Dates: 2005 – 2009 ❌Country: ❌
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Universiteit Utrecht
1.
Bruijnincx, P.C.A.
Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.
Degree: 2007, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/19232
► The structural and functional modeling of a specific group of non-heme iron enzymes by the synthesis of small synthetic analogues is the topic of this…
(more)
▼ The structural and functional modeling of a specific group of non-heme iron enzymes by the synthesis of small synthetic analogues is the topic of this thesis. The group of non-heme iron enzymes with the 2-His-1-carboxylate facial triad has recently been established as a common platform for the activation of dioxygen in Nature. The oxidative transformations catalyzed by these enzymes are very diverse and many of them are unprecedented in synthetic organic chemistry. This makes this group of enzymes an attractive target for synthetic modeling studies. A new family of biomimetic N,N,O ligands that accurate model this facial triad has been developed. Structurally characterized copper complexes showed the potential of the new ligands as mimics of the facial triad. Mononuclear iron complexes of these ligands were also synthesized and in this way accurate models of the active sites of these enzymes were obtained. For instance, model complexes of the enzyme-substrate complexes of extradiol cleaving catechol dioxygenases were built and the reactivity of these complexes showed that the compounds were able to mimic the enzymes both in structure and function. Very accurate models of the closely related intradiol cleaving catechol dioxygenases were also synthesized with a slightly modified ligand system. These studies provided further insight into the factors governing the respective selectivities of these interesting enzymes. Furthermore, the reactivity of several non-heme iron complexes as oxidation catalysts was explored. Non-heme iron model complexes of the 2-His-1-carboxylate facial triad structural motif proved to be interesting oxidation catalysts and displayed both epoxidation as well as cis-dihydroxylation activity. Other catalysts showed promising reactivities in the oxidation of alkanes and alkenes. All complexes were characterized by variety of techniques including UV-Vis, IR, EPR spectroscopy, magnetic and mass spectrometric measurements, and X-ray crystal structure determinations. In the last part of the thesis, the focus is shifted to the exploration of the coordination of the new ligands with the transitions metals zinc and copper. The obtained results show that the ligands are quite versatile and interesting reactivities were discovered. The zinc complexes for instance mediate the conversion of pyruvate, an important metabolic junction, to oxalate. The copper complexes converted tetrachlorocatechol, a persistent organic pollutant, to chloranilic acid via an oxidative double dehalogenation. Both of these discovered reactivities are unprecedented.
Subjects/Keywords: Scheikunde; bioinorganic chemistry; non-heme iron enzymes; 2-His-1-carboxylate facial triad; N,N,O ligands; small synthetic analogues; oxidation catalysis; epoxidation; cis-dihydroxylation; copper; zinc
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APA (6th Edition):
Bruijnincx, P. C. A. (2007). Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/19232
Chicago Manual of Style (16th Edition):
Bruijnincx, P C A. “Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.” 2007. Doctoral Dissertation, Universiteit Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl:8080/handle/1874/19232.
MLA Handbook (7th Edition):
Bruijnincx, P C A. “Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.” 2007. Web. 12 Dec 2019.
Vancouver:
Bruijnincx PCA. Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl:8080/handle/1874/19232.
Council of Science Editors:
Bruijnincx PCA. Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. [Doctoral Dissertation]. Universiteit Utrecht; 2007. Available from: http://dspace.library.uu.nl:8080/handle/1874/19232

Universiteit Utrecht
2.
Schooten, C.J.M. van.
Von Willebrand Factor: clearance as regulator of plasma levels.
