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Molecular Systems Biology

Karthik Sekar, Roberto Rusconi, John T Sauls, Tobias Fuhrer, Elad Noor, Jen Nguyen, Vicente I Fernandez, Marieke F Buffing, Michael Berney, Suckjoon Jun, Roman Stocker, Uwe Sauer
In natural environments, microbes are typically non-dividing and gauge when nutrients permit division. Current models are phenomenological and specific to nutrient-rich, exponentially growing cells, thus cannot predict the first division under limiting nutrient availability. To assess this regime, we supplied starving Escherichia coli with glucose pulses at increasing frequencies. Real-time metabolomics and microfluidic single-cell microscopy revealed unexpected, rapid protein, and nucleic acid synthesis already from minuscule glucose pulses in non-dividing cells...
November 5, 2018: Molecular Systems Biology
Chee Sheng Ng, Ameya Sinha, Yaw Aniweh, Qianhui Nah, Indrakanti Ramesh Babu, Chen Gu, Yok Hian Chionh, Peter C Dedon, Peter R Preiser
Among components of the translational machinery, ribonucleoside modifications on tRNAs are emerging as critical regulators of cell physiology and stress response. Here, we demonstrate highly coordinated behavior of the repertoire of tRNA modifications of Plasmodium falciparum throughout the intra-erythrocytic developmental cycle (IDC). We observed both a synchronized increase in 22 of 28 modifications from ring to trophozoite stage, consistent with tRNA maturation during translational up-regulation, and asynchronous changes in six modifications...
October 4, 2018: Molecular Systems Biology
Koji L Ode, Hiroki R Ueda
No abstract text is available yet for this article.
September 24, 2018: Molecular Systems Biology
Yolanda Schaerli, Alba Jiménez, José M Duarte, Ljiljana Mihajlovic, Julien Renggli, Mark Isalan, James Sharpe, Andreas Wagner
Phenotypic variation is the raw material of adaptive Darwinian evolution. The phenotypic variation found in organismal development is biased towards certain phenotypes, but the molecular mechanisms behind such biases are still poorly understood. Gene regulatory networks have been proposed as one cause of constrained phenotypic variation. However, most pertinent evidence is theoretical rather than experimental. Here, we study evolutionary biases in two synthetic gene regulatory circuits expressed in Escherichia coli that produce a gene expression stripe-a pivotal pattern in embryonic development...
September 10, 2018: Molecular Systems Biology
Lucia Durrieu, Daniel Kirrmaier, Tatjana Schneidt, Ilia Kats, Sarada Raghavan, Lars Hufnagel, Timothy E Saunders, Michael Knop
Embryogenesis relies on instructions provided by spatially organized signaling molecules known as morphogens. Understanding the principles behind morphogen distribution and how cells interpret locally this information remains a major challenge in developmental biology. Here, we introduce morphogen-age measurements as a novel approach to test models of morphogen gradient formation. Using a tandem fluorescent timer as a protein age sensor, we find a gradient of increasing age of Bicoid along the anterior-posterior axis in the early Drosophila embryo...
September 4, 2018: Molecular Systems Biology
Samuel C Wolff, Katarzyna M Kedziora, Raluca Dumitru, Cierra D Dungee, Tarek M Zikry, Adriana S Beltran, Rachel A Haggerty, JrGang Cheng, Margaret A Redick, Jeremy E Purvis
It is well known that clonal cells can make different fate decisions, but it is unclear whether these decisions are determined during, or before, a cell's own lifetime. Here, we engineered an endogenous fluorescent reporter for the pluripotency factor OCT4 to study the timing of differentiation decisions in human embryonic stem cells. By tracking single-cell OCT4 levels over multiple cell cycle generations, we found that the decision to differentiate is largely determined before the differentiation stimulus is presented and can be predicted by a cell's preexisting OCT4 signaling patterns...
September 3, 2018: Molecular Systems Biology
Emanuel Rognoni, Angela Oliveira Pisco, Toru Hiratsuka, Kalle H Sipilä, Julio M Belmonte, Seyedeh Atefeh Mobasseri, Christina Philippeos, Rui Dilão, Fiona M Watt
Murine dermis contains functionally and spatially distinct fibroblast lineages that cease to proliferate in early postnatal life. Here, we propose a model in which a negative feedback loop between extracellular matrix (ECM) deposition and fibroblast proliferation determines dermal architecture. Virtual-tissue simulations of our model faithfully recapitulate dermal maturation, predicting a loss of spatial segregation of fibroblast lineages and dictating that fibroblast migration is only required for wound healing...
