Publications by authors named "Esther Willems"

10 Publications

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Technologies to improve the participation of stroke patients in their home environment.

Disabil Rehabil 2021 Oct 5:1-11. Epub 2021 Oct 5.

Care and Public Health Research Institute, Department of Health Services Research, Maastricht University, Maastricht, The Netherlands.

Purpose: To identify possible technological solutions that can contribute to stroke patients' participation at home.

Methods: In this qualitative case study, data on factors that negatively influenced participation at home were collected semi-structured interviews with stroke patients ( = 6). Additionally, data on possible technologies to improve this participation were collected a group interview with experts ( = 4). The domains "cognition, mobility, self-care, and getting along" (International Classification of Functioning, Disability and Health) guided the data collection and interpretation; open, axial and selective coding was part of the analysis.

Results: Patients reported 21 factors negatively influencing participation at home, including psychological, cognitive, and physical factors. Experts suggested technological solutions regarding these factors to increase participation of stroke patients; digital assistants, apps, and virtual reality were frequently mentioned. To facilitate the use of these technologies, experts indicated the importance of involving patients in their design. They also suggested that rehabilitation specialists and family members could support the uptake and use of technologies.

Conclusions: Various technologies were identified by experts as having the potential to improve the participation of stroke patients in their homes. Future research may study the influence of these technologies on the actual participation of stroke patients at home.Implications for rehabilitationThe identified technological solutions can support rehabilitation specialists in guiding stroke patients towards technologies that can support a patient's participation at home.Rehabilitation specialists can be champions in introducing, recommending and promoting technologies to stroke patients and their families, as well as in training them to use technologies.Virtual reality as a technology can be part of rehabilitation, not only to train stroke patients in daily life activities but also to increase empathy and understanding in caregivers and carers on stroke impairments.Rehabilitation specialists can recommend technologies integrated in daily life and presented as general consumer goods; stroke patients are more likely to adopt these kind of technologies.
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http://dx.doi.org/10.1080/09638288.2021.1983041DOI Listing
October 2021

Common haplotypes at the CFH locus and low-frequency variants in CFHR2 and CFHR5 associate with systemic FHR concentrations and age-related macular degeneration.

Am J Hum Genet 2021 08 13;108(8):1367-1384. Epub 2021 Jul 13.

Department of Ophthalmology, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Center, Nijmegen, 6525EX, the Netherlands; Department of Human Genetics, Donders Institute for Brain, Cognition and Behaviour, Radboud University Medical Centre, 6525GA, the Netherlands. Electronic address:

Age-related macular degeneration (AMD) is the principal cause of blindness in the elderly population. A strong effect on AMD risk has been reported for genetic variants at the CFH locus, encompassing complement factor H (CFH) and the complement-factor-H-related (CFHR) genes, but the underlying mechanisms are not fully understood. We aimed to dissect the role of factor H (FH) and FH-related (FHR) proteins in AMD in a cohort of 202 controls and 216 individuals with AMD. We detected elevated systemic levels of FHR-1 (p = 1.84 × 10), FHR-2 (p = 1.47 × 10), FHR-3 (p = 1.05 × 10) and FHR-4A (p = 1.22 × 10) in AMD, whereas FH concentrations remained unchanged. Common AMD genetic variants and haplotypes at the CFH locus strongly associated with FHR protein concentrations (e.g., FH p.Tyr402His and FHR-2 concentrations, p = 3.68 × 10), whereas the association with FH concentrations was limited. Furthermore, in an International AMD Genomics Consortium cohort of 17,596 controls and 15,894 individuals with AMD, we found that low-frequency and rare protein-altering CFHR2 and CFHR5 variants associated with AMD independently of all previously reported genome-wide association study (GWAS) signals (p = 5.03 × 10 and p = 2.81 × 10, respectively). Low-frequency variants in CFHR2 and CFHR5 led to reduced or absent FHR-2 and FHR-5 concentrations (e.g., p.Cys72Tyr in CFHR2 and FHR-2, p = 2.46 × 10). Finally, we showed localization of FHR-2 and FHR-5 in the choriocapillaris and in drusen. Our study identifies FHR proteins as key proteins in the AMD disease mechanism. Consequently, therapies that modulate FHR proteins might be effective for treating or preventing progression of AMD. Such therapies could target specific individuals with AMD on the basis of their genotypes at the CFH locus.
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http://dx.doi.org/10.1016/j.ajhg.2021.06.002DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387287PMC
August 2021

Quantitative multiplex profiling of the complement system to diagnose complement-mediated diseases.

