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Articles by Markus Ralser
Proteome-guided drug discovery maps and mitigates therapeutic degrader toxicity
Abstract Heterobifunctional targeted degraders (HBDs) enable potent removal of protein targets but their clinical success can be hindered by de novo toxicity inherent to their bivalent chemistry. Here we introduce a drug discovery framework that exploits high-throughput proteomics to map and mitigate toxicity mechanisms of emerging drug modalities.
Proteome signatures in ICU patients with COVID-19 and acute brain dysfunction: an observational cohort study
Abstract Deep sedation and delirium are common in COVID-19 intensive care unit (ICU) patients. Biomarkers for prediction, detection, and monitoring are missing. Unbiased omics analyses are warranted to gain a systems biology view on pathophysiology. This prospective observational satellite study analysed the proteome signatures of COVID-19 ICU patients with and without acute brain dysfunction (ABD).
Proteomics identify disease-associated variants in patients with rare diseases undiagnosed after genome sequencing
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Abstract Supplementary Materials REFERENCES AND NOTES Information & Authors Metrics & Citations Check Access References Figures Tables Media Share This article has 0 eLetter . Abstract Despite the introduction of genome sequencing (GS) for rare disease diagnostics, a genetic cause is not identified in most patients. Here, we explored the potential of proteomics to improve the diagnostic yield in 424 patients with rare diseases from the 100,000 Genomes Project (100kGP) without a genetic diagnosis.
By Ki Baek Lee, Anne Maguire, Joshua Levitt, Julia Carrasco-Zanini, JORGE ANDRADE, Maik Pietzner, Athanasios Kousathanas, Julius O. B. Jacobsen, Jenny Lord, Narasimha Swamy Telugu, Sebastian Diecke, Michael Mülleder, Letizia Vestito, Peter Robinson Verified, Markus Ralser, Diana Baralle, Nicholas J Wareham, Greg Elgar, Michael Potente, Matthew Brown Verified, Mark Caulfield, Damian Smedley, Claudia Langenberg, Dominik Bierbaum
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Science Magazine
Verified
Genome-wide analysis of 439 mass spectrometry-based proteomic profiles in a population of 15,035 Scottish individuals
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Abstract Understanding the genetic architecture of the circulating proteome can help determine if a protein is causally linked to disease. Previous large-scale genome-wide association studies of proteins have mostly been conducted on pre-defined, targeted subsets of the proteome, and have often concentrated on low-abundance proteins, many of which don’t exert their main function in serum.
By Anne Richmond, Josephine Robertson, Hannah Smith, Robert F. Hillary, Aleksej Zelezniak, Spyros I. Vernardis, Aleksandra Chybowska, Arturas Grauslys, Jure Mur, Archie Campbell, Camilla Drake, Hannah Grant, Matthew White, Christoph B. Messner, David Porteous, Caroline Hayward, ANDREW McIntosh, Andrew Mcintosh, Daniel L. McCartney, Markus Ralser, Riccardo E Marioni, Poppy Adkin, Charles Brigden
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Nature
Verified
AI proteomics: from protein identification to virtual cells
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Abstract Artificial intelligence (AI) is transforming scientific research, including proteomics. In this Perspective, we highlight key mass spectrometry (MS)-based proteomics areas where AI is driving innovation, ranging from protein identification to building AI virtual cells.
By Yingying Sun, Zhiwei Liu, Rui Sun, Liujia Qian, Samuel Payne, Wout Bittremieux, Markus Ralser, Chen Li, Yi Chen, Zhen Dong, Yasset Perez-Riverol, Asif Khan, Chris Sander, Ruedi Aebersold, Juan Antonio Vizcaino, Jonathan Krieger, Jianhua Yao, Linfeng Zhang, Yunping Zhu, Yue Xuan, Liang Qiao, Henning Hermjakob, Haixu Tang, Huanhuan Gao, Yamin Deng, Qing Zhong, Cheng Chang, Nuno Bandeira, Ming Li, Siqi Sun, Yuedong Yang, Gilbert S. Omenn, Yue Zhang, Ping Xu, Xiaowen Liu, Christopher M. Overall, Yu Wang, Eric Deutsch, Luonan Chen, Jürgen Cox, Vadim Demichev, Fuchu He, Jiaxing Huang, Huilin Jin, Chao Liu, Nan Li, Zhongzhi Luan, Jiangning Song, Kaicheng Yu, Wanggen Wan, Tai Wang, Kang Zhang, Le Peng Zhang, Peter Bell, Matthias Mann, Bing Zhang, Tiannan Guo, Benjamin Boyang Sun
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Nature
Verified
Towards the construction of a virtual yeast
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Abstract To advance the computational simulation of cellular life, we propose a virtual yeast, an artificial intelligence (AI)-driven agent that models eukaryotic cellular behaviours by integrating multimodal biological data, mechanistic reasoning and active experimentation using Saccharomyces cerevisiae as a genetically tractable and data-rich model system.
