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1. PARK7/DJ-1 deficiency impairs microglial activation in response to LPS-induced inflammation

Author

Lind-Holm Mogensen, Frida, Sousa, Carole, Ameli, Corrado, Badanjak, Katja, Pereira, Sandro L., Muller, Arnaud, Kaoma, Tony, Coowar, Djalil, Scafidi, Andrea, Poovathingal, Suresh K., Tziortziou, Maria, Antony, Paul M. A., Nicot, Nathalie, Ginolhac, Aurélien, Vogt Weisenhorn, Daniela M., Wurst, Wolfgang, Poli, Aurélie, Nazarov, Petr V., Skupin, Alexander, Grünewald, Anne, and Michelucci, Alessandro

Published
2024
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3. Glioblastoma-instructed microglia transition to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

Author

Yabo, Yahaya A., Moreno-Sanchez, Pilar M., Pires-Afonso, Yolanda, Kaoma, Tony, Nosirov, Bakhtiyor, Scafidi, Andrea, Ermini, Luca, Lipsa, Anuja, Oudin, Anaïs, Kyriakis, Dimitrios, Grzyb, Kamil, Poovathingal, Suresh K., Poli, Aurélie, Muller, Arnaud, Toth, Reka, Klink, Barbara, Berchem, Guy, Berthold, Christophe, Hertel, Frank, Mittelbronn, Michel, Heiland, Dieter H., Skupin, Alexander, Nazarov, Petr V., Niclou, Simone P., Michelucci, Alessandro, and Golebiewska, Anna

Published
2024
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5. Nonequilibrium calcium dynamics optimizes the energetic efficiency of mitochondrial metabolism

Author

Voorsluijs, Valérie, Avanzini, Francesco, Falasco, Gianmaria, Esposito, Massimiliano, and Skupin, Alexander

Subjects
Quantitative Biology - Molecular Networks, Condensed Matter - Other Condensed Matter, Condensed Matter - Statistical Mechanics
Abstract

Living organisms continuously harness energy to perform complex functions for their adaptation and survival while part of that energy is dissipated in the form of heat or chemical waste. Determining the energetic cost and the efficiency of specific cellular processes remains a largely open problem. Here, we analyze the efficiency of mitochondrial adenosine triphosphate (ATP) production through the tricarboxylic acid (TCA) cycle and oxidative phosphorylation that generates most of the cellular chemical energy in eukaryotes. The regulation of this pathway by calcium signaling represents a well-characterized example of a regulatory cross-talk that can affect the energetic output of a metabolic pathway, but its concrete energetic impact remains elusive. On the one hand, calcium enhances ATP production by activating key enzymes of the TCA cycle, but on the other hand calcium homeostasis depends on ATP availability. To evaluate how calcium signaling impacts the efficiency of mitochondrial metabolism, we propose a detailed kinetic model describing the calcium-mitochondria cross-talk and we analyze it using a nonequilibrium thermodynamic approach: after identifying the effective reactions driving mitochondrial metabolism out of equilibrium, we quantify the thermodynamic efficiency of the metabolic machinery for different physiological conditions. We find that calcium oscillations increase the efficiency with a maximum close to substrate-limited conditions, suggesting a compensatory effect of calcium signaling on the energetics of mitochondrial metabolism.

Published
2023

6. Buffering variability in cell regulation motifs close to criticality

Author

Proverbio, Daniele, Montanari, Arthur N., Skupin, Alexander, and Gonçalves, Jorge

Subjects
Nonlinear Sciences - Adaptation and Self-Organizing Systems, Quantitative Biology - Quantitative Methods
Abstract

Bistable biological regulatory systems need to cope with stochastic noise to fine-tune their function close to bifurcation points. Here, we study stability properties of this regime in generic systems to demonstrate that cooperative interactions buffer system variability, hampering noise-induced regime shifts. Our analysis also shows that, in the considered cooperativity range, impending regime shifts can be generically detected by statistical early warning signals from distributional data. Our generic framework, based on minimal models, can be used to extract robustness and variability properties of more complex models and empirical data close to criticality.