Degree: 2007, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/23898
► Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to…
(more)
▼ Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to stabilize the FVIII heterodimer and to prevent its premature clearance. The half-life of FVIII mimics that of the FVIII/VWF complex, suggesting that the complex is cleared as a single entity. The objectives of studies presented in this thesis were to identify parameters that affect VWF plasma levels and to elucidate elements that contribute to the VWF clearance mechanism. Little is known about the clearance mechanism of VWF. However, a number of parameters have been identified that influence VWF plasma levels. One of these factors is its glycosylation profile. VWF contains both N- and O-linked glycosylation. The blood group sugars on VWF all belong to the N-linked glycans and average VWF plasma levels are decreased in persons with blood group O. We investigated the influence of O-linked glycans on VWF plasma levels. Therefore we set up an assay that could determine the level O-linked glycans present on plasma VWF. We showed an inverse correlation between the extend of O-linked glycosylation and VWF plasma levels. Moreover, the amount of O-linked glycosylation is proportional to the VWF/ propeptide ratio. Because increased ratios may be indicative for increased clearance of VWF, the possibility exists that also modifications in O-linked glycosylation affect clearance of VWF. Also mutation in VWF may affect its plasma levels. We investigated the in vivo survival of three cysteine mutations, expressed in patients suffering from Von Willebrand Disease (VWD). We observed decreased survival of the VWF mutants in both patients an in an experimental mouse model. We explored the possibility that FVIII half-life can be predicted using VWF plasma level concentrations. Therefore we determined FVIII half-life and VWF antigen levels in severe haemophiliacs. VWF antigen levels correlated well with FVIII half-life in blood-group non-O, but poorly in severe haemophiliacs. This poor correlation for blood-group O patients could be considerably improved when VWF/propeptide ratios were used. Thus determination of VWF antigen levels and propeptide allows prediction of FVIII half-life. In order to gain more insight into the clearance mechanism of FVIII and VWF, VWF clearance was investigated in mice deficient for VWF. VWF was mainly targeted to the liver and spleen. Analysis of liver and spleen sections of VWF-deficient mice infused with FVII, VWF or the VWF/FVIII complex revealed co-localisation of all proteins with macrophages in both tissues. We also tested the contribution of macrophages to the in vivo clearance of VWF. Treatment of mice with gadolinium chloride (GdCl3) prior to VWF infusion resulted in decreased macrophage cell numbers. This resulted in a 2-fold increase of endogenous VWF in wild-type mice pre-treated with GdCl3. In addition, the survival of infused VWF was prolonged almost 2-fold in VWF-deficient mice. To study the uptake of the VWF by macrophages, we…
Subjects/Keywords: Geneeskunde; Von Willebrand Factor; Von Willebrand Disease; O-linked glycosylation; cysteine mutations; clearance mechanism; factor VIII; Von Willebrand factor/factor VIII complex; half-life; macrophages; Staphylococcus aureus protein A
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APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Schooten, C. J. M. v. (2007). Von Willebrand Factor: clearance as regulator of plasma levels. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/23898
Chicago Manual of Style (16th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Doctoral Dissertation, Universiteit Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl:8080/handle/1874/23898.
MLA Handbook (7th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Web. 12 Dec 2019.
Vancouver:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2007. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl:8080/handle/1874/23898.
Council of Science Editors:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Doctoral Dissertation]. Universiteit Utrecht; 2007. Available from: http://dspace.library.uu.nl:8080/handle/1874/23898
3.
Karawajczyk, Anna.
Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids.
Degree: 2007, LIC/SSNMR, Faculty of Science, Leiden University
URL: http://hdl.handle.net/1887/12409
► The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck…
(more)
▼ The thesis is focused on the DNA-cleaving antibiotic bleomycin that is successfully used in the chemotherapy against several types of cancer like head and neck cancer or certain lymphomas and testicular cancer. Although it has been in use for more than two decades, the mechanism of its action is not known. Thus the harmful side effects are difficult to eliminate. On the other hand the process of design or improvement of pharmaceuticals is extremely complex and expensive. Therefore a new trend within drug discovery is emerging with the application of clean chemistry, by performing molecular modeling of new compounds and by running virtual tests to assess their suitability before an expensive synthesis attempt is made. In the thesis, the contribution of different computational methods into this field is discussed, emphasizing the growing role played by quantum mechanical methods. Using state-of-the-art methods, an insight into the mechanism of bleomycin action was gained. The possible reaction pathways of the active bleomycin-Fe(III)-OOH complex with the deoxyribose sugar of DNA were investigated. The simulations show that a facile decaying process involves a homolytic O-O bond cleavage with an almost simultaneous hydrogen atom abstraction. The formation of a hydrogen bond appears to be crucial for the O-O bond cleavage in the Fe(III)-OOH species. The highly selective reaction between the bleomycin drug and the genetic material comes from the selectivity of the created hydrogen bond
Subjects/Keywords: Bleomycin; Density Functional Theory; Drug-DNA interactions; First principles Molecular Dynamics; Ligands of bilitranslocase; O-O bond cleavage; QM/MM; Bleomycin; Density Functional Theory; Drug-DNA interactions; First principles Molecular Dynamics; Ligands of bilitranslocase; O-O bond cleavage; QM/MM
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Karawajczyk, A. (2007). Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids. (Doctoral Dissertation). LIC/SSNMR, Faculty of Science, Leiden University. Retrieved from http://hdl.handle.net/1887/12409
Chicago Manual of Style (16th Edition):
Karawajczyk, Anna. “Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids.” 2007. Doctoral Dissertation, LIC/SSNMR, Faculty of Science, Leiden University. Accessed December 12, 2019.
http://hdl.handle.net/1887/12409.
MLA Handbook (7th Edition):
Karawajczyk, Anna. “Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids.” 2007. Web. 12 Dec 2019.
Vancouver:
Karawajczyk A. Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids. [Internet] [Doctoral dissertation]. LIC/SSNMR, Faculty of Science, Leiden University; 2007. [cited 2019 Dec 12].
