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Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W. Grill, Francisco Pan-Montojo#, Andreas Hermann#
Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.
Life Sci Alliance, 7(8) Art. No. e202302535 (2024)
Open Access PubMed Source   

Amyotrophic lateral sclerosis (ALS) leads to death within 2-5 yr. Currently, available drugs only slightly prolong survival. We present novel insights into the pathophysiology of Superoxide Dismutase 1 (SOD1)- and in particular Fused In Sarcoma (FUS)-ALS by revealing a supposedly central role of glycolic acid (GA) and D-lactic acid (DL)-both putative products of the Parkinson's disease associated glyoxylase DJ-1. Combined, not single, treatment with GA/DL restored axonal organelle phenotypes of mitochondria and lysosomes in FUS- and SOD1-ALS patient-derived motoneurons (MNs). This was not only accompanied by restoration of mitochondrial membrane potential but even dependent on it. Despite presenting an axonal transport deficiency as well, TDP43 patient-derived MNs did not share mitochondrial depolarization and did not respond to GA/DL treatment. GA and DL also restored cytoplasmic mislocalization of FUS and FUS recruitment to DNA damage sites, recently reported being upstream of the mitochondrial phenotypes in FUS-ALS. Whereas these data point towards the necessity of individualized (gene-) specific therapy stratification, it also suggests common therapeutic targets across different neurodegenerative diseases characterized by mitochondrial depolarization.
@article{Pal8722,
author={Arun Pal, Dajana Grossmann, Hannes Glaß, Vitaly Zimyanin, René Günther, Marica Catinozzi, Tobias M Boeckers, Jared Sterneckert, Erik Storkebaum, Susanne Petri, Florian Wegner, Stephan W. Grill, Francisco Pan-Montojo, Andreas Hermann},
title={Glycolic acid and D-lactate-putative products of DJ-1-restore neurodegeneration in FUS - and SOD1-ALS.},
journal ={Life science alliance},
volume={7},
issue ={8},
pages={null--null},
year=2024
}

Rasmus K Norrild, Thomas O Mason, Lars Boyens-Thiele, Soumik Ray, Joachim B Mortensen, Anatol Fritsch, Juan M Iglesias-Artola, Louise K Klausen, Emil G P Stender, Henrik Jensen, Alexander K Buell
Taylor Dispersion-Induced Phase Separation for the Efficient Characterisation of Protein Condensate Formation.
Angew Chem Int Ed Engl, 63(25) Art. No. e202404018 (2024)
Open Access PubMed Source   

Biomolecular condensates have emerged as important structures in cellular function and disease, and are thought to form through liquid-liquid phase separation (LLPS). Thorough and efficient in vitro experiments are therefore needed to elucidate the driving forces of protein LLPS and the possibility to modulate it with drugs. Here we present Taylor dispersion-induced phase separation (TDIPS), a method to robustly measure condensation phenomena using a commercially available microfluidic platform. It uses only nanoliters of sample, does not require extrinsic fluorescent labels, and is straightforward to implement. We demonstrate TDIPS by screening the phase behaviour of two proteins that form biomolecular condensates in vivo, PGL-3 and Ddx4. Uniquely accessible to this method, we find an unexpected re-entrant behaviour at very low ionic strength, where LLPS is inhibited for both proteins. TDIPS can also probe the reversibility of assemblies, which was shown for both α-synuclein and for lysozyme, relevant for health and biotechnology, respectively. Finally, we highlight how effective inhibition concentrations and partitioning of LLPS-modifying compounds can be screened highly efficiently.
@article{Norrild8729,
author={Rasmus K Norrild, Thomas O Mason, Lars Boyens-Thiele, Soumik Ray, Joachim B Mortensen, Anatol Fritsch, Juan M Iglesias-Artola, Louise K Klausen, Emil G P Stender, Henrik Jensen, Alexander K Buell},
title={Taylor Dispersion-Induced Phase Separation for the Efficient Characterisation of Protein Condensate Formation.},
journal ={Angewandte Chemie (International ed. in English)},
volume={63},
issue ={25},
pages={null--null},
year=2024
}

