References of "Skupin, Alexander 50003110"
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See detailSingle-cell transcriptomics reveals multiple neuronal cell types in human midbrain-specific organoids
Smith, Lisa M.; 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 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 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 detailData-driven dynamical model indicates that the heat shock response in Chlamydomonas reinhardtii is tailored to handle natural temperature variation
Magni, Stefano UL; Succurro, Antonella; Skupin, Alexander UL et al

in Journal of the Royal Society, Interface (2018), 15(142), 20170965

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR ... [more ▼]

Global warming exposes plants to severe heat stress, with consequent crop yield reduction. Organisms exposed to high temperature stresses typically protect themselves with a heat shock response (HSR), where accumulation of unfolded proteins initiates the synthesis of heat shock proteins through the heat shock transcription factor HSF1. While the molecular mechanisms are qualitatively well characterized, our quantitative understanding of the under- lying dynamics is still very limited. Here, we study the dynamics of HSR in the photosynthetic model organism Chlamydomonas reinhardtii with a data-driven mathematical model of HSR. We based our dynamical model mostly on mass action kinetics, with a few nonlinear terms. The model was parametrized and validated by several independent datasets obtained from the literature. We demonstrate that HSR quantitatively and significantly differs if an increase in temperature of the same magnitude occurs abruptly, as often applied under laboratory conditions, or gradually, which would rather be expected under natural conditions. In contrast to rapid temperature increases, under gradual changes only negligible amounts of misfolded proteins accumulate, indicating that the HSR of C. reinhardtii efficiently avoids the accumulation of misfolded proteins under conditions most likely to prevail in nature. The mathematical model we developed is a flexible tool to simulate the HSR to different conditions and complements the current experimental approaches. [less ▲]

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See detailCaSiAn: a Calcium Signaling Analyzer tool
Moein, Mahsa UL; Grzyb, Kamil UL; Gonçalves Martins, Teresa et al

in Bioinformatics (2018), 1

Ca2þ is a central second messenger in eukaryotic cells that regulates many cellular proc- esses. Recently, we have indicated that typical Ca2þ signals are not purely oscillatory as widely assumed, but ... [more ▼]

Ca2þ is a central second messenger in eukaryotic cells that regulates many cellular proc- esses. Recently, we have indicated that typical Ca2þ signals are not purely oscillatory as widely assumed, but exhibit stochastic spiking with cell type and pathway specific characteristics. Here, we present the Calcium Signaling Analyzer (CaSiAn), an open source software tool that allows for quantifying these signal characteristics including individual spike properties and time course statis- tics in a semi-automated manner. CaSiAn provides an intuitive graphical user interface allowing experimentalists to easily process a large amount of Ca2þ signals, interactively tune peak detection, revise statistical measures and access the quantified signal properties as excel or text files. [less ▲]

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See detailOn the phase space structure of IP3 induced Ca2+ signalling and concepts for predictive modeling
Falcke, Martin; Moein, Mahsa UL; Tilunaite et al

in Chaos (2018), 28(4), 045115

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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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See detailHow to address cellular heterogeneity by distribution biology
Skupin, Alexander UL; Komin, Niko UL

in Current Opinion in Systems Biology (2017), 3

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 ... [more ▼]

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 dy- namics at single cell resolution by integrative approaches that combine methods from non-equilibrium statistical physics, in- formation theory and omics biology. [less ▲]

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See detailInhibition of the mitochondrial calcium uniporter rescues dopaminergic neurons in pink1-/- zebrafish
Soman, Smijin; Keatinge, Marcus; Moein, Mahsa et al

in European Journal of Neuroscience (2017), 45(4), 528

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See detailAnalysis of mitochondrial metabolism in situ: Combining stable isotope labeling with selective permeabilization
Nonnenmacher, Yannic; Palorini, Roberta; d’ Herouël, Aymeric Fouquier et al

in Metabolic Engineering (2016)

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See detailCell Fate Decision as High-Dimensional Critical State Transition
Mojtahedi, Mitra; Skupin, Alexander UL; Zhou, Joseph et al

in PLOS Biology (2016), 14(12), 2000640

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See detailNeurological Diseases from a Systems Medicine Point of View.
Ostaszewski, Marek UL; Skupin, Alexander UL; Balling, Rudi UL

in Methods in molecular biology (Clifton, N.J.) (2016), 1386

The difficulty to understand, diagnose, and treat neurological disorders stems from the great complexity of the central nervous system on different levels of physiological granularity. The individual ... [more ▼]

