394 results on '"Aalten P"'
Search Results
2. Inhibition of glycogen synthase kinase-3 enhances NRF2 protein stability, nuclear localisation and target gene transcription in pancreatic beta cells
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Chinmai Patibandla, Lidy van Aalten, Albena T. Dinkova-Kostova, Tadashi Honda, Antonio Cuadrado, Raquel Fernández-Ginés, Alison D. McNeilly, John D. Hayes, James Cantley, and Calum Sutherland
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NRF2 ,GSK3 ,β-TrCP ,β cells ,Islets ,Medicine (General) ,R5-920 ,Biology (General) ,QH301-705.5 - Abstract
Accumulation of reactive oxygen species (i.e., oxidative stress) is a leading cause of beta cell dysfunction and apoptosis in diabetes. NRF2 (NF-E2 p45-related factor-2) regulates the adaptation to oxidative stress, and its activity is negatively regulated by the redox-sensitive CUL3 (cullin-3) ubiquitin ligase substrate adaptor KEAP1 (Kelch-like ECH-associated protein-1). Additionally, NRF2 is repressed by the insulin-regulated Glycogen Synthase Kinase-3 (GSK3). We have demonstrated that phosphorylation of NRF2 by GSK3 enhances β-TrCP (beta-transducin repeat-containing protein) binding and ubiquitylation by CUL1 (cullin-1), resulting in increased proteasomal degradation of NRF2. Thus, we hypothesise that inhibition of GSK3 activity or β-TrCP binding upregulates NRF2 and so protects beta cells against oxidative stress. We have found that treating the pancreatic beta cell line INS-1 832/13 with the KEAP1 inhibitor TBE31 significantly enhanced NRF2 protein levels. The presence of the GSK3 inhibitor CT99021 or the β-TrCP-NRF2 protein-protein interaction inhibitor PHAR, along with TBE31, resulted in prolonged NRF2 stability and enhanced nuclear localisation (P
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- 2024
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3. Neurodevelopmental defects in a mouse model of O-GlcNAc transferase intellectual disability
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Florence Authier, Nina Ondruskova, Andrew T. Ferenbach, Alison D. McNeilly, and Daan M. F. van Aalten
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intellectual disability ,o-glcnacylation ,vertebrate development ,Medicine ,Pathology ,RB1-214 - Published
- 2024
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4. Tissue-specific O-GlcNAcylation profiling identifies substrates in translational machinery in Drosophila mushroom body contributing to olfactory learning
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Haibin Yu, Dandan Liu, Yaowen Zhang, Ruijun Tang, Xunan Fan, Song Mao, Lu Lv, Fang Chen, Hongtao Qin, Zhuohua Zhang, Daan MF van Aalten, Bing Yang, and Kai Yuan
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O-GlcNAcylation ,mushroom body ,olfactory learning ,translation ,ribosome ,Medicine ,Science ,Biology (General) ,QH301-705.5 - Abstract
O-GlcNAcylation is a dynamic post-translational modification that diversifies the proteome. Its dysregulation is associated with neurological disorders that impair cognitive function, and yet identification of phenotype-relevant candidate substrates in a brain-region specific manner remains unfeasible. By combining an O-GlcNAc binding activity derived from Clostridium perfringens OGA (CpOGA) with TurboID proximity labeling in Drosophila, we developed an O-GlcNAcylation profiling tool that translates O-GlcNAc modification into biotin conjugation for tissue-specific candidate substrates enrichment. We mapped the O-GlcNAc interactome in major brain regions of Drosophila and found that components of the translational machinery, particularly ribosomal subunits, were abundantly O-GlcNAcylated in the mushroom body of Drosophila brain. Hypo-O-GlcNAcylation induced by ectopic expression of active CpOGA in the mushroom body decreased local translational activity, leading to olfactory learning deficits that could be rescued by dMyc overexpression-induced increase of protein synthesis. Our study provides a useful tool for future dissection of tissue-specific functions of O-GlcNAcylation in Drosophila, and suggests a possibility that O-GlcNAcylation impacts cognitive function via regulating regional translational activity in the brain.
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- 2024
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5. A smartphone- and wearable-based biomarker for the estimation of unipolar depression severity
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Ahnjili Zhuparris, Ghobad Maleki, Liesbeth van Londen, Ingrid Koopmans, Vincent Aalten, Iris E. Yocarini, Vasileios Exadaktylos, Albert van Hemert, Adam Cohen, Pim Gal, Robert-Jan Doll, Geert Jan Groeneveld, Gabriël Jacobs, and Wessel Kraaij
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Medicine ,Science - Abstract
Abstract Drug development for mood disorders can greatly benefit from the development of robust, reliable, and objective biomarkers. The incorporation of smartphones and wearable devices in clinical trials provide a unique opportunity to monitor behavior in a non-invasive manner. The objective of this study is to identify the correlations between remotely monitored self-reported assessments and objectively measured activities with depression severity assessments often applied in clinical trials. 30 unipolar depressed patients and 29 age- and gender-matched healthy controls were enrolled in this study. Each participant’s daily physiological, physical, and social activity were monitored using a smartphone-based application (CHDR MORE™) for 3 weeks continuously. Self-reported depression anxiety stress scale-21 (DASS-21) and positive and negative affect schedule (PANAS) were administered via smartphone weekly and daily respectively. The structured interview guide for the Hamilton depression scale and inventory of depressive symptomatology–clinical rated (SIGHD-IDSC) was administered in-clinic weekly. Nested cross-validated linear mixed-effects models were used to identify the correlation between the CHDR MORE™ features with the weekly in-clinic SIGHD-IDSC scores. The SIGHD-IDSC regression model demonstrated an explained variance (R2) of 0.80, and a Root Mean Square Error (RMSE) of ± 15 points. The SIGHD-IDSC total scores were positively correlated with the DASS and mean steps-per-minute, and negatively correlated with the travel duration. Unobtrusive, remotely monitored behavior and self-reported outcomes are correlated with depression severity. While these features cannot replace the SIGHD-IDSC for estimating depression severity, it can serve as a complementary approach for assessing depression and drug effects outside the clinic.
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- 2023
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6. A smartphone- and wearable-based biomarker for the estimation of unipolar depression severity
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Zhuparris, Ahnjili, Maleki, Ghobad, van Londen, Liesbeth, Koopmans, Ingrid, Aalten, Vincent, Yocarini, Iris E., Exadaktylos, Vasileios, van Hemert, Albert, Cohen, Adam, Gal, Pim, Doll, Robert-Jan, Groeneveld, Geert Jan, Jacobs, Gabriël, and Kraaij, Wessel
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- 2023
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7. Cross-Cohort Generalizability of Deep and Conventional Machine Learning for MRI-based Diagnosis and Prediction of Alzheimer's Disease
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Bron, Esther E., Klein, Stefan, Papma, Janne M., Jiskoot, Lize C., Venkatraghavan, Vikram, Linders, Jara, Aalten, Pauline, De Deyn, Peter Paul, Biessels, Geert Jan, Claassen, Jurgen A. H. R., Middelkoop, Huub A. M., Smits, Marion, Niessen, Wiro J., van Swieten, John C., van der Flier, Wiesje M., Ramakers, Inez H. G. B., and van der Lugt, Aad
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Electrical Engineering and Systems Science - Image and Video Processing ,Computer Science - Computer Vision and Pattern Recognition ,Physics - Medical Physics - Abstract
This work validates the generalizability of MRI-based classification of Alzheimer's disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI). We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the ADNI (334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia. AD-CN classification based on modulated GM maps resulted in a similar AUC for SVM (0.940) and CNN (0.933). Application to conversion prediction in MCI yielded significantly higher performance for SVM (0.756) than for CNN (0.742). In external validation, performance was slightly decreased. For AD-CN, it again gave similar AUCs for SVM (0.896) and CNN (0.876). For prediction in MCI, performances decreased for both SVM (0.665) and CNN (0.702). Both with SVM and CNN, classification based on modulated GM maps significantly outperformed classification based on minimally processed images. Deep and conventional classifiers performed equally well for AD classification and their performance decreased only slightly when applied to the external cohort. We expect that this work on external validation contributes towards translation of machine learning to clinical practice.
