Disentangling bacterial invasiveness from lethality in an experimental host-pathogen system
Quantifying virulence remains a central problem in human health, pest control, disease ecology, and evolutionary biology. Bacterial virulence is typically quantified by the LT50 (i.e., the time taken to kill 50% of infected hosts); however, such an indicator cannot account for the full complexity of the infection process, such as distinguishing between the pathogen's ability to colonize versus kill the hosts. Indeed, the pathogen needs to breach the primary defenses in order to colonize, find a suitable environment to replicate, and finally express the virulence factors that cause disease. Here, we show that two virulence ...
Source: Molecular Systems Biology - June 10, 2019 Category: Molecular Biology Authors: Biancalani, T., Gore, J. Tags: Microbiology, Virology & Host Pathogen Interaction, Quantitative Biology & Dynamical Systems Articles Source Type: research
INKA, an integrative data analysis pipeline for phosphoproteomic inference of active kinases
(Source: Molecular Systems Biology)
Source: Molecular Systems Biology - May 23, 2019 Category: Molecular Biology Authors: Beekhof, R., van Alphen, C., Henneman, A. A., Knol, J. C., Pham, T. V., Rolfs, F., Labots, M., Henneberry, E., Le Large, T. Y., de Haas, R. R., Piersma, S. R., Vurchio, V., Bertotti, A., Trusolino, L., Verheul, H. M., Jimenez, C. R. Tags: Corrigendum Source Type: research
Linking aberrant chromatin features in chronic lymphocytic leukemia to transcription factor networks
In chronic lymphocytic leukemia (CLL), a diverse set of genetic mutations is embedded in a deregulated epigenetic landscape that drives cancerogenesis. To elucidate the role of aberrant chromatin features, we mapped DNA methylation, seven histone modifications, nucleosome positions, chromatin accessibility, binding of EBF1 and CTCF, as well as the transcriptome of B cells from CLL patients and healthy donors. A globally increased histone deacetylase activity was detected and half of the genome comprised transcriptionally downregulated partially DNA methylated domains demarcated by CTCF. CLL samples displayed a H3K4me3 redi...
Source: Molecular Systems Biology - May 21, 2019 Category: Molecular Biology Authors: Mallm, J.-P., Iskar, M., Ishaque, N., Klett, L. C., Kugler, S. J., Muino, J. M., Teif, V. B., Poos, A. M., Grossmann, S., Erdel, F., Tavernari, D., Koser, S. D., Schumacher, S., Brors, B., König, R., Remondini, D., Vingron, M., Stilgenbauer, S., L Tags: Cancer, Chromatin, Epigenetics, Genomics & Functional Genomics, Genome-Scale & Integrative Biology Articles Source Type: research
Absolute quantification of translational regulation and burden using combined sequencing approaches
Translation of mRNAs into proteins is a key cellular process. Ribosome binding sites and stop codons provide signals to initiate and terminate translation, while stable secondary mRNA structures can induce translational recoding events. Fluorescent proteins are commonly used to characterize such elements but require the modification of a part's natural context and allow only a few parameters to be monitored concurrently. Here, we combine Ribo-seq with quantitative RNA-seq to measure at nucleotide resolution and in absolute units the performance of elements controlling transcriptional and translational processes during prot...
Source: Molecular Systems Biology - May 2, 2019 Category: Molecular Biology Authors: Gorochowski, T. E., Chelysheva, I., Eriksen, M., Nair, P., Pedersen, S., Ignatova, Z. Tags: Genome-Scale & Integrative Biology, Methods & Resources, Synthetic Biology & Biotechnology Articles Source Type: research
Antibody Fab-Fc properties outperform titer in predictive models of SIV vaccine-induced protection
Characterizing the antigen-binding and innate immune-recruiting properties of the humoral response offers the chance to obtain deeper insights into mechanisms of protection than revealed by measuring only overall antibody titer. Here, a high-throughput, multiplexed Fab-Fc Array was employed to profile rhesus macaques vaccinated with a gp120-CD4 fusion protein in combination with different genetically encoded adjuvants, and subsequently subjected to multiple heterologous simian immunodeficiency virus (SIV) challenges. Systems analyses modeling protection and adjuvant differences using Fab-Fc Array measurements revealed a se...