August 29, 2018: Molecular Systems Biology
Andrzej J Rzepiela, Souvik Ghosh, Jeremie Breda, Arnau Vina-Vilaseca, Afzal P Syed, Andreas J Gruber, Katja Eschbach, Christian Beisel, Erik van Nimwegen, Mihaela Zavolan
miRNAs are small RNAs that regulate gene expression post-transcriptionally. By repressing the translation and promoting the degradation of target mRNAs, miRNAs may reduce the cell-to-cell variability in protein expression, induce correlations between target expression levels, and provide a layer through which targets can influence each other's expression as "competing RNAs" (ceRNAs). However, experimental evidence for these behaviors is limited. Combining mathematical modeling with RNA sequencing of individual human embryonic kidney cells in which the expression of two distinct miRNAs was induced over a wide range, we have inferred parameters describing the response of hundreds of miRNA targets to miRNA induction...
August 27, 2018: Molecular Systems Biology
Daniela Michlmayr, Theodore R Pak, Adeeb H Rahman, El-Ad David Amir, Eun-Young Kim, Seunghee Kim-Schulze, Maria Suprun, Michael G Stewart, Guajira P Thomas, Angel Balmaseda, Li Wang, Jun Zhu, Mayte Suaréz-Fariñas, Steven M Wolinsky, Andrew Kasarskis, Eva Harris
Chikungunya virus (CHIKV) is a mosquito-borne alphavirus that causes global epidemics of debilitating disease worldwide. To gain functional insight into the host cellular genes required for virus infection, we performed whole-blood RNA-seq, 37-plex mass cytometry of peripheral blood mononuclear cells (PBMCs), and serum cytokine measurements of acute- and convalescent-phase samples obtained from 42 children naturally infected with CHIKV Semi-supervised classification and clustering of single-cell events into 57 sub-communities of canonical leukocyte phenotypes revealed a monocyte-driven response to acute infection, with the greatest expansions in "intermediate" CD14++ CD16+ monocytes and an activated subpopulation of CD14+ monocytes...
August 27, 2018: Molecular Systems Biology
Gustav N Sundell, Roland Arnold, Muhammad Ali, Piangfan Naksukpaiboon, Julien Orts, Peter Güntert, Celestine N Chi, Ylva Ivarsson
A key function of reversible protein phosphorylation is to regulate protein-protein interactions, many of which involve short linear motifs (3-12 amino acids). Motif-based interactions are difficult to capture because of their often low-to-moderate affinities. Here, we describe phosphomimetic proteomic peptide-phage display, a powerful method for simultaneously finding motif-based interaction and pinpointing phosphorylation switches. We computationally designed an oligonucleotide library encoding human C-terminal peptides containing known or predicted Ser/Thr phosphosites and phosphomimetic variants thereof...
August 20, 2018: Molecular Systems Biology
Fiorella Magani, Eric R Bray, Maria J Martinez, Ning Zhao, Valeria A Copello, Laine Heidman, Stephanie O Peacock, David J Wiley, Gennaro D'Urso, Kerry L Burnstein
Identifying critical pathways governing disease progression is essential for accurate prognosis and effective therapy. We developed a broadly applicable and novel systems-level gene discovery strategy. This approach focused on constitutively active androgen receptor (AR) splice variant-driven pathways as representative of an intractable mechanism of prostate cancer (PC) therapeutic resistance. We performed a meta-analysis of human prostate samples using weighted gene co-expression network analysis combined with experimental AR variant transcriptome analyses...
August 14, 2018: Molecular Systems Biology
Lorenz J Maier, Stefan M Kallenberger, Katharina Jechow, Marcel Waschow, Roland Eils, Christian Conrad
Three-dimensional protein localization intricately determines the functional coordination of cellular processes. The complex spatial context of protein landscape has been assessed by multiplexed immunofluorescent staining or mass spectrometry, applied to 2D cell culture with limited physiological relevance or tissue sections. Here, we present 3D SPECS, an automated technology for 3D Spatial characterization of Protein Expression Changes by microscopic Screening. This workflow comprises iterative antibody staining, high-content 3D imaging, and machine learning for detection of mitoses...
August 13, 2018: Molecular Systems Biology
Christina Ludwig, Ludovic Gillet, George Rosenberger, Sabine Amon, Ben C Collins, Ruedi Aebersold
Many research questions in fields such as personalized medicine, drug screens or systems biology depend on obtaining consistent and quantitatively accurate proteomics data from many samples. SWATH-MS is a specific variant of data-independent acquisition (DIA) methods and is emerging as a technology that combines deep proteome coverage capabilities with quantitative consistency and accuracy. In a SWATH-MS measurement, all ionized peptides of a given sample that fall within a specified mass range are fragmented in a systematic and unbiased fashion using rather large precursor isolation windows...
