References of "Skupin, Alexander 50003110"
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See detailRoles of bacteriophages, plasmids and CRISPR immunity in microbial community dynamics revealed using time-series integrated meta-omics
Martinez Arbas, Susana UL; Narayanasamy, Shaman; Herold, Malte et al

in Nature Microbiology (2020)

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We ... [more ▼]

Viruses and plasmids (invasive mobile genetic elements (iMGEs)) have important roles in shaping microbial communities, but their dynamic interactions with CRISPR-based immunity remain unresolved. We analysed generation-resolved iMGE–host dynamics spanning one and a half years in a microbial consortium from a biological wastewater treatment plant using integrated meta-omics. We identified 31 bacterial metagenome-assembled genomes encoding complete CRISPR–Cas systems and their corresponding iMGEs. CRISPR-targeted plasmids outnumbered their bacteriophage counterparts by at least fivefold, highlighting the importance of CRISPR-mediated defence against plasmids. Linear modelling of our time-series data revealed that the variation in plasmid abundance over time explained more of the observed community dynamics than phages. Community-scale CRISPR-based plasmid–host and phage–host interaction networks revealed an increase in CRISPR-mediated interactions coinciding with a decrease in the dominant ‘Candidatus Microthrix parvicella’ population. Protospacers were enriched in sequences targeting genes involved in the transmission of iMGEs. Understanding the factors shaping the fitness of specific populations is necessary to devise control strategies for undesirable species and to predict or explain community-wide phenotypes. [less ▲]

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See detailROS networks: designs, aging, Parkinson's disease and precision therapies.
Kolodkin, Alexey UL; Colangelo, AM; Ignatenko, A et al

in NPJ Systems Biology and Applications (2020)

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See detailPatient-derived organoids and orthotopic xenografts of primary and recurrent gliomas represent relevant patient avatars for precision oncology.
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anaïs et al

in Acta neuropathologica (2020)

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique ... [more ▼]

Patient-based cancer models are essential tools for studying tumor biology and for the assessment of drug responses in a translational context. We report the establishment a large cohort of unique organoids and patient-derived orthotopic xenografts (PDOX) of various glioma subtypes, including gliomas with mutations in IDH1, and paired longitudinal PDOX from primary and recurrent tumors of the same patient. We show that glioma PDOXs enable long-term propagation of patient tumors and represent clinically relevant patient avatars that retain histopathological, genetic, epigenetic, and transcriptomic features of parental tumors. We find no evidence of mouse-specific clonal evolution in glioma PDOXs. Our cohort captures individual molecular genotypes for precision medicine including mutations in IDH1, ATRX, TP53, MDM2/4, amplification of EGFR, PDGFRA, MET, CDK4/6, MDM2/4, and deletion of CDKN2A/B, PTCH, and PTEN. Matched longitudinal PDOX recapitulate the limited genetic evolution of gliomas observed in patients following treatment. At the histological level, we observe increased vascularization in the rat host as compared to mice. PDOX-derived standardized glioma organoids are amenable to high-throughput drug screens that can be validated in mice. We show clinically relevant responses to temozolomide (TMZ) and to targeted treatments, such as EGFR and CDK4/6 inhibitors in (epi)genetically defined subgroups, according to MGMT promoter and EGFR/CDK status, respectively. Dianhydrogalactitol (VAL-083), a promising bifunctional alkylating agent in the current clinical trial, displayed high therapeutic efficacy, and was able to overcome TMZ resistance in glioblastoma. Our work underscores the clinical relevance of glioma organoids and PDOX models for translational research and personalized treatment studies and represents a unique publicly available resource for precision oncology. [less ▲]

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See detailPrimary and recurrent glioma patient-derived orthotopic xenografts (PDOX) represent relevant patient avatars for precision medicine
Golebiewska, Anna UL; Hau, Ann-Christin; Oudin, Anais et al

E-print/Working paper (2020)

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term ... [more ▼]