By Liujia Qian, Zizhuo Zhou, Peijie Zhou, Zhen Dong, Xudong Zhang, Zhangyang Gao, Siqi Sun, Kevin Roy, Shuaiyao Wang, Nicola Zamboni, Charles Boone, Michael Costanzo, Jianzhe Li, Gianni Liti, Jia-Xing Yue, Markus Ralser, Evan Williams, Mattia Zampieri, Heng Jiang, Tailin Wu, Yalin Wang, Feiran Li, Joseph Schacherer, Rui Sun, Zhaoxing Li, Yaming Deng, Yi Chen, Zhiping Xie, Huiqiang Lou, Xiaowen Wang, Linhai Xie, Liangyi Chen, Kai Lei, George Rosenberger, Xue Cai, Yingrui Wang, Qi Xiao, Huaizong Shen, Gaowen Liu, Lei Ma, Brenda Andrews, HUI LU, Kiryl D. Piatkevich, Yi Zhu, Lei Bai, Yizhi Cai, Yuping Chen, Ge Gao, Fuchu He, Luonan Chen, Stan Z Li, Hongwu Ma, Liang Qiao, Lars M. Steinmetz, Tang K. Tang, Xiaofan Zhang, JING YANG, Yifan Yang, Kaicheng Yu, Jianyang Zeng, Yefeng Zheng, Bowen Zhou, Tiannan Guo, Zhenwu Dai, Leihan Tang
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Nature
Verified
The adaptive molecular landscape of reprogrammed telomeric sequences
Abstract Telomeric sequences vary across the tree of life and intimately co-evolve with telomere-binding protein complexes. However, the molecular mechanisms allowing organisms to adapt to new telomeric sequences are difficult to gauge from extant species. Here, we engineer multiple yeast lines to human-like telomeric repeats to unveil their molecular and fitness response to reprogrammed telomeres.
Interspecies interactions drive bacterial proteome reorganization and emergent metabolism
Abstract Species in microbial communities need to stave off competition and capitalize on new resources that become available because of metabolic activities of others. However, intra-cellular molecular changes that underpin these responses are understudied, preventing mechanistic insights into community function and dynamics.
Comprehensive cross-sectional and longitudinal comparison of sixteen markers of biological aging from the Berlin Aging Study II
Abstract The disproportionate increase in lifespan compared to healthspan over the past decades results in a growing proportion of life marked by diseases, even if incidence rates are falling in some cases. However, not everyone ages at the same pace and some people remain in good health and preserve physical and cognitive function into old age. To quantify inter-individual differences in the biological aging process, numerous indicators of biological age have been developed.
Decreased cytoplasmic crowding via inhibition of ribosome biogenesis can trigger Candida albicans filamentous growth - Nature Microbiology
Abstract The human fungal pathogen Candida albicans undergoes a morphological transition from a budding yeast to a filamentous form, which is associated with pathogenesis. Various cues mediate this transition including intracellular reorganization. The cytoplasm is densely packed with proteins including large macromolecular complexes, such as ribosomes, and hence, molecular crowding can impact a range of cellular processes.
Multicenter evaluation of label-free quantification in human plasma on a high dynamic range benchmark set - Nature Communications
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Abstract Human plasma is routinely collected during clinical care and constitutes a rich source of biomarkers for diagnostics and patient stratification. Liquid chromatography-mass spectrometry (LC-MS)-based proteomics is a key method for plasma biomarker discovery, but the high dynamic range of plasma proteins poses significant challenges for MS analysis and data processing.
By Ute Distler, David Gomez-Zepeda, Christine von Toerne, Juliane Merl-Pham, Johanna Tüshaus, Pieter Giesbertz, Henry Unger, Dario L. Frey, Dominic Helm, Luisa Schwarzmüller, Susanne I. Wudy, Ludwig Sinn, Julia Mergner, Christina Ludwig, Axel Imhof, Bernhard Kuster, Stefan F. Lichtenthaler, Philipp Mertins, Fabian Coscia, Markus Ralser, Michael Mülleder, Stefanie Hauck
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Nature
Verified
A standardized framework for circulating blood proteomics - Nature Genetics
Abstract The circulating blood proteome holds immense potential for biomarker discovery and understanding disease mechanisms. Notable advances in mass spectrometry and affinity-based technologies have been made, but data integration across studies and platforms is hindered by the absence of unified analytical standards. This limitation impedes comprehensive exploration of human biology across diverse phenotypes and cohorts as well as the translation of findings into clinical applications.