Available from: http://hdl.handle.net/1887/12409.
Council of Science Editors:
Karawajczyk A. Chemical activity of anticancer compounds: computational studies on the mechanism of bleomycin and the recognition of flavonoids. [Doctoral Dissertation]. LIC/SSNMR, Faculty of Science, Leiden University; 2007. Available from: http://hdl.handle.net/1887/12409

Universiteit Utrecht
4.
Muntjewerff, J.W.
Homocysteine metabolism and risk of schizophrenia.
Degree: 2006, Universiteit Utrecht
URL: http://dspace.library.uu.nl:8080/handle/1874/14032
► The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine…
(more)
▼ The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine (tHcy) concentrations, and genetic determinants. We observed decreased plasma and elevated RBC folate levels as risk factors for schizophrenia, which appeared to be independent of tHcy concentrations (chapter 2). No deficiencies of vitamin B6 or vitamin B12 levels were found in our study. In a review we only found 7 case-control studies with data on folate levels in schizophrenia patients (chapter 3). These studies showed no substantial support for an aberrant folate metabolism in schizophrenia patients. However, all studies showed a variety of methodological flaws defying a more definite conclusion on the relationship between folate and schizophrenia. The results of a meta-analysis of the current literature (chapter 5) give support to the conclusion presented in our previous report (chapter 4) that elevated tHcy concentration is a risk factor for schizophrenia. We found that a 5 μmol/L higher tHcy concentration was associated with an increased risk of schizophrenia (OR=1.70 [95% CI: 1.27-2.29]). Next to the MTHFR 677TT genotype, we found elevated tHcy concentrations in schizophrenia patients with the heterozygous MTHFR 677C>T genotype compared to patients homozygous for the normal genotype (chapter 4). The MTHFR 677CT genotype itself may result in elevated tHcy concentrations. The results of our initial study showed no increased frequency of the 677TT genotype in schizophrenia patients (chapter 2). However, an enlargement of this initial study showed a nearly significant increased risk (OR=1.6 [95% CI: 0.96-2.8]) of schizophrenia associated with the 677TT genotype in the MTHFR gene (chapter 4). When these data were incorporated in a meta-analysis based on published studies the MTHFR 677C>T mutation in homozygous state appeared to be a significant genetic risk factor for schizophrenia with a pooled risk estimate of 1.36 (95% CI: 1.07-1.72) (chapter 5). We observed no transmission distortion of the 677T allele in 120 families with schizophrenia offspring, which is in accordance with the result of a meta-analysis using data from three family-based studies, including our data (chapter 6). When we applied a log-linear model to the case-parent data no evidence for a strong maternal genetic effect on schizophrenia risk was observed. In chapter 7 the effect of genetic variations of two interconnected enzymes of the methylation pathway, COMT and MTHFR, on schizophrenia risk were subject of study. Despite the low numbers of subjects carrying the combination of the COMT 324AA and MTHFR 677TT genotype an increased risk of schizophrenia was associated with this compound genotype in our study. Four polymorphisms of the COMT gene, and their effect on tHcy levels in population-based controls were examined (chapter 8). Only the COMT 324G>A variant was associated with homocysteine, although the effect of this polymorphism on tHcy…
Subjects/Keywords: Geneeskunde; homocysteine; folate; B-vitamins; schizophrenia; genetics; methylenetetrahydrofolate reductase; catechol-O-methyltransferase; methylation; psychiatric disorders; neurodevelopment
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Muntjewerff, J. W. (2006). Homocysteine metabolism and risk of schizophrenia. (Doctoral Dissertation). Universiteit Utrecht. Retrieved from http://dspace.library.uu.nl:8080/handle/1874/14032
Chicago Manual of Style (16th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Doctoral Dissertation, Universiteit Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl:8080/handle/1874/14032.
MLA Handbook (7th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Web. 12 Dec 2019.
Vancouver:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Internet] [Doctoral dissertation]. Universiteit Utrecht; 2006. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl:8080/handle/1874/14032.
Council of Science Editors:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Doctoral Dissertation]. Universiteit Utrecht; 2006. Available from: http://dspace.library.uu.nl:8080/handle/1874/14032

Vrije Universiteit Amsterdam
5.
Verhoeven, M.O.
Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
.
