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1. Constraint-adaptive MPC for large-scale systems: Satisfying state constraints without imposing them

Author

Nouwens, S. A. N., de Jager, B., Paulides, M. M., and Heemels, W. P. M. H.

Subjects
Electrical Engineering and Systems Science - Systems and Control, Mathematics - Optimization and Control
Abstract

Model Predictive Control (MPC) is a successful control methodology, which is applied to increasingly complex systems. However, real-time feasibility of MPC can be challenging for complex systems, certainly when an (extremely) large number of constraints have to be adhered to. For such scenarios with a large number of state constraints, this paper proposes two novel MPC schemes for general nonlinear systems, which we call constraint-adaptive MPC. These novel schemes dynamically select at each time step a (varying) set of constraints that are included in the on-line optimization problem. Carefully selecting the included constraints can significantly reduce, as we will demonstrate, the computational complexity with often only a slight impact on the closed-loop performance. Although not all (state) constraints are imposed in the on-line optimization, the schemes still guarantee recursive feasibility and constraint satisfaction. A numerical case study illustrates the proposed MPC schemes and demonstrates the achieved computation time improvements exceeding two orders of magnitude without loss of performance., Comment: 6 pages, 4 figures, IFAC NMPC 2021 conference

Published
2024
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2. Constraint Removal for MPC with Performance Preservation and a Hyperthermia Cancer Treatment Case Study

Author

Nouwens, S. A. N., de Jager, B., Paulides, M. M., and Heemels, W. P. M. H.

Subjects
Electrical Engineering and Systems Science - Systems and Control, Mathematics - Optimization and Control
Abstract

Model predictive control (MPC) is an optimization-based control strategy with broad industrial adoption. Unfortunately, the required computation time to solve the receding-horizon MPC optimization problem can become prohibitively large for many applications with a large number of state constraints. This large number of state constraints can, for instance, originate from spatially discretizing a partial differential equation of which the solution has to satisfy constraints over the full spatial domain. This is particularly the case in MPC for RF-based hyperthermia cancer treatments, which forms a strong motivation for this study. To address this problem, we propose a novel constraint-adaptive MPC framework for linear discrete-time systems. In this framework, we select at each time-step a subset of the state constraints that are included in the optimization problem, thereby reducing the online computational burden. Critically, our framework guarantees the same closed-loop performance, recursive feasibility, and constraint satisfaction properties as the original (non-reduced) MPC scheme. We achieve this result by efficiently exploiting reachable set computations and the MPC cost function. We will demonstrate our novel method using a hyperthermia cancer treatment case study showing a two-orders of magnitude improvement in computation time, with identical closed-loop performance as the original (non-reduced) MPC scheme., Comment: 6 pages, 3 figures, CDC 2021 conference

Published
2024
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3. Phase behavior and crystal nucleation of hard triangular prisms

Author

de Jager, Marjolein, Slaats, Nena, and Filion, Laura

Subjects
Condensed Matter - Soft Condensed Matter
Abstract

The interplay between densification and positional ordering during the process of crystal nucleation is a greatly investigated topic. Even for the simplest colloidal model -- hard spheres -- there has been much debate regarding the potential foreshadowing of nucleation by significant fluctuations in either local density or local structure. Considering anisotropic particles instead of spheres adds a third degree of freedom to the self-organization process of crystal nucleation: orientational ordering. Here, we investigate the crystal nucleation of hard triangular prisms. Using Monte Carlo simulations, we first carefully determine the crystal-fluid coexistence values and calculate the nucleation barriers for two degrees of supersaturation. Next, we use brute force simulations to obtain a large set of spontaneous nucleation events. By studying the time evolution of the local density, positional ordering, and orientational ordering in the region in which the nucleus first arises, we demonstrate that all local order parameters increase simultaneously from the very start of the nucleation process. We thus conclude that we observe no precursor for the crystal nucleation of hard triangular prisms.

Published
2024

4. Statistical mechanics of crystal nuclei of hard spheres

Author

de Jager, Marjolein, Vega, Carlos, de Hijes, Pablo Montero, Smallenburg, Frank, and Filion, Laura

Subjects
Condensed Matter - Soft Condensed Matter
Abstract

In the study of crystal nucleation via computer simulations, hard spheres are arguably the most extensively explored model system. Nonetheless, even in this simple model system, the complex thermodynamics of crystal nuclei can sometimes give rise to counterintuitive results, such as the recent observation that the pressure inside a critical nucleus is lower than that of the surrounding fluid, seemingly clashing with the strictly positive Young--Laplace pressure we would expect in liquid droplets. Here, we re-derive many of the founding equations associated with crystal nucleation, and use the hard-sphere model to demonstrate how they give rise to this negative pressure difference. We exploit the fact that, in the canonical ensemble, a nucleus can be in a (meta)stable equilibrium with the fluid, and measure the surface stress for both flat and curved interfaces. Additionally, we explain the effect of defects on the chemical potential inside the crystal nucleus. Lastly, we present a simple, fitted thermodynamic model to capture the properties of the nucleus, including the work required to form critical nuclei.

Published
2024

5. A simple and accurate method to determine fluid-crystal phase boundaries from direct coexistence simulations

Author

Smallenburg, Frank, Del Monte, Giovanni, de Jager, Marjolein, and Filion, Laura

Subjects
Condensed Matter - Soft Condensed Matter, Condensed Matter - Statistical Mechanics
Abstract

One method for computationally determining phase boundaries is to explicitly simulate a direct coexistence between the two phases of interest. Although this approach works very well for fluid-fluid coexistences, it is often considered to be less useful for fluid-crystal transitions, as additional care must be taken to prevent the simulation boundaries from imposing unwanted strains on the crystal phase. Here, we present a simple adaptation to the direct coexistence method that nonetheless allows us to obtain highly accurate predictions of fluid-crystal coexistence conditions. We test our approach on hard spheres, the screened Coulomb potential, and a 2D patchy-particle model. In all cases, we find excellent agreement between the direct coexistence approach and (much more cumbersome) free-energy calculation methods. Moreover, the method is sufficiently accurate to resolve the (tiny) free-energy difference between the face-centered cubic and hexagonally close-packed crystal of hard spheres in the thermodynamic limit. The simplicity of this method also ensures that it can be trivially implemented in essentially any simulation method or package. Hence, this approach provides an excellent alternative to free-energy based methods for the precise determination of phase boundaries., Comment: Consists of a manuscript, SI, and sample LAMMPS script

Published
2024

7. Genomic analysis of intracranial and subcortical brain volumes yields polygenic scores accounting for variation across ancestries