Cell Differentiation, Oxidative Stress, and Oxygen Radicals-in Honor of Prof. Michael Breitenbach
Edited by ISBN978-3-7258-2616-2 (Hardback) ISBN978-3-7258-2615-5 (PDF) This is a Reprint of the Special Issue Cell Differentiation, Oxidative Stress, and Oxygen Radicals—in Honor of Prof.
The ability of pentose pathways to form all essential metabolites provides clues to the origins of metabolism
The remarkable conservation of metabolic networks across all living systems suggests that the fundamental structure of metabolism was established during the earliest stages of life on Earth, which emerged at least 4 billion years ago. In modern organisms, the metabolic network spans over hundreds of enzymes turning over thousands of different metabolites [1].
Uridylation regulates mRNA decay directionality in fission yeast - Nature Communications
Abstract Cytoplasmic mRNA decay is effected by exonucleolytic degradation in either the 5’ to 3’ or 3’ to 5’ direction. Pervasive terminal uridylation is implicated in mRNA degradation, however, its functional relevance for bulk mRNA turnover remains poorly understood. In this study, we employ genome-wide 3’-RACE (gw3’-RACE) in the model system fission yeast to elucidate the role of uridylation in mRNA turnover.
Human aneuploid cells depend on the RAF/MEK/ERK pathway for overcoming increased DNA damage - Nature Communications
Abstract Aneuploidy is a hallmark of human cancer, yet the molecular mechanisms to cope with aneuploidy-induced cellular stresses remain largely unknown. Here, we induce chromosome mis-segregation in non-transformed RPE1-hTERT cells and derive multiple stable clones with various degrees of aneuploidy. We perform a systematic genomic, transcriptomic and proteomic profiling of 6 isogenic clones, using whole-exome DNA, mRNA and miRNA sequencing, as well as proteomics.
Editorial on the Research Topic ‘Cell Differentiation, Oxidative Stress, and Oxygen Radicals-In Honor of Prof. Michael Breitenbach’
All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess.
Proteomic and transcriptomic profiling of brainstem, cerebellum and olfactory tissues in early- and late-phase COVID-19 - Nature Neuroscience
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Abstract Neurological symptoms, including cognitive impairment and fatigue, can occur in both the acute infection phase of coronavirus disease 2019 (COVID-19) and at later stages, yet the mechanisms that contribute to this remain unclear. Here we profiled single-nucleus transcriptomes and proteomes of brainstem tissue from deceased individuals at various stages of COVID-19. We detected an inflammatory type I interferon response in acute COVID-19 cases, which resolves in the late disease phase.
By Josefine Radke, Jenny Meinhardt, Tom Aschman, Sören Lukassen, Ekaterina Friebel, Naveed Ishaque, Jonas Franz, Carolina Thomas, Dirk Reinhold, Sefer Elezkurtaj, Florian Kurth, Marcel A. Müller, Nils C. Gassen, Julia Melchert, Camila Fernandez-Zapata, Chotima Böttcher, Elke Krüger, Markus Landthaler, Emanuel Wyler, Victor Max Corman, Christine Stadelmann, Markus Ralser, Frank L. Heppner, Michael Mülleder, Christian Conrad
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Nature
Verified
Monogenic Disorders of ROS Production and the Primary Anti-Oxidative Defense
All articles published by MDPI are made immediately available worldwide under an open access license. No special permission is required to reuse all or part of the article published by MDPI, including figures and tables. For articles published under an open access Creative Common CC BY license, any part of the article may be reused without permission provided that the original article is clearly cited. For more information, please refer to https://www.mdpi.com/openaccess.
Metabolic sensing tips the balance of drug tolerance in fungal meningitis - Nature Microbiology
Sensing of brain glucose by the fungal pathogen Cryptococcus neoformans alters lipid metabolism and membrane composition in the fungus, rendering it drug tolerant. Human fungal pathogens are underappreciated killers. Invasive infections with Cryptococcus are estimated to cause over 1 million life-threatening infections, largely meningitis, per year worldwide1.
Genetic and environmental determinants of multicellular-like phenotypes in fission yeast
Abstract Multicellular fungi have repeatedly given rise to primarily unicellular yeast species. Some of these, including Schizosaccharomyces pombe, are able to revert to multicellular-like phenotypes (MLP). Our bioinformatic analysis of existing data suggested that, besides some regulatory proteins, most proteins involved in MLP formation are not functionally conserved between S. pombe and budding yeast. We developed high-throughput assays for two types of MLP in S.
