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  • Integrative proteomics reveals principles of dynamic phosphosignaling networks in human erythropoiesis
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-01
    Özge Karayel; Peng Xu; Isabell Bludau; Senthil Velan Bhoopalan; Yu Yao; Freitas Colaco Ana Rita; Alberto Santos; Brenda A Schulman; Arno F Alpi; Mitchell J Weiss; Matthias Mann

    Human erythropoiesis is an exquisitely controlled multistep developmental process, and its dysregulation leads to numerous human diseases. Transcriptome and epigenome studies provided insights into system‐wide regulation, but we currently lack a global mechanistic view on the dynamics of proteome and post‐translational regulation coordinating erythroid maturation. We established a mass spectrometry

    更新日期:2020-12-30
  • An incoherent feedforward loop interprets NFκB/RelA dynamics to determine TNF‐induced necroptosis decisions
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-14
    Marie Oliver Metzig; Ying Tang; Simon Mitchell; Brooks Taylor; Robert Foreman; Roy Wollman; Alexander Hoffmann

    Balancing cell death is essential to maintain healthy tissue homeostasis and prevent disease. Tumor necrosis factor (TNF) not only activates nuclear factor κB (NFκB), which coordinates the cellular response to inflammation, but may also trigger necroptosis, a pro‐inflammatory form of cell death. Whether TNF‐induced NFκB affects the fate decision to undergo TNF‐induced necroptosis is unclear. Live‐cell

    更新日期:2020-12-30
  • The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-08
    Noam Auslander; Daniel M Ramos; Ivette Zelaya; Hiren Karathia; Thomas O. Crawford; Alejandro A Schäffer; Charlotte J Sumner; Eytan Ruppin

    Modifier genes are believed to account for the clinical variability observed in many Mendelian disorders, but their identification remains challenging due to the limited availability of genomics data from large patient cohorts. Here, we present GENDULF (GENetic moDULators identiFication), one of the first methods to facilitate prediction of disease modifiers using healthy and diseased tissue gene expression

    更新日期:2020-12-30
  • Large‐scale survey and database of high affinity ligands for peptide recognition modules
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-08
    Joan Teyra; Abdellali Kelil; Shobhit Jain; Mohamed Helmy; Raghav Jajodia; Yogesh Hooda; Jun Gu; Akshay A D’Cruz; Sandra E Nicholson; Jinrong Min; Marius Sudol; Philip M Kim; Gary D Bader; Sachdev S Sidhu

    Many proteins involved in signal transduction contain peptide recognition modules (PRMs) that recognize short linear motifs (SLiMs) within their interaction partners. Here, we used large‐scale peptide‐phage display methods to derive optimal ligands for 163 unique PRMs representing 79 distinct structural families. We combined the new data with previous data that we collected for the large SH3, PDZ,

    更新日期:2020-12-30
  • Phosphoproteomics identifies microglial Siglec‐F inflammatory response during neurodegeneration
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-08
    Nader Morshed; William T Ralvenius; Alexi Nott; L Ashley Watson; Felicia H Rodriguez; Leyla A Akay; Brian A Joughin; Ping‐Chieh Pao; Jay Penney; Lauren LaRocque; Diego Mastroeni; Li‐Huei Tsai; Forest M White

    Alzheimer’s disease (AD) is characterized by the appearance of amyloid‐β plaques, neurofibrillary tangles, and inflammation in brain regions involved in memory. Using mass spectrometry, we have quantified the phosphoproteome of the CK‐p25, 5XFAD, and Tau P301S mouse models of neurodegeneration. We identified a shared response involving Siglec‐F which was upregulated on a subset of reactive microglia

    更新日期:2020-12-30
  • Protein quality control and regulated proteolysis in the genome‐reduced organism Mycoplasma pneumoniae
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-15
    Raul Burgos; Marc Weber; Sira Martinez; Maria Lluch‐Senar; Luis Serrano

    Protein degradation is a crucial cellular process in all‐living systems. Here, using Mycoplasma pneumoniae as a model organism, we defined the minimal protein degradation machinery required to maintain proteome homeostasis. Then, we conditionally depleted the two essential ATP‐dependent proteases. Whereas depletion of Lon results in increased protein aggregation and decreased heat tolerance, FtsH depletion

    更新日期:2020-12-30
  • Levels of autonomy in synthetic biology engineering
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-17
    Jacob Beal; Miles Rogers

    Engineering biological organisms is a complex, challenging, and often slow process. Other engineering domains have addressed such challenges with a combination of standardization and automation, enabling a divide‐and‐conquer approach to complexity and greatly increasing productivity. For example, standardization and automation allow rapid and predictable translation of prototypes into fielded applications

