292 research outputs found
Low-Density Lipoprotein receptor: its structure, function, and mutations
No full textUptake of cholesterol, mediated by the low-density lipoprotein (LDL)-receptor, plays a crucial role in lipoprotein metabolism. The LDL-receptor is responsible for the binding and subsequent cellular uptake of apolipoprotein B- and E-containing lipoproteins. To accomplish this, the receptor has to be transported from the site of synthesis, the membranes of the rough endoplasmatic reticulum (ER), through the Golgi apparatus, to its position on the surface of the cellular membrane. The translation of LDL-receptor messenger RNA into the polypeptide chain for the receptor protein takes place on the surface-bound ribosomes of the rough ER. Immature O-linked carbohydrate chains are attached to this integral precursor membrane protein. The molecular weight of the receptor at this stage is 120.000 d. The precursor-protein is transported from the rough ER to the Golgi apparatus, where the O-linked sugar chains are elongated until their final size is reached. The molecular weight has then increased to 160.000 d. The mature LDL-receptor is subsequently guided to the "coated pits" on the cell surface. These specialized areas of the cell membrane are rich in clathrin and interact with the LDL-receptor protein. Only here can the LDL-receptor bind LDL-particles. Within 3 to 5 minutes of its formation, the LDL-particle-receptor complex is internalized through endocytosis and is further metabolized through the receptor-mediated endocytosis pathway. Mutations in the gene coding for the LDL-receptor can interfere to a varying extent with all the different stages of the posttranslational processing, binding, uptake, and subsequent dissociation of the LDL-particle-LDL-receptor complex, but invariably the mutations lead to familial hypercholesterolemia. Thus, mutations in the LDL-receptor gene give rise to a substantially varying clinical expression of familial hypercholesterolemi
Open Data Exposed
No full textThis book is about open data, i.e. data that does not have any barriers in the (re)use. Open data aims to optimize access, sharing and using data from a technical, legal, financial, and intellectual perspective. Data increasingly determines the way people live their lives today. Nowadays, we cannot imagine a life without real-time traffic information about our route to work, information of the daily news or information about the local weather. At the same time, citizens themselves now are constantly generating and sharing data and information via many different devices and social media systems. Especially for governments, collection, management, exchange, and use of data and information have always been key tasks, since data is both the primary input to and output of government activities. Also for businesses, non-profit organizations, researchers and various other actors, data and information are essential.Green Open Access added to TU Delft Institutional Repository 'You share, we take care!' - Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public.Geo Informatio
Defining the challenges of FH screening for familial hypercholesterolemia
No full textThe purpose of this article is to briefly review but also to highlight the rationale, motivation, and methods in the process of identifying patients of all ages with familial hypercholesterolemia (FH), an often hidden but very important genetic disorder. Since the initiation of population screening for FH in 1994 in the Netherlands, a vast amount of experience has been gathered, addressing almost all issues that are encountered in population screenin
Blueprint for the STIG1.0: setting the performance indicators
No full textSpatial Data Infrastructures (SDIs) have been developed over the last decades all over the world. SDI is the integration of several components to create a platform which enables a wide variety of stakeholders to access, share and use spatial data in an efficient and effective way. To stimulate the SDI development effectively and efficiently, it is key to assess the progress and benefits of the SDI. Currently, several SDI assessment methods exist. However, most assessment methods are analyzing the SDI as a whole, which does not allow understanding their internal dynamics and none of these appear to meet the requirements of practitioners. Thus, SDI decision makers are still without any guidance on the success of their SDI.The research on this paper stands on an ongoing PhD research project on the development of a sound foundation for an academic theoretical framework for the STIG, Stress Test for Infrastructure of Geographic information. The last paper was focused on the similarities of the Financial infrastructures with the Spatial Data Infrastructures and if the financial stress testing which is commonly used to assess the sustainability and success of the financial system can be used for SDI assessment. Based