An enzyme activation network provides evidence for extensive regulatory crosstalk between metabolic pathways
Abstract Enzyme activation by cellular metabolites plays a pivotal role in regulating metabolic processes. Nevertheless, our comprehension of such activation events on a global network scale remains incomplete. In this study, we conducted a comprehensive investigation into the optimization of cell-intrinsic activation interactions within Saccharomyces cerevisiae. To achieve this, we integrated a genome-scale metabolic model with enzyme kinetic data sourced from the BRENDA database.
The cycle that sculpted evolution - Nature Reviews Chemistry
Transformer: The Deep Chemistry of Life and Death Nick Lane Profile Books (2023) 400pp, £25.00 This is a preview of subscription content, access via your institution Access options Access Nature and 54 other Nature Portfolio journals Get Nature+, our best-value online-access subscription $29.99 / 30 days cancel any time Subscribe to this journal Receive 12 digital issues and online access to articles $119.00 per year only $9.92 per issue Rent or buy this article Prices vary by article type...
The pentose phosphate pathway in health and disease - Nature Metabolism
Abstract The pentose phosphate pathway (PPP) is a glucose-oxidizing pathway that runs in parallel to upper glycolysis to produce ribose 5-phosphate and nicotinamide adenine dinucleotide phosphate (NADPH). Ribose 5-phosphate is used for nucleotide synthesis, while NADPH is involved in redox homoeostasis as well as in promoting biosynthetic processes, such as the synthesis of tetrahydrofolate, deoxyribonucleotides, proline, fatty acids and cholesterol.
MSBooster: improving peptide identification rates using deep learning-based features - Nature Communications
MSBooster workflow Workflows with and without MSBooster are depicted in Fig. 1. In DDA experiments, MS/MS spectra are searched using MSFragger. For peptide identification from DIA data, either full MS/MS spectra are searched using MSFragger-DIA, or DIA-Umpire extracted pseudo-MS/MS spectra are searched using MSFragger as conventional DDA files. MSFragger produces pepXML and pin files, and the latter is used as input into MSBooster.
Spontaneously established syntrophic yeast communities improve bioproduction - Nature Chemical Biology
Abstract Nutritional codependence (syntrophy) has underexplored potential to improve biotechnological processes by using cooperating cell types. So far, design of yeast syntrophic communities has required extensive genetic manipulation, as the co-inoculation of most eukaryotic microbial auxotrophs does not result in cooperative growth. Here we employ high-throughput phenotypic screening to systematically test pairwise combinations of auxotrophic Saccharomyces cerevisiae deletion mutants.
The GAPDH redox switch safeguards reductive capacity and enables survival of stressed tumour cells - Nature Metabolism
Abstract Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is known to contain an active-site cysteine residue undergoing oxidation in response to hydrogen peroxide, leading to rapid inactivation of the enzyme. Here we show that human and mouse cells expressing a GAPDH mutant lacking this redox switch retain catalytic activity but are unable to stimulate the oxidative pentose phosphate pathway and enhance their reductive capacity.
dia-PASEF data analysis using FragPipe and DIA-NN for deep proteomics of low sample amounts - Nature Communications
Abstract The dia-PASEF technology uses ion mobility separation to reduce signal interferences and increase sensitivity in proteomic experiments. Here we present a two-dimensional peak-picking algorithm and generation of optimized spectral libraries, as well as take advantage of neural network-based processing of dia-PASEF data.
The next decade of metabolism
Over the past decade, the field of metabolism has witnessed remarkable scientific discoveries that reshaped the understanding of metabolic physiology and disease. As we launch Nature Metabolism, we look at what the future holds for metabolic research.
DIA-NN: neural networks and interference correction enable deep proteome coverage in high throughput
Abstract We present an easy-to-use integrated software suite, DIA-NN, that exploits deep neural networks and new quantification and signal correction strategies for the processing of data-independent acquisition (DIA) proteomics experiments.
Freeing Yeast from Alcohol Addiction (Just) to Make (It) Fat Instead
Synthetically re-designing eukaryotic metabolism has proven immensely challenging, raising the question of whether evolution has metabolically hardwired eukaryotic cells. Yu et al. now report that, through orchestrating multiple genetic changes and laboratory evolution, Saccharomyces metabolism can be reprogrammed from its evolutionary objective of producing ethanol to produce large amounts of free fatty acids.
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