Author

García-Marín, Luis M., Campos, Adrian I., Diaz-Torres, Santiago, Rabinowitz, Jill A., Ceja, Zuriel, Mitchell, Brittany L., Grasby, Katrina L., Thorp, Jackson G., Agartz, Ingrid, Alhusaini, Saud, Ames, David, Amouyel, Philippe, Andreassen, Ole A., Arfanakis, Konstantinos, Arias-Vasquez, Alejandro, Armstrong, Nicola J., Athanasiu, Lavinia, Bastin, Mark E., Beiser, Alexa S., Bennett, David A., Bis, Joshua C., Boks, Marco P. M., Boomsma, Dorret I., Brodaty, Henry, Brouwer, Rachel M., Buitelaar, Jan K., Burkhardt, Ralph, Cahn, Wiepke, Calhoun, Vince D., Carmichael, Owen T., Chakravarty, Mallar, Chen, Qiang, Ching, Christopher R. K., Cichon, Sven, Crespo-Facorro, Benedicto, Crivello, Fabrice, Dale, Anders M., Smith, George Davey, de Geus, Eco J. C., De Jager, Philip L., de Zubicaray, Greig I., Debette, Stéphanie, DeCarli, Charles, Depondt, Chantal, Desrivières, Sylvane, Djurovic, Srdjan, Ehrlich, Stefan, Erk, Susanne, Espeseth, Thomas, Fernández, Guillén, Filippi, Irina, Fisher, Simon E., Fleischman, Debra A., Fletcher, Evan, Fornage, Myriam, Forstner, Andreas J., Francks, Clyde, Franke, Barbara, Ge, Tian, Goldman, Aaron L., Grabe, Hans J., Green, Robert C., Grimm, Oliver, Groenewold, Nynke A., Gruber, Oliver, Gudnason, Vilmundur, Håberg, Asta K., Haukvik, Unn K., Heinz, Andreas, Hibar, Derrek P., Hilal, Saima, Himali, Jayandra J., Ho, Beng-Choon, Hoehn, David F., Hoekstra, Pieter J., Hofer, Edith, Hoffmann, Wolfgang, Holmes, Avram J., Homuth, Georg, Hosten, Norbert, Ikram, M. Kamran, Ipser, Jonathan C., Jack Jr, Clifford R., Jahanshad, Neda, Jönsson, Erik G., Kahn, Rene S., Kanai, Ryota, Klein, Marieke, Knol, Maria J., Launer, Lenore J., Lawrie, Stephen M., Hellard, Stephanie Le, Lee, Phil H., Lemaître, Hervé, Li, Shuo, Liewald, David C. M., Lin, Honghuang, Longstreth, Jr, W. T., Lopez, Oscar L., Luciano, Michelle, Maillard, Pauline, Marquand, Andre F., Martin, Nicholas G., Martinot, Jean-Luc, Mather, Karen A., Mattay, Venkata S., McMahon, Katie L., Mecocci, Patrizia, Melle, Ingrid, Meyer-Lindenberg, Andreas, Mirza-Schreiber, Nazanin, Milaneschi, Yuri, Mosley, Thomas H., Mühleisen, Thomas W., Müller-Myhsok, Bertram, Maniega, Susana Muñoz, Nauck, Matthias, Nho, Kwangsik, Niessen, Wiro J., Nöthen, Markus M., Nyquist, Paul A., Oosterlaan, Jaap, Pandolfo, Massimo, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W. J. H., Pike, G. Bruce, Psaty, Bruce M., Pütz, Benno, Reppermund, Simone, Rietschel, Marcella D., Risacher, Shannon L., Romanczuk-Seiferth, Nina, Romero-Garcia, Rafael, Roshchupkin, Gennady V., Rotter, Jerome I., Sachdev, Perminder S., Sämann, Philipp G., Saremi, Arvin, Sargurupremraj, Muralidharan, Saykin, Andrew J., Schmaal, Lianne, Schmidt, Helena, Schmidt, Reinhold, Schofield, Peter R., Scholz, Markus, Schumann, Gunter, Schwarz, Emanuel, Shen, Li, Shin, Jean, Sisodiya, Sanjay M., Smith, Albert V., Smoller, Jordan W., Soininen, Hilkka S., Steen, Vidar M., Stein, Dan J., Stein, Jason L., Thomopoulos, Sophia I., Toga, Arthur W., Tordesillas-Gutiérrez, Diana, Trollor, Julian N., Valdes-Hernandez, Maria C., van ′t Ent, Dennis, van Bokhoven, Hans, van der Meer, Dennis, van der Wee, Nic J. A., Vázquez-Bourgon, Javier, Veltman, Dick J., Vernooij, Meike W., Villringer, Arno, Vinke, Louis N., Völzke, Henry, Walter, Henrik, Wardlaw, Joanna M., Weinberger, Daniel R., Weiner, Michael W., Wen, Wei, Westlye, Lars T., Westman, Eric, White, Tonya, Witte, A. Veronica, Wolf, Christiane, Yang, Jingyun, Zwiers, Marcel P., Ikram, M. Arfan, Seshadri, Sudha, Thompson, Paul M., Satizabal, Claudia L., Medland, Sarah E., and Rentería, Miguel E.

Published
2024
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12. Genetic variants for head size share genes and pathways with cancer

Author

Knol, Maria J, Poot, Raymond A, Evans, Tavia E, Satizabal, Claudia L, Mishra, Aniket, Sargurupremraj, Muralidharan, van der Auwera, Sandra, Duperron, Marie-Gabrielle, Jian, Xueqiu, Hostettler, Isabel C, van Dam-Nolen, Dianne HK, Lamballais, Sander, Pawlak, Mikolaj A, Lewis, Cora E, Carrion-Castillo, Amaia, van Erp, Theo GM, Reinbold, Céline S, Shin, Jean, Scholz, Markus, Håberg, Asta K, Kämpe, Anders, Li, Gloria HY, Avinun, Reut, Atkins, Joshua R, Hsu, Fang-Chi, Amod, Alyssa R, Lam, Max, Tsuchida, Ami, Teunissen, Mariël WA, Aygün, Nil, Patel, Yash, Liang, Dan, Beiser, Alexa S, Beyer, Frauke, Bis, Joshua C, Bos, Daniel, Bryan, R Nick, Bülow, Robin, Caspers, Svenja, Catheline, Gwenaëlle, Cecil, Charlotte AM, Dalvie, Shareefa, Dartigues, Jean-François, DeCarli, Charles, Enlund-Cerullo, Maria, Ford, Judith M, Franke, Barbara, Freedman, Barry I, Friedrich, Nele, Green, Melissa J, Haworth, Simon, Helmer, Catherine, Hoffmann, Per, Homuth, Georg, Ikram, M Kamran, Jack, Clifford R, Jahanshad, Neda, Jockwitz, Christiane, Kamatani, Yoichiro, Knodt, Annchen R, Li, Shuo, Lim, Keane, Longstreth, WT, Macciardi, Fabio, Consortium, The Cohorts for Heart and Aging Research in Genomic Epidemiology, Amouyel, Philippe, Arfanakis, Konstantinos, Aribisala, Benjamin S, Bastin, Mark E, Chauhan, Ganesh, Chen, Christopher, Cheng, Ching-Yu, de Jager, Philip L, Deary, Ian J, Fleischman, Debra A, Gottesman, Rebecca F, Gudnason, Vilmundur, Hilal, Saima, Hofer, Edith, Janowitz, Deborah, Jukema, J Wouter, Liewald, David CM, Lopez, Lorna M, Lopez, Oscar, Luciano, Michelle, Martinez, Oliver, Niessen, Wiro J, Nyquist, Paul, Rotter, Jerome I, Rundek, Tatjana, Sacco, Ralph L, Schmidt, Helena, Tiemeier, Henning, Trompet, Stella, van der Grond, Jeroen, Völzke, Henry, Wardlaw, Joanna M, Yanek, Lisa, Yang, Jingyun, and Consortium, The Enhancing NeuroImaging Genetics through Meta-Analysis