The difficulty to understand, diagnose, and treat neurological disorders stems from the great complexity of the central nervous system on different levels of physiological granularity. The individual components, their interactions, and dynamics involved in brain development and function can be represented as molecular, cellular, or functional networks, where diseases are perturbations of networks. These networks can become a useful research tool in investigating neurological disorders if they are properly tailored to reflect corresponding mechanisms. Here, we review approaches to construct networks specific for neurological disorders describing disease-related pathology on different scales: the molecular, cellular, and brain level. We also briefly discuss cross-scale network analysis as a necessary integrator of these scales. [less ▲]

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See detailLoss of DJ-1 impairs antioxidant response by altered glutamine and serine metabolism
Meiser, Johannes UL; Delcambre, Sylvie UL; Wegner, André UL et al

in Neurobiology of disease (2016), 89

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an ... [more ▼]

The oncogene DJ-1 has been originally identified as a suppressor of PTEN. Further on, loss-of-function mutations have been described as a causative factor in Parkinson's disease (PD). DJ-1 has an important function in cellular antioxidant responses, but its role in central metabolism of neurons is still elusive. We applied stable isotope assisted metabolic profiling to investigate the effect of a functional loss of DJ-1 and show that DJ-1 deficient neuronal cells exhibit decreased glutamine influx and reduced serine biosynthesis. By providing precursors for GSH synthesis, these two metabolic pathways are important contributors to cellular antioxidant response. Down-regulation of these pathways, as a result of loss of DJ-1 leads to an impaired antioxidant response. Furthermore, DJ-1 deficient mouse microglia showed a weak but constitutive pro-inflammatory activation. The combined effects of altered central metabolism and constitutive activation of glia cells raise the susceptibility of dopaminergic neurons towards degeneration in patients harboring mutated DJ-1. Our work reveals metabolic alterations leading to increased cellular instability and identifies potential new intervention points that can further be studied in the light of novel translational medicine approaches. [less ▲]

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See detailImproved Parkinson’s disease classification from diffusion MRI data by Fisher vector descriptors
Salamanca Mino, Luis UL; Vlassis, Nikos UL; Diederich, Nico UL et al

in Improved Parkinson’s disease classification from diffusion MRI data by Fisher vector descriptors (2015, October)

Due to the complex clinical picture of Parkinson’s disease (PD), the reliable diagnosis of patients is still challenging. A promising approach is the structural characterization of brain areas affected in ... [more ▼]

Due to the complex clinical picture of Parkinson’s disease (PD), the reliable diagnosis of patients is still challenging. A promising approach is the structural characterization of brain areas affected in PD by diffusion magnetic resonance imaging (dMRI). Standard classification methods depend on an accurate non-linear alignment of all images to a common reference template, and are challenged by the resulting huge dimensionality of the extracted feature space. Here, we propose a novel diagnosis pipeline based on the Fisher vector algorithm. This technique allows for a precise encoding into a high-level descriptor of standard diffusion measures like the fractional anisotropy and the mean diffusivity, extracted from the regions of interest (ROIs) typically involved in PD. The obtained low dimensional, fixed-length descriptors are independent of the image alignment and boost the linear separability of the problem in the description space, leading to more efficient and accurate diagnosis. In a test cohort of 50 PD patients and 50 controls, the implemented methodology outperforms previous methods when using a logistic linear regressor for classification of each ROI independently, which are subsequently combined into a single classification decision. [less ▲]

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See detailCritical transitions in chronic disease: transferring concepts from ecology to systems medicine
Trefois, Christophe UL; Antony, Paul UL; Goncalves, Jorge UL et al

in Current Opinion in Biotechnology (2015), 34

Ecosystems and biological systems are known to be inherently complex and to exhibit nonlinear dynamics. Diseases such as microbiome dysregulation or depression can be seen as complex systems as well and ... [more ▼]