Clin Transl Immunology 2020 9;9(12):e1225. Epub 2020 Dec 9.

Laboratory of Medical Immunology Department of Laboratory Medicine Radboud Institute for Molecular Life Sciences Radboud University Medical Center Nijmegen The Netherlands.

Objectives: Complement deficiencies are difficult to diagnose because of the variability of symptoms and the complexity of the diagnostic process. Here, we applied a novel 'complementomics' approach to study the impact of various complement deficiencies on circulating complement levels.

Methods: Using a quantitative multiplex mass spectrometry assay, we analysed 44 peptides to profile 34 complement proteins simultaneously in 40 healthy controls and 83 individuals with a diagnosed deficiency or a potential pathogenic variant in 14 different complement proteins.

Results: Apart from confirming near or total absence of the respective protein in plasma of complement-deficient patients, this mass spectrometry-based profiling method led to the identification of additional deficiencies. In many cases, partial depletion of the pathway up- and/or downstream of the absent protein was measured. This was especially found in patients deficient for complement inhibitors, such as angioedema patients with a C1-inhibitor deficiency. The added value of complementomics was shown in three patients with poorly defined complement deficiencies.

Conclusion: Our study shows the potential clinical utility of profiling circulating complement proteins as a comprehensive read-out of various complement deficiencies. Particularly, our approach provides insight into the intricate interplay between complement proteins due to functional coupling, which contributes to the better understanding of the various disease phenotypes and improvement of care for patients with complement-mediated diseases.
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http://dx.doi.org/10.1002/cti2.1225DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7724921PMC
December 2020

Biosynthetic homeostasis and resilience of the complement system in health and infectious disease.

EBioMedicine 2019 Jul 29;45:303-313. Epub 2019 Jun 29.

Section Pediatric Infectious Diseases, Laboratory of Medical Immunology, Department of Laboratory Medicine, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands; Radboud Center for Infectious Diseases, Radboud University Medical Center, Nijmegen, The Netherlands.

Background: The complement system is a central component of the innate immune system. Constitutive biosynthesis of complement proteins is essential for homeostasis. Dysregulation as a consequence of genetic or environmental cues can lead to inflammatory syndromes or increased susceptibility to infection. However, very little is known about steady state levels in children or its kinetics during infection.

Methods: With a newly developed multiplex mass spectrometry-based method we analyzed the levels of 32 complement proteins in healthy individuals and in a group of pediatric patients infected with bacterial or viral pathogens.

Findings: In plasma from young infants we found reduced levels of C4BP, ficolin-3, factor B, classical pathway components C1QA, C1QB, C1QC, C1R, and terminal pathway components C5, C8, C9, as compared to healthy adults; whereas the majority of complement regulating (inhibitory) proteins reach adult levels at very young age. Both viral and bacterial infections in children generally lead to a slight overall increase in complement levels, with some exceptions. The kinetics of complement levels during invasive bacterial infections only showed minor changes, except for a significant increase and decrease of CRP and clusterin, respectively.

Interpretation: The combination of lower levels of activating and higher levels of regulating complement proteins, would potentially raise the threshold of activation, which might lead to suppressed complement activation in the first phase of life. There is hardly any measurable complement consumption during bacterial or viral infection. Altogether, expression of the complement proteins appears surprisingly stable, which suggests that the system is continuously replenished. FUND: European Union's Horizon 2020, project PERFORM, grant agreement No. 668303.
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http://dx.doi.org/10.1016/j.ebiom.2019.06.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642076PMC
July 2019

Promoter Mutations Ablate GABP Transcription Factor Binding in Melanoma.

Cancer Res 2017 04 20;77(7):1649-1661. Epub 2017 Jan 20.

Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, NCI, NIH, Bethesda, Maryland.

encodes subunit D of the succinate dehydrogenase complex, an integral membrane protein. Across cancer types, recurrent promoter mutations were reported to occur exclusively in melanomas, at a frequency of 4% to 5%. These mutations are predicted to disrupt consensus ETS transcription factor-binding sites and are correlated with both reduced gene expression and poor prognosis. However, the consequence of these mutations on expression in melanoma is still unclear. Here, we found that expression of in melanoma correlated with the expression of multiple ETS transcription factors, particularly in promoter wild-type samples. Consistent with the predicted loss of ETS transcription factor binding, we observed that recurrent hotspot mutations resulted in decreased luciferase activity in reporter assays. Furthermore, we demonstrated specific GABPA and GABPB1 binding to probes containing the wild-type promoter sequences, with binding disrupted by the hotspot promoter mutations in both quantitative mass spectrometry and band-shift experiments. Finally, using siRNA-mediated knockdown across multiple melanoma cell lines, we determined that loss of GABPA resulted in reduced SDHD expression at both RNA and protein levels. These data are consistent with a key role for GABPA/B1 as the critical ETS transcription factors deregulating expression in the context of highly recurrent promoter mutations in melanoma and warrant a detailed search for other recurrent promoter mutations that create or disrupt GABPA consensus sequences. .
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http://dx.doi.org/10.1158/0008-5472.CAN-16-0919DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6711603PMC
April 2017