on a review of the nature and concept of the SDI and Financial Infrastructure (FI) we conclude that there is significant similarity between these two infrastructures and the stress test methodology is likely to be an appealing alternative way of assessing SDIs.The purpose of this paper is to define the Core SDI Principles based on the 29 Basel Core Principles and setting up the Core SDI performance indicators. Additionally, a set of essential and additional assessment criteria for each Core SDI Principle will be defined. From all the examined types of risk factors and methods to construct financial stress tests, the Multi-factor Stress tests (Hypothetical and a Non-systematic Subjective scenario model) are most promising as a basis for SDI assessment. This hypothetical scenario first chooses and then stresses risk factors based on expert inputs including users, producers, data owners, management, consultants etc. SDI practitioners can construct hypothetical scenarios when no historical scenarios match the special features of their situation or when they want to stress new combinations of risk factors. Stress testing as a SDI assessment method once implemented in the decision-making process, can effectively increase system robustness of a SDI. When implementing stress testing, challenges remain in modeling the interaction of different risk factors and their impacts. Such things as: integrating stress testing at different levels and making stress tests workable, realistic and timely remain complicated. These issues will be addressed in the research further developing the Stress Test for Infrastructure of Geographic information: the STIG. The paper ends with a shortlist of issues for discussion on the way to move forward.OLD Geo-information and Land Developmen
The journey of the A-Portable: The pioneering movable abortion clinic designed by Joep Van Lieshout for Women on Waves
No full textThis paper analyzes the case study of the artwork A-Portable (2001) by Joep Van Lieshout commissioned by the organization for abortion rights Women on Waves (WoW), as a pioneering example of art activism. When abortion was considered a controversial topic in society, this work has successfully contributed to sharing public awareness about the risks of illegal unsafe abortions performed in countries in which this medical practice was not allowed by the government. This abortion clinic inside a shipping container sailed the ocean in several sea campaigns, and later made its debut in the art world, such as in the Exhibition at the Venice Biennale in 2001. The A-Portable is not a stand-alone example in the history of feminism, and since the 19th century with the suffragist movements, art has been frequently used as a medium in feminist history. Other examples of art activism are mentioned in the paper, such as the public performance of the feminist Serbian artist Tanja Ostojić at the same Venice Biennale, and the more recent research of the American architect and author Lori Brown, who in 2013 published the book “Contested Spaces”, about improving the architectural features of abortion clinics for women’s wellbeing.The following research takes into consideration several sources regarding the history of abortion rights and the action of WoW, to contextualize and explain the influence of art in the women’s emancipation process. Moreover, through an interview with Joep Van Lieshout, the artist’s point of view has also been crucial to find a complete answer to the research question. The final findings will demonstrate that art has always been a powerful media used by politics, and in this case, has created an opportunity for WoW to make a change in the public and private spheres. In the public, it served to stimulate people’s empathy around the topic of legal abortion, while in the private it created a safe space and a shelter from the violent opposition movements, finding physical and psychological help while performing this delicate medical procedure. Architectural History ThesisAR2A011Architecture, Urbanism and Building Science
EFFICACY OF ALIROCUMAB IN 1,191 PATIENTS WITH A WIDE SPECTRUM OF MUTATIONS IN GENES CAUSATIVE FOR FAMILIAL HYPERCHOLESTEROLEMIA
No full textBackground: Next Generation Sequencing was performed to examine treatment response with alirocumab in patients carrying one or
more causative mutation(s) in five familial hypercholesterolemia (FH) genes.
Methods: From 6 clinical trials of alirocumab (one Phase 2, five Phase 3), 1191 patients with elevated LDL-C and phenotypic FH (including
758 treated with alirocumab) were sequenced for mutations using the SEQPRO LIPO platform in LDL receptor (LDLR), apolipoprotein B
(APOB), PCSK9 (PCSK9), LDL receptor adaptor protein 1 (LDLRAP1), and signal-transducing adaptor protein 1 (STAP1) genes. New
mutations were confirmed by Sanger sequencing and MLPA analysis in case of large gene rearrangements in the original DNA samples.
