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Objective Trained immunity (TI) is a de facto memory program of innate immune cells, characterized by immunometabolic and epigenetic changes sustaining enhanced production of cytokines. TI evolved as a protective mechanism against infections; however, inappropriate activation can cause detrimental inflammation and might be implicated in the pathogenesis of chronic inflammatory diseases. In this study, we investigated the role of TI in the pathogenesis of giant cell arteritis (GCA), a large-vessel vasculitis characterized by aberrant macrophage activation and excess cytokine production. Methods Monocytes from GCA patients and from age- and sex-matched healthy donors were subjected to polyfunctional studies, including cytokine production assays at baseline and following stimulation, intracellular metabolomics, chromatin immunoprecipitation-qPCR, and combined ATAC/RNA sequencing. Immunometabolic activation (i.e. glycolysis) was assessed in inflamed vessels of GCA patients with FDG-PET and immunohistochemistry (IHC), and the role of this pathway in sustaining cytokine production was confirmed with selective pharmacologic inhibition in GCA monocytes. Results GCA monocytes exhibited hallmark molecular features of TI. Specifically, these included enhanced IL-6 production upon stimulation, typical immunometabolic changes (e.g. increased glycolysis and glutaminolysis) and epigenetic changes promoting enhanced transcription of genes governing pro-inflammatory activation. Immunometabolic changes of TI (i.e. glycolysis) were a feature of myelomonocytic cells in GCA lesions and were required for enhanced cytokine production. Conclusions Myelomonocytic cells in GCA activate TI programs sustaining enhanced inflammatory activation with excess cytokine production. [ABSTRACT FROM AUTHOR]

The transcription factor family of nuclear factor kappa B (NF-κB) proteins is widely recognized as a key player in inflammation and the immune responses, where it plays a fundamental role in translating external inflammatory cues into precise transcriptional programs, including the timely expression of a wide variety of cytokines/chemokines. Live cell imaging in single cells showed approximately 15 years ago that the canonical activation of NF-κB upon stimulus is very dynamic, including oscillations of its nuclear localization with a period close to 1.5 hours. This observation has triggered a fruitful interdisciplinary research line that has provided novel insights on the NF-κB system: how its heterogeneous response differs between cell types but also within homogeneous populations; how NF-κB dynamics translate external cues into intracellular signals and how NF-κB dynamics affects gene expression. Here we review the main features of this live cell imaging approach to the study of NF-κB, highlighting the key findings, the existing gaps of knowledge and hinting towards some of the potential future steps of this thriving research field. [ABSTRACT FROM AUTHOR]

Boosting antitumor immunity has emerged as a powerful strategy in cancer treatment. While releasing T‐cell brakes has received most attention, tumor recognition by T cells is a pre‐requisite. Radiotherapy and certain cytotoxic drugs induce the release of damage‐associated molecular patterns, which promote tumor antigen cross‐presentation and T‐cell priming. Antibodies against the "do not eat me" signal CD47 cause macrophage phagocytosis of live tumor cells and drive the emergence of antitumor T cells. Here we show that CXCR4 activation, so far associated only with tumor progression and metastasis, also flags tumor cells to immune recognition. Both CXCL12, the natural CXCR4 ligand, and BoxA, a fragment of HMGB1, promote the release of DAMPs and the internalization of CD47, leading to protective antitumor immunity. We designate as Immunogenic Surrender the process by which CXCR4 turns in tumor cells to macrophages, thereby subjecting a rapidly growing tissue to immunological scrutiny. Importantly, while CXCL12 promotes tumor cell proliferation, BoxA reduces it, and might be exploited for the treatment of malignant mesothelioma and a variety of other tumors. Synopsis: Induction of antitumor immunity is a successful strategy in cancer treatment. This study reports that BoxA, a fragment of the alarmin HMGB1, induces tumor remission and antitumor immunity in mouse models of mesothelioma and colon carcinoma. Both BoxA and the chemokine CXCL12 bind the G‐Protein Coupled Receptor CXCR4.CXCR4 and CD47 are in contact on the surface of tumor cells and co‐internalize upon CXCR4 engagement by either BoxA or CXCL12.Both CXCL12 and BoxA induce the phagocytosis of tumor cells by macrophages.BoxA inhibits tumor cell growth and induces antitumor immunological memory in syngeneic mouse models of mesothelioma or colon carcinoma.CXCL12 is suggested to mediate a similar response (Immunogenic Surrender) in a fraction of untreated tumor‐bearing mice. [ABSTRACT FROM AUTHOR]