Patient-derived cancer models are essential tools for studying tumor biology and preclinical interventions. Here, we show that glioma patient-derived orthotopic xenografts (PDOXs) enable long-term propagation of patient tumors and represent clinically relevant patient avatars. We created a large collection of PDOXs from primary and recurrent gliomas with and without mutations in IDH1, which retained histopathological, genetic, epigenetic and transcriptomic features of patient tumors with no mouse-specific clonal evolution. Longitudinal PDOX models recapitulate the limited genetic evolution of gliomas observed in patient tumors following treatment. PDOX-derived standardized tumor organoid cultures enabled assessment of drug responses, which were validated in mice. PDOXs showed clinically relevant responses to Temozolomide and to targeted treatments such as EGFR and CDK4/6 inhibitors in (epi)genetically defined groups, according to MGMT promoter and EGFR/CDK status respectively. Dianhydrogalactitol, a bifunctional alkylating agent, showed promising potential against glioblastoma. Our study underlines the clinical relevance of glioma PDOX models for translational research and personalized treatment studies. [less ▲]

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See detailAssessing suppression strategies against epidemicoutbreaks like COVID-19: the SPQEIR model
Proverbio, Daniele UL; Kemp, Francoise UL; Magni, Stefano UL et al

E-print/Working paper (2020)

The current COVID-19 outbreak represents a most serious challenge for societies worldwide. It isendangering the health of millions of people, and resulting in severe socioeconomic challenges dueto lock ... [more ▼]

The current COVID-19 outbreak represents a most serious challenge for societies worldwide. It isendangering the health of millions of people, and resulting in severe socioeconomic challenges dueto lock-down measures. Governments worldwide aim to devise exit strategies to revive the economywhile keeping the pandemic under control. The problem is that the effects of distinct measures arenot well quantified. This paper compares several suppression approaches and potential exit strategiesusing a new extended epidemic SEIR model. It concludes that while rapid and strong lock-down isan effective pandemic suppression measure, a combination of other strategies such as social distanc-ing, active protection and removal can achieve similar suppression synergistically. This quantitativeunderstanding will support the establishment of mid- and long-term interventions. Finally, the paperprovides an online tool that allows researchers and decision makers to interactively simulate diversescenarios with our model. [less ▲]

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See detailCOVID-19 Crisis Management in Luxembourg: Insights from an Epidemionomic Approach
burzynski, Michal; Machado, Joel; Aalto, Atte UL et al

E-print/Working paper (2020)

We develop an epidemionomic model that jointly analyzes the health and economic responses to the COVID-19 crisis and to the related containment and public health policy measures implemented in Luxembourg ... [more ▼]

We develop an epidemionomic model that jointly analyzes the health and economic responses to the COVID-19 crisis and to the related containment and public health policy measures implemented in Luxembourg and in the Greater Region. The model has a weekly structure and covers the whole year 2020. With a limited number of parameters, the model is calibrated to depict the pre-crisis evolution of the Luxembourg economy, and to match post-lockdown leading economic indicators and industry-specific infection curves. The nowcasting part of our analysis reveals that each week of lockdown reduces national output by about 28% (and annual GDP by 0.54%). A first peak of the infection curve was observed at the very beginning of April. If the lockdown measures had been permanent, annual GDP would have decreased by 22% in 2020, the number of COVID-19 cases would have reached zero around mid-June, and the proportion of recovered people would have reached 1.4% of the population. In an economy heavily relying on skill-intensive services, we show that the role of teleworking has been instrumental to limiting the weekly economic output loss (almost by one half) and the propagation of the virus. In the forecasting part of the analysis, we quantify the epidemiological and economic responses to gradual deconfinement measures under various public health scenarios. If the post-lockdown transmission rates could be kept constant throughout the deconfinement period, restarting all sectors would have huge effects on the economy (limiting the annual GDP loss to about 7%) and no effect on the aggregate infection curve. While it is a good time for lifting containment measures, there is also a risk that increasing the density of employees at the workplace and resuming social activities would induce a rebound in the infection curve. Preventing such a relapse is possible with PCR testing of both national and cross-border workers, and with accompanying measures such as (i) maintaining teleworking practices, (ii) reopening hotels, restaurants and cafes at half of their full capacity or with equivalent physical distancing measures and last but not least, (iii) sustaining distancing measures in social activities. Overall, in our worst-case scenario, combining bi-monthly testing with contact tracing and quarantining measures appear to be a suficient (perhaps not necessary) policy option in the aftermath of the deconfinement plan. [less ▲]

