Tumor necrosis factor alpha (TNFα) is a well-known modulator of apoptosis by maintaining a balance between proliferation and cell-death in normal cells. Cancer cells often evade apoptotic response ...following TNFα stimulation by altering signaling cross-talks. Thus, varying the extent of signaling cross-talk could enable optimal TNFα mediated apoptotic dynamics. Herein, we use an experimental data-driven mathematical modeling to quantitate the extent of synergistic signaling cross-talk between the intracellular entities phosphorylated JNK (pJNK) and phosphorylated AKT (pAKT) that orchestrate the phenotypic apoptosis level by modulating the activated Caspase3 dynamics. Our study reveals that this modulation is orchestrated by the distinct dynamic nature of the synergism at early and late phases. We show that this synergism in signal flow is governed by branches originating from either TNFα receptor and NFκB, which facilitates signaling through survival pathways. We demonstrate that the experimentally quantified apoptosis levels semi-quantitatively correlates with the model simulated Caspase3 transients. Interestingly, perturbing pJNK and pAKT transient dynamics fine-tunes this accumulated Caspase3 guided apoptotic response. Thus, our study offers useful insights for identifying potential targeted therapies for optimal apoptotic response.
Activated phosphorylation-dephosphorylation biochemical reaction cycles are a class of enzymatic futile cycles. A futile cycle such as a single MAPK cascade governed by two underlying enzymatic ...reactions permits Hyperbolic (H), Signal transducing (ST), Threshold-hyperbolic (TH) and Ultrasensitive (U) operating regimes that characterize input-output behaviour. Retroactive signalling caused by load due to sequestration of phosphorylated or unphosphorylated form of the substrate in a single enzymatic cascade without explicit feedback can introduce two-way communication, a feature not possible otherwise. We systematically characterize the operating regimes of a futile cycle subject to retroactivity in either of the substrate forms. We demonstrate that increasing retroactivity strength, which quantifies the downstream load, can trigger five possible regime transitions. Retroactivity strength is a reflection of the fraction of the substrate sequestered by its downstream target. Remarkably, the minimum required retroactivity strength to evidence any sequestration triggered regime transition demands 23% of the substrate bound to its downstream target. This minimum retroactivity strength corresponds to the transition of the dose-response curve from ST to H regime. We show that modulation of the saturation and unsaturation levels of the enzymatic reactions by retroactivity is the fundamental mechanism governing operating regime transition.
Single enzymatic cascade, ubiquitously found in cellular signaling networks, is a phosphorylation-dephosphorylation reaction cycle causing a transition between inactive and active states of a protein ...catalysed by kinase and phosphatase, respectively. Steady-state information processing ability of such a cycle (e.g., MAPK cascade) has been classified into four qualitatively different operating regimes, viz., hyperbolic (H), signal-transducing (ST), threshold-hyperbolic (TH) and ultrasensitive (U). These four regimes represent qualitatively different dose-response curves, that is, relationship between concentrations of input kinase (e.g., pMEK) and response activated protein (e.g., pERK). Regimes were identified using a deterministic model accounting for population-averaged behavior only. Operating regimes can be strongly influenced by the inherently present cell-to-cell variability in an ensemble of cells which is captured in the form of pMEK and pERK distributions using reporter-based single-cell experimentation. In this study, we show that such experimentally acquired snapshot pMEK and pERK distribution data of a single MAPK cascade can be directly used to infer the underlying operating regime even in the absence of a dose-response curve. This deduction is possible primarily due to the presence of a monotonic relationship between experimental observables RIQR, ratio of the inter-quartile range of the pERK and pMEK distribution pairs and RM, ratio of the medians of the distribution pair. We demonstrate this relationship by systematic analysis of a quasi-steady state approximated model superimposed with an input gamma distribution constrained by the stimulus strength specific pMEK distribution measured on Jurkat-T cells stimulated with PMA. As a first, we show that introduction of cell-to-cell variability only in the upstream kinase achieved by superimposition of an appropriate input pMEK distribution on the dose-response curve can predict bimodal response pERK distribution in ST regime. Implementation of the proposed method on the input-response distribution pair obtained in stimulated Jurkat-T cells revealed that while low-dosage PMA stimulation preserves the H regime observed in resting cells, high-dosage causes H to ST regime transition.
