The transcription factor network of E. coli steers global responses to shifts in RNAP concentration.

The robustness and sensitivity of gene networks to environmental changes is critical for cell survival. How gene networks produce specific, chronologically ordered responses to genome-wide perturbations, while robustly maintaining homeostasis, remains an open question. We analysed if short- and mid-term genome-wide responses to shifts in RNA polymerase (RNAP) concentration are influenced by the known topology and logic of the transcription factor network (TFN) of Escherichia coli.

Is Coamplified with in Breast Tumors and Encodes an Ubiquitin Ligase That Limits MYC-Dependent Apoptosis.

For maximal oncogenic activity, cellular MYC protein levels need to be tightly controlled so that they do not induce apoptosis. Here, we show how ubiquitin ligase UBR5 functions as a molecular rheostat to prevent excess accumulation of MYC protein. UBR5 ubiquitinates MYC and its effects on MYC protein stability are independent of FBXW7.

A normalized drug response metric improves accuracy and consistency of anticancer drug sensitivity quantification in cell-based screening.

Accurate quantification of drug effects is crucial for identifying pharmaceutically actionable cancer vulnerabilities. Current cell viability-based measurements often lead to biased response estimates due to varying growth rates and experimental artifacts that explain part of the inconsistency in high-throughput screening results. We developed an improved drug scoring model, normalized drug response (NDR), which makes use of both positive and negative control conditions to account for differences in cell growth rates, and experimental noise to better characterize drug-induced effects.

Network pharmacology modeling identifies synergistic Aurora B and ZAK interaction in triple-negative breast cancer.

Cancer cells with heterogeneous mutation landscapes and extensive functional redundancy easily develop resistance to monotherapies by emerging activation of compensating or bypassing pathways. To achieve more effective and sustained clinical responses, synergistic interactions of multiple druggable targets that inhibit redundant cancer survival pathways are often required. Here, we report a systematic polypharmacology strategy to predict, test, and understand the selective drug combinations for MDA-MB-231 triple-negative breast cancer cells.

An Overview of Network-Based and -Free Approaches for Stochastic Simulation of Biochemical Systems.

Stochastic simulation has been widely used to model the dynamics of biochemical reaction networks. Several algorithms have been proposed that are exact solutions of the chemical master equation, following the work of Gillespie. These stochastic simulation approaches can be broadly classified into two categories: network-based and -free simulation.

Drug Target Commons: A Community Effort to Build a Consensus Knowledge Base for Drug-Target Interactions.

Knowledge of the full target space of bioactive substances, approved and investigational drugs as well as chemical probes, provides important insights into therapeutic potential and possible adverse effects. The existing compound-target bioactivity data resources are often incomparable due to non-standardized and heterogeneous assay types and variability in endpoint measurements. To extract higher value from the existing and future compound target-profiling data, we implemented an open-data web platform, named Drug Target Commons (DTC), which features tools for crowd-sourced compound-target bioactivity data annotation, standardization, curation, and intra-resource integration.

Robustness of the Process of Nucleoid Exclusion of Protein Aggregates in Escherichia coli.

Unlabelled: Escherichia coli segregates protein aggregates to the poles by nucleoid exclusion. Combined with cell divisions, this generates heterogeneous aggregate distributions in subsequent cell generations. We studied the robustness of this process with differing medium richness and antibiotics stress, which affect nucleoid size, using multimodal, time-lapse microscopy of live cells expressing both a fluorescently tagged chaperone (IbpA), which identifies in vivo the location of aggregates, and HupA-mCherry, a fluorescent variant of a nucleoid-associated protein.

Increased cytoplasm viscosity hampers aggregate polar segregation in Escherichia coli.

In Escherichia coli, under optimal conditions, protein aggregates associated with cellular aging are excluded from midcell by the nucleoid. We study the functionality of this process under sub-optimal temperatures from population and time lapse images of individual cells and aggregates and nucleoids within. We show that, as temperature decreases, aggregates become homogeneously distributed and uncorrelated with nucleoid size and location.

Robustness of the division symmetry in Escherichia coli and functional consequences of symmetry breaking.

The morphological symmetry of the division process of Escherichia coli is well-known. Recent studies verified that, in optimal growth conditions, most divisions are symmetric, although there are exceptions. We investigate whether such morphological asymmetries in division introduce functional asymmetries between sister cells, and assess the robustness of the symmetry in division to mild chemical stresses and sub-optimal temperatures.

In silico analysis of division times of Escherichia coli populations as a function of the partitioning scheme of non-functional proteins.

Recent evidence suggests that cells employ functionally asymmetric partitioning schemes in division to cope with aging. We explore various schemes in silico, with a stochastic model of Escherichia coli that includes gene expression, non-functional proteins generation, aggregation and polar retention, and molecule partitioning in division. The model is implemented in SGNS2, which allows stochastic, multi-delayed reactions within hierarchical, transient, interlinked compartments.

In vivo kinetics of segregation and polar retention of MS2-GFP-RNA complexes in Escherichia coli.

The cytoplasm of Escherichia coli is a crowded, heterogeneous environment. From single cell live imaging, we investigated the spatial kinetics and heterogeneities of synthetic RNA-protein complexes. First, although their known tendency to accumulate at the cell poles does not appear to introduce asymmetries between older and newer cell poles within a cell lifetime, these emerge with cell divisions.

Regulation of mean and noise of the in vivo kinetics of transcription under the control of the lac/ara-1 promoter.

The kinetics of transcription initiation in Escherichia coli depend on the duration of two rate-limiting steps, the closed and the open complex formation. In a lac promoter variant, P(lac/ara-1), the kinetics of these steps is controlled by IPTG and arabinose. From in vivo single-RNA measurements, we find that induction affects the mean and normalized variance of the intervals between consecutive RNA productions.

SGNS2: a compartmentalized stochastic chemical kinetics simulator for dynamic cell populations.

Motivation: Cell growth and division affect the kinetics of internal cellular processes and the phenotype diversity of cell populations. Since the effects are complex, e.g.

Robustness and information propagation in attractors of Random Boolean Networks.

Attractors represent the long-term behaviors of Random Boolean Networks. We study how the amount of information propagated between the nodes when on an attractor, as quantified by the average pairwise mutual information (I(A)), relates to the robustness of the attractor to perturbations (R(A)). We find that the dynamical regime of the network affects the relationship between I(A) and R(A).

In vivo kinetics of transcription initiation of the lar promoter in Escherichia coli. Evidence for a sequential mechanism with two rate-limiting steps.

Background: In Escherichia coli the mean and cell-to-cell diversity in RNA numbers of different genes vary widely. This is likely due to different kinetics of transcription initiation, a complex process with multiple rate-limiting steps that affect RNA production.

Results: We measured the in vivo kinetics of production of individual RNA molecules under the control of the lar promoter in E.