Published
2022
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7. How to address cellular heterogeneity by distribution biology

Author

Komin, Niko and Skupin, Alexander

Subjects
Quantitative Biology - Quantitative Methods
Abstract

Cellular heterogeneity is an immanent property of biological systems that covers very different aspects of life ranging from genetic diversity to cell-to-cell variability driven by stochastic molecular interactions, and noise induced cell differentiation. Here, we review recent developments in characterizing cellular heterogeneity by distributions and argue that understanding multicellular life requires the analysis of heterogeneity dynamics at single cell resolution by integrative approaches that combine methods from non-equilibrium statistical physics, information theory and omics biology.

Published
2021
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8. Early-to-mid stage idiopathic Parkinson’s disease shows enhanced cytotoxicity and differentiation in CD8 T-cells in females

Author

Capelle, Christophe M., Ciré, Séverine, Hedin, Fanny, Hansen, Maxime, Pavelka, Lukas, Grzyb, Kamil, Kyriakis, Dimitrios, Hunewald, Oliver, Konstantinou, Maria, Revets, Dominique, Tslaf, Vera, Marques, Tainá M., Gomes, Clarissa P. C., Baron, Alexandre, Domingues, Olivia, Gomez, Mario, Zeng, Ni, Betsou, Fay, May, Patrick, Skupin, Alexander, Cosma, Antonio, Balling, Rudi, Krüger, Rejko, Ollert, Markus, and Hefeng, Feng Q.

Published
2023
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9. Morphological principles of neuronal mitochondria

Author

Mendelsohn, Rachel, Garcia, Guadalupe C, Bartol, Thomas M, Lee, Christopher T, Khandelwal, Priya, Liu, Emily, Spencer, Donald J, Husar, Adam, Bushong, Eric A, Phan, Sebastien, Perkins, Guy, Ellisman, Mark H, Skupin, Alexander, Sejnowski, Terrence J, and Rangamani, Padmini

Subjects
Neurosciences, Neurological, Animals, Cerebellum, Mice, Mitochondria, Neurons, Neuropil, EM tomography, energetics, mitochondria, morphology, neuronal, Zoology, Medical Physiology, Neurology & Neurosurgery
Abstract

In the highly dynamic metabolic landscape of a neuron, mitochondrial membrane architectures can provide critical insight into the unique energy balance of the cell. Current theoretical calculations of functional outputs like adenosine triphosphate and heat often represent mitochondria as idealized geometries, and therefore, can miscalculate the metabolic fluxes. To analyze mitochondrial morphology in neurons of mouse cerebellum neuropil, 3D tracings of complete synaptic and axonal mitochondria were constructed using a database of serial transmission electron microscopy (TEM) tomography images and converted to watertight meshes with minimal distortion of the original microscopy volumes with a granularity of 1.64 nanometer isotropic voxels. The resulting in-silico representations were subsequently quantified by differential geometry methods in terms of the mean and Gaussian curvatures, surface areas, volumes, and membrane motifs, all of which can alter the metabolic output of the organelle. Finally, we identify structural motifs present across this population of mitochondria, which may contribute to future modeling studies of mitochondrial physiology and metabolism in neurons.

Published
2022

12. Single-cell transcriptomics of human iPSC differentiation dynamics reveal a core molecular network of Parkinson’s disease

Author

Novak, Gabriela, Kyriakis, Dimitrios, Grzyb, Kamil, Bernini, Michela, Rodius, Sophie, Dittmar, Gunnar, Finkbeiner, Steven, and Skupin, Alexander

Subjects
Biochemistry and Cell Biology, Bioinformatics and Computational Biology, Genetics, Biological Sciences, Aging, Stem Cell Research - Induced Pluripotent Stem Cell - Human, Neurosciences, Biotechnology, Stem Cell Research - Nonembryonic - Human, Stem Cell Research - Induced Pluripotent Stem Cell, Stem Cell Research, Brain Disorders, Parkinson's Disease, Neurodegenerative, Aetiology, 2.1 Biological and endogenous factors, Neurological, Cell Differentiation, Gene Expression Profiling, Humans, Induced Pluripotent Stem Cells, Mutation, Neurogenesis, Parkinson Disease, Protein Kinases, Sequence Analysis, RNA, Single-Cell Analysis, Transcriptome, Biological sciences, Biomedical and clinical sciences
Abstract

