• Biocatalytic cascade
• DNAzyme
• Dissipative system
• Photodeprotection
• Thrombin inhibition

• 2049/20 Israel Science Foundation

• Algorithms
• Models, Biological
• Computer Simulation
• Signal Transduction/physiology
• Computational Biology/methods
• Systems Biology/methods
• Metabolic Networks and Pathways

• CEFIPRA
• DBT India
• DAE India

• Drug delivery
• Dynamic circuits
• Nanomedicine
• Nanoparticle
• Sensor

• DNA/chemistry
• Nanostructures/chemistry
• Humans
• Nanotechnology/methods
• Nanomedicine

• 2049/20 Israel Science Foundation

• cell signaling pathway
• epidermal growth factor
• inference
• mathematical model
• mitogen-activated protein kinase
• single cell

• Humans
• MAP Kinase Signaling System/drug effects
• Epidermal Growth Factor/metabolism
• Epidermal Growth Factor/pharmacology
• Mitogen-Activated Protein Kinases/metabolism
• Animals
• Models, Biological
• Proteomics/methods
• Signal Transduction/drug effects
• Models, Theoretical
• Single-Cell Analysis/methods

• 11871238, 11931019, 12371486 National Natural Science Foundation of China

• aromatic substitution
• dynamic covalent chemistry
• nonequilibrium processes
• self-sorting
• tetrazine

• PID2022-136566NB-I00 Ministerio de Ciencia e Innovación
• PDC2022-133706-I00 Ministerio de Ciencia e Innovación

• Cell biology
• Fibrosis
• Molecular biology
• Protein kinases
• Pulmonology

• Animals
• Mice
• Dual Specificity Phosphatase 1/metabolism
• Dual Specificity Phosphatase 1/genetics
• Myofibroblasts/pathology
• Myofibroblasts/metabolism
• Myofibroblasts/enzymology
• Mitogen-Activated Protein Kinase 14/metabolism
• Mitogen-Activated Protein Kinase 14/genetics
• Mitogen-Activated Protein Kinase 14/antagonists & inhibitors
• Pulmonary Fibrosis/pathology
• Pulmonary Fibrosis/metabolism
• Pulmonary Fibrosis/genetics
• Pulmonary Fibrosis/enzymology
• Pulmonary Fibrosis/chemically induced
• Lung/pathology
• Lung/metabolism
• Bleomycin/toxicity
• Humans
• Mice, Knockout
• Mice, Transgenic
• Apoptosis

• R01 HL127203 NHLBI NIH HHS
• R01 AR080152 NIAMS NIH HHS
• R35 HL160770 NHLBI NIH HHS
• R01 HL162963 NHLBI NIH HHS
• R01 HL158876 NHLBI NIH HHS
• R35 HL144979 NHLBI NIH HHS
• K08 HL163178 NHLBI NIH HHS
• NHLBI

• DNA, Catalytic/metabolism
• NAD
• DNA/genetics
• Biocatalysis
• Oligonucleotides

• Israel Science Foundation

• Dendritic Spines/physiology
• Neuronal Plasticity/physiology
• Signal Transduction
• Neurons
• Synapses/physiology

• CLL
• CP: Cancer
• DNA damage
• MAPK
• apoptosis
• phosphatases

• Humans
• Leukemia, Lymphocytic, Chronic, B-Cell
• Feedback
• Mitogen-Activated Protein Kinases

• MC_PC_17230 Medical Research Council

• Bombax ceiba Linn. leaf extract
• intelectin-1
• non-alcoholic fatty liver disease
• peroxisome proliferator-activated receptor alpha
• phenol compounds

• diabetes
• hyperglycemia
• insulin resistance
• long-chain non-coding RNA (lncRNAs)
• signal pathway

• 82072718 National Natural Science Foundation of China
• 32072220 National Natural Science Foundation of China
• YDZJSX2022A005 Project of the Central Government Guiding Local Science and Technology

• Cell-fate regulation
• Coordinated expression
• Multistability
• Mutual activation
• Mutual inhibition
• Self-activation
• Self-inhibition

• Cell Differentiation
• Humans
• Models, Biological
• Feedback, Physiological
• Gene Regulatory Networks
• Computer Simulation

• Cellular metabolism
• Chemometrics
• Dynamics
• Glycolysis
• Modelling
• Systems biology
• Vibrational spectroscopy