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- 2020
8. Long-term oncological outcomes after local excision of T1 rectal cancer
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Leijtens, J. W. A., Smits, L. J. H., Koedam, T. W. A., Orsini, R. G., van Aalten, S. M., Verseveld, M., Doornebosch, P. G., de Graaf, E. J. R., and Tuynman, J. B.
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- 2023
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9. Metformin increases the uptake of glucose into the gut from the circulation in high-fat diet-fed male mice, which is enhanced by a reduction in whole-body Slc2a2 expression
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Nicola Morrice, Susanne Vainio, Kirsi Mikkola, Lidy van Aalten, Jennifer R. Gallagher, Michael L.J. Ashford, Alison D. McNeilly, Rory J. McCrimmon, Alexandra Grosfeld, Patricia Serradas, Jukka Koffert, Ewan R. Pearson, Pirjo Nuutila, and Calum Sutherland
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Diabetes ,Metformin ,Slc2a2 ,Glucose-uptake ,[18F]FDG-PET ,Internal medicine ,RC31-1245 - Abstract
Objectives: Metformin is the first line therapy recommended for type 2 diabetes. However, the precise mechanism of action remains unclear and up to a quarter of patients show some degree of intolerance to the drug, with a similar number showing poor response to treatment, limiting its effectiveness. A better understanding of the mechanism of action of metformin may improve its clinical use. SLC2A2 (GLUT2) is a transmembrane facilitated glucose transporter, with important roles in the liver, gut and pancreas. Our group previously identified single nucleotide polymorphisms in the human SLC2A2 gene, which were associated with reduced transporter expression and an improved response to metformin treatment. The aims of this study were to model Slc2a2 deficiency and measure the impact on glucose homoeostasis and metformin response in mice. Methods: We performed extensive metabolic phenotyping and 2-deoxy-2-[18F]fluoro-d-glucose ([18F]FDG)-positron emission tomography (PET) analysis of gut glucose uptake in high-fat diet-fed (HFD) mice with whole-body reduced Slc2a2 (Slc2a2+/−) and intestinal Slc2a2 KO, to assess the impact of metformin treatment. Results: Slc2a2 partial deficiency had no major impact on body weight and insulin sensitivity, however mice with whole-body reduced Slc2a2 expression (Slc2a2+/−) developed an age-related decline in glucose homoeostasis (as measured by glucose tolerance test) compared to wild-type (Slc2a2+/+) littermates. Glucose uptake into the gut from the circulation was enhanced by metformin exposure in Slc2a2+/+ animals fed HFD and this action of the drug was significantly higher in Slc2a2+/− animals. However, there was no effect of specifically knocking-out Slc2a2 in the mouse intestinal epithelial cells. Conclusions: Overall, this work identifies a differential metformin response, dependent on expression of the SLC2A2 glucose transporter, and also adds to the growing evidence that metformin efficacy includes modifying glucose transport in the gut. We also describe a novel and important role for this transporter in maintaining efficient glucose homoeostasis during ageing.
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- 2023
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10. Diagnostic and economic evaluation of new biomarkers for Alzheimer’s disease: the research protocol of a prospective cohort study
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Handels Ron LH, Aalten Pauline, Wolfs Claire AG, OldeRikkert Marcel, Scheltens Philip, Visser Pieter, Joore Manuela A, Severens Johan L, and Verhey Frans RJ
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Neurology. Diseases of the nervous system ,RC346-429 - Abstract
Abstract Background New research criteria for the diagnosis of Alzheimer’s disease (AD) have recently been developed to enable an early diagnosis of AD pathophysiology by relying on emerging biomarkers. To enable efficient allocation of health care resources, evidence is needed to support decision makers on the adoption of emerging biomarkers in clinical practice. The research goals are to 1) assess the diagnostic test accuracy of current clinical diagnostic work-up and emerging biomarkers in MRI, PET and CSF, 2) perform a cost-consequence analysis and 3) assess long-term cost-effectiveness by an economic model. Methods/design In a cohort design 241 consecutive patients suspected of having a primary neurodegenerative disease are approached in four academic memory clinics and followed for two years. Clinical data and data on quality of life, costs and emerging biomarkers are gathered. Diagnostic test accuracy is determined by relating the clinical practice and new research criteria diagnoses to a reference diagnosis. The clinical practice diagnosis at baseline is reflected by a consensus procedure among experts using clinical information only (no biomarkers). The diagnosis based on the new research criteria is reflected by decision rules that combine clinical and biomarker information. The reference diagnosis is determined by a consensus procedure among experts based on clinical information on the course of symptoms over a two-year time period. A decision analytic model is built combining available evidence from different resources among which (accuracy) results from the study, literature and expert opinion to assess long-term cost-effectiveness of the emerging biomarkers. Discussion Several other multi-centre trials study the relative value of new biomarkers for early evaluation of AD and related disorders. The uniqueness of this study is the assessment of resource utilization and quality of life to enable an economic evaluation. The study results are generalizable to a population of patients who are referred to a memory clinic due to their memory problems. Trial registration NCT01450891
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- 2012
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11. An O-GlcNAc transferase pathogenic variant linked to intellectual disability affects pluripotent stem cell self-renewal
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Michaela Omelková, Christina Dühring Fenger, Marta Murray, Trine Bjørg Hammer, Veronica M. Pravata, Sergio Galan Bartual, Ignacy Czajewski, Allan Bayat, Andrew T. Ferenbach, Marios P. Stavridis, and Daan M. F. van Aalten
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ogt ,o-glcnac ,congenital disorders of glycosylation ,intellectual disability ,stem cells ,self-renewal ,Medicine ,Pathology ,RB1-214 - Published
- 2023
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12. O-GlcNAcylation enhances CPS1 catalytic efficiency for ammonia and promotes ureagenesis
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Soria, Leandro R., Makris, Georgios, D’Alessio, Alfonso M., De Angelis, Angela, Boffa, Iolanda, Pravata, Veronica M., Rüfenacht, Véronique, Attanasio, Sergio, Nusco, Edoardo, Arena, Paola, Ferenbach, Andrew T., Paris, Debora, Cuomo, Paola, Motta, Andrea, Nitzahn, Matthew, Lipshutz, Gerald S., Martínez-Pizarro, Ainhoa, Richard, Eva, Desviat, Lourdes R., Häberle, Johannes, van Aalten, Daan M. F., and Brunetti-Pierri, Nicola
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- 2022
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13. Author Correction: The active site of O-GlcNAc transferase imposes constraints on substrate sequence
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Pathak, Shalini, Alonso, Jana, Schimpl, Marianne, Rafie, Karim, Blair, David E., Borodkin, Vladimir S., Schüttelkopf, Alexander W., Albarbarawi, Osama, and van Aalten, Daan M. F.