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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smits, Lisa UL; Magni, Stefano UL; Kinugawa, Kaoru et al

in Cell and Tissue Research (2020)

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See detailNew insights into the early mechanisms of epileptogenesis in a zebrafish model of Dravet syndrome
Tiraboschi, Ettore; Martina, Silvia UL; van der Ent, Wietske et al

in Epilepsia (2020)

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See detailA Statistical View on Calcium Oscillations.
Powell, Jake; Falcke, Martin; Skupin, Alexander UL et al

in Advances in experimental medicine and biology (2020), 1131

Transient rises and falls of the intracellular calcium concentration have been observed in numerous cell types and under a plethora of conditions. There is now a growing body of evidence that these whole ... [more ▼]

Transient rises and falls of the intracellular calcium concentration have been observed in numerous cell types and under a plethora of conditions. There is now a growing body of evidence that these whole-cell calcium oscillations are stochastic, which poses a significant challenge for modelling. In this review, we take a closer look at recently developed statistical approaches to calcium oscillations. These models describe the timing of whole-cell calcium spikes, yet their parametrisations reflect subcellular processes. We show how non-stationary calcium spike sequences, which e.g. occur during slow depletion of intracellular calcium stores or in the presence of time-dependent stimulation, can be analysed with the help of so-called intensity functions. By utilising Bayesian concepts, we demonstrate how values of key parameters of the statistical model can be inferred from single cell calcium spike sequences and illustrate what information whole-cell statistical models can provide about the subcellular mechanistic processes that drive calcium oscillations. In particular, we find that the interspike interval distribution of HEK293 cells under constant stimulation is captured by a Gamma distribution. [less ▲]

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See detailFrom Diagnosing Diseases to Predicting Diseases
Balling, Rudi UL; Goncalves, Jorge UL; Magni, Stefano UL et al

in Betz, Ulrich A.K. (Ed.) Curious2018 (2019)

Chronic diseases can be considered as perturbations of complex adaptive systems. Transitions from healthy states to chronic diseases are often characterized by sudden and unexpected onset of diseases ... [more ▼]

Chronic diseases can be considered as perturbations of complex adaptive systems. Transitions from healthy states to chronic diseases are often characterized by sudden and unexpected onset of diseases. These critical transitions or catastrophic shifts have been studied in theoretical and applied physics, ecology, social science, economics and recently also in biomedical applications. If we could understand the underlying mechanisms and the dynamics of critical transitions involved in the development of diseases, we would be better equipped to predict and eventually prevent them from arising. The current paper gives an overview of the potential application of the concept of critical transitions to biomedical applications. [less ▲]

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See detailMutations in RHOT1 disrupt ER-mitochondria contact sites interfering with calcium homeostasis and mitochondrial dynamics in Parkinson's disease.
Grossmann, Dajana UL; Berenguer, Clara UL; Bellet, Marie Estelle et al

in Antioxidants & redox signaling (2019)

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial ... [more ▼]

OBJECTIVE: The outer mitochondrial membrane protein Miro1 is a crucial player in mitochondrial dynamics and calcium homeostasis. Recent evidence indicated that Miro1 mediates calcium-induced mitochondrial shape transition (MiST), which is a prerequisite for the initiation of mitophagy. Moreover, altered Miro1 protein levels have emerged as a shared feature of monogenic and sporadic Parkinson's disease (PD), but, so far, no disease-associated variants in RHOT1 have been identified. RESULTS: Here, for the first time, we describe heterozygous RHOT1 mutations in two PD patients (het c.815G>A; het c.1348C>T) and identified mitochondrial phenotypes with reduced mitochondrial mass in patient-derived cellular models. Both mutations lead to decreased ER-mitochondrial contact sites and calcium dyshomeostasis. As a consequence, energy metabolism was impaired, which in turn lead to increased mitophagy. CONCLUSION: In summary, our data support the role of Miro1 in maintaining calcium homeostasis and mitochondrial quality control in PD. [less ▲]

