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Lydia Reinhardt, Susanne Kordes, Peter Reinhardt, Michael Glatza, Michael Baumann, Hannes C A Drexler, Sascha Menninger, Gunther Zischinsky, Jan Eickhoff, Claudia Fröb, Prabesh Bhattarai, Guruchandar Arulmozhivarman, Lara Marrone, Antje Janosch, Kenjiro Adachi, Martin Stehling, Eric D Anderson, Masin Abo-Rady, Marc Bickle, Udai Pandey, Michell M Reimer, Caghan Kizil, Hans R Schöler, Peter Nussbaumer, Bert Klebl, Jared Sterneckert
Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo.
Stem Cell Reports, 12(3) 502-517 (2019)
PubMed Source   

Neuroinflammation is a hallmark of neurological disorders and is accompanied by the production of neurotoxic agents such as nitric oxide. We used stem cell-based phenotypic screening and identified small molecules that directly protected neurons from neuroinflammation-induced degeneration. We demonstrate that inhibition of CDK5 is involved in, but not sufficient for, neuroprotection. Instead, additional inhibition of GSK3β is required to enhance the neuroprotective effects of CDK5 inhibition, which was confirmed using short hairpin RNA-mediated knockdown of CDK5 and GSK3β. Quantitative phosphoproteomics and high-content imaging demonstrate that neurite degeneration is mediated by aberrant phosphorylation of multiple microtubule-associated proteins. Finally, we show that our hit compound protects neurons in vivo in zebrafish models of motor neuron degeneration and Alzheimer's disease. Thus, we demonstrate an overlap of CDK5 and GSK3β in mediating the regulation of the neuronal cytoskeleton and that our hit compound LDC8 represents a promising starting point for neuroprotective drugs.
@article{Reinhardt7348,
author={Lydia Reinhardt, Susanne Kordes, Peter Reinhardt, Michael Glatza, Michael Baumann, Hannes C A Drexler, Sascha Menninger, Gunther Zischinsky, Jan Eickhoff, Claudia Fröb, Prabesh Bhattarai, Guruchandar Arulmozhivarman, Lara Marrone, Antje Janosch, Kenjiro Adachi, Martin Stehling, Eric D Anderson, Masin Abo-Rady, Marc Bickle, Udai Pandey, Michell M Reimer, Caghan Kizil, Hans R Schöler, Peter Nussbaumer, Bert Klebl, Jared Sterneckert},
title={Dual Inhibition of GSK3β and CDK5 Protects the Cytoskeleton of Neurons from Neuroinflammatory-Mediated Degeneration In Vitro and In Vivo.},
journal ={Stem cell reports},
volume={12},
issue ={3},
pages={502--517},
year=2019
}

Marc Bickle
The Academic Pill: How Academia Contributes to Curing Diseases.
SLAS Discov, 24(3) 203-212 (2019)
PubMed Source  

@article{Bickle7345,
author={Marc Bickle},
title={The Academic Pill: How Academia Contributes to Curing Diseases.},
journal ={SLAS discovery : advancing life sciences R & D},
volume={24},
issue ={3},
pages={203--212},
year=2019
}

Stephan Daetwyler, Ulrik Günther, Carl D. Modes, Kyle Harrington, Jan Huisken
Multi-sample SPIM image acquisition, processing and analysis of vascular growth in zebrafish.
Development, Art. No. doi: 10.1242/dev.173757 (2019)
PubMed Source   

To quantitatively understand biological processes that occur over many hours or days, it is desirable to image multiple samples simultaneously and automatically process and analyze the resulting datasets. Here, we present a complete multi-sample preparation, imaging, processing, and analysis workflow to determine the development of the vascular volume in zebrafish. Up to five live embryos were mounted and imaged simultaneously over several days using selective plane illumination microscopy (SPIM). The resulting large imagery dataset of several terabytes was processed in an automated manner on a high-performance computer cluster and segmented with a novel segmentation approach that uses images of red blood cells as training data. This analysis yielded a precise quantification of growth characteristics of the whole vascular network, head vasculature, and tail vasculature over development. Our multi-sample platform demonstrates effective upgrades to conventional single-sample imaging platforms and paves the way for diverse quantitative long-term imaging studies.
@article{Daetwyler7354,
author={Stephan Daetwyler, Ulrik Günther, Carl D. Modes, Kyle Harrington, Jan Huisken},
title={Multi-sample SPIM image acquisition, processing and analysis of vascular growth in zebrafish.},
journal ={Development (Cambridge, England)},
volume={},
pages={null--null},
year=2019
}

