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The impact of the genetic background on gene deletion phenotypes in Saccharomyces cerevisiae
(2019)Molecular Systems BiologyLoss-of-function (LoF) mutations associated with disease do not manifest equally in different individuals. The impact of the genetic background on the consequences of LoF mutations remains poorly characterized. Here, we systematically assessed the changes in gene deletion phenotypes for 3,786 gene knockouts in four Saccharomyces cerevisiae strains and 38 conditions. We observed 18.5% of deletion phenotypes changing between pairs of strains ...Journal Article -
Differential genetic interactions of yeast stress response MAPK pathways
(2015)Molecular Systems BiologyGenetic interaction screens have been applied with great success in several organisms to study gene function and the genetic architecture of the cell. However, most studies have been performed under optimal growth conditions even though many functional interactions are known to occur under specific cellular conditions. In this study, we have performed a large-scale genetic interaction analysis in Saccharomyces cerevisiae involving ...Journal Article -
Evolution of protein kinase substrate recognition at the active site
(2019)PLoS BiologyProtein kinases catalyse the phosphorylation of target proteins, controlling most cellular processes. The specificity of serine/threonine kinases is partly determined by interactions with a few residues near the phospho-acceptor residue, forming the so-called kinase-substrate motif. Kinases have been extensively duplicated throughout evolution, but little is known about when in time new target motifs have arisen. Here, we show that sequence ...Journal Article -
A human B-cell interactome identifies MYB and FOXM1 as master regulators of proliferation in germinal centers
(2010)Molecular Systems BiologyAssembly of a transcriptional and post-translational molecular interaction network in B cells, the human B-cell interactome (HBCI), reveals a hierarchical, transcriptional control module, where MYB and FOXM1 act as synergistic master regulators of proliferation in the germinal center (GC). Eighty percent of genes jointly regulated by these transcription factors are activated in the GC, including those encoding proteins in a complex ...Journal Article -
SARS-CoV-2 infection remodels the host protein thermal stability landscape
(2021)Molecular Systems BiologyThe severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global threat to human health and has compromised economic stability. In addition to the development of an effective vaccine, it is imperative to understand how SARS-CoV-2 hijacks host cellular machineries on a system-wide scale so that potential host-directed therapies can be developed. In situ proteome-wide abundance and thermal stability measurements using thermal ...Journal Article -
Evolution of enhanced innate immune evasion by SARS-CoV-2
(2022)NatureThe emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission1,2. Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha ...Journal Article -
Exploring amino acid functions in a deep mutational landscape
(2021)Molecular Systems BiologyAmino acids fulfil a diverse range of roles in proteins, each utilising its chemical properties in different ways in different contexts to create required functions. For example, cysteines form disulphide or hydrogen bonds in different circumstances and charged amino acids do not always make use of their charge. The repertoire of amino acid functions and the frequency at which they occur in proteins remains understudied. Measuring large ...Journal Article -
Prediction of Signed Protein Kinase Regulatory Circuits
(2020)Cell SystemsComplex networks of regulatory relationships between protein kinases comprise a major component of intracellular signaling. Although many kinase-kinase regulatory relationships have been described in detail, these tend to be limited to well-studied kinases whereas the majority of possible relationships remains unexplored. Here, we implement a data-driven, supervised machine learning method to predict human kinase-kinase regulatory ...Journal Article -
High blood flow shear stress values are associated with circulating tumor cells cluster disaggregation in a multi-channel microfluidic device
(2021)PLoS ONEMetastasis represents a dynamic succession of events involving tumor cells which disseminate through the organism via the bloodstream. Circulating tumor cells (CTCs) can flow the bloodstream as single cells or as multicellular aggregates (clusters), which present a different potential to metastasize. The effects of the bloodstream-related physical constraints, such as hemodynamic wall shear stress (WSS), on CTC clusters are still unclear. ...Journal Article -
Noninvasive electron microscopy with interaction-free quantum measurements
(2009)Physical Review AWe propose the use of interaction-free quantum measurements with electrons to eliminate sample damage in electron microscopy. This might allow noninvasive molecular-resolution imaging. We show the possibility of such measurements in the presence of experimentally measured quantum decoherence rates and using a scheme based on existing charged particle trapping techniques.Journal Article