• Glycolysis

• Humans
• Proto-Oncogene Proteins B-raf/genetics
• Carcinoma, Non-Small-Cell Lung/drug therapy
• Antineoplastic Agents/pharmacology
• Lung Neoplasms/drug therapy
• Protein Kinase Inhibitors/pharmacology
• Protein Kinase Inhibitors/therapeutic use
• Mutation

• R01 CA193970 NCI NIH HHS
• UM1 CA186709 NCI NIH HHS
• P30 CA008748 NCI NIH HHS
• R01 CA238229 NCI NIH HHS
• R01 CA233736 NCI NIH HHS
• R01 CA204314 NCI NIH HHS
• U54 CA224068 NCI NIH HHS
• R01 CA229851 NCI NIH HHS
• R01 CA240362 NCI NIH HHS

• Crippled Growth
• MAP kinase
• Podospora anserina
• Signaling pathways
• hysteresis

Neurons and synapses manifest pronounced variability in the amount of plasticity induced by identical activity patterns. The mechanisms underlying such plasticity heterogeneity, which have been implicated in context‐specific resource allocation during encoding, have remained unexplored. Here, we employed a systematic physiologically constrained parametric search to identify the cellular mechanisms behind plasticity heterogeneity in dentate gyrus granule cells. We used heterogeneous model populations to ensure that our conclusions were not biased by parametric choices in a single hand‐tuned model. We found that each of intrinsic, synaptic, and structural heterogeneities independently yielded heterogeneities in synaptic plasticity profiles obtained with two different induction protocols. However, among the disparate forms of neural‐circuit heterogeneities, our analyses demonstrated the dominance of neurogenesis‐induced structural heterogeneities in driving plasticity heterogeneity in granule cells. We found that strong relationships between neuronal intrinsic excitability and plasticity emerged only when adult neurogenesis‐induced heterogeneities in neural structure were accounted for. Importantly, our analyses showed that it was not imperative that the manifestation of neural‐circuit heterogeneities must translate to heterogeneities in plasticity profiles. Specifically, despite the expression of heterogeneities in structural, synaptic, and intrinsic neuronal properties, similar plasticity profiles were attainable across all models through synergistic interactions among these heterogeneities. We assessed the parametric combinations required for the manifestation of such degeneracy in the expression of plasticity profiles. We found that immature cells showed physiological plasticity profiles despite receiving afferent inputs with weak synaptic strengths. Thus, the high intrinsic excitability of immature granule cells was sufficient to counterbalance their low excitatory drive in the expression of plasticity profile degeneracy. Together, our analyses demonstrate that disparate forms of neural‐circuit heterogeneities could mechanistically drive plasticity heterogeneity, but also caution against treating neural‐circuit heterogeneities as proxies for plasticity heterogeneity. Our study emphasizes the need for quantitatively characterizing the relationship between neural‐circuit and plasticity heterogeneities across brain regions.

• BCM rule
• adult neurogenesis
• calcium signaling
• degeneracy
• dentate gyrus
• heterogeneity
• intrinsic excitability
• synaptic plasticity
• theta burst stimulation

Biochemical reactions often occur in small volumes within a cell, restricting the number of molecules to the hundreds or even tens. At this scale, reactions are discrete and stochastic, making reliable signaling difficult. This paper shows that the transition between discrete, stochastic reactions and macroscopic reactions can be exploited to make a self-regulating switch. This constitutes a previously unidentified kind of reaction network that may be present in small structures, such as synapses.

Many kinds of cellular compartments comprise decision-making mechanisms that control growth and shrinkage of the compartment in response to external signals. Key examples include synaptic plasticity mechanisms that regulate the size and strength of synapses in the nervous system. However, when synaptic compartments and postsynaptic densities are small, such mechanisms operate in a regime where chemical reactions are discrete and stochastic due to low copy numbers of the species involved. In this regime, fluctuations are large relative to mean concentrations, and inherent discreteness leads to breakdown of mass-action kinetics. Understanding how synapses and other small compartments achieve reliable switching in the low–copy number limit thus remains a key open problem. We propose a self-regulating signaling motif that exploits the breakdown of mass-action kinetics to generate a reliable size-regulated switch. We demonstrate this in simple two- and three-species chemical reaction systems and uncover a key role for inhibitory loops among species in generating switching behavior. This provides an elementary motif that could allow size-dependent regulation in more complex reaction pathways and may explain discrepant experimental results on well-studied biochemical pathways.