Antje Janosch, Carolin Kaffka, Marc Bickle
Unbiased Phenotype Detection Using Negative Controls.
SLAS Discov, 24(3) 234-241 (2019)
Supplementary Website PubMed Source   

Phenotypic screens using automated microscopy allow comprehensive measurement of the effects of compounds on cells due to the number of markers that can be scored and the richness of the parameters that can be extracted. The high dimensionality of the data is both a rich source of information and a source of noise that might hide information. Many methods have been proposed to deal with this complex data in order to reduce the complexity and identify interesting phenotypes. Nevertheless, the majority of laboratories still only use one or two parameters in their analysis, likely due to the computational challenges of carrying out a more sophisticated analysis. Here, we present a novel method that allows discovering new, previously unknown phenotypes based on negative controls only. The method is compared with L1-norm regularization, a standard method to obtain a sparse matrix. The analytical pipeline is implemented in the open-source software KNIME, allowing the implementation of the method in many laboratories, even ones without advanced computing knowledge.
@article{Janosch7217,
author={Antje Janosch, Carolin Kaffka, Marc Bickle},
title={Unbiased Phenotype Detection Using Negative Controls.},
journal ={SLAS discovery : advancing life sciences R & D},
volume={24},
issue ={3},
pages={234--241},
year=2019
}

Björn Langer, Michael Hiller
TFforge utilizes large-scale binding site divergence to identify transcriptional regulators involved in phenotypic differences.
Nucleic Acids Res, 47(4) Art. No. e19 (2019)
  PubMed Source   

Changes in gene regulation are important for phenotypic and in particular morphological evolution. However, it remains challenging to identify the transcription factors (TFs) that contribute to differences in gene regulation and thus to phenotypic differences between species. Here, we present TFforge (Transcription Factor forward genomics), a computational method to identify TFs that are involved in the loss of phenotypic traits. TFforge screens an input set of regulatory genomic regions to detect TFs that exhibit a significant binding site divergence signature in species that lost a particular phenotypic trait. Using simulated data of modular and pleiotropic regulatory elements, we show that TFforge can identify the correct TFs for many different evolutionary scenarios. We applied TFforge to available eye regulatory elements to screen for TFs that exhibit a significant binding site decay signature in subterranean mammals. This screen identified interacting and co-binding eye-related TFs, and thus provides new insights into which TFs likely contribute to eye degeneration in these species. TFforge has broad applicability to identify the TFs that contribute to phenotypic changes between species, and thus can help to unravel the gene-regulatory differences that underlie phenotypic evolution.
@article{Langer7252,
author={Björn Langer, Michael Hiller},
title={TFforge utilizes large-scale binding site divergence to identify transcriptional regulators involved in phenotypic differences.},
journal ={Nucleic acids research},
volume={47},
issue ={4},
pages={null--null},
year=2019
}

Kerstin Klinkert, Nicolas Levernier, Peter Gross, Christian Gentili, Lukas von Tobel, Marie Pierron, Coralie Busso, Sarah Herrman, Stephan W. Grill, Karsten Kruse, Pierre Gönczy
Aurora A depletion reveals centrosome-independent polarization mechanism in C. elegans.
Elife, 8 Art. No. e44552 (2019)
PubMed Source   

