future with a majority of Muslims would have for the establishment of their horizontal identity in narrow sense, i.e. their relation to their religious community, and their vertical identity, i.e. their relation with God. Furthermore, this ambiguity is also reflected in their preferences as to the solution to the refugee problem: here distinction can be made between macro and micro level. At the micro level participants show solidarity towards immigrants, while at the macro level they advocate restrictions on immigration policy.

Contains fulltext : 173621.pdf (publisher's version ) (Open Access)