Degree: 2007, Vrije Universiteit Amsterdam
URL: http://hdl.handle.net/1871/12930
► Oestrogenen en asymmetrische dimethylarginine Hart- en vaatziekten (HVZ) vormen de belangrijkste doodsoorzaak in de Westerse wereld. Premenopauzale vrouwen hebben een lager risico op HVZ dan…
(more)
▼ Oestrogenen en asymmetrische dimethylarginine Hart- en vaatziekten (HVZ) vormen de belangrijkste doodsoorzaak in de Westerse wereld. Premenopauzale vrouwen hebben een lager risico op HVZ dan mannen van dezelfde leeftijd, maar na de menopauze neemt de kans op HVZ bij vrouwen snel toe. Door de eierstokken geproduceerde hormonen (oestrogenen en progestagenen) spelen waarschijnlijk een rol bij de bescherming van premenopauzale vrouwen tegen HVZ en mogelijk kan toediening van deze hormonen na de menopauze vrouwen enigszins beschermen tegen de versnelde toename van het risico van HVZ. Asymmetrische dimethylarginine (ADMA) is een stof die door het lichaam zelf wordt gemaakt. Een hoge concentratie van ADMA vermindert een goed functioneren van de bloedvaten en leidt tot een verhoogde kans op HVZ. Of ADMA ook een rol speelt bij de verhoogde kans op HVZ na de menopauze is nog niet eerder onderzocht. Dit proefschrift behandeld het onderzoek naar de relatie tussen oestrogenen en aan oestrogeen verwante stoffen en ADMA bij vrouwen van middelbare leeftijd. Er werd gekeken naar de invloed van de menopauze en naar de effecten van verschillende (hormonale) menopauzale therapieën op ADMA concentraties.
De voornaamste bevinding was dat hogere oestrogeen concentraties gepaard gaan met lagere ADMA concentraties. Het ADMA verlagende effect van oestrogeensuppletie was groter bij orale toediening dan bij gebruik van pleisters of spray en bovendien
afhankelijk van de gebruikte oestrogeen/progestageen combinatie. Hoewel dit onderzoek laat zien dat vrouwelijke geslachtshormonen ADMA spiegels in gunstige zin beïnvloeden, moeten de klinische consequenties hiervan nog nader onderzocht worden.
Subjects/Keywords: Menopausal therapy and asymmetric dimethylarginine;
Menopause;
Menopausal therapies;
asymmetric dimethylarginine;
cardiovascular risk factor;
(o)estradiol
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Verhoeven, M. O. (2007). Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
. (Doctoral Dissertation). Vrije Universiteit Amsterdam. Retrieved from http://hdl.handle.net/1871/12930
Chicago Manual of Style (16th Edition):
Verhoeven, M O. “Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
.” 2007. Doctoral Dissertation, Vrije Universiteit Amsterdam. Accessed December 12, 2019.
http://hdl.handle.net/1871/12930.
MLA Handbook (7th Edition):
Verhoeven, M O. “Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
.” 2007. Web. 12 Dec 2019.
Vancouver:
Verhoeven MO. Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
. [Internet] [Doctoral dissertation]. Vrije Universiteit Amsterdam; 2007. [cited 2019 Dec 12].
Available from: http://hdl.handle.net/1871/12930.
Council of Science Editors:
Verhoeven MO. Menopause, menopausal therapies and asymmetric dimethylarginine, an emerging cardiovascular risk factor
. [Doctoral Dissertation]. Vrije Universiteit Amsterdam; 2007. Available from: http://hdl.handle.net/1871/12930
6.
Muntjewerff, J.W.
Homocysteine metabolism and risk of schizophrenia.
Degree: 2006, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/14032
;
URN:NBN:NL:UI:10-1874-14032
;
urn:isbn:90-9021133-0
;
URN:NBN:NL:UI:10-1874-14032
;
http://dspace.library.uu.nl/handle/1874/14032
► The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine…
(more)
▼ The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine (tHcy) concentrations, and genetic determinants. We observed decreased plasma and elevated RBC folate levels as risk factors for schizophrenia, which appeared to be independent of tHcy concentrations (chapter 2). No deficiencies of vitamin B6 or vitamin B12 levels were found in our study. In a review we only found 7 case-control studies with data on folate levels in schizophrenia patients (chapter 3). These studies showed no substantial support for an aberrant folate metabolism in schizophrenia patients. However, all studies showed a variety of methodological flaws defying a more definite conclusion on the relationship between folate and schizophrenia. The results of a meta-analysis of the current literature (chapter 5) give support to the conclusion presented in our previous report (chapter 4) that elevated tHcy concentration is a risk factor for schizophrenia. We found that a 5 μmol/L higher tHcy concentration was associated with an increased risk of schizophrenia (OR=1.70 [95% CI: 1.27-2.29]). Next to the MTHFR 677TT genotype, we found elevated tHcy concentrations in schizophrenia patients with the heterozygous MTHFR 677C>T genotype compared to patients homozygous for the normal genotype (chapter 4). The MTHFR 677CT genotype itself may result in elevated tHcy concentrations. The results of our initial study showed no increased frequency of the 677TT genotype in schizophrenia patients (chapter 2). However, an enlargement of this initial study showed a nearly significant increased risk (OR=1.6 [95% CI: 0.96-2.8]) of schizophrenia associated with the 677TT genotype in the MTHFR gene (chapter 4). When these data were incorporated in a meta-analysis based on published studies the MTHFR 677C>T mutation in homozygous state appeared to be a significant genetic risk factor for schizophrenia with a pooled risk estimate of 1.36 (95% CI: 1.07-1.72) (chapter 5). We observed no transmission distortion of the 677T allele in 120 families with schizophrenia offspring, which is in accordance with the result of a meta-analysis using data from three family-based studies, including our data (chapter 6). When we applied a log-linear model to the case-parent data no evidence for a strong maternal genetic effect on schizophrenia risk was observed. In chapter 7 the effect of genetic variations of two interconnected enzymes of the methylation pathway, COMT and MTHFR, on schizophrenia risk were subject of study. Despite the low numbers of subjects carrying the combination of the COMT 324AA and MTHFR 677TT genotype an increased risk of schizophrenia was associated with this compound genotype in our study. Four polymorphisms of the COMT gene, and their effect on tHcy levels in population-based controls were examined (chapter 8). Only the COMT 324G>A variant was associated with homocysteine, although the effect of this polymorphism on tHcy…