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See detailMitochondrial morphology provides a mechanism for energy buffering at synapses
Garcia, Guadalupe Clara UL; Bartol, Thomas M.; Phan, Sebastien A. et al

E-print/Working paper (2019)

Mitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these ... [more ▼]

Mitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these processes are well established, substantial evidence indicates that the internal structure is also highly variable in dependence on metabolic conditions. However, a quantitative mechanistic understanding of how mitochondrial morphology affects energetic states is still elusive. To address this question, we here present an agent-based dynamic model using three-dimensional morphologies from electron microscopy tomography which considers the molecular dynamics of the main ATP production components. We apply our modeling approach to mitochondria at the synapse which is the largest energy consumer within the brain. Interestingly, comparing the spatiotemporal simulations with a corresponding space-independent approach, we find minor space dependence when the system relaxes toward equilibrium but a qualitative difference in fluctuating environments. These results suggest that internal mitochondrial morphology is not only optimized for ATP production but also provides a mechanism for energy buffering and may represent a mechanism for cellular robustness. [less ▲]

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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smits, Lisa UL; Magni, Stefano UL; Grzyb, Kamil UL et al

E-print/Working paper (2019)

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an ... [more ▼]

Human stem cell-derived organoids have great potential for modelling physiological and pathological processes. They recapitulate in vitro the organisation and function of a respective organ or part of an organ. Human midbrain organoids (hMOs) have been described to contain midbrain-specific dopaminergic neurons that release the neurotransmitter dopamine. However, the human midbrain contains also additional neuronal cell types, which are functionally interacting with each other. Here, we analysed hMOs at high-resolution by means of single-cell RNA-sequencing (scRNA-seq), imaging and electrophysiology to unravel cell heterogeneity. Our findings demonstrate that hMOs show essential neuronal functional properties as spontaneous electrophysiological activity of different neuronal subtypes, including dopaminergic, GABAergic, and glutamatergic neurons. Recapitulating these in vivo features makes hMOs an excellent tool for in vitro disease phenotyping and drug discovery. [less ▲]

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See detailData-driven multiscale modeling reveals the role of metabolic coupling for the spatio-temporal growth dynamics of yeast colonies.
Intosalmi, Jukka; Scott, Adrian C.; Hays, Michelle et al

in BMC molecular and cell biology (2019), 20

Multicellular entities like mammalian tissues or microbial biofilms typically exhibit complex spatial arrangements that are adapted to their specific functions or environments. These structures result ... [more ▼]

Multicellular entities like mammalian tissues or microbial biofilms typically exhibit complex spatial arrangements that are adapted to their specific functions or environments. These structures result from intercellular signaling as well as from the interaction with the environment that allow cells of the same genotype to differentiate into well-organized communities of diversified cells. Despite its importance, our understanding how this cell-cell and metabolic coupling lead to functionally optimized structures is still limited. Here, we present a data-driven spatial framework to computationally investigate the development of yeast colonies as such a multicellular structure in dependence on metabolic capacity. For this purpose, we first developed and parameterized a dynamic cell state and growth model for yeast based on on experimental data from homogeneous liquid media conditions. The inferred model is subsequently used in a spatially coarse-grained model for colony development to investigate the effect of metabolic coupling by calibrating spatial parameters from experimental time-course data of colony growth using state-of-the-art statistical techniques for model uncertainty and parameter estimations. The model is finally validated by independent experimental data of an alternative yeast strain with distinct metabolic characteristics and illustrates the impact of metabolic coupling for structure formation. We introduce a novel model for yeast colony formation, present a statistical methodology for model calibration in a data-driven manner, and demonstrate how the established model can be used to generate predictions across scales by validation against independent measurements of genetically distinct yeast strains. IM [less ▲]

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See detailStem cell-associated heterogeneity in Glioblastoma results from intrinsic tumor plasticity shaped by the microenvironment
Dirkse, Anne; Golebiewska, Anna; Buder, Thomas et al

in Nature communications (2019), 10(1), 1787

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See detailMitochondrial morphology provides a mechanism for energy buffering at synapses.
Garcia, Guadalupe Clara UL; Bartol, Thomas M.; Phan, Sébastien et al

in Scientific reports (2019), 9

Mitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these ... [more ▼]