Maximilian Driller, Thomas Brown, Shannon E Currie, Michael Hiller, Sylke Winkler, Martin Pippel, Christian C Voigt, Jörns Fickel, Camila J Mazzoni
A Haplotype-resolved reference genome of a long-distance migratory bat, Pipistrellus nathusii (Keyserling & Blasius, 1839).
DNA Res, Art. No. doi: 10.1093/dnares/dsae018 (2024)
Open Access PubMed Source   

We present a complete, chromosome scale reference genome for the long-distance migratory bat Pipistrellus nathusii. The genome encompasses both haplotypic sets of autosomes and separation of both sex chromosomes by utilising highly-accurate long-reads and preserving long-range phasing information through the use of 3-dimensional chromatin conformation capture sequencing (Hi-C). This genome, accompanied by a comprehensive protein-coding sequence annotation, provides a valuable genomic resource for future investigations into the genomic bases of long-distance migratory flight in bats as well as uncovering the genetic architecture, population structure and evolutionary history of Pipistrellus nathusii. The reference-quality genome presented here gives a fundamental resource to further our understanding of bat genetics and evolution, adding to the growing number of high quality genetic resources in this field. Here, we demonstrate its use in the phylogenetic reconstruction of the order Chiroptera and in particular, we present the resources to allow detailed investigations into the genetic drivers and adaptations related to long-distance migration.
@article{Driller8726,
author={Maximilian Driller, Thomas Brown, Shannon E Currie, Michael Hiller, Sylke Winkler, Martin Pippel, Christian C Voigt, Jörns Fickel, Camila J Mazzoni},
title={A Haplotype-resolved reference genome of a long-distance migratory bat, Pipistrellus nathusii (Keyserling & Blasius, 1839).},
journal ={DNA research : an international journal for rapid publication of reports on genes and genomes},
volume={},
pages={1--1},
year=2024
}

Rebecca A. Green✳︎#, Renat N Khaliullin✳︎, Zhiling Zhao, Stacy D Ochoa, Jeffrey M Hendel, Tiffany-Lynn Chow, HongKee Moon, Ronald J Biggs, Arshad Desai, Karen Oegema#
Automated profiling of gene function during embryonic development.
Cell, 187(12) 3141-3160 (2024)
PubMed Source   

Systematic functional profiling of the gene set that directs embryonic development is an important challenge. To tackle this challenge, we used 4D imaging of C. elegans embryogenesis to capture the effects of 500 gene knockdowns and developed an automated approach to compare developmental phenotypes. The automated approach quantifies features-including germ layer cell numbers, tissue position, and tissue shape-to generate temporal curves whose parameterization yields numerical phenotypic signatures. In conjunction with a new similarity metric that operates across phenotypic space, these signatures enabled the generation of ranked lists of genes predicted to have similar functions, accessible in the PhenoBank web portal, for ∼25% of essential development genes. The approach identified new gene and pathway relationships in cell fate specification and morphogenesis and highlighted the utilization of specialized energy generation pathways during embryogenesis. Collectively, the effort establishes the foundation for comprehensive analysis of the gene set that builds a multicellular organism.
@article{Green8723,
author={Rebecca A. Green, Renat N Khaliullin, Zhiling Zhao, Stacy D Ochoa, Jeffrey M Hendel, Tiffany-Lynn Chow, HongKee Moon, Ronald J Biggs, Arshad Desai, Karen Oegema},
title={Automated profiling of gene function during embryonic development.},
journal ={Cell},
volume={187},
issue ={12},
pages={3141--3160},
year=2024
}

Hendrik Frentzel, Marco Kraemer, Ylanna Kelner-Burgos, Laura Uelze, Dorina Bodi
Cereulide production capacities and genetic properties of 31 emetic Bacillus cereus group strains.
Int J Food Microbiol, 417 Art. No. 110694 (2024)
Open Access PubMed Source   

