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See detailSingle‑nuclei chromatin profiling of ventral midbrain reveals cell identity transcription factors and cell‑type‑specific gene regulatory variation
Gui, Yujuan; Grzyb, Kamil UL; Thomas, Melanie UL et al

in Epigenetics and Chromatin (2021)

Background: Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and ... [more ▼]

Background: Cell types in ventral midbrain are involved in diseases with variable genetic susceptibility, such as Parkinson’s disease and schizophrenia. Many genetic variants affect regulatory regions and alter gene expression in a cell-type-specific manner depending on the chromatin structure and accessibility. Results: We report 20,658 single-nuclei chromatin accessibility profiles of ventral midbrain from two genetically and phenotypically distinct mouse strains. We distinguish ten cell types based on chromatin profiles and analysis of accessible regions controlling cell identity genes highlights cell-type-specific key transcription factors. Regulatory variation segregating the mouse strains manifests more on transcriptome than chromatin level. However, cell-type-level data reveals changes not captured at tissue level. To discover the scope and cell-type specificity of cis-acting variation in midbrain gene expression, we identify putative regulatory variants and show them to be enriched at differentially expressed loci. Finally, we find TCF7L2 to mediate trans-acting variation selectively in midbrain neurons. Conclusions: Our data set provides an extensive resource to study gene regulation in mesencephalon and provides insights into control of cell identity in the midbrain and identifies cell-type-specific regulatory variation possibly underlying phenotypic and behavioural differences between mouse strains. [less ▲]

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See detailModelling COVID-19 dynamics and potential for herd immunity by vaccination in Austria, Luxembourg and Sweden
Kemp, Francoise UL; Proverbio, Daniele UL; Aalto, Atte UL et al

in Modelling COVID-19 dynamics and potential for herd immunity by vaccination in Austria, Luxembourg and Sweden (2021)

Against the COVID-19 pandemic, non-pharmaceutical interventions have been widely applied and vaccinations have taken off. The upcoming question is how the interplay between vaccinations and social ... [more ▼]

Against the COVID-19 pandemic, non-pharmaceutical interventions have been widely applied and vaccinations have taken off. The upcoming question is how the interplay between vaccinations and social measures will shape infections and hospitalizations. Hence, we extend the Susceptible-Exposed-Infectious-Removed (SEIR) model including these elements. We calibrate it to data of Luxembourg, Austria and Sweden until 15 December 2020. Sweden results having the highest fraction of undetected, Luxembourg of infected and all three being far from herd immunity in December. We quantify the level of social interaction, showing that a level around 1/3 of before the pandemic was still required in December to keep the effective reproduction number Refft below 1, for all three countries. Aiming to vaccinate the whole population within 1 year at constant rate would require on average 1,700 fully vaccinated people/day in Luxembourg, 24,000 in Austria and 28,000 in Sweden, and could lead to herd immunity only by mid summer. Herd immunity might not be reached in 2021 if too slow vaccines rollout speeds are employed. The model thus estimates which vaccination rates are too low to allow reaching herd immunity in 2021, depending on social interactions. Vaccination will considerably, but not immediately, help to curb the infection; thus limiting social interactions remains crucial for the months to come. [less ▲]

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See detailA cut finite element method for spatially resolved energy metabolism models in complex neuro-cell morphologies with minimal remeshing
Farina, Sofia UL; Claus, Susanne; Hale, Jack UL et al

in Advanced Modeling and Simulation in Engineering Sciences (2021), 8

A thorough understanding of brain metabolism is essential to tackle neurodegenerative diseases. Astrocytes are glial cells which play an important metabolic role by supplying neurons with energy. In ... [more ▼]

A thorough understanding of brain metabolism is essential to tackle neurodegenerative diseases. Astrocytes are glial cells which play an important metabolic role by supplying neurons with energy. In addition, astrocytes provide scaffolding and homeostatic functions to neighboring neurons and contribute to the blood–brain barrier. Recent investigations indicate that the complex morphology of astrocytes impacts upon their function and in particular the efficiency with which these cells metabolize nutrients and provide neurons with energy, but a systematic understanding is still elusive. Modelling and simulation represent an effective framework to address this challenge and to deepen our understanding of brain energy metabolism. This requires solving a set of metabolic partial differential equations on complex domains and remains a challenge. In this paper, we propose, test and verify a simple numerical method to solve a simplified model of metabolic pathways in astrocytes. The method can deal with arbitrarily complex cell morphologies and enables the rapid and simple modification of the model equations by users also without a deep knowledge in the numerical methods involved. The results obtained with the new method (CutFEM) are as accurate as the finite element method (FEM) whilst CutFEM disentangles the cell morphology from its discretisation, enabling us to deal with arbitrarily complex morphologies in two and three dimensions. [less ▲]

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See detailDynamical SPQEIR model assesses the effectiveness of non-pharmaceutical interventions against COVID-19 epidemic outbreaks.
Proverbio, Daniele UL; Kemp, Francoise UL; Magni, Stefano UL et al

in PloS one (2021), 16(5), 0252019

Against the current COVID-19 pandemic, governments worldwide have devised a variety of non-pharmaceutical interventions to mitigate it. However, it is generally difficult to estimate the joint impact of ... [more ▼]

Against the current COVID-19 pandemic, governments worldwide have devised a variety of non-pharmaceutical interventions to mitigate it. However, it is generally difficult to estimate the joint impact of different control strategies. In this paper, we tackle this question with an extended epidemic SEIR model, informed by a socio-political classification of different interventions. First, we inquire the conceptual effect of mitigation parameters on the infection curve. Then, we illustrate the potential of our model to reproduce and explain empirical data from a number of countries, to perform cross-country comparisons. This gives information on the best synergies of interventions to control epidemic outbreaks while minimising impact on socio-economic needs. For instance, our results suggest that, while rapid and strong lockdown is an effective pandemic mitigation measure, a combination of social distancing and early contact tracing can achieve similar mitigation synergistically, while keeping lower isolation rates. This quantitative understanding can support the establishment of mid- and long-term interventions, to prepare containment strategies against further outbreaks. This paper also provides an online tool that allows researchers and decision makers to interactively simulate diverse scenarios with our model. [less ▲]

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

in Economics & Human Biology (2020), 43

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. The model has been used to produce nowcasts and forecasts at various stages of the crisis. We focus here on two key moments in time, namely the deconfinement period following the first lockdown, and the onset of the second wave. In May 2020, we predicted a high risk of a second wave that was mainly explained by the resumption of social life, low participation in large-scale testing, and reduction in teleworking practices. Simulations conducted 5 months later reveal that managing the second wave with moderately coercive measures has been epidemiologically and economically effective. Assuming a massive third (or fourth) wave will not materialize in 2021, the real GDP loss due to the second wave will be smaller than 0.4 percentage points in 2020 and 2021. [less ▲]

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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 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 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 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)

Detailed reference viewed: 84 (2 UL)
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 ▲]

Detailed reference viewed: 136 (10 UL)