    更新日期:2020-12-30
  • Integrative characterization of the near‐minimal bacterium Mesoplasma florum
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-17
    Dominick Matteau; Jean‐Christophe Lachance; Frédéric Grenier; Samuel Gauthier; James M Daubenspeck; Kevin Dybvig; Daniel Garneau; Thomas F Knight; Pierre‐Étienne Jacques; Sébastien Rodrigue

    The near‐minimal bacterium Mesoplasma florum is an interesting model for synthetic genomics and systems biology due to its small genome (~ 800 kb), fast growth rate, and lack of pathogenic potential. However, fundamental aspects of its biology remain largely unexplored. Here, we report a broad yet remarkably detailed characterization of M. florum by combining a wide variety of experimental approaches

    更新日期:2020-12-30
  • A single cell atlas of the human liver tumor microenvironment
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-17
    Hassan Massalha; Keren Bahar Halpern; Samir Abu‐Gazala; Tamar Jana; Efi E Massasa; Andreas E Moor; Lisa Buchauer; Milena Rozenberg; Eli Pikarsky; Ido Amit; Gideon Zamir; Shalev Itzkovitz

    Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA‐sequencing and spatial analysis of malignant and adjacent non‐malignant

    更新日期:2020-12-30
  • Using single‐plant‐omics in the field to link maize genes to functions and phenotypes
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-21
    Daniel Felipe Cruz; Sam De Meyer; Joke Ampe; Heike Sprenger; Dorota Herman; Tom Van Hautegem; Jolien De Block; Dirk Inzé; Hilde Nelissen; Steven Maere

    Most of our current knowledge on plant molecular biology is based on experiments in controlled laboratory environments. However, translating this knowledge from the laboratory to the field is often not straightforward, in part because field growth conditions are very different from laboratory conditions. Here, we test a new experimental design to unravel the molecular wiring of plants and study gene–phenotype

    更新日期:2020-12-30
  • A quantitative analysis of the interplay of environment, neighborhood, and cell state in 3D spheroids
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-12-26
    Vito RT Zanotelli; Matthias Leutenegger; Xiao‐Kang Lun; Fanny Georgi; Natalie de Souza; Bernd Bodenmiller

    Cells react to their microenvironment by integrating external stimuli into phenotypic decisions via an intracellular signaling network. To analyze the interplay of environment, local neighborhood, and internal cell state effects on phenotypic variability, we developed an experimental approach that enables multiplexed mass cytometric imaging analysis of up to 240 pooled spheroid microtissues. We quantified

    更新日期:2020-12-30
  • The transcriptome dynamics of single cells during the cell cycle
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-11-18
    Daniel Schwabe; Sara Formichetti; Jan Philipp Junker; Martin Falcke; Nikolaus Rajewsky

    The cell cycle is among the most basic phenomena in biology. Despite advances in single‐cell analysis, dynamics and topology of the cell cycle in high‐dimensional gene expression space remain largely unknown. We developed a linear analysis of transcriptome data which reveals that cells move along a planar circular trajectory in transcriptome space during the cycle. Non‐cycling gene expression adds

    更新日期:2020-12-01
  • Dormancy‐to‐death transition in yeast spores occurs due to gradual loss of gene‐expressing ability
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-11-18
    Théo Maire; Tim Allertz; Max A Betjes; Hyun Youk

    Dormancy is colloquially considered as extending lifespan by being still. Starved yeasts form dormant spores that wake‐up (germinate) when nutrients reappear but cannot germinate (die) after some time. What sets their lifespans and how they age are open questions because what processes occur—and by how much—within each dormant spore remains unclear. With single‐cell‐level measurements, we discovered

    更新日期:2020-12-01
  • Gene expression profiling reveals insights into infant immunological and febrile responses to group B meningococcal vaccine
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-11-19
    Daniel O’Connor; Marta Valente Pinto; Dylan Sheerin; Adriana Tomic; Ruth E Drury; Samuel Channon‐Wells; Ushma Galal; Christina Dold; Hannah Robinson; Simon Kerridge; Emma Plested; Harri Hughes; Lisa Stockdale; Manish Sadarangani; Matthew D Snape; Christine S Rollier; Michael Levin; Andrew J Pollard

    Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post‐vaccination reactogenicity and immunogenicity. Infants were

    更新日期:2020-12-01
  • CIGAR‐seq, a CRISPR/Cas‐based method for unbiased screening of novel mRNA modification regulators
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-11-30
    Liang Fang; Wen Wang; Guipeng Li; Li Zhang; Jun Li; Diwen Gan; Jiao Yang; Yisen Tang; Zewen Ding; Min Zhang; Wenhao Zhang; Daqi Deng; Zhengyu Song; Qionghua Zhu; Huanhuan Cui; Yuhui Hu; Wei Chen

    Cellular RNA is decorated with over 170 types of chemical modifications. Many modifications in mRNA, including m6A and m5C, have been associated with critical cellular functions under physiological and/or pathological conditions. To understand the biological functions of these modifications, it is vital to identify the regulators that modulate the modification rate. However, a high‐throughput method