• biochemical switch
• bistability
• calcium/calmodulin kinase CaMKII
• dendritic spine
• synaptic plasticity

• MAGT1
• MAPK
• MYC
• S-phase arrest
• p21

A central theme that governs the functional design of biological networks is their ability to sustain stable function despite widespread parametric variability. Here, we investigated the impact of distinct forms of biological heterogeneities on the stability of a two-dimensional continuous attractor network (CAN) implicated in grid-patterned activity generation. We show that increasing degrees of biological heterogeneities progressively disrupted the emergence of grid-patterned activity and resulted in progressively large perturbations in low-frequency neural activity. We postulated that targeted suppression of low-frequency perturbations could ameliorate heterogeneity-induced disruptions of grid-patterned activity. To test this, we introduced intrinsic resonance, a physiological mechanism to suppress low-frequency activity, either by adding an additional high-pass filter (phenomenological) or by incorporating a slow negative feedback loop (mechanistic) into our model neurons. Strikingly, CAN models with resonating neurons were resilient to the incorporation of heterogeneities and exhibited stable grid-patterned firing. We found CAN models with mechanistic resonators to be more effective in targeted suppression of low-frequency activity, with the slow kinetics of the negative feedback loop essential in stabilizing these networks. As low-frequency perturbations (1/f noise) are pervasive across biological systems, our analyses suggest a universal role for mechanisms that suppress low-frequency activity in stabilizing heterogeneous biological networks.

• continuous attractor network
• grid cells
• heterogeneities
• negative feedback loop
• neuronal resonance
• neuroscience
• none
• stability

Migrating cells need to coordinate distinct leading and trailing edge dynamics but the underlying mechanisms are unclear. Here, we combine experiments and mathematical modeling to elaborate the minimal autonomous biochemical machinery necessary and sufficient for this dynamic coordination and cell movement. RhoA activates Rac1 via DIA and inhibits Rac1 via ROCK, while Rac1 inhibits RhoA through PAK. Our data suggest that in motile, polarized cells, RhoA–ROCK interactions prevail at the rear, whereas RhoA-DIA interactions dominate at the front where Rac1/Rho oscillations drive protrusions and retractions. At the rear, high RhoA and low Rac1 activities are maintained until a wave of oscillatory GTPase activities from the cell front reaches the rear, inducing transient GTPase oscillations and RhoA activity spikes. After the rear retracts, the initial GTPase pattern resumes. Our findings show how periodic, propagating GTPase waves coordinate distinct GTPase patterns at the leading and trailing edge dynamics in moving cells.

• cell biology
• cell migration
• computational biology
• human
• mathematical modeling
• nonlinear dynamics
• oscillations and waves
• rho gtpases
• systems biology

• Evolution, Molecular
• Gene Regulatory Networks
• Models, Genetic
• Monte Carlo Method
• Mutation

• JPSJ

Protein phosphorylation affects conformational change, interaction, catalytic activity, and subcellular localization of proteins. Because the post-modification of proteins regulates diverse cellular signaling pathways, the precise control of phosphorylation states is essential for maintaining cellular homeostasis. Kinases function as phosphorylating enzymes, and phosphatases dephosphorylate their target substrates, typically in a much shorter time. The c-Jun N-terminal kinase (JNK) signaling pathway, a mitogen-activated protein kinase pathway, is regulated by a cascade of kinases and in turn regulates other physiological processes, such as cell differentiation, apoptosis, neuronal functions, and embryonic development. However, the activation of the JNK pathway is also implicated in human pathologies such as cancer, neurodegenerative diseases, and inflammatory diseases. Therefore, the proper balance between activation and inactivation of the JNK pathway needs to be tightly regulated. Dual specificity phosphatases (DUSPs) regulate the magnitude and duration of signal transduction of the JNK pathway by dephosphorylating their substrates. In this review, we will discuss the dynamics of phosphorylation/dephosphorylation, the mechanism of JNK pathway regulation by DUSPs, and the new possibilities of targeting DUSPs in JNK-related diseases elucidated in recent studies.