The eukaryotic transcriptional regulator Nuclear Factor kappa B (NF-κB) plays a central role in the defense to pathogens. Despite this, few studies have analyzed NF-κB activity in single cells during infection. Here, we investigated at the single cell level how NF-κB nuclear localization – a proxy for NF-κB activity – oscillates in infected and uninfected fibroblasts co-existing in cultures exposed toSalmonella entericaserovar Typhimurium. Fibroblasts were used due to the capacity ofS. Typhimurium to persist in this cell type. Real-time dynamics of NF-κB was examined in microfluidics, which prevents cytokine accumulation. In this condition, infected (ST+) cells translocate NF-κB to the nucleus at higher rate than the uninfected (ST-) cells. Surprisingly, in non-flow (static) culture conditions, ST- fibroblasts exhibited higher NF-κB nuclear translocation than the ST+ population, with these latter cells turning refractory to external stimuli such as TNF-α or a second infection. Sorting of ST+ and ST- cell populations confirmed enhanced expression of NF-κB target genes such asIL1B, NFKBIA, TNFAIP3, andTRAF1in uninfected (ST-) fibroblasts. These observations proved thatS. Typhimurium dampens the NF-κB response in the infected fibroblast. Higher expression ofSOCS3, encoding a “suppressor of cytokine signaling,” was also observed in the ST+ population. IntracellularS. Typhimurium subverts NF-κB activity using protein effectors translocated by the secretion systems encoded by pathogenicity islands 1 (T1) and 2 (T2). T1 is required for regulating expression ofSOCS3and all NF-κB target genes analyzed whereas T2 displayed no role in the control ofSOCS3andIL1Bexpression. Collectively, these data demonstrate thatS. Typhimurium attenuates NF-κB signaling in fibroblasts, an effect only perceptible when ST+ and ST- populations are analyzed separately. This tune-down in a central host defense might be instrumental forS. Typhimurium to establish intracellular persistent infections. [ABSTRACT FROM AUTHOR]

NF-κB is a transcription factor that upon activation undergoes cycles of cytoplasmic-to-nuclear and nuclear-to-cytoplasmic transport, giving rise to so called “oscillations”. In turn, oscillations tune the transcriptional output. Since a detailed understanding of oscillations requires a systems biology approach, we developed a method to acquire and analyze large volumes of data on NF-κB dynamics in single cells. We measured the time evolution of the nuclear to total ratio of GFP-p65 in knock-in mouse embryonic fibroblasts using time-lapse imaging. We automatically produced a precise segmentation of nucleus and cytoplasm based on an accurate estimation of the signal and image background. Finally, we defined a set of quantifiers that describe the oscillatory dynamics, which are internally normalized and can be used to compare data recorded by different labs. Using our method, we analyzed NF-κB dynamics in over 2000 cells exposed to different concentrations of TNF- α α. We reproduced known features of the NF-κB system, such as the heterogeneity of the response in the cell population upon stimulation and we confirmed that a fraction of the responding cells does not oscillate. We also unveiled important features: the second and third oscillatory peaks were often comparable to the first one, a basal amount of nuclear NF-κB could be detected in unstimulated cells, and at any time a small fraction of unstimulated cells showed spontaneous random activation of the NF-κB system. Our work lays the ground for systematic, high-throughput, and unbiased analysis of the dynamics of transcription factors that can shuttle between the nucleus and other cell compartments. [ABSTRACT FROM AUTHOR]