    更新日期:2020-12-01
  • DeepCycle reconstructs a cyclic cell cycle trajectory from unsegmented cell images using convolutional neural networks
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-06
    Luca Rappez; Alexander Rakhlin; Angelos Rigopoulos; Sergey Nikolenko; Theodore Alexandrov

    The advent of single‐cell methods is paving the way for an in‐depth understanding of the cell cycle with unprecedented detail. Due to its ramifications in nearly all biological processes, the evaluation of cell cycle progression is critical for an exhaustive cellular characterization. Here, we present DeepCycle, a deep learning method for estimating a cell cycle trajectory from unsegmented single‐cell

    更新日期:2020-10-30
  • Modeling tissue‐relevant Caenorhabditis elegans metabolism at network, pathway, reaction, and metabolite levels
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-06
    Lutfu Safak Yilmaz; Xuhang Li; Shivani Nanda; Bennett Fox; Frank Schroeder; Albertha JM Walhout

    Metabolism is a highly compartmentalized process that provides building blocks for biomass generation during development, homeostasis, and wound healing, and energy to support cellular and organismal processes. In metazoans, different cells and tissues specialize in different aspects of metabolism. However, studying the compartmentalization of metabolism in different cell types in a whole animal and

    更新日期:2020-10-30
  • Aggregation and disaggregation features of the human proteome
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-06
    Tomi A Määttä; Mandy Rettel; Sindhuja Sridharan; Dominic Helm; Nils Kurzawa; Frank Stein; Mikhail M Savitski

    Protein aggregates have negative implications in disease. While reductionist experiments have increased our understanding of aggregation processes, the systemic view in biological context is still limited. To extend this understanding, we used mass spectrometry‐based proteomics to characterize aggregation and disaggregation in human cells after non‐lethal heat shock. Aggregation‐prone proteins were

    更新日期:2020-10-30
  • CEN‐tools: an integrative platform to identify the contexts of essential genes
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-19
    Sumana Sharma; Cansu Dincer; Paula Weidemüller; Gavin J Wright; Evangelia Petsalaki

    An emerging theme from large‐scale genetic screens that identify genes essential for cell fitness is that essentiality of a given gene is highly context‐specific. Identification of such contexts could be the key to defining gene function and also to develop novel therapeutic interventions. Here, we present Context‐specific Essentiality Network‐tools (CEN‐tools), a website and python package, in which

    更新日期:2020-10-30
  • Genome‐wide off‐rates reveal how DNA binding dynamics shape transcription factor function
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-14
    Wim J de Jonge; Mariël Brok; Philip Lijnzaad; Patrick Kemmeren; Frank CP Holstege

    Protein–DNA interactions are dynamic, and these dynamics are an important aspect of chromatin‐associated processes such as transcription or replication. Due to a lack of methods to study on‐ and off‐rates across entire genomes, protein–DNA interaction dynamics have not been studied extensively. Here, we determine in vivo off‐rates for the Saccharomyces cerevisiae chromatin organizing factor Abf1, at

    更新日期:2020-10-30
  • Oncogenic mutant RAS signaling activity is rescaled by the ERK/MAPK pathway
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-10-19
    Taryn E Gillies; Michael Pargett; Jillian M Silva; Carolyn K Teragawa; Frank McCormick; John G Albeck

    Activating mutations in RAS are present in ~ 30% of human tumors, and the resulting aberrations in ERK/MAPK signaling play a central role in oncogenesis. However, the form of these signaling changes is uncertain, with activating RAS mutants linked to both increased and decreased ERK activation in vivo. Rationally targeting the kinase activity of this pathway requires clarification of the quantitative

    更新日期:2020-10-30
  • Systematic analysis of bypass suppression of essential genes.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-09-17
    Jolanda van Leeuwen,Carles Pons,Guihong Tan,Jason Zi Wang,Jing Hou,Jochen Weile,Marinella Gebbia,Wendy Liang,Ermira Shuteriqi,Zhijian Li,Maykel Lopes,Matej Ušaj,Andreia Dos Santos Lopes,Natascha van Lieshout,Chad L Myers,Frederick P Roth,Patrick Aloy,Brenda J Andrews,Charles Boone

    Essential genes tend to be highly conserved across eukaryotes, but, in some cases, their critical roles can be bypassed through genetic rewiring. From a systematic analysis of 728 different essential yeast genes, we discovered that 124 (17%) were dispensable essential genes. Through whole‐genome sequencing and detailed genetic analysis, we investigated the genetic interactions and genome alterations

    更新日期:2020-09-30
  • Proteomic patterns associated with response to breast cancer neoadjuvant treatment.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-09-22
    Anjana Shenoy,Nishanth Belugali Nataraj,Gili Perry,Fabricio Loayza Puch,Remco Nagel,Irina Marin,Nora Balint,Noa Bossel,Anya Pavlovsky,Iris Barshack,Bella Kaufman,Reuven Agami,Yosef Yarden,Maya Dadiani,Tamar Geiger