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- 2023
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14. Association of Cerebral Amyloid-β Aggregation With Cognitive Functioning in Persons Without Dementia
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Jansen, Willemijn J, Ossenkoppele, Rik, Tijms, Betty M, Fagan, Anne M, Hansson, Oskar, Klunk, William E, van der Flier, Wiesje M, Villemagne, Victor L, Frisoni, Giovanni B, Fleisher, Adam S, Lleó, Alberto, Mintun, Mark A, Wallin, Anders, Engelborghs, Sebastiaan, Na, Duk L, Chételat, Gäel, Molinuevo, José Luis, Landau, Susan M, Mattsson, Niklas, Kornhuber, Johannes, Sabri, Osama, Rowe, Christopher C, Parnetti, Lucilla, Popp, Julius, Fladby, Tormod, Jagust, William J, Aalten, Pauline, Lee, Dong Young, Vandenberghe, Rik, de Oliveira, Catarina Resende, Kapaki, Elisabeth, Froelich, Lutz, Ivanoiu, Adrian, Gabryelewicz, Tomasz, Verbeek, Marcel M, Sanchez-Juan, Páscual, Hildebrandt, Helmut, Camus, Vincent, Zboch, Marzena, Brooks, David J, Drzezga, Alexander, Rinne, Juha O, Newberg, Andrew, de Mendonça, Alexandre, Sarazin, Marie, Rabinovici, Gil D, Madsen, Karine, Kramberger, Milica G, Nordberg, Agneta, Mok, Vincent, Mroczko, Barbara, Wolk, David A, Meyer, Philipp T, Tsolaki, Magda, Scheltens, Philip, Verhey, Frans RJ, Visser, Pieter Jelle, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart NM, Blennow, Kaj, van Buchem, Mark A, Cavedo, Enrica, Chen, Kewei, Chipi, Elena, Cohen, Ann D, Förster, Stefan, Fortea, Juan, Frederiksen, Kristian S, Freund-Levi, Yvonne, Gkatzima, Olymbia, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Johannsen, Peter, Klimkowicz-Mrowiec, Aleksandra, Köhler, Sebastian, Koglin, Norman, van Laere, Koen, de Leon, Mony, Lisetti, Viviana, Maier, Wolfgang, Marcusson, Jan, Meulenbroek, Olga, Møllergård, Hanne M, Morris, John C, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Perera, Gayan, Peters, Oliver, and Ramakers, Inez HGB
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Health Services and Systems ,Health Sciences ,Acquired Cognitive Impairment ,Alzheimer's Disease Related Dementias (ADRD) ,Neurosciences ,Aging ,Dementia ,Brain Disorders ,Behavioral and Social Science ,Neurodegenerative ,Alzheimer's Disease ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Clinical Research ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Mental health ,Aged ,Alzheimer Disease ,Amyloid beta-Peptides ,Brain ,Cognition Disorders ,Cognitive Dysfunction ,Cross-Sectional Studies ,Female ,Humans ,Male ,Memory ,Episodic ,Mental Status and Dementia Tests ,Middle Aged ,Positron-Emission Tomography ,Reference Values ,Amyloid Biomarker Study Group ,Other Medical and Health Sciences ,Psychology ,Cognitive Sciences ,Clinical sciences ,Clinical and health psychology - Abstract
ImportanceCerebral amyloid-β aggregation is an early event in Alzheimer disease (AD). Understanding the association between amyloid aggregation and cognitive manifestation in persons without dementia is important for a better understanding of the course of AD and for the design of prevention trials.ObjectiveTo investigate whether amyloid-β aggregation is associated with cognitive functioning in persons without dementia.Design, setting, and participantsThis cross-sectional study included 2908 participants with normal cognition and 4133 with mild cognitive impairment (MCI) from 53 studies in the multicenter Amyloid Biomarker Study. Normal cognition was defined as having no cognitive concerns for which medical help was sought and scores within the normal range on cognitive tests. Mild cognitive impairment was diagnosed according to published criteria. Study inclusion began in 2013 and is ongoing. Data analysis was performed in January 2017.Main outcomes and measuresGlobal cognitive performance as assessed by the Mini-Mental State Examination (MMSE) and episodic memory performance as assessed by a verbal word learning test. Amyloid aggregation was measured with positron emission tomography or cerebrospinal fluid biomarkers and dichotomized as negative (normal) or positive (abnormal) according to study-specific cutoffs. Generalized estimating equations were used to examine the association between amyloid aggregation and low cognitive scores (MMSE score ≤27 or memory z score≤-1.28) and to assess whether this association was moderated by age, sex, educational level, or apolipoprotein E genotype.ResultsAmong 2908 persons with normal cognition (mean [SD] age, 67.4 [12.8] years), amyloid positivity was associated with low memory scores after age 70 years (mean difference in amyloid positive vs negative, 4% [95% CI, 0%-7%] at 72 years and 21% [95% CI, 10%-33%] at 90 years) but was not associated with low MMSE scores (mean difference, 3% [95% CI, -1% to 6%], P = .16). Among 4133 patients with MCI (mean [SD] age, 70.2 [8.5] years), amyloid positivity was associated with low memory (mean difference, 16% [95% CI, 12%-20%], P
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- 2018
15. Laparoscopic Lavage in Complicated Diverticulitis with Colonic Perforation, Always Be Closing?
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Jasper Sijberden, Heleen Snijders, and Susanna van Aalten
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colonic diverticulitis ,perforation ,purulent peritonitis ,laparoscopic lavage ,surgical technique ,Diseases of the digestive system. Gastroenterology ,RC799-869 - Abstract
Laparoscopic lavage is seen as an acceptable alternative to colonic resection in selected patients with acute diverticulitis with purulent peritonitis. There is no consensus on what surgical technique should be used when performing this procedure. This case series describes the disease course of 3 patients with acute diverticulitis with purulent peritonitis treated with laparoscopic lavage and direct suturing of a colonic perforation. All patients (38- and 71-year-old males and a 44-year-old female) were seen in the emergency department due to acute lower abdominal pain. Clinical examination and laboratory and imaging studies were suggestive of perforated diverticular disease. Laparoscopic lavage with placement of drain(s) and direct suturing of a colonic perforation was performed. Postoperative treatment with intravenous antibiotics was continued for a variable term. Postoperative courses were uneventful. Patients were discharged on postoperative days 5, 5, and 7. At almost 1-year follow-up, all patients are in good clinical condition and have not had a recurrent episode of diverticulitis. Therefore, this case series shows promising results of laparoscopic lavage with direct suturing of colonic perforation in patients with diverticulitis with perforation and purulent peritonitis.
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- 2021
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16. Phosphoglucose Isomerase Is Important for Aspergillus fumigatus Cell Wall Biogenesis
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Yao Zhou, Kaizhou Yan, Qijian Qin, Olawale G. Raimi, Chao Du, Bin Wang, Chukwuemeka Samson Ahamefule, Bartosz Kowalski, Cheng Jin, Daan M. F. van Aalten, and Wenxia Fang
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fungi ,Aspergillus fumigatus ,carbon flux ,cell wall ,drug target ,phosphoglucose isomerase ,Microbiology ,QR1-502 - Abstract
ABSTRACT Aspergillus fumigatus is a devastating opportunistic fungal pathogen causing hundreds of thousands of deaths every year. Phosphoglucose isomerase (PGI) is a glycolytic enzyme that converts glucose-6-phosphate to fructose-6-phosphate, a key precursor of fungal cell wall biosynthesis. Here, we demonstrate that the growth of A. fumigatus is repressed by the deletion of pgi, which can be rescued by glucose and fructose supplementation in a 1:10 ratio. Even under these optimized growth conditions, the Δpgi mutant exhibits severe cell wall defects, retarded development, and attenuated virulence in Caenorhabditis elegans and Galleria mellonella infection models. To facilitate exploitation of A. fumigatus PGI as an antifungal target, we determined its crystal structure, revealing potential avenues for developing inhibitors, which could potentially be used as adjunctive therapy in combination with other systemic antifungals. IMPORTANCE Aspergillus fumigatus is an opportunistic fungal pathogen causing deadly infections in immunocompromised patients. Enzymes essential for fungal survival and cell wall biosynthesis are considered potential drug targets against A. fumigatus. PGI catalyzes the second step of the glycolysis pathway, linking glycolysis and the pentose phosphate pathway. As such, PGI has been widely considered as a target for metabolic regulation and therefore a therapeutic target against hypoxia-related diseases. Our study here reveals that PGI is important for A. fumigatus survival and exhibit pleiotropic functions, including development, cell wall glucan biosynthesis, and virulence. We also solved the crystal structure of PGI, thus providing the genetic and structural groundwork for the exploitation of PGI as a potential antifungal target.