Subjects/Keywords: homocysteine; folate; B-vitamins; schizophrenia; genetics; methylenetetrahydrofolate reductase; catechol-O-methyltransferase; methylation; psychiatric disorders; neurodevelopment
Record Details
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Share »
Record Details
Similar Records
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Muntjewerff, J. W. (2006). Homocysteine metabolism and risk of schizophrenia. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032
Chicago Manual of Style (16th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032.
MLA Handbook (7th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Web. 12 Dec 2019.
Vancouver:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Internet] [Doctoral dissertation]. University Utrecht; 2006. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032.
Council of Science Editors:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Doctoral Dissertation]. University Utrecht; 2006. Available from: http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032
7.
Muntjewerff, J.W.
Homocysteine metabolism and risk of schizophrenia.
Degree: 2006, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/14032
;
URN:NBN:NL:UI:10-1874-14032
;
urn:isbn:90-9021133-0
;
URN:NBN:NL:UI:10-1874-14032
;
http://dspace.library.uu.nl/handle/1874/14032
► The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine…
(more)
▼ The one-carbon cycle hypothesis initiated research of schizophrenia risk in relation to sensitive markers of aberrant homocysteine metabolism, such as B-vitamin concentrations, plasma total homocysteine (tHcy) concentrations, and genetic determinants. We observed decreased plasma and elevated RBC folate levels as risk factors for schizophrenia, which appeared to be independent of tHcy concentrations (chapter 2). No deficiencies of vitamin B6 or vitamin B12 levels were found in our study. In a review we only found 7 case-control studies with data on folate levels in schizophrenia patients (chapter 3). These studies showed no substantial support for an aberrant folate metabolism in schizophrenia patients. However, all studies showed a variety of methodological flaws defying a more definite conclusion on the relationship between folate and schizophrenia. The results of a meta-analysis of the current literature (chapter 5) give support to the conclusion presented in our previous report (chapter 4) that elevated tHcy concentration is a risk factor for schizophrenia. We found that a 5 μmol/L higher tHcy concentration was associated with an increased risk of schizophrenia (OR=1.70 [95% CI: 1.27-2.29]). Next to the MTHFR 677TT genotype, we found elevated tHcy concentrations in schizophrenia patients with the heterozygous MTHFR 677C>T genotype compared to patients homozygous for the normal genotype (chapter 4). The MTHFR 677CT genotype itself may result in elevated tHcy concentrations. The results of our initial study showed no increased frequency of the 677TT genotype in schizophrenia patients (chapter 2). However, an enlargement of this initial study showed a nearly significant increased risk (OR=1.6 [95% CI: 0.96-2.8]) of schizophrenia associated with the 677TT genotype in the MTHFR gene (chapter 4). When these data were incorporated in a meta-analysis based on published studies the MTHFR 677C>T mutation in homozygous state appeared to be a significant genetic risk factor for schizophrenia with a pooled risk estimate of 1.36 (95% CI: 1.07-1.72) (chapter 5). We observed no transmission distortion of the 677T allele in 120 families with schizophrenia offspring, which is in accordance with the result of a meta-analysis using data from three family-based studies, including our data (chapter 6). When we applied a log-linear model to the case-parent data no evidence for a strong maternal genetic effect on schizophrenia risk was observed. In chapter 7 the effect of genetic variations of two interconnected enzymes of the methylation pathway, COMT and MTHFR, on schizophrenia risk were subject of study. Despite the low numbers of subjects carrying the combination of the COMT 324AA and MTHFR 677TT genotype an increased risk of schizophrenia was associated with this compound genotype in our study. Four polymorphisms of the COMT gene, and their effect on tHcy levels in population-based controls were examined (chapter 8). Only the COMT 324G>A variant was associated with homocysteine, although the effect of this polymorphism on tHcy…
Subjects/Keywords: homocysteine; folate; B-vitamins; schizophrenia; genetics; methylenetetrahydrofolate reductase; catechol-O-methyltransferase; methylation; psychiatric disorders; neurodevelopment
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APA ·
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APA (6th Edition):
Muntjewerff, J. W. (2006). Homocysteine metabolism and risk of schizophrenia. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032
Chicago Manual of Style (16th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032.