Results: In total, 387 patients (32%) and 438 (37%) had single receptor defective and receptor negative mutations in LDLR, respectively;
46 (4%) had single mutations in APOB; 8 (0.7%) had single gain-of-function mutations in PCSK9; 2 (0.17%) were homozygous
for mutations in LDRAP1; 6 (0.5%) were double heterozygotes for mutations in both APOB and LDLR; 10 (0.8%) were compound
heterozygotes in LDLR; 1 (0.08%) was a double heterozygote for mutations in LDLR and PCSK9; 293 (25%) had no identifiable causative
mutation in any of the genes investigated. LDL-C reduction with alirocumab at week 12 was generally similar across background FH
mutations: LDLR defective heterozygotes -51.8% (N=231), LDLR negative heterozygotes -50.2% (N=289); APOB heterozygotes -45.5%
(N=26); PCSK9 heterozygotes -53.3% (N=5); subjects with no identifiable mutation -51.0% (N=171). A similar large decrease in LDL-C
was also seen in the 3 double heterozygotes (LDLR, APOB, -49.2%) and 6 potentially compound heterozygous (LDLR, -48.0%) patients.
Overall rates of TEAEs were similar for alirocumab vs controls, with a higher rate of injection site reactions with alirocumab.
Conclusions: In this large cohort of FH patients, individuals with a wide spectrum of mutations in genes causative for FH responded
substantially to alirocumab treatment. LDL-C-lowering activity by alirocumab in compound heterozygotes and double heterozygotes is likely
attributable to the presence of at least one partially functional allele
EAPC’s ‘Country of the Month’ prevention web section going global
No full textJanssen, A (reprint author), Jessa Hosp, Heartctr Hasselt, Clin Res Dept Cardiol, Hasselt, Belgium.
[email protected]
NLA Symposium on Familial Hypercholesterolemia Defining the challenges of FH Screening for familial hypercholesterolemia
No full textAbstract: The purpose of this article is to briefly review but also to highlight the rationale, motivation, and methods in the process of identifying patients of all ages with familial hypercholesterolemia (FH), an often hidden but very important genetic disorder. Since the initiation of population screening for FH in 1994 in the Netherlands, a vast amount of experience has been gathered, addressing almost all issues that are encountered in population screening
Familial Defective Apolipoprotein B-100 Is Clinically Indistinguishable From Familial Hypercholesterolemia
No full textSuccessful Genetic Screening and Creating Awareness of Familial Hypercholesterolemia and Other Heritable Dyslipidemias in the Netherlands
No full textThe genetic screening program for familial hypercholesterolemia (FH) in the Netherlands, which was embraced by the Dutch Ministry of Health from 1994 to 2014, has led to twenty years of identification of at least 1500 FH cases per year. Although funding by the government was terminated in 2014, the approach had proven its effectiveness and had built the foundation for the development of more sophisticated diagnostic tools, clinical collaborations, and new molecular-based treatments for FH patients. As such, the community was driven to continue the program, insurance companies were convinced to collaborate, and multiple approaches were launched to find new index cases with FH. Additionally, the screening was extended, now also including other heritable dyslipidemias. For this purpose, a diagnostic next-generation sequencing (NGS) panel was developed, which not only comprised the culprit LDLR, APOB, and PCSK9 genes, but also 24 other genes that are causally associated with genetic dyslipidemias. Moreover, the NGS technique enabled further optimization by including pharmacogenomic genes in the panel. Using such a panel, more patients that are prone to cardiovascular diseases are being identified nowadays and receive more personalized treatment. Moreover, the NGS output teaches us more and more about the dyslipidemic landscape that is less straightforward than we originally thought. Still, continuous progress is being made that underlines the strength of genetics in dyslipidemia, such as discovery of alternative genomic pathogenic mechanisms of disease development and polygenic contribution
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