Subjects
Biomedical and Clinical Sciences, Neurosciences, Biotechnology, Genetics, Cancer, Stem Cell Research, Human Genome, 2.1 Biological and endogenous factors, 1.1 Normal biological development and functioning, Neurological, Humans, Genome-Wide Association Study, Head, Neoplasms, Female, Male, Polymorphism, Single Nucleotide, Genetic Variation, Organ Size, Signal Transduction, Adult, Genetic Predisposition to Disease, Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis (ENIGMA) Consortium, cancer, genetics, genome-wide association study, head circumference, head size, intracranial volume, meta-analysis, Biomedical and clinical sciences
Abstract

The size of the human head is highly heritable, but genetic drivers of its variation within the general population remain unmapped. We perform a genome-wide association study on head size (N = 80,890) and identify 67 genetic loci, of which 50 are novel. Neuroimaging studies show that 17 variants affect specific brain areas, but most have widespread effects. Gene set enrichment is observed for various cancers and the p53, Wnt, and ErbB signaling pathways. Genes harboring lead variants are enriched for macrocephaly syndrome genes (37-fold) and high-fidelity cancer genes (9-fold), which is not seen for human height variants. Head size variants are also near genes preferentially expressed in intermediate progenitor cells, neural cells linked to evolutionary brain expansion. Our results indicate that genes regulating early brain and cranial growth incline to neoplasia later in life, irrespective of height. This warrants investigation of clinical implications of the link between head size and cancer.

Published
2024

13. Whole genome‐wide sequence analysis of long‐lived families (Long‐Life Family Study) identifies MTUS2 gene associated with late‐onset Alzheimer's disease

Author

Xicota, Laura, Cosentino, Stephanie, Vardarajan, Badri, Mayeux, Richard, Perls, Thomas T, Andersen, Stacy L, Zmuda, Joseph M, Thyagarajan, Bharat, Yashin, Anatoli, Wojczynski, Mary K, Krinsky‐McHale, Sharon, Handen, Benjamin L, Christian, Bradley T, Head, Elizabeth, Mapstone, Mark E, Schupf, Nicole, Lee, Joseph H, Barral, Sandra, Study, the Long‐Life Family, Abner, Erin, Adams, Perrie M, Aguirre, Alyssa, Albert, Marilyn S, Albin, Roger L, Allen, Mariet, Alvarez, Lisa, Andrews, Howard, Apostolova, Liana G, Arnold, Steven E, Asthana, Sanjay, Atwood, Craig S, Ayres, Gayle, Barber, Robert C, Barnes, Lisa L, Bartlett, Jackie, Beach, Thomas G, Becker, James T, Beecham, Gary W, Benchek, Penelope, Bennett, David A, Bertelson, John, Biber, Sarah A, Bird, Thomas D, Blacker, Deborah, Boeve, Bradley F, Bowen, James D, Boxer, Adam, Brewer, James B, Burke, James R, Burns, Jeffrey M, Bush, William S, Buxbaum, Joseph D, Byrd, Goldie, Cantwell, Laura B, Cao, Chuanhai, Carlsson, Cynthia M, Carrasquillo, Minerva M, Chan, Kwun C, Chasse, Scott, Chen, Yen‐Chi, Chesselet, Marie‐Francoise, Chin, Nathaniel A, Chui, Helena C, Chung, Jaeyoon, Craft, Suzanne, Crane, Paul K, Cranney, Marissa, Cruchaga, Carlos, Cuccaro, Michael L, Culhane, Jessica, Cullum, C Munro, Darby, Eveleen, Davis, Barbara, De Jager, Philip L, DeCarli, Charles, DeToledo, John C, Dickson, Dennis W, Dobbins, Nic, Duara, Ranjan, Ertekin‐Taner, Nilufer, Evans, Denis A, Faber, Kelley M, Fairchild, Thomas J, Fallin, Daniele, Fallon, Kenneth B, Fardo, David W, Farlow, Martin R, Farrell, John, Farrer, Lindsay A, Fernandez‐Hernandez, Victoria, Foroud, Tatiana M, Frosch, Matthew P, Galasko, Douglas R, Gamboa, Adriana, Gauthreaux, Kathryn M, Gefen, Tamar, Geschwind, Daniel H, Ghetti, Bernardino, and Gilbert, John R

Subjects
Biomedical and Clinical Sciences, Biological Psychology, Clinical Sciences, Neurosciences, Psychology, Alzheimer's Disease including Alzheimer's Disease Related Dementias (AD/ADRD), Acquired Cognitive Impairment, Neurodegenerative, Brain Disorders, Dementia, Alzheimer's Disease, Human Genome, Biotechnology, Aging, Genetics, 2.1 Biological and endogenous factors, Aetiology, Neurological, Humans, Alzheimer Disease, Amyloid beta-Peptides, Genetic Predisposition to Disease, Genome-Wide Association Study, Microtubule-Associated Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, genetic risk, late-onset Alzheimer's disease, microtubule protein, MTUS2 gene, whole genome sequence, Long‐Life Family Study, Alzheimer's Disease Genetic Consortium, Alzheimer's Biomarkers Consortium‐Down Syndrome, late‐onset Alzheimer's disease, Geriatrics, Clinical sciences, Biological psychology
Abstract

IntroductionLate-onset Alzheimer's disease (LOAD) has a strong genetic component. Participants in Long-Life Family Study (LLFS) exhibit delayed onset of dementia, offering a unique opportunity to investigate LOAD genetics.MethodsWe conducted a whole genome sequence analysis of 3475 LLFS members. Genetic associations were examined in six independent studies (N = 14,260) with a wide range of LOAD risk. Association analysis in a sub-sample of the LLFS cohort (N = 1739) evaluated the association of LOAD variants with beta amyloid (Aβ) levels.ResultsWe identified several single nucleotide polymorphisms (SNPs) in tight linkage disequilibrium within the MTUS2 gene associated with LOAD (rs73154407, p = 7.6 × 10-9). Association of MTUS2 variants with LOAD was observed in the five independent studies and was significantly stronger within high levels of Aβ42/40 ratio compared to lower amyloid.DiscussionMTUS2 encodes a microtubule associated protein implicated in the development and function of the nervous system, making it a plausible candidate to investigate LOAD biology.HighlightsLong-Life Family Study (LLFS) families may harbor late onset Alzheimer's dementia (LOAD) variants. LLFS whole genome sequence analysis identified MTUS2 gene variants associated with LOAD. The observed LLFS variants generalized to cohorts with wide range of LOAD risk. The association of MTUS2 with LOAD was stronger within high levels of beta amyloid. Our results provide evidence for MTUS2 gene as a novel LOAD candidate locus.