How living systems break symmetry in an organized manner is a fundamental question in biology. In wild type Caenorhabditis elegans zygotes, symmetry breaking during anterior-posterior axis specification is guided by centrosomes, resulting in anterior-directed cortical flows and a single posterior PAR-2 domain. We uncover that C. elegans zygotes depleted of the Aurora A kinase AIR-1 or lacking centrosomes entirely usually establish two posterior PAR-2 domains, one at each pole. We demonstrate that AIR-1 prevents symmetry breaking early in the cell cycle, whereas centrosomal AIR-1 instructs polarity initiation thereafter. Using triangular microfabricated chambers, we establish that bipolarity of air-1(RNAi) embryos occurs effectively in a cell-shape and curvature-dependent manner. Furthermore, we develop an integrated physical description of symmetry breaking, wherein local PAR-2-dependent weakening of the actin cortex, together with mutual inhibition of anterior and posterior PAR proteins, provides a mechanism for spontaneous symmetry breaking without centrosomes.
@article{Klinkert7351,
author={Kerstin Klinkert, Nicolas Levernier, Peter Gross, Christian Gentili, Lukas von Tobel, Marie Pierron, Coralie Busso, Sarah Herrman, Stephan W. Grill, Karsten Kruse, Pierre Gönczy},
title={Aurora A depletion reveals centrosome-independent polarization mechanism in C. elegans.},
journal ={eLife},
volume={8},
pages={null--null},
year=2019
}

Jan Kožusznik, Petr Bainar, Jana Klímová, Michal Krumnikl, Pavel Moravec, Václav Svatoň, Pavel Tomančák
SPIM Workflow Manager for HPC.
Bioinformatics, Art. No. doi: 10.1093/bioinformatics/btz140 (2019)
PubMed Source   

Here we introduce a Fiji plugin utilizing the HPC-as-a-Service concept, significantly mitigating the challenges life scientists face when delegating complex data-intensive processing workflows to HPC clusters. We demonstrate on a common SPIM image processing task that execution of a Fiji workflow on a remote supercomputer leads to improved turnaround time despite the data transfer overhead. The plugin allows the end users to conveniently transfer image data to remote HPC resources, manage pipeline jobs, and visualize processed results directly from the Fiji graphical user interface.
@article{Kožusznik7352,
author={Jan Kožusznik, Petr Bainar, Jana Klímová, Michal Krumnikl, Pavel Moravec, Václav Svatoň, Pavel Tomančák},
title={SPIM Workflow Manager for HPC.},
journal ={Bioinformatics (Oxford, England)},
volume={},
pages={1--1},
year=2019
}

Livia Goto-Silva, Marisa P. McShane, Sara Salinas, Yannis Kalaidzidis, Giampietro Schiavo, Marino Zerial
Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome.
Sci Rep, 9(1) Art. No. 2433 (2019)
PubMed Source   

Long-distance axonal trafficking plays a critical role in neuronal function and transport defects have been linked to neurodegenerative disorders. Various lines of evidence suggest that the small GTPase Rab5 plays a role in neuronal signaling via early endosomal transport. Here, we characterized the motility of Rab5 endosomes in primary cultures of mouse hippocampal pyramidal cells by live-cell imaging and showed that they exhibit bi-directional long-range motility in axons, with a strong bias toward retrograde transport. Characterization of key Rab5 effectors revealed that endogenous Rabankyrin-5, Rabenosyn-5 and APPL1 are all present in axons. Further analysis of APPL1-positive endosomes showed that, similar to Rab5-endosomes, they display more frequent long-range retrograde than anterograde movement, with the endosomal levels of APPL1 correlated with faster retrograde movement. Interestingly, APPL1-endosomes transport the neurotrophin receptor TrkB and mediate retrograde axonal transport of the kinase Akt1. FRET analysis revealed that APPL1 and Akt1 interact in an endocytosis-dependent manner. We conclude that Rab5-APPL1 endosomes exhibit the hallmarks of axonal signaling endosomes to transport Akt1 in hippocampal pyramidal cells.
@article{Goto-Silva7339,
author={Livia Goto-Silva, Marisa P. McShane, Sara Salinas, Yannis Kalaidzidis, Giampietro Schiavo, Marino Zerial},
title={Retrograde transport of Akt by a neuronal Rab5-APPL1 endosome.},
journal ={Scientific reports},
volume={9},
issue ={1},
pages={null--null},
year=2019
}