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- 2022
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17. Intellectual disability-associated disruption of O-GlcNAc cycling impairs habituation learning in Drosophila.
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Michaela Fenckova, Villo Muha, Daniel Mariappa, Marica Catinozzi, Ignacy Czajewski, Laura E R Blok, Andrew T Ferenbach, Erik Storkebaum, Annette Schenck, and Daan M F van Aalten
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Genetics ,QH426-470 - Abstract
O-GlcNAcylation is a reversible co-/post-translational modification involved in a multitude of cellular processes. The addition and removal of the O-GlcNAc modification is controlled by two conserved enzymes, O-GlcNAc transferase (OGT) and O-GlcNAc hydrolase (OGA). Mutations in OGT have recently been discovered to cause a novel Congenital Disorder of Glycosylation (OGT-CDG) that is characterized by intellectual disability. The mechanisms by which OGT-CDG mutations affect cognition remain unclear. We manipulated O-GlcNAc transferase and O-GlcNAc hydrolase activity in Drosophila and demonstrate an important role of O-GlcNAcylation in habituation learning and synaptic development at the larval neuromuscular junction. Introduction of patient-specific missense mutations into Drosophila O-GlcNAc transferase using CRISPR/Cas9 gene editing leads to deficits in locomotor function and habituation learning. The habituation deficit can be corrected by blocking O-GlcNAc hydrolysis, indicating that OGT-CDG mutations affect cognition-relevant habituation via reduced protein O-GlcNAcylation. This study establishes a critical role for O-GlcNAc cycling and disrupted O-GlcNAc transferase activity in cognitive dysfunction, and suggests that blocking O-GlcNAc hydrolysis is a potential strategy to treat OGT-CDG.
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- 2022
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18. An intellectual disability syndrome with single-nucleotide variants in O-GlcNAc transferase
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Pravata, Veronica M., Omelková, Michaela, Stavridis, Marios P., Desbiens, Chelsea M., Stephen, Hannah M., Lefeber, Dirk J., Gecz, Jozef, Gundogdu, Mehmet, Õunap, Katrin, Joss, Shelagh, Schwartz, Charles E., Wells, Lance, and van Aalten, Daan M. F.
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- 2020
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19. Prevalence of Cerebral Amyloid Pathology in Persons Without Dementia: A Meta-analysis
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Jansen, Willemijn J, Ossenkoppele, Rik, Knol, Dirk L, Tijms, Betty M, Scheltens, Philip, Verhey, Frans RJ, Visser, Pieter Jelle, Aalten, Pauline, Aarsland, Dag, Alcolea, Daniel, Alexander, Myriam, Almdahl, Ina S, Arnold, Steven E, Baldeiras, Inês, Barthel, Henryk, van Berckel, Bart NM, Bibeau, Kristen, Blennow, Kaj, Brooks, David J, van Buchem, Mark A, Camus, Vincent, Cavedo, Enrica, Chen, Kewei, Chetelat, Gael, Cohen, Ann D, Drzezga, Alexander, Engelborghs, Sebastiaan, Fagan, Anne M, Fladby, Tormod, Fleisher, Adam S, van der Flier, Wiesje M, Ford, Lisa, Förster, Stefan, Fortea, Juan, Foskett, Nadia, Frederiksen, Kristian S, Freund-Levi, Yvonne, Frisoni, Giovanni B, Froelich, Lutz, Gabryelewicz, Tomasz, Gill, Kiran Dip, Gkatzima, Olymbia, Gómez-Tortosa, Estrella, Gordon, Mark Forrest, Grimmer, Timo, Hampel, Harald, Hausner, Lucrezia, Hellwig, Sabine, Herukka, Sanna-Kaisa, Hildebrandt, Helmut, Ishihara, Lianna, Ivanoiu, Adrian, Jagust, William J, Johannsen, Peter, Kandimalla, Ramesh, Kapaki, Elisabeth, Klimkowicz-Mrowiec, Aleksandra, Klunk, William E, Köhler, Sebastian, Koglin, Norman, Kornhuber, Johannes, Kramberger, Milica G, Van Laere, Koen, Landau, Susan M, Lee, Dong Young, de Leon, Mony, Lisetti, Viviana, Lleó, Alberto, Madsen, Karine, Maier, Wolfgang, Marcusson, Jan, Mattsson, Niklas, de Mendonça, Alexandre, Meulenbroek, Olga, Meyer, Philipp T, Mintun, Mark A, Mok, Vincent, Molinuevo, José Luis, Møllergård, Hanne M, Morris, John C, Mroczko, Barbara, Van der Mussele, Stefan, Na, Duk L, Newberg, Andrew, Nordberg, Agneta, Nordlund, Arto, Novak, Gerald P, Paraskevas, George P, Parnetti, Lucilla, Perera, Gayan, Peters, Oliver, Popp, Julius, Prabhakar, Sudesh, Rabinovici, Gil D, Ramakers, Inez HGB, Rami, Lorena, de Oliveira, Catarina Resende, Rinne, Juha O, Rodrigue, Karen M, and Rodríguez-Rodríguez, Eloy
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Health Services and Systems ,Health Sciences ,Clinical Research ,Alzheimer's Disease ,Vascular Cognitive Impairment/Dementia ,Acquired Cognitive Impairment ,Neurosciences ,Alzheimer's Disease Related Dementias (ADRD) ,Brain Disorders ,Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD) ,Cerebrovascular ,Neurodegenerative ,Prevention ,Dementia ,Aging ,4.2 Evaluation of markers and technologies ,Detection ,screening and diagnosis ,Aetiology ,2.1 Biological and endogenous factors ,Neurological ,Adult ,Age Factors ,Aged ,Aged ,80 and over ,Amyloid beta-Peptides ,Apolipoprotein E4 ,Biomarkers ,Brain ,Cerebrospinal Fluid ,Cognitive Dysfunction ,Female ,Genotype ,Humans ,Male ,Middle Aged ,Positron-Emission Tomography ,Prevalence ,Risk Factors ,Amyloid Biomarker Study Group ,Medical and Health Sciences ,General & Internal Medicine ,Biomedical and clinical sciences ,Health sciences - Abstract
ImportanceCerebral amyloid-β aggregation is an early pathological event in Alzheimer disease (AD), starting decades before dementia onset. Estimates of the prevalence of amyloid pathology in persons without dementia are needed to understand the development of AD and to design prevention studies.ObjectiveTo use individual participant data meta-analysis to estimate the prevalence of amyloid pathology as measured with biomarkers in participants with normal cognition, subjective cognitive impairment (SCI), or mild cognitive impairment (MCI).Data sourcesRelevant biomarker studies identified by searching studies published before April 2015 using the MEDLINE and Web of Science databases and through personal communication with investigators.Study selectionStudies were included if they provided individual participant data for participants without dementia and used an a priori defined cutoff for amyloid positivity.Data extraction and synthesisIndividual records were provided for 2914 participants with normal cognition, 697 with SCI, and 3972 with MCI aged 18 to 100 years from 55 studies.Main outcomes and measuresPrevalence of amyloid pathology on positron emission tomography or in cerebrospinal fluid according to AD risk factors (age, apolipoprotein E [APOE] genotype, sex, and education) estimated by generalized estimating equations.ResultsThe prevalence of amyloid pathology increased from age 50 to 90 years from 10% (95% CI, 8%-13%) to 44% (95% CI, 37%-51%) among participants with normal cognition; from 12% (95% CI, 8%-18%) to 43% (95% CI, 32%-55%) among patients with SCI; and from 27% (95% CI, 23%-32%) to 71% (95% CI, 66%-76%) among patients with MCI. APOE-ε4 carriers had 2 to 3 times higher prevalence estimates than noncarriers. The age at which 15% of the participants with normal cognition were amyloid positive was approximately 40 years for APOE ε4ε4 carriers, 50 years for ε2ε4 carriers, 55 years for ε3ε4 carriers, 65 years for ε3ε3 carriers, and 95 years for ε2ε3 carriers. Amyloid positivity was more common in highly educated participants but not associated with sex or biomarker modality.Conclusions and relevanceAmong persons without dementia, the prevalence of cerebral amyloid pathology as determined by positron emission tomography or cerebrospinal fluid findings was associated with age, APOE genotype, and presence of cognitive impairment. These findings suggest a 20- to 30-year interval between first development of amyloid positivity and onset of dementia.