Parkinson's disease (PD) is the second-most prevalent neurodegenerative disorder, characterized by the loss of dopaminergic neurons (mDA) in the midbrain. The underlying mechanisms are only partly understood and there is no treatment to reverse PD progression. Here, we investigated the disease mechanism using mDA neurons differentiated from human induced pluripotent stem cells (hiPSCs) carrying the ILE368ASN mutation within the PINK1 gene, which is strongly associated with PD. Single-cell RNA sequencing (RNAseq) and gene expression analysis of a PINK1-ILE368ASN and a control cell line identified genes differentially expressed during mDA neuron differentiation. Network analysis revealed that these genes form a core network, members of which interact with all known 19 protein-coding Parkinson's disease-associated genes. This core network encompasses key PD-associated pathways, including ubiquitination, mitochondrial function, protein processing, RNA metabolism, and vesicular transport. Proteomics analysis showed a consistent alteration in proteins of dopamine metabolism, indicating a defect of dopaminergic metabolism in PINK1-ILE368ASN neurons. Our findings suggest the existence of a network onto which pathways associated with PD pathology converge, and offers an inclusive interpretation of the phenotypic heterogeneity of PD.

Published
2022

18. Combinatorial analysis reveals highly coordinated early-stage immune reactions that predict later antiviral immunity in mild COVID-19 patients

Author

Capelle, Christophe M., Ciré, Séverine, Domingues, Olivia, Ernens, Isabelle, Hedin, Fanny, Fischer, Aurélie, Snoeck, Chantal J., Ammerlaan, Wim, Konstantinou, Maria, Grzyb, Kamil, Skupin, Alexander, Carty, Cara L., Hilger, Christiane, Gilson, Georges, Celebic, Aljosa, Wilmes, Paul, Del Sol, Antonio, Kaplan, Ian M., Betsou, Fay, Abdelrahman, Tamir, Cosma, Antonio, Vaillant, Michel, Fagherazzi, Guy, Ollert, Markus, and Hefeng, Feng Q.

Published
2022
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21. A Statistical View on Calcium Oscillations

Author

Powell, Jake, Falcke, Martin, Skupin, Alexander, Bellamy, Tomas C., Kypraios, Theodore, Thul, Rüdiger, Cohen, Irun R., Editorial Board Member, Lajtha, Abel, Editorial Board Member, Lambris, John D., Series Editor, Paoletti, Rodolfo, Editorial Board Member, Rezaei, Nima, Series Editor, and Islam, Md. Shahidul, editor

Published
2020
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23. Roles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics

Author

Martínez Arbas, Susana, Narayanasamy, Shaman, Herold, Malte, Lebrun, Laura A., Hoopmann, Michael R., Li, Sujun, Lam, Tony J., Kunath, Benoît J., Hicks, Nathan D., Liu, Cindy M., Price, Lance B., Laczny, Cedric C., Gillece, John D., Schupp, James M., Keim, Paul S., Moritz, Robert L., Faust, Karoline, Tang, Haixu, Ye, Yuzhen, Skupin, Alexander, May, Patrick, Muller, Emilie E. L., and Wilmes, Paul

Published
2021
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26. Patient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology

Author

Golebiewska, Anna, Hau, Ann-Christin, Oudin, Anaïs, Stieber, Daniel, Yabo, Yahaya A., Baus, Virginie, Barthelemy, Vanessa, Klein, Eliane, Bougnaud, Sébastien, Keunen, Olivier, Wantz, May, Michelucci, Alessandro, Neirinckx, Virginie, Muller, Arnaud, Kaoma, Tony, Nazarov, Petr V., Azuaje, Francisco, De Falco, Alfonso, Flies, Ben, Richart, Lorraine, Poovathingal, Suresh, Arns, Thais, Grzyb, Kamil, Mock, Andreas, Herold-Mende, Christel, Steino, Anne, Brown, Dennis, May, Patrick, Miletic, Hrvoje, Malta, Tathiane M., Noushmehr, Houtan, Kwon, Yong-Jun, Jahn, Winnie, Klink, Barbara, Tanner, Georgette, Stead, Lucy F., Mittelbronn, Michel, Skupin, Alexander, Hertel, Frank, Bjerkvig, Rolf, and Niclou, Simone P.