Germán Camargo Ortega, Sven Falk, Pia A Johansson, Elise Peyre, Loïc Broix, Sanjeeb Kumar Sahu, William Hirst, Thomas Schlichthaerle, Camino De Juan Romero, Kalina Draganova, Stanislav Vinopal, Kaviya Chinnappa, Anna Gavranovic, Tugay Karakaya, Thomas Steininger, Juliane Merl-Pham, Regina Feederle, Wei Shao, Song-Hai Shi, Stefanie M Hauck, Ralf Jungmann, Frank Bradke, Víctor Borrell, Arie Geerlof, Simone Reber, Vijay K Tiwari, Wieland Huttner, Michaela Wilsch-Bräuninger, Laurent Nguyen, Magdalena Götz
The centrosome protein AKNA regulates neurogenesis via microtubule organization.
Nature, Art. No. doi: 10.1038/s41586-019-0962-4 (2019)
PubMed Source   

The expansion of brain size is accompanied by a relative enlargement of the subventricular zone during development. Epithelial-like neural stem cells divide in the ventricular zone at the ventricles of the embryonic brain, self-renew and generate basal progenitors1 that delaminate and settle in the subventricular zone in enlarged brain regions2. The length of time that cells stay in the subventricular zone is essential for controlling further amplification and fate determination. Here we show that the interphase centrosome protein AKNA has a key role in this process. AKNA localizes at the subdistal appendages of the mother centriole in specific subtypes of neural stem cells, and in almost all basal progenitors. This protein is necessary and sufficient to organize centrosomal microtubules, and promote their nucleation and growth. These features of AKNA are important for mediating the delamination process in the formation of the subventricular zone. Moreover, AKNA regulates the exit from the subventricular zone, which reveals the pivotal role of centrosomal microtubule organization in enabling cells to both enter and remain in the subventricular zone. The epithelial-to-mesenchymal transition is also regulated by AKNA in other epithelial cells, demonstrating its general importance for the control of cell delamination.
@article{Ortega7349,
author={Germán Camargo Ortega, Sven Falk, Pia A Johansson, Elise Peyre, Loïc Broix, Sanjeeb Kumar Sahu, William Hirst, Thomas Schlichthaerle, Camino De Juan Romero, Kalina Draganova, Stanislav Vinopal, Kaviya Chinnappa, Anna Gavranovic, Tugay Karakaya, Thomas Steininger, Juliane Merl-Pham, Regina Feederle, Wei Shao, Song-Hai Shi, Stefanie M Hauck, Ralf Jungmann, Frank Bradke, Víctor Borrell, Arie Geerlof, Simone Reber, Vijay K Tiwari, Wieland Huttner, Michaela Wilsch-Bräuninger, Laurent Nguyen, Magdalena Götz},
title={The centrosome protein AKNA regulates neurogenesis via microtubule organization.},
journal ={Nature},
volume={},
pages={1--1},
year=2019
}

Maarten E Witte, Adrian-Minh Schumacher, Christoph F Mahler, Joerg Bewersdorf, Jonas Lehmitz, Alexander Scheiter, Paula Sánchez, Philip R Williams, Oliver Griesbeck, Ronald Naumann, Thomas Misgeld, Martin Kerschensteiner
Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis.
Neuron, 101(4) 615-624 (2019)
PubMed Source   

Axon loss determines persistent disability in multiple sclerosis patients. Here, we use in vivo calcium imaging in a multiple sclerosis model to show that cytoplasmic calcium levels determine the choice between axon loss and survival. We rule out the endoplasmic reticulum, glutamate excitotoxicity, and the reversal of the sodium-calcium exchanger as sources of intra-axonal calcium accumulation and instead identify nanoscale ruptures of the axonal plasma membrane as the critical path of calcium entry.
@article{Witte7319,
author={Maarten E Witte, Adrian-Minh Schumacher, Christoph F Mahler, Joerg Bewersdorf, Jonas Lehmitz, Alexander Scheiter, Paula Sánchez, Philip R Williams, Oliver Griesbeck, Ronald Naumann, Thomas Misgeld, Martin Kerschensteiner},
title={Calcium Influx through Plasma-Membrane Nanoruptures Drives Axon Degeneration in a Model of Multiple Sclerosis.},
journal ={Neuron},
volume={101},
issue ={4},
pages={615--624},
year=2019
}