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- 2015
20. Genetic recoding to dissect the roles of site-specific protein O-GlcNAcylation
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Gorelik, Andrii, Bartual, Sergio Galan, Borodkin, Vladimir S., Varghese, Joby, Ferenbach, Andrew T., and van Aalten, Daan M. F.
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- 2019
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21. The Associations of Common Psychological Problems With Mental Disorders Among College Students
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Pim Cuijpers, Filip Smit, Pauline Aalten, Neeltje Batelaan, Anke Klein, Elske Salemink, Philip Spinhoven, Sascha Struijs, Peter Vonk, Reinout W. Wiers, Leonore de Wit, Claudio Gentili, David Daniel Ebert, Ronny Bruffaerts, Ronald C. Kessler, and Eirini Karyotaki
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college students ,mental disorders ,psychological problems ,depression ,generalized anxiety disorder ,bipolar disorder ,Psychiatry ,RC435-571 - Abstract
Psychological problems like procrastination, perfectionism, low self-esteem, test anxiety and stress are common among college students. There are evidence-based interventions available for these problems that not only have direct effects on these problems, but also indirect effects on mental disorders such as depression and anxiety disorders. Targeting these psychological problems may offer new opportunities to prevent and treat mental disorders in a way that is less stigmatizing to students. In this study we examined the association of five psychological problems with five common mental disorders (panic, generalized anxiety, bipolar, major depressive, and substance use disorder) in a sample of 2,449 students from two Dutch universities. Psychological problems were measured with one item for each problem and mental disorders were measured with the Composite International Diagnostic Interview Screening Scales. Associations were examined with Poisson regression models as relative risks (RR) of the disorders as a function of the psychological problems. The population attributable fraction (PAF) indicates by what percentage the prevalence of the mental disorder would be reduced if the psychological problem was addressed successfully by an intervention. Especially generalized anxiety disorder was strongly associated with psychological problems (strong associations with stress and low self-esteem and moderately with test anxiety). The group with three or more psychological problems had a strongly increased risk for generalized anxiety (RR = 11.25; 95% CI: 7.51–16.85), and a moderately increase risk for major depression (RR = 3.22; 95% CI: 2.63–3.95), panic disorder (RR = 3.19; 95% CI: 1.96–5.20) and bipolar disorder (RR = 3.66; 95% CI: 2.40–5.58). The PAFs for having any of the psychological problems (one or more) were considerable, especially for generalized anxiety (60.8%), but also for panic disorder (35.1%), bipolar disorder (30.6%) and major depression (34.0%). We conclude that common psychological problems are associated with mental disorders and with each other. After adjustment, psychological problems are associated with different patterns of mental disorders. If the impact of the psychological problems could be taken away, the prevalence of several mental disorders would be reduced considerably. The psychological problems may provide a promising target to indirectly prevent and intervene in psychopathology in hard to reach college students with mental disorders.
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- 2021
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22. Mechanisms of redundancy and specificity of the Aspergillus fumigatus Crh transglycosylases
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Wenxia Fang, Ana Belén Sanz, Sergio Galan Bartual, Bin Wang, Andrew T. Ferenbach, Vladimír Farkaš, Ramon Hurtado-Guerrero, Javier Arroyo, and Daan M. F. van Aalten
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Science - Abstract
Transglycosylases strengthen the fungal cell wall by forming a rigid network of crosslinks. Here, Fang et al. show that the five Crh transglycosylases of Aspergillus fumigatus are dispensable for cell wall integrity in vitro, and solve the crystal structure of Crh5 in complex with chitooligosaccharides.
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- 2019
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23. Cross-cohort generalizability of deep and conventional machine learning for MRI-based diagnosis and prediction of Alzheimer’s disease
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Esther E. Bron, Stefan Klein, Janne M. Papma, Lize C. Jiskoot, Vikram Venkatraghavan, Jara Linders, Pauline Aalten, Peter Paul De Deyn, Geert Jan Biessels, Jurgen A.H.R. Claassen, Huub A.M. Middelkoop, Marion Smits, Wiro J. Niessen, John C. van Swieten, Wiesje M. van der Flier, Inez H.G.B. Ramakers, and Aad van der Lugt
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Alzheimer’s disease ,Support vector machine ,Convolutional Neural Network ,External validation ,Computer applications to medicine. Medical informatics ,R858-859.7 ,Neurology. Diseases of the nervous system ,RC346-429 - Abstract
This work validates the generalizability of MRI-based classification of Alzheimer’s disease (AD) patients and controls (CN) to an external data set and to the task of prediction of conversion to AD in individuals with mild cognitive impairment (MCI).We used a conventional support vector machine (SVM) and a deep convolutional neural network (CNN) approach based on structural MRI scans that underwent either minimal pre-processing or more extensive pre-processing into modulated gray matter (GM) maps. Classifiers were optimized and evaluated using cross-validation in the Alzheimer’s Disease Neuroimaging Initiative (ADNI; 334 AD, 520 CN). Trained classifiers were subsequently applied to predict conversion to AD in ADNI MCI patients (231 converters, 628 non-converters) and in the independent Health-RI Parelsnoer Neurodegenerative Diseases Biobank data set. From this multi-center study representing a tertiary memory clinic population, we included 199 AD patients, 139 participants with subjective cognitive decline, 48 MCI patients converting to dementia, and 91 MCI patients who did not convert to dementia.AD-CN classification based on modulated GM maps resulted in a similar area-under-the-curve (AUC) for SVM (0.940; 95%CI: 0.924–0.955) and CNN (0.933; 95%CI: 0.918–0.948). Application to conversion prediction in MCI yielded significantly higher performance for SVM (AUC = 0.756; 95%CI: 0.720-0.788) than for CNN (AUC = 0.742; 95%CI: 0.709-0.776) (p
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- 2021
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24. The genetic association of the transcription factor NPAT with glycemic response to metformin involves regulation of fuel selection.
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Changwei Chen, Jennifer R Gallagher, Jamie Tarlton, Lidy van Aalten, Susan E Bray, Michael L J Ashford, Rory J McCrimmon, Ewan R Pearson, Alison D McNeilly, and Calum Sutherland
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Medicine ,Science - Abstract
The biguanide, metformin, is the first-choice therapeutic agent for type-2 diabetes, although the mechanisms that underpin metformin clinical efficacy remain the subject of much debate, partly due to the considerable variation in patient response to metformin. Identification of poor responders by genotype could avoid unnecessary treatment and provide clues to the underlying mechanism of action. GWAS identified SNPs associated with metformin treatment success at a locus containing the NPAT (nuclear protein, ataxia-telangiectasia locus) and ATM (ataxia-telangiectasia mutated) genes. This implies that gene sequence dictates a subsequent biological function to influence metformin action. Hence, we modified expression of NPAT in immortalized cell lines, primary mouse hepatocytes and mouse tissues, and analysed the outcomes on metformin action using confocal microscopy, immunoblotting and immunocytochemistry. In addition, we characterised the metabolic phenotype of npat heterozygous knockout mice and established the metformin response following development of insulin resistance. NPAT protein was localised in the nucleus at discrete loci in several cell types, but over-expression or depletion of NPAT in immortalised cell models did not change cellular responses to biguanides. In contrast, metformin regulation of respiratory exchange ratio (RER) was completely lost in animals lacking one allele of npat. There was also a reduction in metformin correction of impaired glucose tolerance, however no other metabolic abnormalities, or response to metformin, were found in the npat heterozygous mice. In summary, we provide methodological advancements for the detection of NPAT, demonstrate that minor reductions in NPAT mRNA levels (20-40%) influence metformin regulation of RER, and propose that the association between NPAT SNPs and metformin response observed in GWAS, could be due to loss of metformin modification of cellular fuel usage.