Chaotic scattering in open Hamiltonian systems is relevant for different problems in physics. Particles in such kind of systems can exhibit both bounded or unbounded motions for which escapes from the scattering region can take place. This paper analyzes how to control the escape of the particles from the scattering region in the presence of noise. For that purpose, we apply the partial control technique to the Hénon-Heiles system, which implies that we need to use a control smaller than the noise present in the system. The main finding of our work is the successful control of the particles in the scattering region with a control smaller than noise. We have also analyzed and compared the escapes time of orbits in the scattering region for different situations. Finally, we believe that our results might contribute to a better understanding of both chaotic scattering phenomena and the application of the partial control technique to continuous dynamical systems. [ABSTRACT FROM AUTHOR]

We present an analog circuit implementation of the novel partial control method, that is able to sustain chaotic transient dynamics. The electronic circuit simulates the dynamics of the one-dimensional slope-three tent map, for which the trajectories diverge to infinity for nearly all the initial conditions after behaving chaotically for a while. This is due to the existence of a nonattractive chaotic set: a chaotic saddle. The partial control allows one to keep the trajectories close to the chaotic saddle, even if the control applied is smaller than the effect of the applied noise, introduced into the system. Furthermore, we also show here that similar results can be implemented on a circuit that simulates a horseshoe-like map, which is a simple extension of the previous one. This encouraging result validates the theory and opens new perspectives for the application of this technique to systems with higher dimensions and continuous time dynamics. [ABSTRACT FROM AUTHOR]

In this paper, we study the nonlinear response of the nonlinear mass-spring model with nonsmooth stiffness. For this purpose, we take as prototype model, a system that consists of the double-well smooth potential with an additional spring component acting on the system only for large enough displacement. We focus our study on the analysis of the homoclinic orbits for such nonlinear potential for which we observe the appearance of chaotic motion in the presence of damping effects and an external harmonic force, analyzing the crucial role of the linear spring in the dynamics of our system. The results are shown by using both the Melnikov analysis and numerical simulations. We expect our work to have implications on problems concerning the suspension of vehicles, among others. [ABSTRACT FROM AUTHOR]

We study, both numerically and experimentally, the synchronization of uncoupled excitable systems due to a common noise. We consider two identical FitzHugh-Nagumo systems, which display both spiking and nonspiking behaviours in chaotic or periodic regimes. An electronic circuit provides a laboratory implementation of these dynamics. Synchronization is tested with both white and coloured noise, showing that coloured noise is more effective in inducing synchronization of the systems. We also study the effects on the synchronization of parameter mismatch and of the presence of intrinsic (not common) noise, and we conclude that the best performance of coloured noise is robust under these distortions. [ABSTRACT FROM AUTHOR]

A well-known method to suppress chaos in a periodically forced chaotic system is to add a harmonic perturbation. The phase control of chaos scheme uses the phase difference between a small added harmonic perturbation and the main driving to suppress chaos, leading the system to different periodic orbits. Using the Duffing oscillator as a paradigm, we present here an in-depth study of this technique. A thorough numerical exploration has been made focused in the important role played by the phase, from which new interesting patterns in parameter space have appeared. On the other hand, our novel experimental implementation of phase control in an electronic circuit confirms both the well-known features of this method and the new ones detected numerically. All this may help in future implementations of phase control of chaos, which is globally confirmed here to be robust and easy to implement experimentally. [ABSTRACT FROM AUTHOR]

In this review, we aim at describing the results obtained in the past years on dynamics features defining NF-κB regulatory functions, as we believe that these developments might have a transformative effect on the way in which NF-κB involvement in cancer is studied. We will also describe technical aspects of the studies performed in this context, including the use of different cellular models, culture conditions, microscopy approaches and quantification of the imaging data, balancing their strengths and limitations and pointing out to common features and to some open questions. Our emphasis in the methodology will allow a critical overview of literature and will show how these cutting-edge approaches can contribute to shed light on the involvement of NF-κB deregulation in tumour onset and progression. We hypothesize that this “dynamic point of view” can be fruitfully applied to untangle the complex relationship between NF-κB and cancer and to find new targets to restrain cancer growth. [ABSTRACT FROM AUTHOR]