August 13, 2018: Molecular Systems Biology
Benjamin D Landry, Thomas Leete, Ryan Richards, Peter Cruz-Gordillo, Hannah R Schwartz, Megan E Honeywell, Gary Ren, Alyssa D Schwartz, Shelly R Peyton, Michael J Lee
Due to tumor heterogeneity, most believe that effective treatments should be tailored to the features of an individual tumor or tumor subclass. It is still unclear, however, what information should be considered for optimal disease stratification, and most prior work focuses on tumor genomics. Here, we focus on the tumor microenvironment. Using a large-scale coculture assay optimized to measure drug-induced cell death, we identify tumor-stroma interactions that modulate drug sensitivity. Our data show that the chemo-insensitivity typically associated with aggressive subtypes of breast cancer is not observed if these cells are grown in 2D or 3D monoculture, but is manifested when these cells are cocultured with stromal cells, such as fibroblasts...
August 6, 2018: Molecular Systems Biology
Guillaume Rey, Nikolay B Milev, Utham K Valekunja, Ratnasekhar Ch, Sandipan Ray, Mariana Silva Dos Santos, Andras D Nagy, Robin Antrobus, James I MacRae, Akhilesh B Reddy
Circadian rhythms are cell-autonomous biological oscillations with a period of about 24 h. Current models propose that transcriptional feedback loops are the primary mechanism for the generation of circadian oscillations. Within this framework, Drosophila S2 cells are regarded as "non-rhythmic" cells, as they do not express several canonical circadian components. Using an unbiased multi-omics approach, we made the surprising discovery that Drosophila S2 cells do in fact display widespread daily rhythms...
August 2, 2018: Molecular Systems Biology
Maria Polychronidou
No abstract text is available yet for this article.
July 24, 2018: Molecular Systems Biology
Mikko Taipale
No abstract text is available yet for this article.
July 18, 2018: Molecular Systems Biology
Héloïse Muller, Vittore F Scolari, Nicolas Agier, Aurèle Piazza, Agnès Thierry, Guillaume Mercy, Stéphane Descorps-Declere, Luciana Lazar-Stefanita, Olivier Espeli, Bertrand Llorente, Gilles Fischer, Julien Mozziconacci, Romain Koszul
In chromosome conformation capture experiments (Hi-C), the accuracy with which contacts are detected varies due to the uneven distribution of restriction sites along genomes. In addition, repeated sequences or homologous regions remain indistinguishable because of the ambiguities they introduce during the alignment of the sequencing reads. We addressed both limitations by designing and engineering 144 kb of a yeast chromosome with regularly spaced restriction sites (Syn-HiC design). In the Syn-HiC region, Hi-C signal-to-noise ratio is enhanced and can be used to measure the shape of an unbiased distribution of contact frequencies, allowing to propose a robust definition of a Hi-C experiment resolution...
July 16, 2018: Molecular Systems Biology
Philipp Trepte, Sabrina Kruse, Simona Kostova, Sheila Hoffmann, Alexander Buntru, Anne Tempelmeier, Christopher Secker, Lisa Diez, Aline Schulz, Konrad Klockmeier, Martina Zenkner, Sabrina Golusik, Kirstin Rau, Sigrid Schnoegl, Craig C Garner, Erich E Wanker
Information on protein-protein interactions (PPIs) is of critical importance for studying complex biological systems and developing therapeutic strategies. Here, we present a double-readout bioluminescence-based two-hybrid technology, termed LuTHy, which provides two quantitative scores in one experimental procedure when testing binary interactions. PPIs are first monitored in cells by quantification of bioluminescence resonance energy transfer (BRET) and, following cell lysis, are again quantitatively assessed by luminescence-based co-precipitation (LuC)...
July 11, 2018: Molecular Systems Biology
André Mateus, Jacob Bobonis, Nils Kurzawa, Frank Stein, Dominic Helm, Johannes Hevler, Athanasios Typas, Mikhail M Savitski
Increasing antibiotic resistance urges for new technologies for studying microbes and antimicrobial mechanism of action. We adapted thermal proteome profiling (TPP) to probe the thermostability of Escherichia coli proteins in vivo E. coli had a more thermostable proteome than human cells, with protein thermostability depending on subcellular location-forming a high-to-low gradient from the cell surface to the cytoplasm. While subunits of protein complexes residing in one compartment melted similarly, protein complexes spanning compartments often had their subunits melting in a location-wise manner...
July 6, 2018: Molecular Systems Biology
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