Source: Molecular Systems Biology - May 1, 2019 Category: Molecular Biology Authors: Pittala, S., Bagley, K., Schwartz, J. A., Brown, E. P., Weiner, J. A., Prado, I. J., Zhang, W., Xu, R., Ota-Setlik, A., Pal, R., Shen, X., Beck, C., Ferrari, G., Lewis, G. K., LaBranche, C. C., Montefiori, D. C., Tomaras, G. D., Alter, G., Roederer, M., F Tags: Immunology, Methods & Resources, Microbiology, Virology & Host Pathogen Interaction Articles Source Type: research
INKA, an integrative data analysis pipeline for phosphoproteomic inference of active kinases
Identifying hyperactive kinases in cancer is crucial for individualized treatment with specific inhibitors. Kinase activity can be discerned from global protein phosphorylation profiles obtained with mass spectrometry-based phosphoproteomics. A major challenge is to relate such profiles to specific hyperactive kinases fueling growth/progression of individual tumors. Hitherto, the focus has been on phosphorylation of either kinases or their substrates. Here, we combined label-free kinase-centric and substrate-centric information in an Integrative Inferred Kinase Activity (INKA) analysis. This multipronged, stringent analysi...
Source: Molecular Systems Biology - April 11, 2019 Category: Molecular Biology Authors: Beekhof, R., van Alphen, C., Henneman, A. A., Knol, J. C., Pham, T. V., Rolfs, F., Labots, M., Henneberry, E., Le Large, T. Y., de Haas, R. R., Piersma, S. R., Vurchio, V., Bertotti, A., Trusolino, L., Verheul, H. M., Jimenez, C. R. Tags: Cancer, Methods & Resources, Post-translational Modifications, Proteolysis & Proteomics Source Type: research
The fitness cost and benefit of phase-separated protein deposits
Phase separation of soluble proteins into insoluble deposits is associated with numerous diseases. However, protein deposits can also function as membrane-less compartments for many cellular processes. What are the fitness costs and benefits of forming such deposits in different conditions? Using a model protein that phase-separates into deposits, we distinguish and quantify the fitness contribution due to the loss or gain of protein function and deposit formation in yeast. The environmental condition and the cellular demand for the protein function emerge as key determinants of fitness. Protein deposit formation can influ...
Source: Molecular Systems Biology - April 7, 2019 Category: Molecular Biology Authors: Sanchez de Groot, N., Torrent Burgas, M., Ravarani, C. N., Trusina, A., Ventura, S., Babu, M. M. Tags: Protein Biosynthesis & Quality Control, Quantitative Biology & Dynamical Systems Articles Source Type: research
Enzyme promiscuity shapes adaptation to novel growth substrates
Evidence suggests that novel enzyme functions evolved from low-level promiscuous activities in ancestral enzymes. Yet, the evolutionary dynamics and physiological mechanisms of how such side activities contribute to systems-level adaptations are not well characterized. Furthermore, it remains untested whether knowledge of an organism's promiscuous reaction set, or underground metabolism, can aid in forecasting the genetic basis of metabolic adaptations. Here, we employ a computational model of underground metabolism and laboratory evolution experiments to examine the role of enzyme promiscuity in the acquisition and optimi...
Source: Molecular Systems Biology - April 7, 2019 Category: Molecular Biology Authors: Guzman, G. I., Sandberg, T. E., LaCroix, R. A., Nyerges, A., Papp, H., de Raad, M., King, Z. A., Hefner, Y., Northen, T. R., Notebaart, R. A., Pal, C., Palsson, B. O., Papp, B., Feist, A. M. Tags: Evolution, Genome-Scale & Integrative Biology, Metabolism Reports Source Type: research
Defining the RNA interactome by total RNA-associated protein purification
The RNA binding proteome (RBPome) was previously investigated using UV crosslinking and purification of poly(A)-associated proteins. However, most cellular transcripts are not polyadenylated. We therefore developed total RNA-associated protein purification (TRAPP) based on 254 nm UV crosslinking and purification of all RNA–protein complexes using silica beads. In a variant approach (PAR-TRAPP), RNAs were labelled with 4-thiouracil prior to 350 nm crosslinking. PAR-TRAPP in yeast identified hundreds of RNA binding proteins, strongly enriched for canonical RBPs. In comparison, TRAPP identified many more prote...