Published
2024

14. Multimodal Misinformation Detection in a South African Social Media Environment

Author

De Jager, Amica, Marivate, Vukosi, and Modupe, Abioudun

Subjects
Computer Science - Computation and Language
Abstract

With the constant spread of misinformation on social media networks, a need has arisen to continuously assess the veracity of digital content. This need has inspired numerous research efforts on the development of misinformation detection (MD) models. However, many models do not use all information available to them and existing research contains a lack of relevant datasets to train the models, specifically within the South African social media environment. The aim of this paper is to investigate the transferability of knowledge of a MD model between different contextual environments. This research contributes a multimodal MD model capable of functioning in the South African social media environment, as well as introduces a South African misinformation dataset. The model makes use of multiple sources of information for misinformation detection, namely: textual and visual elements. It uses bidirectional encoder representations from transformers (BERT) as the textual encoder and a residual network (ResNet) as the visual encoder. The model is trained and evaluated on the Fakeddit dataset and a South African misinformation dataset. Results show that using South African samples in the training of the model increases model performance, in a South African contextual environment, and that a multimodal model retains significantly more knowledge than both the textual and visual unimodal models. Our study suggests that the performance of a misinformation detection model is influenced by the cultural nuances of its operating environment and multimodal models assist in the transferability of knowledge between different contextual environments. Therefore, local data should be incorporated into the training process of a misinformation detection model in order to optimize model performance., Comment: Artificial Intelligence Research. SACAIR 2023

Published
2023
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17. CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

Author

Kwangsik Nho, Shannon L. Risacher, Liana G. Apostolova, Paula J. Bice, Jared R. Brosch, Rachael Deardorff, Kelley Faber, Martin R. Farlow, Tatiana Foroud, Sujuan Gao, Thea Rosewood, Jun Pyo Kim, Kelly Nudelman, Meichen Yu, Paul Aisen, Reisa Sperling, Basavaraj Hooli, Sergey Shcherbinin, Diana Svaldi, Clifford R. Jack, William J. Jagust, Susan Landau, Aparna Vasanthakumar, Jeffrey F. Waring, Vincent Doré, Simon M. Laws, Colin L. Masters, Tenielle Porter, Christopher C. Rowe, Victor L. Villemagne, Logan Dumitrescu, Timothy J. Hohman, Julia B. Libby, Elizabeth Mormino, Rachel F. Buckley, Keith Johnson, Hyun-Sik Yang, Ronald C. Petersen, Vijay K. Ramanan, Nilüfer Ertekin-Taner, Prashanthi Vemuri, Ann D. Cohen, Kang-Hsien Fan, M. Ilyas Kamboh, Oscar L. Lopez, David A. Bennett, Muhammad Ali, Tammie Benzinger, Carlos Cruchaga, Diana Hobbs, Philip L. De Jager, Masashi Fujita, Vaishnavi Jadhav, Bruce T. Lamb, Andy P. Tsai, Isabel Castanho, Jonathan Mill, Michael W. Weiner, for the Alzheimer’s Disease Neuroimaging Initiative (ADNI), the Department of Defense Alzheimer’s Disease Neuroimaging Initiative (DoD-ADNI), the Anti-Amyloid Treatment in Asymptomatic Alzheimer’s Study (A4 Study) and Longitudinal Evaluation of Amyloid Risk and Neurodegeneration (LEARN), the Australian Imaging, Biomarker & Lifestyle Study (AIBL), and Andrew J. Saykin

Subjects
Science
Abstract

Abstract Determining the genetic architecture of Alzheimer’s disease pathologies can enhance mechanistic understanding and inform precision medicine strategies. Here, we perform a genome-wide association study of cortical tau quantified by positron emission tomography in 3046 participants from 12 independent studies. The CYP1B1-RMDN2 locus is associated with tau deposition. The most significant signal is at rs2113389, explaining 4.3% of the variation in cortical tau, while APOE4 rs429358 accounts for 3.6%. rs2113389 is associated with higher tau and faster cognitive decline. Additive effects, but no interactions, are observed between rs2113389 and diagnosis, APOE4, and amyloid beta positivity. CYP1B1 expression is upregulated in AD. rs2113389 is associated with higher CYP1B1 expression and methylation levels. Mouse model studies provide additional functional evidence for a relationship between CYP1B1 and tau deposition but not amyloid beta. These results provide insight into the genetic basis of cerebral tau deposition and support novel pathways for therapeutic development in AD.

Published
2024
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18. Image registration of an electromagnetic tracking enabled afterloader and CT using a phantom for the quality control of implant reconstruction

Author

Gomez-Sarmiento, Isaac Neri, Tho, Daline, Dürrbeck, Christopher, de Jager, Wim, Laurendeau, Denis, and Beaulieu, Luc

Subjects
Physics - Medical Physics
Abstract

Electromagnetic tracking (EMT) shows great potential for automating implant reconstruction in brachytherapy. One of the challenges of this technology is that it does not intrinsically share the same reference frame as the patient's medical imaging. The purpose of this work is to register the reference frames of an EMT-enabled afterloader and a CT scan image of a rigid phantom for quality control of EMT-based implant reconstruction. The geometry of twelve 6F catheters and a tandem and ring gynecological applicator were reconstructed using an EMT sensor attached to an afterloader's check cable. All EMT reconstructions were done in three different environments: disturbance free, CT-on-rails brachytherapy suite and MRI brachytherapy suite. Implants were reconstructed using two acquisition methods: step-and-record and continuous motion. A CT scan of the phantom was obtained and manually reconstructed in the treatment planning system, with the help of the solid model of the applicator. Rigid registration algorithms were used to register EMT and CT scan reference frames using corresponding points from the EMT and CT based reconstructions of the phantom, following three approaches: one gynecological applicator, four catheters inside four calibration plates having and S-shaped path, and four ceramic marbles within the calibration plates. The absolute median deviation from the expected value for EMT measurements in all three environments significantly lie below the sensor's expected accuracy of 0.70 mm (p < 0.001), suggesting that the environment did not have a significant impact on the measurements, given that care is taken in the immediate surroundings. In all three environments, the two acquisition and three registration approaches have a mean and median registration errors (perpendicular distance) that lie at or below 1 mm, which is lower than the clinical acceptable threshold of 2 mm.

Published
2023

19. In search of a precursor for crystal nucleation of hard and charged colloids

Author

de Jager, Marjolein, Smallenburg, Frank, and Filion, Laura

Subjects
Condensed Matter - Soft Condensed Matter
Abstract

The interplay between crystal nucleation and the structure of the metastable fluid has been a topic of significant debate over recent years. In particular, it has been suggested that even in simple model systems such as hard or charged colloids, crystal nucleation might be foreshadowed by significant fluctuations in local structure around the location where the first nucleus arises. We investigate this using computer simulations of spontaneous nucleation events in both hard and charged colloidal particles. To detect local structural variations, we use both standard and unsupervised machine learning methods capable of finding hidden structures in the metastable fluid phase. We track numerous nucleation events for the face-centered cubic and body-centered cubic crystal on a local level, and demonstrate that all signs of crystallinity emerge simultaneously from the very start of the nucleation process. We thus conclude that there is no precursor for the nucleation of charged colloids.

Published
2023

20. CYP1B1-RMDN2 Alzheimer’s disease endophenotype locus identified for cerebral tau PET

Author

Nho, Kwangsik, Risacher, Shannon L., Apostolova, Liana G., Bice, Paula J., Brosch, Jared R., Deardorff, Rachael, Faber, Kelley, Farlow, Martin R., Foroud, Tatiana, Gao, Sujuan, Rosewood, Thea, Kim, Jun Pyo, Nudelman, Kelly, Yu, Meichen, Aisen, Paul, Sperling, Reisa, Hooli, Basavaraj, Shcherbinin, Sergey, Svaldi, Diana, Jack, Jr., Clifford R., Jagust, William J., Landau, Susan, Vasanthakumar, Aparna, Waring, Jeffrey F., Doré, Vincent, Laws, Simon M., Masters, Colin L., Porter, Tenielle, Rowe, Christopher C., Villemagne, Victor L., Dumitrescu, Logan, Hohman, Timothy J., Libby, Julia B., Mormino, Elizabeth, Buckley, Rachel F., Johnson, Keith, Yang, Hyun-Sik, Petersen, Ronald C., Ramanan, Vijay K., Ertekin-Taner, Nilüfer, Vemuri, Prashanthi, Cohen, Ann D., Fan, Kang-Hsien, Kamboh, M. Ilyas, Lopez, Oscar L., Bennett, David A., Ali, Muhammad, Benzinger, Tammie, Cruchaga, Carlos, Hobbs, Diana, De Jager, Philip L., Fujita, Masashi, Jadhav, Vaishnavi, Lamb, Bruce T., Tsai, Andy P., Castanho, Isabel, Mill, Jonathan, Weiner, Michael W., and Saykin, Andrew J.