    Tumor relapse as a consequence of chemotherapy resistance is a major clinical challenge in advanced stage breast tumors. To identify processes associated with poor clinical outcome, we took a mass spectrometry‐based proteomic approach and analyzed a breast cancer cohort of 113 formalin‐fixed paraffin‐embedded samples. Proteomic profiling of matched tumors before and after chemotherapy, and tumor‐adjacent

    更新日期:2020-09-30
  • Integrated regulatory models for inference of subtype‐specific susceptibilities in glioblastoma
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-09-25
    Yunpeng Liu; Ning Shi; Aviv Regev; Shan He; Michael T Hemann

    Glioblastoma multiforme (GBM) is a highly malignant form of cancer that lacks effective treatment options or well‐defined strategies for personalized cancer therapy. The disease has been stratified into distinct molecular subtypes; however, the underlying regulatory circuitry that gives rise to such heterogeneity and its implications for therapy remain unclear. We developed a modular computational

    更新日期:2020-09-30
  • Enhancing scientific discoveries in molecular biology with deep generative models
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-09-25
    Romain Lopez; Adam Gayoso; Nir Yosef

    Generative models provide a well‐established statistical framework for evaluating uncertainty and deriving conclusions from large data sets especially in the presence of noise, sparsity, and bias. Initially developed for computer vision and natural language processing, these models have been shown to effectively summarize the complexity that underlies many types of data and enable a range of applications

    更新日期:2020-09-30
  • Implications of initial physiological conditions for bacterial adaptation to changing environments.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-09-01
    Matthias Heinemann,Markus Basan,Uwe Sauer

    This piece discusses how the different observations of two independent studies (Kotte et al, 2014; Basan et al, 2020), regarding population-level heterogeneity and lag times during diauxic shift, can be largely explained by different experimental protocols.

    更新日期:2020-09-01
  • Mapping the nucleolar proteome reveals a spatiotemporal organization related to intrinsic protein disorder.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-03
    Lovisa Stenström,Diana Mahdessian,Christian Gnann,Anthony J Cesnik,Wei Ouyang,Manuel D Leonetti,Mathias Uhlén,Sara Cuylen-Haering,Peter J Thul,Emma Lundberg

    The nucleolus is essential for ribosome biogenesis and is involved in many other cellular functions. We performed a systematic spatiotemporal dissection of the human nucleolar proteome using confocal microscopy. In total, 1,318 nucleolar proteins were identified; 287 were localized to fibrillar components, and 157 were enriched along the nucleoplasmic border, indicating a potential fourth nucleolar

    更新日期:2020-08-29
  • Predictive features of gene expression variation reveal mechanistic link with differential expression.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-07
    Olga M Sigalova,Amirreza Shaeiri,Mattia Forneris,Eileen Em Furlong,Judith B Zaugg

    For most biological processes, organisms must respond to extrinsic cues, while maintaining essential gene expression programmes. Although studied extensively in single cells, it is still unclear how variation is controlled in multicellular organisms. Here, we used a machine‐learning approach to identify genomic features that are predictive of genes with high versus low variation in their expression

    更新日期:2020-08-29
  • Predicting antigen specificity of single T cells based on TCR CDR3 regions.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-11
    David S Fischer,Yihan Wu,Benjamin Schubert,Fabian J Theis

    It has recently become possible to simultaneously assay T‐cell specificity with respect to large sets of antigens and the T‐cell receptor sequence in high‐throughput single‐cell experiments. Leveraging this new type of data, we propose and benchmark a collection of deep learning architectures to model T‐cell specificity in single cells. In agreement with previous results, we found that models that

    更新日期:2020-08-29
  • Precision design of stable genetic circuits carried in highly-insulated E. coli genomic landing pads.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-19
    Yongjin Park,Amin Espah Borujeni,Thomas E Gorochowski,Jonghyeon Shin,Christopher A Voigt

    Genetic circuits have many applications, from guiding living therapeutics to ordering process in a bioreactor, but to be useful they have to be genetically stable and not hinder the host. Encoding circuits in the genome reduces burden, but this decreases performance and can interfere with native transcription. We have designed genomic landing pads in Escherichia coli at high‐expression sites, flanked

    更新日期:2020-08-29
  • Exploring the virulence gene interactome with CRISPR/dCas9 in the human malaria parasite.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-20
    Jessica M Bryant,Sebastian Baumgarten,Florent Dingli,Damarys Loew,Ameya Sinha,Aurélie Claës,Peter R Preiser,Peter C Dedon,Artur Scherf