Mitochondria as the main energy suppliers of eukaryotic cells are highly dynamic organelles that fuse, divide and are transported along the cytoskeleton to ensure cellular energy homeostasis. While these processes are well established, substantial evidence indicates that the internal structure is also highly variable in dependence on metabolic conditions. However, a quantitative mechanistic understanding of how mitochondrial morphology affects energetic states is still elusive. To address this question, we here present an agent-based multiscale model that integrates three-dimensional morphologies from electron microscopy tomography with the molecular dynamics of the main ATP producing components. We apply our modeling approach to mitochondria at the synapse which is the largest energy consumer within the brain. Interestingly, comparing the spatiotemporal simulations with a corresponding space-independent approach, we find minor spatial effects when the system relaxes toward equilibrium but a qualitative difference in fluctuating environments. These results suggest that internal mitochondrial morphology is not only optimized for ATP production but also provides a mechanism for energy buffering and may represent a mechanism for cellular robustness. IM [less ▲]

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See detailSingle-cell transcriptomics reveals distinct inflammation-induced microglia signatures
Sousa, Carole UL; Golebiewska, Anna; Poovathingal, Suresh K et al

in EMBO Reports (2018)

Microglia are specialized parenchymal‐resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are ... [more ▼]

Microglia are specialized parenchymal‐resident phagocytes of the central nervous system (CNS) that actively support, defend and modulate the neural environment. Dysfunctional microglial responses are thought to worsen CNS diseases; nevertheless, their impact during neuroinflammatory processes remains largely obscure. Here, using a combination of single‐cell RNA sequencing and multicolour flow cytometry, we comprehensively profile microglia in the brain of lipopolysaccharide (LPS)‐injected mice. By excluding the contribution of other immune CNS‐resident and peripheral cells, we show that microglia isolated from LPS‐injected mice display a global downregulation of their homeostatic signature together with an upregulation of inflammatory genes. Notably, we identify distinct microglial activated profiles under inflammatory conditions, which greatly differ from neurodegenerative disease‐associated profiles. These results provide insights into microglial heterogeneity and establish a resource for the identification of specific phenotypes in CNS disorders, such as neuroinflammatory and neurodegenerative diseases. [less ▲]

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See detailLoss of inter-cellular cooperation by complete epithelial-mesenchymal transition supports favorable outcomes in basal breast cancer patients
Grosse-Wilde, Anne; Kuestner, Rolf E.; Skelton, Stephanie M. et al

in Oncotarget (2018), 9(28), 20018

According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a ... [more ▼]

According to the sequential metastasis model, aggressive mesenchymal (M) metastasis-initiating cells (MICs) are generated by an epithelial-mesenchymal transition (EMT) which eventually is reversed by a mesenchymal-epithelial transition (MET) and outgrowth of life-threatening epithelial (E) macrometastases. Paradoxically, in breast cancer M signatures are linked with more favorable outcomes than E signatures, and M cells are often dispensable for metastasis in mouse models. Here we present evidence at the cellular and patient level for the cooperation metastasis model, according to which E cells are MICs, while M cells merely support E cell persistence through cooperation. We tracked the fates of co-cultured E and M clones and of fluorescent CDH1-promoter-driven cell lines reporting the E state derived from basal breast cancer HMLER cells. Cells were placed in suspension state and allowed to reattach and select an EMT cell fate. Flow cytometry, single cell and bulk gene expression analyses revealed that only pre-existing E cells generated E cells, mixed E/M populations, or stem-like hybrid E/M cells after suspension and that complete EMT manifest in M clones and CDH1-negative reporter cells resulted in loss of cell plasticity, suggesting full transdifferentiation. Mechanistically, E-M coculture experiments supported the persistence of pre-existing E cells where M cells inhibited EMT of E cells in a mutual cooperation via direct cell-cell contact. Consistently, M signatures were associated with more favorable patient outcomes compared to E signatures in breast cancer, specifically in basal breast cancer patients. These findings suggest a potential benefit of complete EMT for basal breast cancer patients. [less ▲]

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