Published
2024
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22. Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease

Author

Chen, Qiang, Aguirre, Luis, Liang, Guoming, Zhao, Huanhuan, Dong, Tao, Borrego, Felix, de Rojas, Itziar, Hu, Qichan, Reyes, Christopher, Su, Ling-Yan, Zhang, Bao, Lechleiter, James D., Göring, Harald H. H., De Jager, Philip L., Kleinman, Joel E., Hyde, Thomas M., Li, Pan P., Ruiz, Agustín, Weinberger, Daniel R., Seshadri, Sudha, and Ma, Liang

Published
2024
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30. A multimodal precision-prevention approach combining lifestyle intervention with metformin repurposing to prevent cognitive impairment and disability: the MET-FINGER randomised controlled trial protocol

Author

Barbera, Mariagnese, Lehtisalo, Jenni, Perera, Dinithi, Aspö, Malin, Cross, Mary, De Jager Loots, Celeste A., Falaschetti, Emanuela, Friel, Naomi, Luchsinger, José A., Gavelin, Hanna Malmberg, Peltonen, Markku, Price, Geraint, Neely, Anna Stigsdotter, Thunborg, Charlotta, Tuomilehto, Jaakko, Mangialasche, Francesca, Middleton, Lefkos, Ngandu, Tiia, Solomon, Alina, and Kivipelto, Miia

Published
2024
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32. Multi-omics and pathway analyses of genome-wide associations implicate regulation and immunity in verbal declarative memory performance

Author

Mei, Hao, Simino, Jeannette, Li, Lianna, Jiang, Fan, Bis, Joshua C., Davies, Gail, Hill, W David, Xia, Charley, Gudnason, Vilmundur, Yang, Qiong, Lahti, Jari, Smith, Jennifer A., Kirin, Mirna, De Jager, Philip, Armstrong, Nicola J., Ghanbari, Mohsen, Kolcic, Ivana, Moran, Christopher, Teumer, Alexander, Sargurupremraj, Murali, Mahmud, Shamsed, Fornage, Myriam, Zhao, Wei, Satizabal, Claudia L., Polasek, Ozren, Räikkönen, Katri, Liewald, David C., Homuth, Georg, Callisaya, Michele, Mather, Karen A., Windham, B. Gwen, Zemunik, Tatijana, Palotie, Aarno, Pattie, Alison, van der Auwera, Sandra, Thalamuthu, Anbupalam, Knopman, David S., Rudan, Igor, Starr, John M., Wittfeld, Katharina, Kochan, Nicole A., Griswold, Michael E., Vitart, Veronique, Brodaty, Henry, Gottesman, Rebecca, Cox, Simon R., Psaty, Bruce M., Boerwinkle, Eric, Chasman, Daniel I., Grodstein, Francine, Sachdev, Perminder S., Srikanth, Velandai, Hayward, Caroline, Wilson, James F., Eriksson, Johan G., Kardia, Sharon L. R., Grabe, Hans J., Bennett, David A., Ikram, M. Arfan, Deary, Ian J., van Duijn, Cornelia M., Launer, Lenore, Fitzpatrick, Annette L., Seshadri, Sudha, Bressler, Jan, Debette, Stephanie, and Mosley, Jr, Thomas H.

Published
2024
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34. Cell subtype-specific effects of genetic variation in the Alzheimer’s disease brain

Author

Fujita, Masashi, Gao, Zongmei, Zeng, Lu, McCabe, Cristin, White, Charles C., Ng, Bernard, Green, Gilad Sahar, Rozenblatt-Rosen, Orit, Phillips, Devan, Amir-Zilberstein, Liat, Lee, Hyo, Pearse, II, Richard V., Khan, Atlas, Vardarajan, Badri N., Kiryluk, Krzysztof, Ye, Chun Jimmie, Klein, Hans-Ulrich, Wang, Gao, Regev, Aviv, Habib, Naomi, Schneider, Julie A., Wang, Yanling, Young-Pearse, Tracy, Mostafavi, Sara, Bennett, David A., Menon, Vilas, and De Jager, Philip L.

Published
2024
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35. A first-in-class leucyl-tRNA synthetase inhibitor, ganfeborole, for rifampicin-susceptible tuberculosis: a phase 2a open-label, randomized trial

Author

Diacon, Andreas H., Barry, III, Clifton E., Carlton, Alex, Chen, Ray Y., Davies, Matt, de Jager, Veronique, Fletcher, Kim, Koh, Gavin C. K. W., Kontsevaya, Irina, Heyckendorf, Jan, Lange, Christoph, Reimann, Maja, Penman, Sophie L., Scott, Rhona, Maher-Edwards, Gareth, Tiberi, Simon, Vlasakakis, Georgios, Upton, Caryn M., and Aguirre, David Barros

Published
2024
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36. Identification of a specific APOE transcript and functional elements associated with Alzheimer’s disease

Author

Qiang Chen, Luis Aguirre, Guoming Liang, Huanhuan Zhao, Tao Dong, Felix Borrego, Itziar de Rojas, Qichan Hu, Christopher Reyes, Ling-Yan Su, Bao Zhang, James D. Lechleiter, Harald H. H. Göring, Philip L. De Jager, Joel E. Kleinman, Thomas M. Hyde, Pan P. Li, Agustín Ruiz, Daniel R. Weinberger, Sudha Seshadri, and Liang Ma

Subjects
APOE, Alzheimer’s disease, Transcript, Postmortem brain, SNP, Neurology. Diseases of the nervous system, RC346-429, Geriatrics, RC952-954.6
Abstract

Abstract Background The APOE gene is the strongest genetic risk factor for late-onset Alzheimer’s Disease (LOAD). However, the gene regulatory mechanisms at this locus remain incompletely characterized. Methods To identify novel AD-linked functional elements within the APOE locus, we integrated SNP variants with multi-omics data from human postmortem brains including 2,179 RNA-seq samples from 3 brain regions and two ancestries (European and African), 667 DNA methylation samples, and ChIP-seq samples. Additionally, we plotted the expression trajectory of APOE transcripts in human brains during development. Results We identified an AD-linked APOE transcript (jxn1.2.2) particularly observed in the dorsolateral prefrontal cortex (DLPFC). The APOE jxn1.2.2 transcript is associated with brain neuropathological features, cognitive impairment, and the presence of the APOE4 allele in DLPFC. We prioritized two independent functional SNPs (rs157580 and rs439401) significantly associated with jxn1.2.2 transcript abundance and DNA methylation levels. These SNPs are located within active chromatin regions and affect brain-related transcription factor-binding affinities. The two SNPs shared effects on the jxn1.2.2 transcript between European and African ethnic groups. Conclusion The novel APOE functional elements provide potential therapeutic targets with mechanistic insight into the disease etiology.