    Mutually exclusive expression of the var multigene family is key to immune evasion and pathogenesis in Plasmodium falciparum, but few factors have been shown to play a direct role. We adapted a CRISPR‐based proteomics approach to identify novel factors associated with var genes in their natural chromatin context. Catalytically inactive Cas9 (“dCas9”) was targeted to var gene regulatory elements, immunoprecipitated

    更新日期:2020-08-29
  • SBML Level 3: an extensible format for the exchange and reuse of biological models.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-26
    Sarah M Keating,Dagmar Waltemath,Matthias König,Fengkai Zhang,Andreas Dräger,Claudine Chaouiya,Frank T Bergmann,Andrew Finney,Colin S Gillespie,Tomáš Helikar,Stefan Hoops,Rahuman S Malik-Sheriff,Stuart L Moodie,Ion I Moraru,Chris J Myers,Aurélien Naldi,Brett G Olivier,Sven Sahle,James C Schaff,Lucian P Smith,Maciej J Swat,Denis Thieffry,Leandro Watanabe,Darren J Wilkinson,Michael L Blinov,Kimberly

    Systems biology has experienced dramatic growth in the number, size, and complexity of computational models. To reproduce simulation results and reuse models, researchers must exchange unambiguous model descriptions. We review the latest edition of the Systems Biology Markup Language (SBML), a format designed for this purpose. A community of modelers and software authors developed SBML Level 3 over

    更新日期:2020-08-29
  • Community standards to facilitate development and address challenges in metabolic modeling.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-08-26
    Maureen A Carey,Andreas Dräger,Moritz E Beber,Jason A Papin,James T Yurkovich

    Standardization of data and models facilitates effective communication, especially in computational systems biology. However, both the development and consistent use of standards and resources remain challenging. As a result, the amount, quality, and format of the information contained within systems biology models are not consistent and therefore present challenges for widespread use and communication

    更新日期:2020-08-29
  • LymphoAtlas: a dynamic and integrated phosphoproteomic resource of TCR signaling in primary T cells reveals ITSN2 as a regulator of effector functions.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-03
    Marie Locard-Paulet,Guillaume Voisinne,Carine Froment,Marisa Goncalves Menoita,Youcef Ounoughene,Laura Girard,Claude Gregoire,Daiki Mori,Manuel Martinez,Hervé Luche,Jerôme Garin,Marie Malissen,Odile Burlet-Schiltz,Bernard Malissen,Anne Gonzalez de Peredo,Romain Roncagalli

    T‐cell receptor (TCR ) ligation‐mediated protein phosphorylation regulates the activation, cellular responses, and fates of T cells. Here, we used time‐resolved high‐resolution phosphoproteomics to identify, quantify, and characterize the phosphorylation dynamics of thousands of phosphorylation sites in primary T cells during the first 10 min after TCR stimulation. Bioinformatic analysis of the data

    更新日期:2020-08-01
  • Drug mechanism-of-action discovery through the integration of pharmacological and CRISPR screens.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-06
    Emanuel Gonçalves,Aldo Segura-Cabrera,Clare Pacini,Gabriele Picco,Fiona M Behan,Patricia Jaaks,Elizabeth A Coker,Donny van der Meer,Andrew Barthorpe,Howard Lightfoot,Tatiana Mironenko,Alexandra Beck,Laura Richardson,Wanjuan Yang,Ermira Lleshi,James Hall,Charlotte Tolley,Caitlin Hall,Iman Mali,Frances Thomas,James Morris,Andrew R Leach,James T Lynch,Ben Sidders,Claire Crafter,Francesco Iorio,Stephen

    Low success rates during drug development are due, in part, to the difficulty of defining drug mechanism‐of‐action and molecular markers of therapeutic activity. Here, we integrated 199,219 drug sensitivity measurements for 397 unique anti‐cancer drugs with genome‐wide CRISPR loss‐of‐function screens in 484 cell lines to systematically investigate cellular drug mechanism‐of‐action. We observed an enrichment

    更新日期:2020-08-01
  • Using deep mutational scanning to benchmark variant effect predictors and identify disease mutations.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-06
    Benjamin J Livesey,Joseph A Marsh

    To deal with the huge number of novel protein‐coding variants identified by genome and exome sequencing studies, many computational variant effect predictors (VEPs) have been developed. Such predictors are often trained and evaluated using different variant data sets, making a direct comparison between VEPs difficult. In this study, we use 31 previously published deep mutational scanning (DMS) experiments

    更新日期:2020-08-01
  • Dual lysine and N-terminal acetyltransferases reveal the complexity underpinning protein acetylation.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-07
    Willy V Bienvenut,Annika Brünje,Jean-Baptiste Boyer,Jens S Mühlenbeck,Gautier Bernal,Ines Lassowskat,Cyril Dian,Eric Linster,Trinh V Dinh,Minna M Koskela,Vincent Jung,Julian Seidel,Laura K Schyrba,Aiste Ivanauskaite,Jürgen Eirich,Rüdiger Hell,Dirk Schwarzer,Paula Mulo,Markus Wirtz,Thierry Meinnel,Carmela Giglione,Iris Finkemeier