MLA Handbook (7th Edition):
Muntjewerff, J W. “Homocysteine metabolism and risk of schizophrenia.” 2006. Web. 12 Dec 2019.
Vancouver:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Internet] [Doctoral dissertation]. University Utrecht; 2006. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032.
Council of Science Editors:
Muntjewerff JW. Homocysteine metabolism and risk of schizophrenia. [Doctoral Dissertation]. University Utrecht; 2006. Available from: http://dspace.library.uu.nl/handle/1874/14032 ; URN:NBN:NL:UI:10-1874-14032 ; urn:isbn:90-9021133-0 ; URN:NBN:NL:UI:10-1874-14032 ; http://dspace.library.uu.nl/handle/1874/14032
8.
Bruijnincx, P.C.A.
Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.
Degree: 2007, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/19232
;
URN:NBN:NL:UI:10-1874-19232
;
urn:isbn:978-90-393-4438-5
;
URN:NBN:NL:UI:10-1874-19232
;
http://dspace.library.uu.nl/handle/1874/19232
► The structural and functional modeling of a specific group of non-heme iron enzymes by the synthesis of small synthetic analogues is the topic of this…
(more)
▼ The structural and functional modeling of a specific group of non-heme iron enzymes by the synthesis of small synthetic analogues is the topic of this thesis. The group of non-heme iron enzymes with the 2-His-1-carboxylate facial triad has recently been established as a common platform for the activation of dioxygen in Nature. The oxidative transformations catalyzed by these enzymes are very diverse and many of them are unprecedented in synthetic organic chemistry. This makes this group of enzymes an attractive target for synthetic modeling studies. A new family of biomimetic N,N,O ligands that accurate model this facial triad has been developed. Structurally characterized copper complexes showed the potential of the new ligands as mimics of the facial triad. Mononuclear iron complexes of these ligands were also synthesized and in this way accurate models of the active sites of these enzymes were obtained. For instance, model complexes of the enzyme-substrate complexes of extradiol cleaving catechol dioxygenases were built and the reactivity of these complexes showed that the compounds were able to mimic the enzymes both in structure and function. Very accurate models of the closely related intradiol cleaving catechol dioxygenases were also synthesized with a slightly modified ligand system. These studies provided further insight into the factors governing the respective selectivities of these interesting enzymes. Furthermore, the reactivity of several non-heme iron complexes as oxidation catalysts was explored. Non-heme iron model complexes of the 2-His-1-carboxylate facial triad structural motif proved to be interesting oxidation catalysts and displayed both epoxidation as well as cis-dihydroxylation activity. Other catalysts showed promising reactivities in the oxidation of alkanes and alkenes. All complexes were characterized by variety of techniques including UV-Vis, IR, EPR spectroscopy, magnetic and mass spectrometric measurements, and X-ray crystal structure determinations. In the last part of the thesis, the focus is shifted to the exploration of the coordination of the new ligands with the transitions metals zinc and copper. The obtained results show that the ligands are quite versatile and interesting reactivities were discovered. The zinc complexes for instance mediate the conversion of pyruvate, an important metabolic junction, to oxalate. The copper complexes converted tetrachlorocatechol, a persistent organic pollutant, to chloranilic acid via an oxidative double dehalogenation. Both of these discovered reactivities are unprecedented.
Subjects/Keywords: bioinorganic chemistry; non-heme iron enzymes; 2-His-1-carboxylate facial triad; N,N,O ligands; small synthetic analogues; oxidation catalysis; epoxidation; cis-dihydroxylation; copper; zinc
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Bruijnincx, P. C. A. (2007). Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/19232 ; URN:NBN:NL:UI:10-1874-19232 ; urn:isbn:978-90-393-4438-5 ; URN:NBN:NL:UI:10-1874-19232 ; http://dspace.library.uu.nl/handle/1874/19232
Chicago Manual of Style (16th Edition):
Bruijnincx, P C A. “Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.” 2007. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl/handle/1874/19232 ; URN:NBN:NL:UI:10-1874-19232 ; urn:isbn:978-90-393-4438-5 ; URN:NBN:NL:UI:10-1874-19232 ; http://dspace.library.uu.nl/handle/1874/19232.