Published
2024
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37. SR-TWAS: leveraging multiple reference panels to improve transcriptome-wide association study power by ensemble machine learning

Author

Randy L. Parrish, Aron S. Buchman, Shinya Tasaki, Yanling Wang, Denis Avey, Jishu Xu, Philip L. De Jager, David A. Bennett, Michael P. Epstein, and Jingjing Yang

Subjects
Science
Abstract

Abstract Multiple reference panels of a given tissue or multiple tissues often exist, and multiple regression methods could be used for training gene expression imputation models for transcriptome-wide association studies (TWAS). To leverage expression imputation models (i.e., base models) trained with multiple reference panels, regression methods, and tissues, we develop a Stacked Regression based TWAS (SR-TWAS) tool which can obtain optimal linear combinations of base models for a given validation transcriptomic dataset. Both simulation and real studies show that SR-TWAS improves power, due to increased training sample sizes and borrowed strength across multiple regression methods and tissues. Leveraging base models across multiple reference panels, tissues, and regression methods, our real studies identify 6 independent significant risk genes for Alzheimer’s disease (AD) dementia for supplementary motor area tissue and 9 independent significant risk genes for Parkinson’s disease (PD) for substantia nigra tissue. Relevant biological interpretations are found for these significant risk genes.

Published
2024
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38. Single cell transcriptomes and multiscale networks from persons with and without Alzheimer’s disease

Author

Qi Wang, Jerry Antone, Eric Alsop, Rebecca Reiman, Cory Funk, Jaroslav Bendl, Joel T. Dudley, Winnie S. Liang, Timothy L. Karr, Panos Roussos, David A. Bennett, Philip L. De Jager, Geidy E. Serrano, Thomas G. Beach, Kendall Van Keuren-Jensen, Diego Mastroeni, Eric M. Reiman, and Benjamin P. Readhead

Subjects
Science
Abstract

Abstract The emergence of single nucleus RNA sequencing (snRNA-seq) offers to revolutionize the study of Alzheimer’s disease (AD). Integration with complementary multiomics data such as genetics, proteomics and clinical data provides powerful opportunities to link cell subpopulations and molecular networks with a broader disease-relevant context. We report snRNA-seq profiles from superior frontal gyrus samples from 101 well characterized subjects from the Banner Brain and Body Donation Program in combination with whole genome sequences. We report findings that link common AD risk variants with CR1 expression in oligodendrocytes as well as alterations in hematological parameters. We observed an AD-associated CD83(+) microglial subtype with unique molecular networks and which is associated with immunoglobulin IgG4 production in the transverse colon. Our major observations were replicated in two additional, independent snRNA-seq data sets. These findings illustrate the power of multi-tissue molecular profiling to contextualize snRNA-seq brain transcriptomics and reveal disease biology.

Published
2024
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39. Cold exposure increases circulating fibroblast growth factor 21 in the evening in males and females

Author

Carlijn A Hoekx, Borja Martinez-Tellez, Maaike E Straat, Magdalena M A Verkleij, Mirjam Kemmeren, Sander Kooijman, Martin Uhrbom, Saskia C A de Jager, Patrick C N Rensen, and Mariëtte R Boon

Subjects
circadian rhythm, energy metabolism, cold stimulus, brown adipose tissue, Diseases of the endocrine glands. Clinical endocrinology, RC648-665
Abstract

Objectives: Cold exposure is linked to cardiometabolic benefits. Cold activates brown adipose tissue (BAT), increases energy expenditure, and induces secretion of the hormones fibroblast growth factor 21 (FGF21) and growth differentiation factor 15 (GDF15). The cold-induced increase in energy expenditure exhibits a diurnal rhythm in men. Therefore, we aimed to investigate the effect of cold exposure on serum FGF21 and GDF15 levels in humans and whether cold-induced changes in FGF21 and GDF15 levels differ between morning and evening in males and females. Method: In this randomized cross-over study, serum FGF21 and GDF15 levels were measured in healthy lean males (n = 12) and females (n = 12) before, during, and after 90 min of stable cold exposure in the morning (07:45 h) and evening (19:45 h) with a 1-day washout period in between. Results: Cold exposure increased FGF21 levels in the evening compared to the morning both in males (+61% vs −13%; P < 0.001) and in females (+58% vs +8%; P < 0.001). In contrast, cold exposure did not significantly modify serum GDF15 levels, and no diurnal variation was found. Changes in FGF21 and GDF15 levels did not correlate with changes in cold-induced energy expenditure in the morning and evening. Conclusion: Cold exposure increased serum FGF21 levels in the evening, but not in the morning, in both males and females. GDF15 levels were not affected by cold exposure. Thus, this study suggests that the timing of cold exposure may influence cold-induced changes in FGF21 levels but not GDF15 levels and seems to be independent of changes in energy expenditure.

Published
2024
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40. Xenografted human iPSC-derived neurons with the familial Alzheimer’s disease APPV717I mutation reveal dysregulated transcriptome signatures linked to synaptic function and implicate LINGO2 as a disease signaling mediator

Author

Qu, Wenhui, Lam, Matti, McInvale, Julie J., Mares, Jason A., Kwon, Sam, Humala, Nelson, Mahajan, Aayushi, Nguyen, Trang, Jakubiak, Kelly A., Mun, Jeong-Yeon, Tedesco, Thomas G., Al-Dalahmah, Osama, Hussaini, Syed A., Sproul, Andrew A., Siegelin, Markus D., De Jager, Philip L., Canoll, Peter, Menon, Vilas, and Hargus, Gunnar

Published
2024
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41. Efficacy and safety of three antiretroviral therapy regimens started in pregnancy up to 50 weeks post partum: a multicentre, open-label, randomised, controlled, phase 3 trial

Author

Chinula, Lameck, Ziemba, Lauren, Brummel, Sean, McCarthy, Katie, Coletti, Anne, Krotje, Chelsea, Johnston, Benjamin, Knowles, Kevin, Moyo, Sikhulile, Stranix-Chibanda, Lynda, Hoffman, Risa, Sax, Paul E, Stringer, Jeffrey, Chakhtoura, Nahida, Jean-Philippe, Patrick, Korutaro, Violet, Cassim, Haseena, Fairlie, Lee, Masheto, Gaerolwe, Boyce, Ceejay, Frenkel, Lisa M, Amico, K Rivet, Purdue, Lynette, Shapiro, Roger, Mmbaga, Blandina Theophil, Patel, Faeezah, van Wyk, Jean, Rooney, James F, Currier, Judith S, Lockman, Shahin, Best, Brookie M, Blanchette, Cheryl D, Browning, Renee, Jaliaah, Nagawa, Mirochnick, Mark, Murtaugh, William A, Patras, Emmanuel, Whalen, Frances, Momper, Jeremiah D, Ponatshego, Ponego L, Tirelo, Lesedi, Seme, Boitshepo J, Modise, Georginah O, Raesi, Mpho S, Budu, Marian E, Ramogodiri, Moakanyi, Oliveira, Ricardo H, Hofe, Cristina B, de Abreu, Thalita Fernandes, Pestanha, Lorena M, João, Esaú, Sidi, Leon C, Fuller, Trevon, Cruz, Maria LS, Pinto, Jorge, Ferreira, Flãvia, Correa, Mãrio, Romeiro, Juliana, Pilotto, Jose H, Fernandes, Luis EBC, Moreira, Luiz F, Gomes, Ivete M, Naik, Shilpa, Nevrekar, Neetal, Mave, Vidya, Kinikar, Aarti, Horne, Elizea, Soma-Kasiram, Hamisha, Violari, Avy, Mathiba, Sisinyana R, Nyati, Mandisa, Theron, Gerhard, de Jager, Jeanne, Rossouw, Magdel, Rossouw, Lindie, Hanley, Sherika, Desmond, Alicia C, Gazu, Rosemary, Govender, Vani, Chalermchockcharoenkit, Amphan, Thamkhantho, Manopchai, Werarak, Peerawong, Rungmaitree, Supattra, Achalapong, Jullapong, Sitiritkawin, Lukkana, Cressey, Tim R, Sukrakanchana, Pra-ornsuda, Aurpibul, Linda, Tongprasert, Fuanglada, Khamrong, Chintana, Kiattivej, Sopida, Wabwire, Deo, Kabugo, Enid, Maena, Joel, Nakayiwa, Frances, Ndyanabangi, Victoria, Nagaddya, Beatrice, Sekabira, Rogers, Ashaba, Justus, and Mitchell, Charles D