Published
2020
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30. Multiscale Modeling Indicates That Temperature Dependent [Ca2+]i Spiking in Astrocytes Is Quantitatively Consistent with Modulated SERCA Activity

Author

Komin, Niko, Moein, Mahsa, Ellisman, Mark H, and Skupin, Alexander

Subjects
Medical Physiology, Biomedical and Clinical Sciences, Neurosciences, Networking and Information Technology R&D (NITRD), Neurological, Algorithms, Animals, Astrocytes, Calcium Signaling, Cells, Cultured, Cytosol, Endoplasmic Reticulum, Kinetics, Mice, Models, Neurological, Sarcoplasmic Reticulum Calcium-Transporting ATPases, Temperature, Cognitive Sciences, Neurology & Neurosurgery, Biological psychology
Abstract

Changes in the cytosolic Ca(2+) concentration ([Ca(2+)]i) are the most predominant active signaling mechanism in astrocytes that can modulate neuronal activity and is assumed to influence neuronal plasticity. Although Ca(2+) signaling in astrocytes has been intensively studied in the past, our understanding of the signaling mechanism and its impact on tissue level is still incomplete. Here we revisit our previously published data on the strong temperature dependence of Ca(2+) signals in both cultured primary astrocytes and astrocytes in acute brain slices of mice. We apply multiscale modeling to test the hypothesis that the temperature dependent [Ca(2+)]i spiking is mainly caused by the increased activity of the sarcoendoplasmic reticulum ATPases (SERCAs) that remove Ca(2+) from the cytosol into the endoplasmic reticulum. Quantitative comparison of experimental data with multiscale simulations supports the SERCA activity hypothesis. Further analysis of multiscale modeling and traditional rate equations indicates that the experimental observations are a spatial phenomenon where increasing pump strength leads to a decoupling of Ca(2+) release sites and subsequently to vanishing [Ca(2+)]i spikes.

Published
2015

31. Mesoscopic behavior from microscopic Markov dynamics and its application to calcium release channels

Author

Christian, Nils, Skupin, Alexander, Morante, Silvia, Jansen, Karl, Rossi, Giancarlo, and Ebenhöh, Oliver

Subjects
Quantitative Biology - Molecular Networks
Abstract

A major challenge in biology is to understand how molecular processes determine phenotypic features. We address this fundamental problem in a class of model systems by developing a general mathematical framework that allows the calculation of mesoscopic properties from the knowledge of microscopic Markovian transition probabilities. We show how exact analytic formulae for the first and second moments of resident time distributions in mesostates can be derived from microscopic resident times and transition probabilities even for systems with a large number of microstates. We apply our formalism to models of the inositol trisphosphate receptor, which plays a key role in generating calcium signals triggering a wide variety of cellular responses. We demonstrate how experimentally accessible quantities, such as opening and closing times and the coefficient of variation of inter-spike intervals, and other, more elaborated, quantities can be analytically calculated from the underlying microscopic Markovian dynamics. A virtue of our approach is that we do not need to follow the detailed time evolution of the whole system, as we derive the relevant properties of its steady state without having to take into account the often extremely complicated transient features. We emphasize that our formulae fully agree with results obtained by stochastic simulations and approaches based on a full determination of the microscopic system's time evolution. We also illustrate how experiments can be devised to discriminate between alternative molecular models of the inositol trisphosphate receptor. The developed approach is applicable to any system described by a Markov process and, owing to the analytic nature of the resulting formulae, provides an easy way to characterize also rare events that are of particular importance to understand the intermittency properties of complex dynamic systems.