The highly potent toxin cereulide is a frequent cause of foodborne intoxications. This extremely resistant toxin is produced by Bacillus cereus group strains carrying the plasmid encoded cesHPTABCD gene cluster. It is known that the capacities to produce cereulide vary greatly between different strains but the genetic background of these variations is not clear. In this study, cereulide production capacities were associated with genetic characteristics. For this, cereulide levels in cultures of 31 strains were determined after incubation in tryptic soy broth for 24 h at 24 °C, 30 °C and 37 °C. Whole genome sequencing based data were used for an in-depth characterization of gene sequences related to cereulide production. The taxonomy, population structure and phylogenetic relationships of the strains were evaluated based on average nucleotide identity, multi-locus sequence typing (MLST), core genome MLST and single nucleotide polymorphism analyses. Despite a limited strain number, the approach of a genome wide association study (GWAS) was tested to link genetic variation with cereulide quantities. Our study confirms strain-dependent differences in cereulide production. For most strains, these differences were not explainable by sequence variations in the cesHPTABCD gene cluster or the regulatory genes abrB, spo0A, codY and pagRBc. Likewise, the population structure and phylogeny of the tested strains did not comprehensively reflect the cereulide production capacities. GWAS yielded first hints for associated proteins, while their possible effect on cereulide synthesis remains to be further investigated.
@article{Frentzel8707,
author={Hendrik Frentzel, Marco Kraemer, Ylanna Kelner-Burgos, Laura Uelze, Dorina Bodi},
title={Cereulide production capacities and genetic properties of 31 emetic Bacillus cereus group strains.},
journal ={International journal of food microbiology},
volume={417},
pages={null--null},
year=2024
}

Maria Luisa Romero Romero#, Jonas Poehls, Anastasiia Kirilenko, Doris Richter, Tobias Jumel, Anna Shevchenko, Agnes Toth-Petroczy#
Environment modulates protein heterogeneity through transcriptional and translational stop codon readthrough.
Nat Commun, 15(1) Art. No. 4446 (2024)
Open Access PubMed Source   

Stop codon readthrough events give rise to longer proteins, which may alter the protein's function, thereby generating short-lasting phenotypic variability from a single gene. In order to systematically assess the frequency and origin of stop codon readthrough events, we designed a library of reporters. We introduced premature stop codons into mScarlet, which enabled high-throughput quantification of protein synthesis termination errors in E. coli using fluorescent microscopy. We found that under stress conditions, stop codon readthrough may occur at rates as high as 80%, depending on the nucleotide context, suggesting that evolution frequently samples stop codon readthrough events. The analysis of selected reporters by mass spectrometry and RNA-seq showed that not only translation but also transcription errors contribute to stop codon readthrough. The RNA polymerase was more likely to misincorporate a nucleotide at premature stop codons. Proteome-wide detection of stop codon readthrough by mass spectrometry revealed that temperature regulated the expression of cryptic sequences generated by stop codon readthrough in E. coli. Overall, our findings suggest that the environment affects the accuracy of protein production, which increases protein heterogeneity when the organisms need to adapt to new conditions.
@article{Romero8732,
author={Maria Luisa Romero Romero, Jonas Poehls, Anastasiia Kirilenko, Doris Richter, Tobias Jumel, Anna Shevchenko, Agnes Toth-Petroczy},
title={Environment modulates protein heterogeneity through transcriptional and translational stop codon readthrough.},
journal ={Nature communications},
volume={15},
issue ={1},
pages={null--null},
year=2024
}

Suse Seidemann✳︎, Florian Salomon✳︎, Karl Hoffmann, Thomas Kurth, Ivo F. Sbalzarini, Robert Haase, Marius Ader
Automated quantification of photoreceptor outer segments in developing and degenerating retinas on microscopy images across scales.
Front Mol Neurosci, 17 Art. No. 1398447 (2024)
Open Access PubMed Source   