Clinical diagnostics and therapy monitoring in the congenital disorders of glycosylation.

Glycoconj J 2016 06 7;33(3):345-58. Epub 2016 Jan 7.

Translational Metabolic Laboratory, Radboud University Medical Center, Geert Grooteplein 10, Nijmegen, 6525 GA, The Netherlands.

Abnormal protein glycosylation is observed in many common disorders like cancer, inflammation, Alzheimer's disease and diabetes. However, the actual use of this information in clinical diagnostics is still very limited. Information is usually derived from analysis of total serum N-glycan profiling methods, whereas the current use of glycoprotein biomarkers in the clinical setting is commonly based on protein levels. It can be envisioned that combining protein levels and their glycan isoforms would increase specificity for early diagnosis and therapy monitoring. To establish diagnostic assays, based on the mass spectrometric analysis of protein-specific glycosylation abnormalities, still many technical improvements have to be made. In addition, clinical validation is equally important as well as an understanding of the genetic and environmental factors that determine the protein-specific glycosylation abnormalities. Important lessons can be learned from the group of monogenic disorders in the glycosylation pathway, the Congenital Disorders of Glycosylation (CDG). Now that more and more genetic defects are being unraveled, we start to learn how genetic factors influence glycomics profiles of individual and total serum proteins. Although only in its initial stages, such studies suggest the importance to establish diagnostic assays for protein-specific glycosylation profiling, and the need to look beyond the single glycoprotein diagnostic test. Here, we review progress in and lessons from genetic disease, and review the increasing opportunities of mass spectrometry to analyze protein glycosylation in the clinical diagnostic setting. Furthermore, we will discuss the possibilities to expand current CDG diagnostics and how this can be used to approach glycoprotein biomarkers for more common diseases.
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http://dx.doi.org/10.1007/s10719-015-9639-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4891361PMC
June 2016

Cross-linking immunoprecipitation-MS (xIP-MS): Topological Analysis of Chromatin-associated Protein Complexes Using Single Affinity Purification.

Mol Cell Proteomics 2016 Mar 11;15(3):854-65. Epub 2015 Nov 11.

From the ‡Radboud Institute for Molecular Life Sciences, Radboud University Nijmegen, Geert Grooteplein 28, 6525 GA Nijmegen, the Netherlands; §Cancer Genomics Netherlands, University Medical Center Utrecht, 3584 CG Utrecht, the Netherlands

In recent years, cross-linking mass spectrometry has proven to be a robust and effective method of interrogating macromolecular protein complex topologies at peptide resolution. Traditionally, cross-linking mass spectrometry workflows have utilized homogenous complexes obtained through time-limiting reconstitution, tandem affinity purification, and conventional chromatography workflows. Here, we present cross-linking immunoprecipitation-MS (xIP-MS), a simple, rapid, and efficient method for structurally probing chromatin-associated protein complexes using small volumes of mammalian whole cell lysates, single affinity purification, and on-bead cross-linking followed by LC-MS/MS analysis. We first benchmarked xIP-MS using the structurally well-characterized phosphoribosyl pyrophosphate synthetase complex. We then applied xIP-MS to the chromatin-associated cohesin (SMC1A/3), XRCC5/6 (Ku70/86), and MCM complexes, and we provide novel structural and biological insights into their architectures and molecular function. Of note, we use xIP-MS to perform topological studies under cell cycle perturbations, showing that the xIP-MS protocol is sufficiently straightforward and efficient to allow comparative cross-linking experiments. This work, therefore, demonstrates that xIP-MS is a robust, flexible, and widely applicable methodology for interrogating chromatin-associated protein complex architectures.
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http://dx.doi.org/10.1074/mcp.M115.053082DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4813705PMC
March 2016

An interaction proteomics survey of transcription factor binding at recurrent TERT promoter mutations.