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- 2021
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25. A mouse model for functional dissection of TAB1 O-GlcNAcylation [version 2; peer review: 2 approved]
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Florence Authier, Villő Muha, and Daan M.F. van Aalten
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Medicine ,Science - Abstract
Background: O-GlcNAcylation is a posttranslational modification associated with various physiological and pathophysiological processes including diabetes, cancer, neurodegeneration and inflammation. However, the biological mechanisms underlying the role of specific O-GlcNAc sites and their link to phenotypes remain largely unexplored due to lack of suitable in vivo models. TGF-β activated kinase-1 binding protein-1 (TAB1) is a scaffolding protein required for TGF-β activated kinase-1 (TAK1) mediated signalling. A single O-GlcNAc site has been identified on human TAB1 that modulates TAK1-mediated cytokine release in cells. Methods: Here, we report the generation of the Tab1S393A mouse model using a constitutive knock-in strategy. The Tab1S393A mice carry a Ser393Ala (S393A) mutation that leads to loss of O-GlcNAcylation site on TAB1. Results: We did not observe any obvious phenotype in Tab1S393A mice. Loss of O-GlcNAcylation on TAB1 has no consequences on TAB1 protein level or on TAB1-TAK1 interaction. Conclusions: The homozygous Tab1S393A mice are viable and develop with no obvious abnormalities, providing a powerful tool to further investigate the role of O-GlcNAc on TAB1 in the inflammatory response in the context of a whole organism.
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- 2020
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26. Ongeval op de thuiswerkplek? : een onderzoek naar de reikwijdte van de zorgplicht en aansprakelijkheid van de werkgever tijdens het thuiswerken
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Aalten, L.H. and Aalten, L.H.
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- 2023
27. Reducing Glut2 throughout the body does not result in cognitive behaviour differences in aged male mice
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Morrice, Nicola, van Aalten, Lidy, McNeilly, Alison, McCrimmon, Rory J., Pearson, Ewan R., Langston, Rosamund, and Sutherland, Calum
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- 2020
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28. Activity-based E3 ligase profiling uncovers an E3 ligase with esterification activity
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Pao, Kuan-Chuan, Wood, Nicola T., Knebel, Axel, Rafie, Karim, Stanley, Mathew, Mabbitt, Peter D., Sundaramoorthy, Ramasubramanian, Hofmann, Kay, van Aalten, Daan M. F., and Virdee, Satpal
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- 2018
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29. 'Ons vak vraagt om kwaliteit'
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Van Aalten, Margriet
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- 2018
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30. Structure and function of a broad-specificity chitin deacetylase from Aspergillus nidulans FGSC A4
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Zhanliang Liu, Laurie M. Gay, Tina R. Tuveng, Jane W. Agger, Bjørge Westereng, Geir Mathiesen, Svein J. Horn, Gustav Vaaje-Kolstad, Daan M. F. van Aalten, and Vincent G. H. Eijsink
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Medicine ,Science - Abstract
Abstract Enzymatic conversion of chitin, a β-1,4 linked polymer of N-acetylglucosamine, is of major interest in areas varying from the biorefining of chitin-rich waste streams to understanding how medically relevant fungi remodel their chitin-containing cell walls. Although numerous chitinolytic enzymes have been studied in detail, relatively little is known about enzymes capable of deacetylating chitin. We describe the structural and functional characterization of a 237 residue deacetylase (AnCDA) from Aspergillus nidulans FGSC A4. AnCDA acts on chito-oligomers, crystalline chitin, chitosan, and acetylxylan, but not on peptidoglycan. The K m and k cat of AnCDA for the first deacetylation of penta-N-acetyl-chitopentaose are 72 µM and 1.4 s−1, respectively. Combining mass spectrometry and analyses of acetate release, it was shown that AnCDA catalyses mono-deacetylation of (GlcNAc)2 and full deacetylation of (GlcNAc)3–6 in a non-processive manner. Deacetylation of the reducing end sugar was much slower than deacetylation of the other sugars in chito-oligomers. These enzymatic characteristics are discussed in the light of the crystal structure of AnCDA, providing insight into how the chitin deacetylase may interact with its substrates. Interestingly, AnCDA activity on crystalline chitin was enhanced by a lytic polysaccharide monooxygenase that increases substrate accessibility by oxidative cleavage of the chitin chains.
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- 2017
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31. Recruitment, Retainment, and Biomarkers of Response; A Pilot Trial of Lithium in Humans With Mild Cognitive Impairment
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Ashleigh Duthie, Lidy van Aalten, Cara MacDonald, Alison McNeilly, Jennifer Gallagher, John Geddes, Simon Lovestone, and Calum Sutherland
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lithium ,GSK3 ,clinical trial ,biomarker ,safety ,Neurosciences. Biological psychiatry. Neuropsychiatry ,RC321-571 - Abstract
Lithium has been used for decades to treat Bipolar Disorder. Some of its therapeutic benefits may be through inhibition of Glycogen Synthase Kinase (GSK)-3. Enhanced GSK3 activity associates with development of Alzheimer’s disease (AD), therefore lithium is a currently used therapeutic with potential to be repurposed for prevention of Dementia. An important step toward a clinical trial for AD prevention using lithium is to establish the dose of lithium that blocks GSK3 in Mild Cognitive Impairment (MCI), a high-risk condition for progression to AD. We investigated volunteer recruitment, retention, and tolerance in this population, and assessed biomarkers of GSK3 in MCI compared to control and after lithium treatment. Recruitment was close to target, with higher than anticipated interest. Drop out was not related to lithium blood concentration. Indeed, 33% of the withdrawals were in the first week of very low dose lithium. Most made it through to the highest dose of lithium with no adverse events. We analyzed 18 potential biomarkers of GSK3 biology in rat PBMCs, but only four of these gave a robust reproducible baseline signal. The only biomarker that was modified by acute lithium injection in the rat was the inhibitory phosphorylation of Ser9 of GSK3beta (enhanced in PBMCs) and this associated with reduced activity of GSK3beta. In contrast to the rat PBMC preparations the protein quality of the human PBMC preparations was extremely variable. There was no difference between GSK3 biomarkers in MCI and control PBMC preparations and no significant effect of chronic lithium on the robust GSK3 biomarkers, indicating that the dose reached may not be sufficient to modify these markers. In summary, the high interest from the MCI population, and the lack of any adverse events, suggest that it would be relatively straightforward and safe to recruit to a larger clinical trial within this dosing regimen. However, it is clear that we will need an improved PBMC isolation process along with more robust, sensitive, and validated biomarkers of GSK3 function, in order to use GSK3 pathway regulation in human PBMC preparations as a biomarker of GSK3 inhibitor efficacy, within a clinical trial setting.
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- 2019
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32. Prevalence of Comorbidity in Patients With Young-Onset Alzheimer Disease Compared With Late-Onset: A Comparative Cohort Study
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Oosterveld, S.M., Kessels, R.P., Olde Rikkert, M.G., Hamel, R., Ramakers, I.H., Aalten, P., Sistermans, N., Smits, L.L., Pijnenburg, Y.A., van der Flier, W.M., Gerritsen, Adrie A.J., Bakker, Christian, Verhey, Frans R.J., de Vugt, Marjolein E., Melis, René J.F., and Koopmans, Raymond T.C.M.