    Protein acetylation is a highly frequent protein modification. However, comparatively little is known about its enzymatic machinery. N‐α‐acetylation (NTA ) and ε‐lysine acetylation (KA ) are known to be catalyzed by distinct families of enzymes (NAT s and KAT s, respectively), although the possibility that the same GCN 5‐related N‐acetyltransferase (GNAT ) can perform both functions has been debated

    更新日期:2020-08-01
  • Programmable CRISPR-Cas transcriptional activation in bacteria.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-13
    Hsing-I Ho,Jennifer R Fang,Jacky Cheung,Harris H Wang

    Programmable gene activation enables fine‐tuned regulation of endogenous and synthetic gene circuits to control cellular behavior. While CRISPR‐Cas‐mediated gene activation has been extensively developed for eukaryotic systems, similar strategies have been difficult to implement in bacteria. Here, we present a generalizable platform for screening and selection of functional bacterial CRISPR‐Cas transcription

    更新日期:2020-08-01
  • A new model for the HPA axis explains dysregulation of stress hormones on the timescale of weeks.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-16
    Omer Karin,Moriya Raz,Avichai Tendler,Alon Bar,Yael Korem Kohanim,Tomer Milo,Uri Alon

    Stress activates a complex network of hormones known as the hypothalamic–pituitary–adrenal (HPA) axis. The HPA axis is dysregulated in chronic stress and psychiatric disorders, but the origin of this dysregulation is unclear and cannot be explained by current HPA models. To address this, we developed a mathematical model for the HPA axis that incorporates changes in the total functional mass of the

    更新日期:2020-08-01
  • Multiplexing cell-cell communication.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-16
    John T Sexton,Jeffrey J Tabor

    The engineering of advanced multicellular behaviors, such as the programmed growth of biofilms or tissues, requires cells to communicate multiple aspects of physiological information. Unfortunately, few cell‐cell communication systems have been developed for synthetic biology. Here, we engineer a genetically encoded channel selector device that enables a single communication system to transmit two

    更新日期:2020-08-01
  • Developmental function and state transitions of a gene expression oscillator in Caenorhabditis elegans.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-20
    Milou Wm Meeuse,Yannick P Hauser,Lucas J Morales Moya,Gert-Jan Hendriks,Jan Eglinger,Guy Bogaarts,Charisios Tsiairis,Helge Großhans

    Gene expression oscillators can structure biological events temporally and spatially. Different biological functions benefit from distinct oscillator properties. Thus, finite developmental processes rely on oscillators that start and stop at specific times, a poorly understood behavior. Here, we have characterized a massive gene expression oscillator comprising > 3,700 genes in Caenorhabditis elegans

    更新日期:2020-08-01
  • Building biosecurity for synthetic biology.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-21
    Benjamin D Trump,S E Galaitsi,Evan Appleton,Diederik A Bleijs,Marie-Valentine Florin,Jimmy D Gollihar,R Alexander Hamilton,Todd Kuiken,Filippa Lentzos,Ruth Mampuys,Myriam Merad,Tatyana Novossiolova,Kenneth Oye,Edward Perkins,Natàlia Garcia-Reyero,Catherine Rhodes,Igor Linkov

    The fast‐paced field of synthetic biology is fundamentally changing the global biosecurity framework. Current biosecurity regulations and strategies are based on previous governance paradigms for pathogen‐oriented security, recombinant DNA research, and broader concerns related to genetically modified organisms (GMO s). Many scholarly discussions and biosecurity practitioners are therefore concerned

    更新日期:2020-08-01
  • Disentangling molecular mechanisms regulating sensitization of interferon alpha signal transduction.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-21
    Frédérique Kok,Marcus Rosenblatt,Melissa Teusel,Tamar Nizharadze,Vladimir Gonçalves Magalhães,Christopher Dächert,Tim Maiwald,Artyom Vlasov,Marvin Wäsch,Silvana Tyufekchieva,Katrin Hoffmann,Georg Damm,Daniel Seehofer,Tobias Boettler,Marco Binder,Jens Timmer,Marcel Schilling,Ursula Klingmüller

    Tightly interlinked feedback regulators control the dynamics of intracellular responses elicited by the activation of signal transduction pathways. Interferon alpha (IFNα) orchestrates antiviral responses in hepatocytes, yet mechanisms that define pathway sensitization in response to prestimulation with different IFNα doses remained unresolved. We establish, based on quantitative measurements obtained

    更新日期:2020-08-01
  • The Cancer Dependency Map enables drug mechanism-of-action investigations.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-21
    Francisca Vazquez,Jesse S Boehm