Proteomics 2016 Feb 8;16(3):417-26. Epub 2016 Jan 8.

Radboud Institute of Molecular Life Sciences, Radboud University Nijmegen, Nijmegen, The Netherlands.

Aberrant telomerase reactivation in differentiated cells represents a major event in oncogenic transformation. Recurrent somatic mutations in the human telomerase reverse transcriptase (TERT) promoter region, predominantly localized to two nucleotide positions, are highly prevalent in many cancer types. Both mutations create novel consensus E26 transformation-specific (ETS) motifs and are associated with increased TERT expression. Here, we perform an unbiased proteome-wide survey of transcription factor binding at TERT promoter mutations in melanoma. We observe ELF1 binding at both mutations in vitro and we show that increased recruitment of GABP is enabled by the spatial architecture of native and novel ETS motifs in the TERT promoter region. We characterize the dynamics of competitive binding between ELF1 and GABP and provide evidence for ELF1 exclusion by transcriptionally active GABP. This study thus provides an important description of proteome-wide, mutation-specific binding at the recurrent, oncogenic TERT promoter mutations.
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http://dx.doi.org/10.1002/pmic.201500327DOI Listing
February 2016

The effect of tissue degradation on detection of infectious virus and viral RNA to diagnose classical swine fever virus.

Vet Microbiol 2010 Mar 26;141(3-4):275-81. Epub 2009 Sep 26.

Department of Virology, Central Veterinary Institute of Wageningen UR, P.O. Box 65, 8200 AB Lelystad, The Netherlands.

A considerable part of tissue samples that are collected for the monitoring of classical swine fever (CSF) from the wild boar population or from domestic pigs are unsuitable for virus detection using the fluorescent antibody test (FAT) or virus isolation (VI), due to tissue degradation. Reverse transcription polymerase chain reaction (RT-PCR) has a higher sensitivity than the FAT and VI, and is supposed to be less sensitive to sample degradation. Reliable and quantitative information on how long viral RNA and infectious virus can be detected in organs and which organs are most susceptible to degradation is, however, lacking. In the present study we generated survival curves of infectious CSF virus (CSFV) and viral RNA in the tonsil, mesenteric lymph node, spleen and kidney, obtained from 24 pigs infected with a moderately virulent CSFV strain. Tissue samples were stored at room temperature and tested by VI and RT-PCR, directly after storage and 1, 2, 3, 4, 7, 14 and 21 days later. It was shown that the RT-PCR is not only more sensitive than VI on fresh tissue samples, but RT-PCR is also less vulnerable to sample degradation. Average half-life values of viral RNA in the tissues ranged from 0.95 to 2.55 days, while half-life values of infectious virus ranged from 0.21 to 0.31 days. The tonsil and spleen are regarded as the most appropriate organs for the detection of infectious virus and viral RNA, not only in fresh samples, but also in samples that suffer from tissue degradation.
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http://dx.doi.org/10.1016/j.vetmic.2009.09.028DOI Listing
March 2010

The mitochondrial prohibitin complex is essential for embryonic viability and germline function in Caenorhabditis elegans.

J Biol Chem 2003 Aug 6;278(34):32091-9. Epub 2003 Jun 6.

Swammerdam Institute for Life Sciences, Section for Molecular Biology, University of Amsterdam, Kruislaan 318, Amsterdam 1098 SM, The Netherlands.

Prohibitins in eukaryotes consist of two subunits (PHB1 and PHB2) that together form a high molecular weight complex in the mitochondrial inner membrane. The evolutionary conservation and the ubiquitous expression in mammalian tissues of the prohibitin complex suggest an important function among eukaryotes. The PHB complex has been shown to play a role in the stabilization of newly synthesized subunits of mitochondrial respiratory enzymes in the yeast Saccharomyces cerevisiae. We have used Caenorhabditis elegans as model system to study the role of the PHB complex during development of a multicellular organism. We demonstrate that prohibitins in C. elegans form a high molecular weight complex in the mitochondrial inner membrane similar to that of yeast and humans. By using RNA-mediated gene inactivation, we show that PHB proteins are essential during embryonic development and are required for somatic and germline differentiation in the larval gonad. We further demonstrate that a deficiency in PHB proteins results in altered mitochondrial biogenesis in body wall muscle cells. This paper reports a strong loss of function phenotype for prohibitin gene inactivation in a multicellular organism and shows for the first time that prohibitins serve an essential role in mitochondrial function during organismal development.
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http://dx.doi.org/10.1074/jbc.M304877200DOI Listing
August 2003
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