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- 2016
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33. Gat in de markt?
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van Aalten, Margriet
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- 2020
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34. Mechanisms of redundancy and specificity of the Aspergillus fumigatus Crh transglycosylases
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Fang, Wenxia, Sanz, Ana Belén, Bartual, Sergio Galan, Wang, Bin, Ferenbach, Andrew T., Farkaš, Vladimír, Hurtado-Guerrero, Ramon, Arroyo, Javier, and van Aalten, Daan M. F.
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- 2019
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35. Imaging Markers of Post-Stroke Depression and Apathy: a Systematic Review and Meta-Analysis
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Douven, Elles, Köhler, Sebastian, Rodriguez, Maria M. F., Staals, Julie, Verhey, Frans R. J., and Aalten, Pauline
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- 2017
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36. Automatic speech analysis for the assessment of patients with predementia and Alzheimer's disease
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Alexandra König, Aharon Satt, Alexander Sorin, Ron Hoory, Orith Toledo‐Ronen, Alexandre Derreumaux, Valeria Manera, Frans Verhey, Pauline Aalten, Phillipe H. Robert, and Renaud David
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Dementia ,Alzheimer's ,Mild cognitive impairment ,Speech analyses ,Assessment ,Information and communication technology (ICT) ,Neurology. Diseases of the nervous system ,RC346-429 ,Geriatrics ,RC952-954.6 - Abstract
Abstract Background To evaluate the interest of using automatic speech analyses for the assessment of mild cognitive impairment (MCI) and early‐stage Alzheimer's disease (AD). Methods Healthy elderly control (HC) subjects and patients with MCI or AD were recorded while performing several short cognitive vocal tasks. The voice recordings were processed, and the first vocal markers were extracted using speech signal processing techniques. Second, the vocal markers were tested to assess their “power” to distinguish among HC, MCI, and AD. The second step included training automatic classifiers for detecting MCI and AD, using machine learning methods and testing the detection accuracy. Results The classification accuracy of automatic audio analyses were as follows: between HCs and those with MCI, 79% ± 5%; between HCs and those with AD, 87% ± 3%; and between those with MCI and those with AD, 80% ± 5%, demonstrating its assessment utility. Conclusion Automatic speech analyses could be an additional objective assessment tool for elderly with cognitive decline.
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- 2015
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37. Correction to: Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline
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Bos, Isabelle, Verhey, Frans R., Ramakers, Inez H. G. B., Jacobs, Heidi I. L., Soininen, Hilkka, Freund-Levi, Yvonne, Hampel, Harald, Tsolaki, Magda, Wallin, Åsa K., van Buchem, Mark A., Oleksik, Ania, Verbeek, Marcel M., Rikkert, Marcel Olde, van der Flier, Wiesje M., Scheltens, Philip, Aalten, Pauline, Visser, Pieter Jelle, and Vos, Stephanie J. B.
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- 2018
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38. Cerebrovascular and amyloid pathology in predementia stages: the relationship with neurodegeneration and cognitive decline
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Bos, Isabelle, Verhey, Frans R., Ramakers, Inez H.G.B., Jacobs, Heidi I. L., Soininen, Hilkka, Freund-Levi, Yvonne, Hampel, Harald, Tsolaki, Magda, Wallin, Åsa K., van Buchem, Mark A., Oleksik, Ania, Verbeek, Marcel M., Olde Rikkert, Marcel, van der Flier, Wiesje M., Scheltens, Philip, Aalten, Pauline, Visser, Pieter Jelle, and Vos, Stephanie J. B.
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- 2017
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39. The active site of O-GlcNAc transferase imposes constraints on substrate sequence
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Pathak, Shalini, Alonso, Jana, Schimpl, Marianne, Rafie, Karim, Blair, David E, Borodkin, Vladimir S, Schüttelkopf, Alexander W, Albarbarawi, Osama, and van Aalten, Daan M F
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- 2015
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40. Neuropsychiatrische syndromen na een beroerte
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Schievink, Syenna, Douven, Elles, Aalten, Pauline, and Köhler, Sebastian
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- 2015
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41. Neuropsychiatrische syndromen na een beroerte
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Schievink, Syenna, Douven, Elles, Aalten, Pauline, and Köhler, Sebastian
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- 2014
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42. The Association Between Biomarkers and Neuropsychiatric Symptoms Across the Alzheimer's Disease Spectrum
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Banning, L.C.P., Ramakers, I.H.G.B., Kohler, S., Bron, E.E., Verhey, F.R.J., Deyn, P.P. de, Claassen, J.A.H.R., Koek, H.L., Middelkoop, H.A.M., Flier, W.M. van der, Lugt, A. van der, Aalten, P., Alzheimers Dis Neuroimaging Initia, Parelsnoer Inst Neurodegenerative, Alzheimer's Disease Neuroimaging Initiative1, Parelsnoer Institute Neurodegenerative Diseases study group, Molecular Neuroscience and Ageing Research (MOLAR), Neurology, Amsterdam Neuroscience - Neurodegeneration, APH - Personalized Medicine, APH - Methodology, Psychiatrie & Neuropsychologie, RS: MHeNs - R3 - Neuroscience, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Psychiatrie (9), UM Student Desk - CSA, and Radiology & Nuclear Medicine
- Subjects
Male ,MILD COGNITIVE IMPAIRMENT ,Alzheimer`s disease Donders Center for Medical Neuroscience [Radboudumc 1] ,neurocognitive disorders ,Alzheimer's disease dementia ,PROGRESSION ,Disease ,Anxiety ,Neuropsychological Tests ,Hippocampus ,0302 clinical medicine ,Apathy ,Longitudinal Studies ,Cognitive decline ,Depression (differential diagnoses) ,Netherlands ,Aged, 80 and over ,CEREBROSPINAL-FLUID BIOMARKERS ,Middle Aged ,Magnetic Resonance Imaging ,Irritable Mood ,Neuropsychiatric symptoms ,PREVALENCE ,Psychiatry and Mental health ,DEPRESSIVE SYMPTOMS ,Disease Progression ,EARLY-STAGE ,Female ,medicine.symptom ,MRI ,medicine.medical_specialty ,CSF BIOMARKERS ,tau Proteins ,Irritability ,03 medical and health sciences ,All institutes and research themes of the Radboud University Medical Center ,Neuroimaging ,Alzheimer Disease ,Internal medicine ,medicine ,Dementia ,Humans ,Cognitive Dysfunction ,Aged ,MODERATORS ,Amyloid beta-Peptides ,030214 geriatrics ,business.industry ,medicine.disease ,Logistic Models ,MEDIATORS ,Human medicine ,Geriatrics and Gerontology ,business ,Biomarkers - Abstract
Objective: To investigate the relationship between Alzheimer's disease biomarkers and neuropsychiatric symptoms. Methods: Data from two large cohort studies, the Dutch Parelsnoer Institute – Neurodegenerative Diseases and the Alzheimer's Disease Neuroimaging Initiative was used, including subjects with subjective cognitive decline (N = 650), mild cognitive impairment (N = 887), and Alzheimer's disease dementia (N = 626). Cerebrospinal fluid (CSF) levels of Aβ42, t-tau, p-tau, and hippocampal volume were associated with neuropsychiatric symptoms (measured with the Neuropsychiatric Inventory) using multiple logistic regression analyses. The effect of the Mini-Mental State Examination (as proxy for cognitive functioning) on these relationships was assessed with mediation analyses. Results: Alzheimer's disease biomarkers were not associated with depression, agitation, irritability, and sleep disturbances. Lower levels of CSF Aβ42, higher levels of t- and p-tau were associated with presence of anxiety. Lower levels of CSF Aβ42 and smaller hippocampal volumes were associated with presence of apathy. All associations were mediated by cognitive functioning. Conclusion: The association between Alzheimer's disease pathology and anxiety and apathy is partly due to impairment in cognitive functioning.