    How do small molecules exert their effects in mammalian cells? This seemingly simple question continues to represent one of the fundamental challenges of modern translational science and as such has long been the subject of intense scientific scrutiny. In their recent study, Garnett and colleagues (Gonçalves et al , 2020) demonstrate proof‐of‐concept for a new way to attack this problem systematically

    更新日期:2020-08-01
  • A substrate-based ontology for human solute carriers.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-22
    Eva Meixner,Ulrich Goldmann,Vitaly Sedlyarov,Stefania Scorzoni,Manuele Rebsamen,Enrico Girardi,Giulio Superti-Furga

    Solute carriers (SLCs) are the largest family of transmembrane transporters in the human genome with more than 400 members. Despite the fact that SLCs mediate critical biological functions and several are important pharmacological targets, a large proportion of them is poorly characterized and present no assigned substrate. A major limitation to systems‐level de‐orphanization campaigns is the absence

    更新日期:2020-08-01
  • The protein expression profile of ACE2 in human tissues.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-26
    Feria Hikmet,Loren Méar,Åsa Edvinsson,Patrick Micke,Mathias Uhlén,Cecilia Lindskog

    The novel SARS‐coronavirus 2 (SARS‐CoV‐2) poses a global challenge on healthcare and society. For understanding the susceptibility for SARS‐CoV‐2 infection, the cell type‐specific expression of the host cell surface receptor is necessary. The key protein suggested to be involved in host cell entry is angiotensin I converting enzyme 2 (ACE2). Here, we report the expression pattern of ACE2 across > 150

    更新日期:2020-08-01
  • Can ACE2 expression explain SARS-CoV-2 infection of the respiratory epithelia in COVID-19?
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-26
    Martijn C Nawijn,Wim Timens

    Infection with severe acute respiratory syndrome coronavirus‐2 (SARS ‐CoV‐2) leads to coronavirus disease 2019 (COVID ‐19), which poses an unprecedented worldwide health crisis, and has been declared a pandemic by the World Health Organization (WHO ) on March 11, 2020. The angiotensin converting enzyme 2 (ACE 2) has been suggested to be the key protein used by SARS ‐CoV‐2 for host cell entry. In their

    更新日期:2020-08-01
  • In vitro and in vivo identification of clinically approved drugs that modify ACE2 expression.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-07-29
    Sanju Sinha,Kuoyuan Cheng,Alejandro A Schäffer,Kenneth Aldape,Eyal Schiff,Eytan Ruppin

    The COVID ‐19 pandemic caused by SARS ‐CoV‐2 has is a global health challenge. Angiotensin‐converting enzyme 2 (ACE 2 ) is the host receptor for SARS ‐CoV‐2 entry. Recent studies have suggested that patients with hypertension and diabetes treated with ACE inhibitors (ACEI s) or angiotensin receptor blockers have a higher risk of COVID ‐19 infection as these drugs could upregulate ACE 2 , motivating

    更新日期:2020-08-01
  • How to catch the N - An inter-species exchange with the right chemistry.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-03
    Tonni Grube Andersen

    While classical breeding traits have focussed on above‐ground tissues, it is becoming clear that underground aspects of plant life are a hidden treasure of tools applicable for resilient crop production. Plants of the legume family develop specialized organs, called nodules, which serve as hosts for Rhizobium bacteroids. A highly specialized symbiotic relationship exists deep inside the nodules. In

    更新日期:2020-06-30
  • Co-catabolism of arginine and succinate drives symbiotic nitrogen fixation.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-03
    Carlos Eduardo Flores-Tinoco,Flavia Tschan,Tobias Fuhrer,Céline Margot,Uwe Sauer,Matthias Christen,Beat Christen

    Biological nitrogen fixation emerging from the symbiosis between bacteria and crop plants holds promise to increase the sustainability of agriculture. One of the biggest hurdles for the engineering of nitrogen‐fixing organisms is an incomplete knowledge of metabolic interactions between microbe and plant. In contrast to the previously assumed supply of only succinate, we describe here the CATCH ‐N

    更新日期:2020-06-30
  • Proteome profiling in cerebrospinal fluid reveals novel biomarkers of Alzheimer's disease.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-02
    Jakob M Bader,Philipp E Geyer,Johannes B Müller,Maximilian T Strauss,Manja Koch,Frank Leypoldt,Peter Koertvelyessy,Daniel Bittner,Carola G Schipke,Enise I Incesoy,Oliver Peters,Nikolaus Deigendesch,Mikael Simons,Majken K Jensen,Henrik Zetterberg,Matthias Mann

    Neurodegenerative diseases are a growing burden, and there is an urgent need for better biomarkers for diagnosis, prognosis, and treatment efficacy. Structural and functional brain alterations are reflected in the protein composition of cerebrospinal fluid (CSF ). Alzheimer's disease (AD ) patients have higher CSF levels of tau, but we lack knowledge of systems‐wide changes of CSF protein levels that