Transversal temperature pattern formation has been observed in laboratory and industrial catalytic packed-bed reactors (PBRs) used for conducting exothermic reactions. These patterns or nonuniform ...states can strongly affect reactor performance and pose severe safety issues. Recent studies show that symmetry-breaking bifurcations may cause transversal pattern formation in a reactor operated under nonadiabatic conditions. In this study, we show that wall temperature, which dictates the instantaneous and overall heat exchange rate, strongly influences the selection and dynamics of various target and rotating patterns exhibited in a shallow nonadiabatic PBR. We demonstrate this by linear stability analysis-guided extensive numerical simulations of a shallow reactor model assuming periodic blocking-reactivation kinetics for the catalytic reaction. Transversal spatiotemporal patterns predicted in lab-scale (∼6 cm diameter) and/or bench-scale (∼60 cm) reactors, include rotating patterns, inward/outward/multi-ring targets, quasi-stationary moving patterns, and symmetric and asymmetric spirals. We show that wall temperature modulates the transition between these targets and rotating transversal nonuniform states at both scales. We argue that rich and intricate patterns observed much more in bench-scale reactors than those in lab-scale reactors are possibly due to reduction in the heat removal time upon increase in diameter by 10-fold. We further classify the simulated transversal patterns into three regimes, viz., (i) heating, (ii) heating and cooling, and (iii) cooling, based on the nature of wall heat exchange rate dynamics dictated by the (instantaneous) local temperature near the reactor wall. Wall heat exchange rate dynamics being an experimental observable makes it a signature of a nonuniform state present inside the reactor.
Cancer is a multifactorial disease. Aberrant functioning of the underlying complex signaling network that orchestrates cellular response to external or internal cues governs incidence, progression, ...and recurrence of cancer. Detailed understanding of cancer's etiology can offer useful insights into arriving at novel therapeutic and disease management strategies. Such an understanding for most cancers is currently limited due to unavailability of a predictive large‐scale, integrated signaling model accounting for all tumor orchestrating factors. We suggest that the potential of Boolean dynamic (BD) modeling approaches, though qualitative, can be harnessed for developing holistic models capturing multi‐scale, multi‐cellular signaling processes involved in cancer incidence and progression. We believe that constraining such an integrated BD model with variety of omics data at different scales from laboratory and clinical settings could offer deeper insights into causal mechanisms governing the disease leading to better prognosis. We review the recent literature employing different BD modeling strategies to model variety of cancer signaling programs leading to identification of cancer‐specific prognostic markers such as SMAD proteins, which may also serve as early predictors of tumor cells hijacking the epithelial‐mesenchymal plasticity program. In silico simulations of BD models of different cancer signaling networks combined with attractor landscape analysis and validated with experimental data predicted the nature of short‐ and long‐term response of standard targeted therapeutic agents such as Nutlin‐3, a small molecule inhibitor for p53‐MDM2 interaction. BD simulations also offered a mechanistic view of emerging resistance to drugs such as Trastuzumab for HER+ breast cancer, analysis of which suggested new combination therapies to circumvent them. We believe future improvements in BD modeling techniques, and tools can lead to development of a comprehensive platform that can drive holistic approaches toward better decision‐making in the clinical settings, and thereby help identify novel therapeutic strategies for improved cancer treatment at personalised levels.
Cell-to-cell variability during TNFα stimulated Tumor Necrosis Factor Receptor 1 (TNFR1) signaling can lead to single-cell level pro-survival and apoptotic responses. This variability stems from the ...heterogeneity in signal flow through intracellular signaling entities that regulate the balance between these two phenotypes. Using systematic Boolean dynamic modeling of a TNFR1 signaling network, we demonstrate that the signal flow path variability can be modulated to enable cells favour apoptosis. We developed a computationally efficient approach "Boolean Modeling based Prediction of Steady-state probability of Phenotype Reachability (BM-ProSPR)" to accurately predict the network's ability to settle into different phenotypes. Model analysis juxtaposed with the experimental observations revealed that NFκB and PI3K transient responses guide the XIAP behaviour to coordinate the crucial dynamic cross-talk between the pro-survival and apoptotic arms at the single-cell level. Model predicted the experimental observations that ~31% apoptosis increase can be achieved by arresting Comp1 - IKK
activity which regulates the NFκB and PI3K dynamics. Arresting Comp1 - IKK
activity causes signal flow path re-wiring towards apoptosis without significantly compromising NFκB levels, which govern adequate cell survival. Priming an ensemble of cancerous cells with inhibitors targeting the specific interaction involving Comp1 and IKK
prior to TNFα exposure could enable driving them towards apoptosis.