MLA Handbook (7th Edition):
Bruijnincx, P C A. “Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif.” 2007. Web. 12 Dec 2019.
Vancouver:
Bruijnincx PCA. Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. [Internet] [Doctoral dissertation]. University Utrecht; 2007. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl/handle/1874/19232 ; URN:NBN:NL:UI:10-1874-19232 ; urn:isbn:978-90-393-4438-5 ; URN:NBN:NL:UI:10-1874-19232 ; http://dspace.library.uu.nl/handle/1874/19232.
Council of Science Editors:
Bruijnincx PCA. Structural and Functional Models of Non-Heme Iron Enzymes : A Study of the 2-His-1-Carboxylate Facial Triad Structural Motif. [Doctoral Dissertation]. University Utrecht; 2007. Available from: http://dspace.library.uu.nl/handle/1874/19232 ; URN:NBN:NL:UI:10-1874-19232 ; urn:isbn:978-90-393-4438-5 ; URN:NBN:NL:UI:10-1874-19232 ; http://dspace.library.uu.nl/handle/1874/19232
9.
Schooten, C.J.M. van.
Von Willebrand Factor: clearance as regulator of plasma levels.
Degree: 2007, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/23898
;
URN:NBN:NL:UI:10-1874-23898
;
urn:isbn:978-90-393-4649-5
;
URN:NBN:NL:UI:10-1874-23898
;
http://dspace.library.uu.nl/handle/1874/23898
► Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to…
(more)
▼ Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to stabilize the FVIII heterodimer and to prevent its premature clearance. The half-life of FVIII mimics that of the FVIII/VWF complex, suggesting that the complex is cleared as a single entity. The objectives of studies presented in this thesis were to identify parameters that affect VWF plasma levels and to elucidate elements that contribute to the VWF clearance mechanism. Little is known about the clearance mechanism of VWF. However, a number of parameters have been identified that influence VWF plasma levels. One of these factors is its glycosylation profile. VWF contains both N- and O-linked glycosylation. The blood group sugars on VWF all belong to the N-linked glycans and average VWF plasma levels are decreased in persons with blood group O. We investigated the influence of O-linked glycans on VWF plasma levels. Therefore we set up an assay that could determine the level O-linked glycans present on plasma VWF. We showed an inverse correlation between the extend of O-linked glycosylation and VWF plasma levels. Moreover, the amount of O-linked glycosylation is proportional to the VWF/ propeptide ratio. Because increased ratios may be indicative for increased clearance of VWF, the possibility exists that also modifications in O-linked glycosylation affect clearance of VWF. Also mutation in VWF may affect its plasma levels. We investigated the in vivo survival of three cysteine mutations, expressed in patients suffering from Von Willebrand Disease (VWD). We observed decreased survival of the VWF mutants in both patients an in an experimental mouse model. We explored the possibility that FVIII half-life can be predicted using VWF plasma level concentrations. Therefore we determined FVIII half-life and VWF antigen levels in severe haemophiliacs. VWF antigen levels correlated well with FVIII half-life in blood-group non-O, but poorly in severe haemophiliacs. This poor correlation for blood-group O patients could be considerably improved when VWF/propeptide ratios were used. Thus determination of VWF antigen levels and propeptide allows prediction of FVIII half-life. In order to gain more insight into the clearance mechanism of FVIII and VWF, VWF clearance was investigated in mice deficient for VWF. VWF was mainly targeted to the liver and spleen. Analysis of liver and spleen sections of VWF-deficient mice infused with FVII, VWF or the VWF/FVIII complex revealed co-localisation of all proteins with macrophages in both tissues. We also tested the contribution of macrophages to the in vivo clearance of VWF. Treatment of mice with gadolinium chloride (GdCl3) prior to VWF infusion resulted in decreased macrophage cell numbers. This resulted in a 2-fold increase of endogenous VWF in wild-type mice pre-treated with GdCl3. In addition, the survival of infused VWF was prolonged almost 2-fold in VWF-deficient mice. To study the uptake of the VWF by macrophages, we…
Subjects/Keywords: Von Willebrand Factor; Von Willebrand Disease; O-linked glycosylation; cysteine mutations; clearance mechanism; factor VIII; Von Willebrand factor/factor VIII complex; half-life; macrophages; Staphylococcus aureus protein A
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Schooten, C. J. M. v. (2007). Von Willebrand Factor: clearance as regulator of plasma levels. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898
Chicago Manual of Style (16th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898.
MLA Handbook (7th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Web. 12 Dec 2019.
Vancouver:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Internet] [Doctoral dissertation]. University Utrecht; 2007. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898.
Council of Science Editors:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Doctoral Dissertation]. University Utrecht; 2007. Available from: http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898
10.
