Rule-Based Cell Systems Model of Aging using Feedback Loop Motifs Mediated by Stress Responses

Investigating the complex systems dynamics of the aging process requires integration of a broad range of cellular processes describing damage and functional decline co-existing with adaptive and protective regulatory mechanisms. We evolve an integrated generic cell network to represent the connectivity of key cellular mechanisms structured into positive and negative feedback loop motifs centrally important for aging. The conceptual network is casted into a fuzzy-logic, hybrid-intelligent framework based on interaction rules assembled from a priori knowledge. Based upon a classical homeostatic representation of cellular energy metabolism, we first demonstrate how positive-feedback loops accelerate damage and decline consistent with a vicious cycle. This model is iteratively extended towards an adaptive response model by incorporating protective negative-feedback loop circuits. Time-lapse simulations of the adaptive response model uncover how transcriptional and translational changes, mediated by stress sensors NF-κB and mTOR, counteract accumulating damage and dysfunction by modulating mitochondrial respiration, metabolic fluxes, biosynthesis, and autophagy, crucial for cellular survival. The model allows consideration of lifespan optimization scenarios with respect to fitness criteria using a sensitivity analysis. Our work establishes a novel extendable and scalable computational approach capable to connect tractable molecular mechanisms with cellular network dynamics underlying the emerging aging phenotype

Oxidative protein labeling in mass-spectrometry-based proteomics

Oxidation of proteins and peptides is a common phenomenon, and can be employed as a labeling technique for mass-spectrometry-based proteomics. Nonspecific oxidative labeling methods can modify almost any amino acid residue in a protein or only surface-exposed regions. Specific agents may label reactive functional groups in amino acids, primarily cysteine, methionine, tyrosine, and tryptophan. Nonspecific radical intermediates (reactive oxygen, nitrogen, or halogen species) can be produced by chemical, photochemical, electrochemical, or enzymatic methods. More targeted oxidation can be achieved by chemical reagents but also by direct electrochemical oxidation, which opens the way to instrumental labeling methods. Oxidative labeling of amino acids in the context of liquid chromatography(LC)–mass spectrometry (MS) based proteomics allows for differential LC separation, improved MS ionization, and label-specific fragmentation and detection. Oxidation of proteins can create new reactive groups which are useful for secondary, more conventional derivatization reactions with, e.g., fluorescent labels. This review summarizes reactions of oxidizing agents with peptides and proteins, the corresponding methodologies and instrumentation, and the major, innovative applications of oxidative protein labeling described in selected literature from the last decade

Temperature stress and redox homeostasis: The synergistic network of redox and chaperone system in response to stress in plants

A remarkable number of strategies has been developed by living organisms to mitigate conflict with environmental changes. The global environment rising with ambient temperature has a wide range of effects on plant growth, and therefore activation of various molecular defenses before the appearance of heat damage. Evidence revealed key components of stress that trigger enhanced tolerance, and some determinants for plant tolerance have been identified. The interplay between heat shock proteins (HSP) and redox proteins is supposed to be vital for the survival under extreme stress conditions. Any circumstance in which cellular redox homeostasis is disrupted can lead to the generation of reactive oxygen species (ROS) that are continuously generated in cells as an unavoidable consequence of aerobic life. Integrative network analysis of synthetic genetic interactions, protein-protein interactions, and functional annotations revealed many new functional processes linked to heat stress (HS) and oxidative stress (OS) tolerance, implicated upstream regulators activated by the either HS or OS, and revealed new connections between them. We present different models of acquired stress resistance to interpret the condition-specific involvement of genes. Considering the basic concepts and the recent advances, the following subsections provide an overview of calcium ion (Ca2+) and ROS interplay in abiotic signaling pathways; further we introduce several examples of chaperone and redox proteins that respond the change of cellular redox status under environmental circumstances. Thus, the involvement or contribution of redox proteins through the functional switching in conjunction with the HSP that prevent heat- and oxidative-induced protein aggregation in plants