• c-Jun N-terminal kinase pathway
• dephosphorylation
• dual-specificity phosphatase
• mitogen-activated protein kinase pathway

• Pulicaria jaubertii
• cancer treatment
• multi-kinase inhibitors
• mutant K-Ras/B-Raf proteins
• plant flavonoids

• DNA-nanotechnology
• DNAzyme
• Switch
• fluorescence resonance energy transfer
• strand-displacement

• Biocatalysis
• Cations, Divalent/chemistry
• DNA/chemistry
• DNA, Catalytic/chemistry
• Fluorescence Resonance Energy Transfer
• Fluorescent Dyes/chemistry
• Magnesium/chemistry
• Nanostructures/chemistry
• Nanotechnology

• Bistable
• Chemical reaction network
• Hopf bifurcation
• Mixed volume
• Newton polytope
• Oscillation

• Catalysis
• Cellular Microenvironment
• DNA/metabolism
• DNA, Catalytic/metabolism
• Electrophoresis, Polyacrylamide Gel
• Metabolic Networks and Pathways
• Models, Biological
• Spectrometry, Fluorescence

• Israel Science Foundation
• Minerva Center for Biohybrid Complex Systems

• Epigenetics
• Fungi
• Genetics
• Phenotype
• Phenotypic instability

Microdomains that emerge from spatially constricted spread of biochemical signaling components play a central role in several neuronal computations. Although dendrites, endowed with several voltage-gated ion channels, form a prominent structural substrate for microdomain physiology, it is not known if these channels regulate the spatiotemporal spread of signaling microdomains. Here, we employed a multiscale, morphologically realistic, conductance-based model of the hippocampal pyramidal neuron that accounted for experimental details of electrical and calcium-dependent biochemical signaling. We activated synaptic N-Methyl-d-Aspartate receptors through theta-burst stimulation (TBS) or pairing (TBP) and assessed microdomain propagation along a signaling pathway that included calmodulin, calcium/calmodulin-dependent protein kinase II (CaMKII) and protein phosphatase 1. We found that the spatiotemporal spread of the TBS-evoked microdomain in phosphorylated CaMKII (pCaMKII) was amplified in comparison to that of the corresponding calcium microdomain. Next, we assessed the role of two dendritically expressed inactivating channels, one restorative (A-type potassium) and another regenerative (T-type calcium), by systematically varying their conductances. Whereas A-type potassium channels suppressed the spread of pCaMKII microdomains by altering the voltage response to TBS, T-type calcium channels enhanced this spread by modulating TBS-induced calcium influx without changing the voltage. Finally, we explored cross-dependencies of these channels with other model components, and demonstrated the heavy mutual interdependence of several biophysical and biochemical properties in regulating microdomains and their spread. Our conclusions unveil a pivotal role for dendritic voltage-gated ion channels in actively amplifying or suppressing biochemical signals and their spatiotemporal spread, with critical implications for clustered synaptic plasticity, robust information transfer and efficient neural coding.

The spatiotemporal spread of biochemical signals in neurons and other cells regulate signaling specificity, tuning of signal propagation, along with specificity and clustering of adaptive plasticity. Theoretical and experimental studies have demonstrated a critical role for cellular morphology and the topology of signaling networks in regulating this spread. In this study, we add a significantly complex dimension to this narrative by demonstrating that voltage-gated ion channels on the plasma membrane could actively amplify or suppress the strength and spread of downstream signaling components. Given the expression of different ion channels with wide-ranging heterogeneity in gating kinetics, localization and density, our results point to an increase in complexity of and degeneracy in signaling spread, and unveil a powerful mechanism for regulating biochemical-signaling pathways across different cell types.

• Action Potentials/physiology
• Animals
• Calcium Channels, T-Type/chemistry
• Calcium Channels, T-Type/metabolism
• Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism
• Dendrites/physiology
• Humans
• Ion Channel Gating
• Phosphorylation
• Potassium Channels/chemistry
• Potassium Channels/metabolism
• Protein Domains
• Protein Phosphatase 1/metabolism
• Pyramidal Cells/physiology
• Receptors, N-Methyl-D-Aspartate/metabolism
• Signal Transduction/physiology
• Synapses/metabolism

• IA/S/16/2/502727 DBT-Wellcome Trust India Alliance
• Wellcome Trust DBT India Alliance
• Human Frontier Science Program
• Department of Biotechnology, Ministry of Science and Technology (IN)
• University Grants Commission
• Ministry of Human Resource Development