Schooten, C.J.M. van.
Von Willebrand Factor: clearance as regulator of plasma levels.
Degree: 2007, University Utrecht
URL: http://dspace.library.uu.nl/handle/1874/23898
;
URN:NBN:NL:UI:10-1874-23898
;
urn:isbn:978-90-393-4649-5
;
URN:NBN:NL:UI:10-1874-23898
;
http://dspace.library.uu.nl/handle/1874/23898
► Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to…
(more)
▼ Von Willebrand factor (VWF) and coagulation factor VIII (FVIII) are plasma proteins that circulate in a tight, noncovalent complex. Binding to VWF is required to stabilize the FVIII heterodimer and to prevent its premature clearance. The half-life of FVIII mimics that of the FVIII/VWF complex, suggesting that the complex is cleared as a single entity. The objectives of studies presented in this thesis were to identify parameters that affect VWF plasma levels and to elucidate elements that contribute to the VWF clearance mechanism. Little is known about the clearance mechanism of VWF. However, a number of parameters have been identified that influence VWF plasma levels. One of these factors is its glycosylation profile. VWF contains both N- and O-linked glycosylation. The blood group sugars on VWF all belong to the N-linked glycans and average VWF plasma levels are decreased in persons with blood group O. We investigated the influence of O-linked glycans on VWF plasma levels. Therefore we set up an assay that could determine the level O-linked glycans present on plasma VWF. We showed an inverse correlation between the extend of O-linked glycosylation and VWF plasma levels. Moreover, the amount of O-linked glycosylation is proportional to the VWF/ propeptide ratio. Because increased ratios may be indicative for increased clearance of VWF, the possibility exists that also modifications in O-linked glycosylation affect clearance of VWF. Also mutation in VWF may affect its plasma levels. We investigated the in vivo survival of three cysteine mutations, expressed in patients suffering from Von Willebrand Disease (VWD). We observed decreased survival of the VWF mutants in both patients an in an experimental mouse model. We explored the possibility that FVIII half-life can be predicted using VWF plasma level concentrations. Therefore we determined FVIII half-life and VWF antigen levels in severe haemophiliacs. VWF antigen levels correlated well with FVIII half-life in blood-group non-O, but poorly in severe haemophiliacs. This poor correlation for blood-group O patients could be considerably improved when VWF/propeptide ratios were used. Thus determination of VWF antigen levels and propeptide allows prediction of FVIII half-life. In order to gain more insight into the clearance mechanism of FVIII and VWF, VWF clearance was investigated in mice deficient for VWF. VWF was mainly targeted to the liver and spleen. Analysis of liver and spleen sections of VWF-deficient mice infused with FVII, VWF or the VWF/FVIII complex revealed co-localisation of all proteins with macrophages in both tissues. We also tested the contribution of macrophages to the in vivo clearance of VWF. Treatment of mice with gadolinium chloride (GdCl3) prior to VWF infusion resulted in decreased macrophage cell numbers. This resulted in a 2-fold increase of endogenous VWF in wild-type mice pre-treated with GdCl3. In addition, the survival of infused VWF was prolonged almost 2-fold in VWF-deficient mice. To study the uptake of the VWF by macrophages, we…
Subjects/Keywords: Von Willebrand Factor; Von Willebrand Disease; O-linked glycosylation; cysteine mutations; clearance mechanism; factor VIII; Von Willebrand factor/factor VIII complex; half-life; macrophages; Staphylococcus aureus protein A
Record Details
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Record Details
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❌
APA ·
Chicago ·
MLA ·
Vancouver ·
CSE |
Export
to Zotero / EndNote / Reference
Manager
APA (6th Edition):
Schooten, C. J. M. v. (2007). Von Willebrand Factor: clearance as regulator of plasma levels. (Doctoral Dissertation). University Utrecht. Retrieved from http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898
Chicago Manual of Style (16th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Doctoral Dissertation, University Utrecht. Accessed December 12, 2019.
http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898.
MLA Handbook (7th Edition):
Schooten, C J M van. “Von Willebrand Factor: clearance as regulator of plasma levels.” 2007. Web. 12 Dec 2019.
Vancouver:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Internet] [Doctoral dissertation]. University Utrecht; 2007. [cited 2019 Dec 12].
Available from: http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898.
Council of Science Editors:
Schooten CJMv. Von Willebrand Factor: clearance as regulator of plasma levels. [Doctoral Dissertation]. University Utrecht; 2007. Available from: http://dspace.library.uu.nl/handle/1874/23898 ; URN:NBN:NL:UI:10-1874-23898 ; urn:isbn:978-90-393-4649-5 ; URN:NBN:NL:UI:10-1874-23898 ; http://dspace.library.uu.nl/handle/1874/23898
.