Subjects
Reproductive Medicine, Biomedical and Clinical Sciences, Mental Health, Infectious Diseases, Pediatric, HIV/AIDS, Clinical Research, Clinical Trials and Supportive Activities, 6.1 Pharmaceuticals, Evaluation of treatments and therapeutic interventions, Reproductive health and childbirth, Infection, Good Health and Well Being, Pregnancy, Child, Female, Humans, Male, HIV Infections, Anti-HIV Agents, Tenofovir, Benzoxazines, Emtricitabine, Adenine, RNA, Viral Load, IMPAACT 2010/VESTED Study Team and Investigators, Medical and Health Sciences, Biomedical and clinical sciences, Health sciences
Abstract

BackgroundDrugs taken during pregnancy can affect maternal and child health outcomes, but few studies have compared the safety and virological efficacy of different antiretroviral therapy (ART) regimens. We report the primary safety outcomes from enrolment up to 50 weeks post partum and a secondary virological efficacy outcome at 50 weeks post partum of three commonly used ART regimens for HIV-1.MethodsIn this multicentre, open-label, randomised, controlled, phase 3 trial, we enrolled pregnant women aged 18 years or older with confirmed HIV-1 infection at 14-28 weeks of gestation. Women were enrolled at 22 clinical research sites in nine countries (Botswana, Brazil, India, South Africa, Tanzania, Thailand, Uganda, the USA, and Zimbabwe). Participants were randomly assigned (1:1:1) to one of three oral regimens: dolutegravir, emtricitabine, and tenofovir alafenamide; dolutegravir, emtricitabine, and tenofovir disoproxil fumarate; or efavirenz, emtricitabine, and tenofovir disoproxil fumarate. Up to 14 days of antepartum ART before enrolment was permitted. Women with known multiple gestation, fetal anomalies, acute significant illness, transaminases more than 2·5 times the upper limit of normal, or estimated creatinine clearance of less than 60 mL/min were excluded. Primary safety analyses were pairwise comparisons between ART regimens of the proportion of maternal and infant adverse events of grade 3 or higher up to 50 weeks post partum. Secondary efficacy analyses at 50 weeks post partum included a comparison of the proportion of women with plasma HIV-1 RNA of less than 200 copies per mL in the combined dolutegravir-containing groups versus the efavirenz-containing group. Analyses were done in the intention-to-treat population, which included all randomly assigned participants with available data. This trial was registered with ClinicalTrials.gov, NCT03048422.FindingsBetween Jan 19, 2018, and Feb 8, 2019, we randomly assigned 643 pregnant women to the dolutegravir, emtricitabine, and tenofovir alafenamide group (n=217), the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group (n=215), and the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (n=211). At enrolment, median gestational age was 21·9 weeks (IQR 18·3-25·3), median CD4 count was 466 cells per μL (308-624), and median HIV-1 RNA was 903 copies per mL (152-5183). 607 (94%) women and 566 (92%) of 617 liveborn infants completed the study. Up to the week 50 post-partum visit, the estimated probability of experiencing an adverse event of grade 3 or higher was 25% in the dolutegravir, emtricitabine, and tenofovir alafenamide group; 31% in the dolutegravir, emtricitabine, and tenofovir disoproxil fumarate group; and 28% in the efavirenz, emtricitabine, and tenofovir disoproxil fumarate group (no significant difference between groups). Among infants, the estimated probability of experiencing at least one adverse event of grade 3 or higher by postnatal week 50 was 28% overall, with small and non-statistically significant differences between groups. By postnatal week 50, 14 infants whose mothers were in the efavirenz-containing group (7%) died, compared with six in the combined dolutegravir groups (1%). 573 (89%) women had HIV-1 RNA data available at 50 weeks post partum: 366 (96%) in the dolutegravir-containing groups and 186 (96%) in the efavirenz-containing group had HIV-1 RNA less than 200 copies per mL, with no significant difference between groups.InterpretationSafety and efficacy data during pregnancy and up to 50 weeks post partum support the current recommendation of dolutegravir-based ART (particularly in combination with emtricitabine and tenofovir alafenamide) rather than efavirenz, emtricitabine, and tenofovir disoproxil fumarate, when started in pregnancy.FundingNational Institute of Allergy and Infectious Diseases, the Eunice Kennedy Shriver National Institute of Child Health and Human Development, and the National Institute of Mental Health.

Published
2023

42. Switched-Actuator Systems with Setup Times: Efficient Modeling, MPC, and Application to Hyperthermia Therapy

Author

Deenen, D. A., Maljaars, E., Sebeke, L. C., de Jager, B., Heijman, E., Grüll, H., and Heemels, W. P. M. H.

Subjects
Electrical Engineering and Systems Science - Systems and Control
Abstract

Switched-actuator systems with setup times (SAcSSs) are systems in which the actuator configuration has to be switched during operation, and where the switching induces non-negligible actuator downtime. Optimally controlling SAcSSs requires the online solving of both a discrete actuator allocation problem, in which the switch-induced actuator downtime is taken into account, as well as an optimization problem for the (typically continuous) control inputs. Mixed-integer model predictive control (MI-MPC) offers a powerful framework for tackling such problems. However, the efficient modeling of SAcSSs for MI-MPC is not straightforward, and real-time feasibility is often a major hurdle in practice. It is the objective of this paper to provide an intuitive and systematic modeling procedure tailored to SAcSSs, which is specifically designed to allow for user-friendly controller synthesis, and to yield efficient MI-MPCs. We apply these new results in a case study of large-volume magnetic-resonance-guided high-intensity focused ultrasound hyperthermia, which involves the heating of tumors (using real-valued local heating controls, as well as discrete range-extending actuator relocation during which no heating is allowed) to enhance the efficacy of radio- and chemotherapy., Comment: 34 pages, 9 figures

Published
2022

45. Osimertinib and palbociclib in an EGFR-mutated NSCLC with primary CDK4 amplification after progression under osimertinib

Author

Vincent D. de Jager, Jos A. Stigt, Maarten Niemantsverdriet, Arja ter Elst, and Anthonie J. van der Wekken

Subjects
Neoplasms. Tumors. Oncology. Including cancer and carcinogens, RC254-282
Abstract

Abstract Precision cancer medicine has changed the treatment paradigm of patients with non-small cell lung cancer (NSCLC) with specific molecular aberrations. A major challenge is management of the resistance that tumor cells eventually develop against targeted therapies, either through primary or acquired resistance mechanisms. We report a 61 year-old male patient with metastatic NSCLC harboring an EGFR exon 19 deletion, a PIK3CA mutation, and CDK4 amplification. After an initial partial response to osimertinib as mono-therapy (third-generation EGFR tyrosine kinase inhibitor), the patient had progression of disease after 4 months of treatment and was referred for combined osimertinib and palbociclib (CDK4/6 inhibitor) treatment. Though complicated by transient pneumonitis, the patient has an ongoing partial response for > 10 months and has experienced clinical improvement on this treatment regimen. As amplification of CDK4 occurs in ~ 10% of treatment-naïve patients with EGFR-mutated NSCLC, the successful treatment of our patient with osimertinib and palbociclib may be highly relevant for future patients with NSCLC.