• Cable theory
• charged proteins
• electrotonic processing
• epigenetic mechanisms
• memory engram
• nonsynaptic diffusion neurotransmission
• nonsynaptic plasticity
• signaling cascades

KRAS has proven difficult to target pharmacologically. Two strategies have recently been described for covalently targeting the most common KRAS mutant in lung cancer, KRAS G12C. Previously, we developed a computational model of the processes that regulate Ras activation. Here, we use this model to investigate KRAS G12C covalent inhibitors. We updated the model to include Ras protein turnover, and validation demonstrates that our model performs well in areas of G12C targeting where conventional wisdom struggles. We then used the model to investigate possible strategies to improve KRAS G12C inhibitors and identified GEF loading as a mechanism that could improve efficacy. Our simulations also found resistance‐promoting mutations may reverse which class of KRAS G12C inhibitor inhibits the system better, suggesting that there may be value to pursuing both types of KRAS G12C inhibitors. Overall, this work demonstrates areas in which systems biology approaches can inform Ras drug development.

Biological networks consisting of molecular components and interactions are represented by a graph model. There have been some studies based on that model to analyze a relationship between structural characteristics and dynamical behaviors in signaling network. However, little attention has been paid to changes of modularity and robustness in mutant networks.

In this paper, we investigated the changes of modularity and robustness by edge-removal mutations in three signaling networks. We first observed that both the modularity and robustness increased on average in the mutant network by the edge-removal mutations. However, the modularity change was negatively correlated with the robustness change. This implies that it is unlikely that both the modularity and the robustness values simultaneously increase by the edge-removal mutations. Another interesting finding is that the modularity change was positively correlated with the degree, the number of feedback loops, and the edge betweenness of the removed edges whereas the robustness change was negatively correlated with them. We note that these results were consistently observed in randomly structure networks. Additionally, we identified two groups of genes which are incident to the highly-modularity-increasing and the highly-robustness-decreasing edges with respect to the edge-removal mutations, respectively, and observed that they are likely to be central by forming a connected component of a considerably large size. The gene-ontology enrichment of each of these gene groups was significantly different from the rest of genes. Finally, we showed that the highly-robustness-decreasing edges can be promising edgetic drug-targets, which validates the usefulness of our analysis.

Taken together, the analysis of changes of robustness and modularity against edge-removal mutations can be useful to unravel novel dynamical characteristics underlying in signaling networks.

The online version of this article (10.1186/s12918-017-0505-2) contains supplementary material, which is available to authorized users.

• Boolean dynamics
• Centrality
• Drug-targets
• Edge-removal mutations
• Feedback loops
• Gene-ontology
• Modularity
• Robustness

• CL
• CRLS1
• MAPK
• NSCLC
• SCC

• liver
• metabolism
• mitogen-activated protein kinase
• obesity
• signal transduction
• type 2 diabetes

• Animals
• Diabetes Mellitus, Type 2/enzymology
• Diabetes Mellitus, Type 2/metabolism
• Humans
• Liver/metabolism
• Mitogen-Activated Protein Kinases/genetics
• Mitogen-Activated Protein Kinases/metabolism
• Non-alcoholic Fatty Liver Disease/enzymology
• Non-alcoholic Fatty Liver Disease/metabolism
• Signal Transduction/genetics
• Signal Transduction/physiology

• P01 DK057751 NIDDK NIH HHS
• R01 AG066671 NIA NIH HHS

• Actin cytoskeleton
• Filopodia
• OPC
• U0126
• pERK1/2

• Animals
• Butadienes/pharmacology
• Cell Movement/drug effects
• Cell Movement/physiology
• Cells, Cultured
• Fibronectins/metabolism
• Fibronectins/pharmacology
• MAP Kinase Signaling System/drug effects
• MAP Kinase Signaling System/physiology
• Nitriles/pharmacology
• Oligodendroglia/drug effects
• Oligodendroglia/metabolism
• Platelet-Derived Growth Factor/metabolism
• Platelet-Derived Growth Factor/pharmacology
• Protein Binding/physiology
• Pseudopodia/drug effects
• Pseudopodia/metabolism
• Rats
• Stem Cells/drug effects
• Stem Cells/metabolism

• Science and Engineering Research Board (IN)