Ecosystems and biological systems are known to be inherently complex and to exhibit nonlinear dynamics. Diseases such as microbiome dysregulation or depression can be seen as complex systems as well and were shown to exhibit patterns of nonlinearity in their response to perturbations. These nonlinearities can be revealed by a sudden shift in system states, for instance from health to disease. The identification and characterization of early warning signals which could predict upcoming critical transitions is of primordial interest as prevention of disease onset is a major aim in health care. In this review, we focus on recent evidence for critical transitions in diseases and discuss the potential of such studies for therapeutic applications. [less ▲]

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See detailStemness of the hybrid Epithelial/Mesenchymal State in Breast Cancer and Its Association with Poor Survival.
Grosse-Wilde, Anne; Fouquier d'Hérouël, Aymeric UL; McIntosh, Ellie et al

in PLoS ONE (2015), 10(5), 0126522

Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since ... [more ▼]

Breast cancer stem cells (CSCs) are thought to drive recurrence and metastasis. Their identity has been linked to the epithelial to mesenchymal transition (EMT) but remains highly controversial since-depending on the cell-line studied-either epithelial (E) or mesenchymal (M) markers, alone or together have been associated with stemness. Using distinct transcript expression signatures characterizing the three different E, M and hybrid E/M cell-types, our data support a novel model that links a mixed EM signature with stemness in 1) individual cells, 2) luminal and basal cell lines, 3) in vivo xenograft mouse models, and 4) in all breast cancer subtypes. In particular, we found that co-expression of E and M signatures was associated with poorest outcome in luminal and basal breast cancer patients as well as with enrichment for stem-like cells in both E and M breast cell-lines. This link between a mixed EM expression signature and stemness was explained by two findings: first, mixed cultures of E and M cells showed increased cooperation in mammosphere formation (indicative of stemness) compared to the more differentiated E and M cell-types. Second, single-cell qPCR analysis revealed that E and M genes could be co-expressed in the same cell. These hybrid E/M cells were generated by both E or M cells and had a combination of several stem-like traits since they displayed increased plasticity, self-renewal, mammosphere formation, and produced ALDH1+ progenies, while more differentiated M cells showed less plasticity and E cells showed less self-renewal. Thus, the hybrid E/M state reflecting stemness and its promotion by E-M cooperation offers a dual biological rationale for the robust association of the mixed EM signature with poor prognosis, independent of cellular origin. Together, our model explains previous paradoxical findings that breast CSCs appear to be M in luminal cell-lines but E in basal breast cancer cell-lines. Our results suggest that targeting E/M heterogeneity by eliminating hybrid E/M cells and cooperation between E and M cell-types could improve breast cancer patient survival independent of breast cancer-subtype. [less ▲]

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See detailProtocols and programs for high-throughput growth and aging phenotyping in yeast.
Jung, Paul UL; Christian, Nils UL; Kay, Daniel UL et al

in PloS one (2015), 10(3), 0119807

In microorganisms, and more particularly in yeasts, a standard phenotyping approach consists in the analysis of fitness by growth rate determination in different conditions. One growth assay that combines ... [more ▼]

In microorganisms, and more particularly in yeasts, a standard phenotyping approach consists in the analysis of fitness by growth rate determination in different conditions. One growth assay that combines high throughput with high resolution involves the generation of growth curves from 96-well plate microcultivations in thermostated and shaking plate readers. To push the throughput of this method to the next level, we have adapted it in this study to the use of 384-well plates. The values of the extracted growth parameters (lag time, doubling time and yield of biomass) correlated well between experiments carried out in 384-well plates as compared to 96-well plates or batch cultures, validating the higher-throughput approach for phenotypic screens. The method is not restricted to the use of the budding yeast Saccharomyces cerevisiae, as shown by consistent results for other species selected from the Hemiascomycete class. Furthermore, we used the 384-well plate microcultivations to develop and validate a higher-throughput assay for yeast Chronological Life Span (CLS), a parameter that is still commonly determined by a cumbersome method based on counting "Colony Forming Units". To accelerate analysis of the large datasets generated by the described growth and aging assays, we developed the freely available software tools GATHODE and CATHODE. These tools allow for semi-automatic determination of growth parameters and CLS behavior from typical plate reader output files. The described protocols and programs will increase the time- and cost-efficiency of a number of yeast-based systems genetics experiments as well as various types of screens. [less ▲]

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