The functionality of photoreceptors, rods, and cones is highly dependent on their outer segments (POS), a cellular compartment containing highly organized membranous structures that generate biochemical signals from incident light. While POS formation and degeneration are qualitatively assessed on microscopy images, reliable methodology for quantitative analyses is still limited. Here, we developed methods to quantify POS (QuaPOS) maturation and quality on retinal sections using automated image analyses. POS formation was examined during the development and in adulthood of wild-type mice via light microscopy (LM) and transmission electron microscopy (TEM). To quantify the number, size, shape, and fluorescence intensity of POS, retinal cryosections were immunostained for the cone POS marker S-opsin. Fluorescence images were used to train the robust classifier QuaPOS-LM based on supervised machine learning for automated image segmentation. Characteristic features of segmentation results were extracted to quantify the maturation of cone POS. Subsequently, this quantification method was applied to characterize POS degeneration in "cone photoreceptor function loss 1" mice. TEM images were used to establish the ultrastructural quantification method QuaPOS-TEM for the alignment of POS membranes. Images were analyzed using a custom-written MATLAB code to extract the orientation of membranes from the image gradient and their alignment (coherency). This analysis was used to quantify the POS morphology of wild-type and two inherited retinal degeneration ("retinal degeneration 19" and "rhodopsin knock-out") mouse lines. Both automated analysis technologies provided robust characterization and quantification of POS based on LM or TEM images. Automated image segmentation by the classifier QuaPOS-LM and analysis of the orientation of membrane stacks by QuaPOS-TEM using fluorescent or TEM images allowed quantitative evaluation of POS formation and quality. The assessments showed an increase in POS number, volume, and membrane coherency during wild-type postnatal development, while a decrease in all three observables was detected in different retinal degeneration mouse models. All the code used for the presented analysis is open source, including example datasets to reproduce the findings. Hence, the QuaPOS quantification methods are useful for in-depth characterization of POS on retinal sections in developmental studies, for disease modeling, or after therapeutic interventions affecting photoreceptors.
@article{Seidemann8727,
author={Suse Seidemann, Florian Salomon, Karl Hoffmann, Thomas Kurth, Ivo F. Sbalzarini, Robert Haase, Marius Ader},
title={Automated quantification of photoreceptor outer segments in developing and degenerating retinas on microscopy images across scales.},
journal ={Frontiers in molecular neuroscience},
volume={17},
pages={null--null},
year=2024
}

Mrityunjoy Kar, Laura T Vogel, Gaurav Chauhan, Suren Felekyan, Hannes Ausserwöger, Timothy J Welsh, Furqan Dar, Anjana R Kamath, Tuomas P J Knowles, Anthony Hyman#, Claus A M Seidel, Rohit V Pappu#
Solutes unmask differences in clustering versus phase separation of FET proteins.
Nat Commun, 15(1) Art. No. 4408 (2024)
Open Access PubMed Source   

Phase separation and percolation contribute to phase transitions of multivalent macromolecules. Contributions of percolation are evident through the viscoelasticity of condensates and through the formation of heterogeneous distributions of nano- and mesoscale pre-percolation clusters in sub-saturated solutions. Here, we show that clusters formed in sub-saturated solutions of FET (FUS-EWSR1-TAF15) proteins are affected differently by glutamate versus chloride. These differences on the nanoscale, gleaned using a suite of methods deployed across a wide range of protein concentrations, are prevalent and can be unmasked even though the driving forces for phase separation remain unchanged in glutamate versus chloride. Strikingly, differences in anion-mediated interactions that drive clustering saturate on the micron-scale. Beyond this length scale the system separates into coexisting phases. Overall, we find that sequence-encoded interactions, mediated by solution components, make synergistic and distinct contributions to the formation of pre-percolation clusters in sub-saturated solutions, and to the driving forces for phase separation.
@article{Kar8725,
author={Mrityunjoy Kar, Laura T Vogel, Gaurav Chauhan, Suren Felekyan, Hannes Ausserwöger, Timothy J Welsh, Furqan Dar, Anjana R Kamath, Tuomas P J Knowles, Anthony Hyman, Claus A M Seidel, Rohit V Pappu},
title={Solutes unmask differences in clustering versus phase separation of FET proteins.},
journal ={Nature communications},
volume={15},
issue ={1},
pages={null--null},
year=2024
}


✳︎ joint first authors, # joint corresponding authors
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