Published
2024
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46. G-protein coupled estrogen receptor 1, amyloid-β, and tau tangles in older adults

Author

Shahram Oveisgharan, Lei Yu, Katia de Paiva Lopes, Vladislav A. Petyuk, Shinya Tasaki, Ricardo Vialle, Vilas Menon, Yanling Wang, Philip L. De Jager, Julie A. Schneider, and David A. Bennett

Subjects
Biology (General), QH301-705.5
Abstract

Abstract Accumulation of amyloid-β (Aβ) and tau tangles are hallmarks of Alzheimer’s disease. Aβ is extracellular while tau tangles are typically intracellular, and it is unknown how these two proteinopathies are connected. Here, we use data of 1206 elders and test that RNA expression levels of GPER1, a transmembrane protein, modify the association of Aβ with tau tangles. GPER1 RNA expression is related to more tau tangles (p = 0.001). Moreover, GPER1 expression modifies the association of immunohistochemistry-derived Aβ load with tau tangles (p = 0.044). Similarly, GPER1 expression modifies the association between Aβ proteoforms and tau tangles: total Aβ protein (p = 0.030) and Aβ38 peptide (p = 0.002). Using single nuclei RNA-seq indicates that GPER1 RNA expression in astrocytes modifies the relation of Aβ load with tau tangles (p = 0.002), but not GPER1 in excitatory neurons or endothelial cells. We conclude that GPER1 may be a link between Aβ and tau tangles driven mainly by astrocytic GPER1 expression.

Published
2024
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47. Lung behavior during a staircase high-frequency oscillatory ventilation recruitment maneuver

Author

Pauline de Jager, Alette A. Koopman, Dick G. Markhorst, and Martin C. J. Kneyber

Subjects
High-frequency oscillatory ventilation, Pediatric acute respiratory distress syndrome, Recruitment, Time constant, Medical emergencies. Critical care. Intensive care. First aid, RC86-88.9
Abstract

Abstract Background Lung volume optimization maneuvers (LVOM) are necessary to make physiologic use of high-frequency oscillatory ventilation (HFOV), but lung behavior during such maneuvers has not been studied to determine lung volume changes after initiation of HFOV, to quantify recruitment versus derecruitment during the LVOM and to calculate the time to stabilization after a pressure change. Methods We performed a secondary analysis of prospectively collected data in subjects

Published
2024
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48. The Driving Factors of Digital Banking Intention and the Role of Customer Experience in Indonesia Banking Industry

Author

Nuri Wulandari, Johan W. De Jager, and Syarifah Endolusia Mahry

Subjects
component, customer experience, marketing, digital banking, service quality, unified theory of acceptance, Business, HF5001-6182
Abstract

As one of the most important industries of a country’s economy, banking is now faced the challenge of competition and demand from the customers to provide excellent service. In addition, the advancement of technology has opened up opportunities to increase service quality of banking offerings. One of the newest approaches is digital banking. Unfortunately, the literature is still limited in this area especially on the customer adoption of this service. The objective of this study is to find driving factors that contributes to the intention to use and reuse digital banking especially in generation Z and Millenials. It is hypothesized that there are six factors that might drive the intention, includes performance expectancy, effort expectancy, social influence, perceived service quality and hedonic motivation. It has also argued that intention is mediated by customer experience. Quantitative research was conducted to 105 respondents in Indonesia where digital banking is flourishing. The results provide valuable insights to the factors of digital banking usage intention in the future.

Published
2024
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49. Crystal Nucleation of Highly-Screened Charged Colloids

Author

de Jager, Marjolein and Filion, Laura

Subjects
Condensed Matter - Soft Condensed Matter
Abstract

We study the nucleation of nearly-hard charged colloidal particles. We use Monte Carlo simulations in combination with free-energy calculations to accurately predict the phase diagrams of these particles and map them via the freezing density to hard spheres, then we use umbrella sampling to explore the nucleation process. Surprisingly, we find that even very small amounts of charge can have a significant effect on the phase behavior. Specifically, we find that phase boundaries and nucleation barriers are mostly dependent on the Debye screening length, and that even screening lengths as small as 2% of the particle diameter are sufficient to show marked differences in both. This work demonstrates clearly that even mildly charged colloids are not effectively hard spheres.

Published
2022
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50. Genetic architecture of epigenetic cortical clock age in brain tissue from older individuals: alterations in CD46 and other loci

Author

Francine Grodstein, Bernardo Lemos, Jingyun Yang, Katia de Paiva Lopes, Ricardo A. Vialle, Nicholas Seyfried, Yanling Wang, Gemma Shireby, Eilis Hannon, Alan Thomas, Keeley Brookes, Jonathan Mill, Philip L. De Jager, and David A. Bennett

Subjects
Aging, epigenetics, brain, dementia, Genetics, QH426-470
Abstract

The cortical epigenetic clock was developed in brain tissue as a biomarker of brain aging. As one way to identify mechanisms underlying aging, we conducted a GWAS of cortical age. We leveraged postmortem cortex tissue and genotyping array data from 694 participants of the Rush Memory and Aging Project and Religious Orders Study (ROSMAP; 11000,000 SNPs), and meta-analysed ROSMAP with 522 participants of Brains for Dementia Research (5,000,000 overlapping SNPs). We confirmed results using eQTL (cortical bulk and single nucleus gene expression), cortical protein levels (ROSMAP), and phenome-wide association studies (clinical/neuropathologic phenotypes, ROSMAP). In the meta-analysis, the strongest association was rs4244620 (p = 1.29 × 10−7), which also exhibited FDR-significant cis-eQTL effects for CD46 in bulk and single nucleus (microglia, astrocyte, oligodendrocyte, neuron) cortical gene expression. Additionally, rs4244620 was nominally associated with lower cognition, faster slopes of cognitive decline, and greater Parkinsonian signs (n ~ 1700 ROSMAP with SNP/phenotypic data; all p ≤ 0.04). In ROSMAP alone, the top SNP was rs4721030 (p = 8.64 × 10−8) annotated to TMEM106B and THSD7A. Further, in ROSMAP (n = 849), TMEM106B and THSD7A protein levels in cortex were related to many phenotypes, including greater AD pathology and lower cognition (all p ≤ 0.0007). Overall, we identified converging evidence of CD46 and possibly TMEM106B/THSD7A for potential roles in cortical epigenetic clock age.

Published
2024
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