Published
2013
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32. Describing the complexity of systems: multi-variable 'set complexity' and the information basis of systems biology

Author

Galas, David J., Sakhanenko, Nikita A., Skupin, Alexander, and Ignac, Tomasz

Subjects
Computer Science - Information Theory, Quantitative Biology - Quantitative Methods
Abstract

Context dependence is central to the description of complexity. Keying on the pairwise definition of "set complexity" we use an information theory approach to formulate general measures of systems complexity. We examine the properties of multi-variable dependency starting with the concept of interaction information. We then present a new measure for unbiased detection of multi-variable dependency, "differential interaction information." This quantity for two variables reduces to the pairwise "set complexity" previously proposed as a context-dependent measure of information in biological systems. We generalize it here to an arbitrary number of variables. Critical limiting properties of the "differential interaction information" are key to the generalization. This measure extends previous ideas about biological information and provides a more sophisticated basis for study of complexity. The properties of "differential interaction information" also suggest new approaches to data analysis. Given a data set of system measurements differential interaction information can provide a measure of collective dependence, which can be represented in hypergraphs describing complex system interaction patterns. We investigate this kind of analysis using simulated data sets. The conjoining of a generalized set complexity measure, multi-variable dependency analysis, and hypergraphs is our central result. While our focus is on complex biological systems, our results are applicable to any complex system., Comment: 44 pages, 12 figures; made revisions after peer review

Published
2013

34. Formate promotes invasion and metastasis in reliance on lipid metabolism

Author

Delbrouck, Catherine, primary, Kiweler, Nicole, additional, Chen, Oleg, additional, Pozdeev, Vitaly I., additional, Haase, Lara, additional, Neises, Laura, additional, Oudin, Anaïs, additional, Fouquier d’Hérouël, Aymeric, additional, Shen, Ruolin, additional, Schlicker, Lisa, additional, Halder, Rashi, additional, Lesur, Antoine, additional, Schuster, Anne, additional, Lorenz, Nadja I., additional, Jaeger, Christian, additional, Feucherolles, Maureen, additional, Frache, Gilles, additional, Szpakowska, Martyna, additional, Chevigne, Andy, additional, Ronellenfitsch, Michael W., additional, Moussay, Etienne, additional, Piraud, Marie, additional, Skupin, Alexander, additional, Schulze, Almut, additional, Niclou, Simone P., additional, Letellier, Elisabeth, additional, and Meiser, Johannes, additional

Published
2023
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41. Improved Parkinson’s Disease Classification from Diffusion MRI Data by Fisher Vector Descriptors

Author

Salamanca, Luis, Vlassis, Nikos, Diederich, Nico, Bernard, Florian, Skupin, Alexander, Hutchison, David, Series editor, Kanade, Takeo, Series editor, Kittler, Josef, Series editor, Kleinberg, Jon M., Series editor, Mattern, Friedemann, Series editor, Mitchell, John C., Series editor, Naor, Moni, Series editor, Pandu Rangan, C., Series editor, Steffen, Bernhard, Series editor, Terzopoulos, Demetri, Series editor, Tygar, Doug, Series editor, Weikum, Gerhard, Series editor, Navab, Nassir, editor, Hornegger, Joachim, editor, Wells, William M., editor, and Frangi, Alejandro, editor

Published
2015
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42. Glioblastoma-instructed microglia transit to heterogeneous phenotypic states with phagocytic and dendritic cell-like features in patient tumors and patient-derived orthotopic xenografts

Author

Yabo, Yahaya A., primary, Moreno-Sanchez, Pilar M., additional, Pires-Afonso, Yolanda, additional, Kaoma, Tony, additional, Kyriakis, Dimitrios, additional, Grzyb, Kamil, additional, Poovathingal, Suresh K., additional, Poli, Aurélie, additional, Scafidi, Andrea, additional, Muller, Arnaud, additional, Toth, Reka, additional, Oudin, Anaïs, additional, Klink, Barbara, additional, Berchem, Guy, additional, Berthold, Christophe, additional, Hertel, Frank, additional, Mittelbronn, Michel, additional, Heiland, Dieter H., additional, Skupin, Alexander, additional, Nazarov, Petr V., additional, Niclou, Simone P., additional, Michelucci, Alessandro, additional, and Golebiewska, Anna, additional