- Published
- 2020
43. The Associations of Common Psychological Problems With Mental Disorders Among College Students
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Cuijpers, P., Smit, F., Aalten, P., Batelaan, N., Klein, A., Salemink, E., Spinhoven, P., Struijs, S., Vonk, P., Wiers, R.W., de Wit, L., Gentili, C., Ebert, D.D, Bruffaerts, R., Kessler, R.C., Karyotaki, E., Experimental psychopathology, Leerstoel Engelhard, Epidemiology and Data Science, APH - Mental Health, Psychiatry, Experimental psychopathology, Leerstoel Engelhard, Clinical Psychology, World Health Organization (WHO) Collaborating Center, APH - Global Health, Clinical, Neuro- & Developmental Psychology, RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, UM Student Desk - CSA, Research of the Student Medical Service, and Ontwikkelingspsychologie (Psychologie, FMG)
- Subjects
Generalized anxiety disorder ,Psychological intervention ,RC435-571 ,medicine.disease_cause ,IDENTIFICATION TEST AUDIT ,INTERVIEW SCREENING SCALES ,SDG 3 - Good Health and Well-being ,ADOLESCENTS ,medicine ,Bipolar disorder ,panic disorder ,generalized anxiety disorder ,METAANALYSIS ,Original Research ,Psychiatry ,bipolar disorder ,business.industry ,Panic disorder ,PSYCHOPATHOLOGY ,college students ,Perfectionism (psychology) ,medicine.disease ,PROCRASTINATION ,mental disorders ,Substance abuse ,Psychiatry and Mental health ,depression ,UNIVERSITY-STUDENTS ,Anxiety ,COGNITION ,psychological problems ,HEALTH ,medicine.symptom ,business ,Psychopathology ,Clinical psychology ,INTERVENTIONS - Abstract
Psychological problems like procrastination, perfectionism, low self-esteem, test anxiety and stress are common among college students. There are evidence-based interventions available for these problems that not only have direct effects on these problems, but also indirect effects on mental disorders such as depression and anxiety disorders. Targeting these psychological problems may offer new opportunities to prevent and treat mental disorders in a way that is less stigmatizing to students. In this study we examined the association of five psychological problems with five common mental disorders (panic, generalized anxiety, bipolar, major depressive, and substance use disorder) in a sample of 2,449 students from two Dutch universities. Psychological problems were measured with one item for each problem and mental disorders were measured with the Composite International Diagnostic Interview Screening Scales. Associations were examined with Poisson regression models as relative risks (RR) of the disorders as a function of the psychological problems. The population attributable fraction (PAF) indicates by what percentage the prevalence of the mental disorder would be reduced if the psychological problem was addressed successfully by an intervention. Especially generalized anxiety disorder was strongly associated with psychological problems (strong associations with stress and low self-esteem and moderately with test anxiety). The group with three or more psychological problems had a strongly increased risk for generalized anxiety (RR = 11.25; 95% CI: 7.51-16.85), and a moderately increase risk for major depression (RR = 3.22; 95% CI: 2.63-3.95), panic disorder (RR = 3.19; 95% CI: 1.96-5.20) and bipolar disorder (RR = 3.66; 95% CI: 2.40-5.58). The PAFs for having any of the psychological problems (one or more) were considerable, especially for generalized anxiety (60.8%), but also for panic disorder (35.1%), bipolar disorder (30.6%) and major depression (34.0%). We conclude that common psychological problems are associated with mental disorders and with each other. After adjustment, psychological problems are associated with different patterns of mental disorders. If the impact of the psychological problems could be taken away, the prevalence of several mental disorders would be reduced considerably. The psychological problems may provide a promising target to indirectly prevent and intervene in psychopathology in hard to reach college students with mental disorders. ispartof: FRONTIERS IN PSYCHIATRY vol:12 ispartof: location:Switzerland status: published
- Published
- 2021
44. Dual functionality of O-GlcNAc transferase is required for Drosophila development
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Daniel Mariappa, Xiaowei Zheng, Marianne Schimpl, Olawale Raimi, Andrew T. Ferenbach, H.-Arno J. Müller, and Daan M. F. van Aalten
- Subjects
o-glcnac ,o-glcnac transferase ,drosophila development ,hox ,Biology (General) ,QH301-705.5 - Abstract
Post-translational modification of intracellular proteins with O-linked N-acetylglucosamine (O-GlcNAc) catalysed by O-GlcNAc transferase (OGT) has been linked to regulation of diverse cellular functions. OGT possesses a C-terminal glycosyltransferase catalytic domain and N-terminal tetratricopeptide repeats that are implicated in protein–protein interactions. Drosophila OGT (DmOGT) is encoded by super sex combs (sxc), mutants of which are pupal lethal. However, it is not clear if this phenotype is caused by reduction of O-GlcNAcylation. Here we use a genetic approach to demonstrate that post-pupal Drosophila development can proceed with negligible OGT catalysis, while early embryonic development is OGT activity-dependent. Structural and enzymatic comparison between human OGT (hOGT) and DmOGT informed the rational design of DmOGT point mutants with a range of reduced catalytic activities. Strikingly, a severely hypomorphic OGT mutant complements sxc pupal lethality. However, the hypomorphic OGT mutant-rescued progeny do not produce F2 adults, because a set of Hox genes is de-repressed in F2 embryos, resulting in homeotic phenotypes. Thus, OGT catalytic activity is required up to late pupal stages, while further development proceeds with severely reduced OGT activity.
- Published
- 2015
- Full Text
- View/download PDF
45. The trajectory of cognitive decline in the pre-dementia phase in memory clinic visitors: findings from the 4C-MCI study
- Author
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Hamel, R., Köhler, S., Sistermans, N., Koene, T., Pijnenburg, Y., van der Flier, W., Scheltens, P., Aalten, P., Verhey, F., Visser, P. J., and Ramakers, I.
- Published
- 2015
- Full Text
- View/download PDF
46. Heffing naar draagkracht over onroerende zaken
- Author
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Aalten, B.L.G. van and Aalten, B.L.G. van
- Abstract
The full text of this thesis is not available due to privacy or embargo reasons.
- Published
- 2021
47. Proposed diagnostic criteria for apathy in Alzheimer's disease and other neuropsychiatric disorders
- Author
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Robert, P., Onyike, C.U., Leentjens, A.F.G., Dujardin, K., Aalten, P., Starkstein, S., Verhey, F.R.J., Yessavage, J., Clement, J.P., Drapier, D., Bayle, F., Benoit, M., Boyer, P., Lorca, P.M., Thibaut, F., Gauthier, S., Grossberg, G., Vellas, B., and Byrne, J.
- Published
- 2009
- Full Text
- View/download PDF
48. Recently introduced biomarkers for screening of hepatocellular carcinoma: a systematic review and meta-analysis
- Author
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Witjes, Caroline D. M., van Aalten, Susanna M., Steyerberg, Ewout W., Borsboom, Gerard J. J. M., de Man, Robert A., Verhoef, Cornelis, and IJzermans, Jan N. M.
- Published
- 2013
- Full Text
- View/download PDF
49. De meerwaarde van diffusie gewogen beeldvorming bij de vroegdiagnostiek van de ziekte van Alzheimer
- Author
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Clerx, Lies and Aalten, Pauline
- Published
- 2012
- Full Text
- View/download PDF
50. Substrate and product analogues as human O-GlcNAc transferase inhibitors
- Author
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Dorfmueller, Helge C., Borodkin, Vladimir S., Blair, David E., Pathak, Shalini, Navratilova, Iva, and van Aalten, Daan M. F.
- Published
- 2011
- Full Text
- View/download PDF
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