Transversal hot zones have been reported to form in packed-bed reactors used to conduct exothermic reactions. Packed-bed reactors are usually operated under non-adiabatic conditions. Previous ...attempts to predict the formation of transversal hot zones have been made on both shallow and long reactors under adiabatic conditions; that is, wall heat transport is zero. We show that a rich variety of slowly oscillating transversal hot zones, such as rotating patterns, targets, and spirals, may form in shallow, non-adiabatic reactors. Under certain conditions, azimuthally symmetric target patterns coexist with azimuthally non-symmetric rotating patterns. Surprisingly, a small wall heat transport can force a traveling wave or band motion observed under adiabatic conditions into a rotating pattern. A transition from the rotating patterns and/or target patterns to spiral waves depends on the residence time, the reactor length scale, and the wall heat transfer coefficient. A shallow reactor model predicts that the spatiotemporal patterns oscillate at a very low frequency (order of 10–5 Hz), which is in agreement with predictions based on laboratory experiments.
If the graph is signed (i.e., the positive or negative regulatory effects of each interaction that may be obtained from primary literature are specified), Boolean network analysis can be used to ...identify the semi-quantitative features such as positive/negative feedback loops and minimal cut sets in the pathway. A, automated curation; B, both manual and automated curation; BIND, Biomolecular Interaction Network Database; BioPP, Biological Pathway Publisher; DIP, Database of Interacting Proteins; EcoCyc, Encyclopaedia of E. coli Genes and Metabolism; GNPV, Genome Network Platform Viewer; HPRD, Human Protein Reference Database; KEGG, Kyoto Encyclopedia of Genes and Genomes; M, manual curation; MetaCyc, a Metabolic Pathway database; MINT, Molecular Interation Database; MIPS, Munich Information Center for Protein Sequences; N, No; OPHID, Online Predicted Human Interaction Database; PANTHER, Protein Analysis through Evolutionary Relationship Database; PID, The Pathway Interaction Database; STKE, Signal Transduction Knowledge Environment, UNIHI, Unified Human Interactome; Y, yes.
Unicellular diazotrophic cyanobacteria such as Cyanothece sp. ATCC 51142 (henceforth Cyanothece), temporally separate the oxygen sensitive nitrogen fixation from oxygen evolving photosynthesis not ...only under diurnal cycles (LD) but also in continuous light (LL). However, recent reports demonstrate that the oscillations in LL occur with a shorter cycle time of ~11 h. We find that indeed, majority of the genes oscillate in LL with this cycle time. Genes that are upregulated at a particular time of day under diurnal cycle also get upregulated at an equivalent metabolic phase under LL suggesting tight coupling of various cellular events with each other and with the cell's metabolic status. A number of metabolic processes get upregulated in a coordinated fashion during the respiratory phase under LL including glycogen degradation, glycolysis, oxidative pentose phosphate pathway, and tricarboxylic acid cycle. These precede nitrogen fixation apparently to ensure sufficient energy and anoxic environment needed for the nitrogenase enzyme. Photosynthetic phase sees upregulation of photosystem II, carbonate transport, carbon concentrating mechanism, RuBisCO, glycogen synthesis and light harvesting antenna pigment biosynthesis. In Synechococcus elongates PCC 7942, a non-nitrogen fixing cyanobacteria, expression of a relatively smaller fraction of genes oscillates under LL condition with the major periodicity being 24 h. In contrast, the entire cellular machinery of Cyanothece orchestrates coordinated oscillation in anticipation of the ensuing metabolic phase in both LD and LL. These results may have important implications in understanding the timing of various cellular events and in engineering cyanobacteria for biofuel production.
PDF