Published
2023
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43. Multiomics Integration by Non-Negative Tri-Matrix Factorization Reveals New Target Genes in Parkinson’s Disease

Author

Skupin, Alexander and Skupin, Alexander

Abstract

Parkinson’s disease (PD) is the second most common neurodegenerative disease which is characterized by neuronal loss of dopaminergic neurons (mDA) in the substantia nigra. The underlying complexity of the disease and limited amount of patient material limits current interventions to only symptomatic and no curative treatment despite intensive research. We use patient-derived induced pluripotent stem cells to generate mDAs and investigate disease mechanisms by multiomics characterization including single cell RNA-sequencing and bulk proteomics and metabolomics. For this purpose, we developed an extended Non- Negative TriMatrix Factorization approache that allows to integrate the heterogeneous omics data with knowledge of molecular databases including protein-protein, genetic and metabolic interactions as well as co-expression profiles. Our approach was able to identify already PD-associated but also new druggable candidate genes of PD development.

Published
2023

44. Stem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment

Author

Dirkse, Anne, Golebiewska, Anna, Buder, Thomas, Nazarov, Petr V., Muller, Arnaud, Poovathingal, Suresh, Brons, Nicolaas H. C., Leite, Sonia, Sauvageot, Nicolas, Sarkisjan, Dzjemma, Seyfrid, Mathieu, Fritah, Sabrina, Stieber, Daniel, Michelucci, Alessandro, Hertel, Frank, Herold-Mende, Christel, Azuaje, Francisco, Skupin, Alexander, Bjerkvig, Rolf, Deutsch, Andreas, Voss-Böhme, Anja, and Niclou, Simone P.

Published
2019
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45. Formate Promotes Invasion and Metastasis by Activating Fatty Acid Synthesis and Matrix Metalloproteinases

Author

Delbrouck, Catherine, primary, Kiweler, Nicole, additional, Pozdeev, Vitaly I., additional, Neises, Laura, additional, Oudin, Anaïs, additional, Schuster, Anne, additional, d’Hérouël, Aymeric Fouquier, additional, Shen, Ruolin, additional, Halder, Rashi, additional, Lesur, Antoine, additional, Ogris, Christoph, additional, Lorenz, Nadia I., additional, Jaeger, Christian, additional, Ronellenfitsch, Michael W., additional, Piraud, Marie, additional, Skupin, Alexander, additional, Niclou, Simone P., additional, Letellier, Elisabeth, additional, and Meiser, Johannes, additional

Published
2023
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49. Single-Cell Transcriptional Profiling and Gene Regulatory Network Modeling in Tg2576 Mice Reveal Gender-Dependent Molecular Features Preceding Alzheimer-Like Pathologies

Author

Ali, Muhammad, primary, Huarte, Oihane Uriarte, additional, Heurtaux, Tony, additional, Garcia, Pierre, additional, Rodriguez, Beatriz Pardo, additional, Grzyb, Kamil, additional, Halder, Rashi, additional, Skupin, Alexander, additional, Buttini, Manuel, additional, and Glaab, Enrico, additional

Published
2022
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50. Elucidating tumour‐associated microglia/macrophage diversity along glioblastoma progression and underACOD1deficiency

Author

Pires‐Afonso, Yolanda, primary, Muller, Arnaud, additional, Grzyb, Kamil, additional, Oudin, Anaïs, additional, Yabo, Yahaya A., additional, Sousa, Carole, additional, Scafidi, Andrea, additional, Poli, Aurélie, additional, Cosma, Antonio, additional, Halder, Rashi, additional, Coowar, Djalil, additional, Golebiewska, Anna, additional, Skupin, Alexander, additional, Niclou, Simone P., additional, and Michelucci, Alessandro, additional

Published
2022
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