    更新日期:2020-06-30
  • CRISPR-TAPE: protein-centric CRISPR guide design for targeted proteome engineering.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-02
    Daniel Paolo Anderson,Henry James Benns,Edward William Tate,Matthew Andrew Child

    Rational molecular engineering of proteins with CRISPR ‐based approaches is challenged by the gene‐centric nature of gRNA design tools. To address this, we have developed CRISPR ‐TAPE , a protein‐centric gRNA design algorithm that allows users to target specific residues, or amino acid types within proteins. gRNA outputs can be customized to support maximal efficacy of homology‐directed repair for

    更新日期:2020-06-30
  • Bayesian modeling reveals metabolite-dependent ultrasensitivity in the cyanobacterial circadian clock.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-04
    Lu Hong,Danylo O Lavrentovich,Archana Chavan,Eugene Leypunskiy,Eileen Li,Charles Matthews,Andy LiWang,Michael J Rust,Aaron R Dinner

    Mathematical models can enable a predictive understanding of mechanism in cell biology by quantitatively describing complex networks of interactions, but such models are often poorly constrained by available data. Owing to its relative biochemical simplicity, the core circadian oscillator in Synechococcus elongatus has become a prototypical system for studying how collective dynamics emerge from molecular

    更新日期:2020-06-30
  • High-throughput, microscope-based sorting to dissect cellular heterogeneity.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-05
    Nicholas Hasle,Anthony Cooke,Sanjay Srivatsan,Heather Huang,Jason J Stephany,Zachary Krieger,Dana Jackson,Weiliang Tang,Sriram Pendyala,Raymond J Monnat,Cole Trapnell,Emily M Hatch,Douglas M Fowler

    Microscopy is a powerful tool for characterizing complex cellular phenotypes, but linking these phenotypes to genotype or RNA expression at scale remains challenging. Here, we present Visual Cell Sorting, a method that physically separates hundreds of thousands of live cells based on their visual phenotype. Automated imaging and phenotypic analysis directs selective illumination of Dendra2, a photoconvertible

    更新日期:2020-06-30
  • Slower growth of Escherichia coli leads to longer survival in carbon starvation due to a decrease in the maintenance rate.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-05
    Elena Biselli,Severin Josef Schink,Ulrich Gerland

    Fitness of bacteria is determined both by how fast cells grow when nutrients are abundant and by how well they survive when conditions worsen. Here, we study how prior growth conditions affect the death rate of Escherichia coli during carbon starvation. We control the growth rate prior to starvation either via the carbon source or via a carbon‐limited chemostat. We find a consistent dependence where

    更新日期:2020-06-30
  • Controlling spatiotemporal pattern formation in a concentration gradient with a synthetic toggle switch.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-12
    Içvara Barbier,Rubén Perez-Carrasco,Yolanda Schaerli

    The formation of spatiotemporal patterns of gene expression is frequently guided by gradients of diffusible signaling molecules. The toggle switch subnetwork, composed of two cross‐repressing transcription factors, is a common component of gene regulatory networks in charge of patterning, converting the continuous information provided by the gradient into discrete abutting stripes of gene expression

    更新日期:2020-06-30
  • (Photo)convert to pooled visual screening.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-16
    Elena Ivanova,Anton Khmelinskii

    Pooled genetic screening is a powerful method to systematically link genotype to phenotype and gain insights into biological processes, but applying it to visual phenotypes such as cell morphology or protein localization has remained a challenge. In their recent work, Fowler and colleagues (Hasle et al , 2020) describe an elegant approach for high‐throughput cell sorting according to visual phenotypes

    更新日期:2020-06-30
  • Reduced proteasome activity in the aging brain results in ribosome stoichiometry loss and aggregation.
    Mol. Syst. Biol. (IF 8.991) Pub Date : 2020-06-18
    Erika Kelmer Sacramento,Joanna M Kirkpatrick,Mariateresa Mazzetto,Mario Baumgart,Aleksandar Bartolome,Simone Di Sanzo,Cinzia Caterino,Michele Sanguanini,Nikoletta Papaevgeniou,Maria Lefaki,Dorothee Childs,Sara Bagnoli,Eva Terzibasi Tozzini,Domenico Di Fraia,Natalie Romanov,Peter H Sudmant,Wolfgang Huber,Niki Chondrogianni,Michele Vendruscolo,Alessandro Cellerino,Alessandro Ori

    A progressive loss of protein homeostasis is characteristic of aging and a driver of neurodegeneration. To investigate this process quantitatively, we characterized proteome dynamics during brain aging in the short‐lived vertebrate Nothobranchius furzeri combining transcriptomics and proteomics. We detected a progressive reduction in the correlation between protein and mRNA , mainly due to post‐transcriptional

    更新日期:2020-06-30