Source: Molecular Systems Biology - April 7, 2019 Category: Molecular Biology Authors: Shchepachev, V., Bresson, S., Spanos, C., Petfalski, E., Fischer, L., Rappsilber, J., Tollervey, D. Tags: Methods & Resources, Post-translational Modifications, Proteolysis & Proteomics, RNA Biology Source Type: research
Eternal sunshine of the spotless cycle
Understanding the quantitative principles underlying the durations of each of the four cell cycle phases has remained a challenge, despite the extensive knowledge on the molecular components and mechanisms related to cell cycle control. In their recent study, Purvis and colleagues (Chao et al, 2019) quantify cell cycle phase durations in human cells and propose a model whereby cell cycle progression in single cells is a succession of uncoupled, memoryless phases, each composed of a characteristic rate and number of steps. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - April 4, 2019 Category: Molecular Biology Authors: Gelens, L., Santos, S. D. Tags: Cell Cycle, Quantitative Biology & Dynamical Systems News [amp ] Views Source Type: research
Tree-ensemble analysis assesses presence of multifurcations in single cell data
We introduce TreeTop, an algorithm for single cell data analysis to identify and assign a branching score to branch points in biological processes which may have multi-level branching hierarchies. We demonstrate branch point identification for processes with varying topologies, including T-cell maturation, B-cell differentiation and hematopoiesis. Our analyses are consistent with recent experimental studies suggesting a shallower hierarchy of differentiation events in hematopoiesis, rather than the classical multi-level hierarchy. (Source: Molecular Systems Biology)
Source: Molecular Systems Biology - March 26, 2019 Category: Molecular Biology Authors: Macnair, W., De Vargas Roditi, L., Ganscha, S., Claassen, M. Tags: Computational Biology, Genome-Scale & Integrative Biology, Methods & Resources Source Type: research
Evidence that the human cell cycle is a series of uncoupled, memoryless phases
The cell cycle is canonically described as a series of four consecutive phases: G1, S, G2, and M. In single cells, the duration of each phase varies, but the quantitative laws that govern phase durations are not well understood. Using time-lapse microscopy, we found that each phase duration follows an Erlang distribution and is statistically independent from other phases. We challenged this observation by perturbing phase durations through oncogene activation, inhibition of DNA synthesis, reduced temperature, and DNA damage. Despite large changes in durations in cell populations, phase durations remained uncoupled in indiv...
Source: Molecular Systems Biology - March 17, 2019 Category: Molecular Biology Authors: Chao, H. X., Fakhreddin, R. I., Shimerov, H. K., Kedziora, K. M., Kumar, R. J., Perez, J., Limas, J. C., Grant, G. D., Cook, J. G., Gupta, G. P., Purvis, J. E. Tags: Cell Cycle, Quantitative Biology & Dynamical Systems Articles Source Type: research
netDx: interpretable patient classification using integrated patient similarity networks
We describe netDx, a novel supervised patient classification framework based on patient similarity networks, which meets these criteria. In a cancer survival benchmark dataset integrating up to six data types in four cancer types, netDx significantly outperforms most other machine-learning approaches across most cancer types. Compared to traditional machine-learning-based patient classifiers, netDx results are more interpretable, visualizing the decision boundary in the context of patient similarity space. When patient similarity is defined by pathway-level gene expression, netDx identifies biological pathways important fo...
Source: Molecular Systems Biology - March 13, 2019 Category: Molecular Biology Authors: Pai, S., Hui, S., Isserlin, R., Shah, M. A., Kaka, H., Bader, G. D. Tags: Computational Biology, Genome-Scale & Integrative Biology, Systems Medicine Articles Source Type: research
Wave patterns organize cellular protrusions and control cortical dynamics
Cellular protrusions are typically considered as distinct structures associated with specific regulators. However, we found that these regulators coordinately localize as propagating cortical waves, suggesting a common underlying mechanism. These molecular events fell into two excitable networks, the signal transduction network STEN and the cytoskeletal network CEN with different wave substructures. Computational studies using a coupled-network model reproduced these features and showed that the morphology and kinetics of the waves depended on strengths of feedback loops. Chemically induced dimerization at multiple nodes p...
Source: Molecular Systems Biology - March 10, 2019 Category: Molecular Biology Authors: Miao, Y., Bhattacharya, S., Banerjee, T., Abubaker-Sharif, B., Long, Y., Inoue, T., Iglesias, P. A., Devreotes, P. N. Tags: Cell Adhesion, Polarity & Cytoskeleton, Quantitative Biology & Dynamical Systems, Signal Transduction Articles Source Type: research
Genome-wide prediction of synthetic rescue mediators of resistance to targeted and immunotherapy
Most patients with advanced cancer eventually acquire resistance to targeted therapies, spurring extensive efforts to identify molecular events mediating therapy resistance. Many of these events involve synthetic rescue (SR) interactions, where the reduction in cancer cell viability caused by targeted gene inactivation is rescued by an adaptive alteration of another gene (the rescuer). Here, we perform a genome-wide in silico prediction of SR rescuer genes by analyzing tumor transcriptomics and survival data of 10,000 TCGA cancer patients. Predicted SR interactions are validated in new experimental screens. We show that SR...
Source: Molecular Systems Biology - March 10, 2019 Category: Molecular Biology Authors: Sahu, A. D., S Lee, J., Wang, Z., Zhang, G., Iglesias-Bartolome, R., Tian, T., Wei, Z., Miao, B., Nair, N. U., Ponomarova, O., Friedman, A. A., Amzallag, A., Moll, T., Kasumova, G., Greninger, P., Egan, R. K., Damon, L. J., Frederick, D. T., Jerby-Arnon, Tags: Cancer, Computational Biology, Genome-Scale & Integrative Biology Articles Source Type: research
