Gas Plasma Protein Oxidation Increases Immunogenicity and Human Antigen-Presenting Cell Maturation and Activation

Protein vaccines rely on eliciting immune responses. Inflammation is a prerequisite for immune responses to control infection and cancer but is also associated with disease onset. Reactive oxygen species (ROSs) are central during inflammation and are capable of inducing non-enzymatic oxidative protein modifications (oxMods) associated with chronic disease, which alter the functionality or immunogenicity of proteins that are relevant in cancer immunotherapy. Specifically, antigen-presenting cells (APCs) take up and degrade extracellular native and oxidized proteins to induce adaptive immune responses. However, it is less clear how oxMods alter the protein’s immunogenicity, especially in inflammation-related short-lived reactive species. Gas plasma technology simultaneously generates a multitude of ROSs to modify protein antigens in a targeted and controlled manner to study the immunogenicity of oxMods. As model proteins relevant to chronic inflammation and cancer, we used gas plasma-treated insulin and CXCL8. We added those native or oxidized proteins to human THP-1 monocytes or primary monocyte-derived cells (moDCs). Both oxidized proteins caused concentration-independent maturation phenotype alterations in moDCs and THP-1 cells concerning surface marker expression and chemokine and cytokine secretion profiles. Interestingly, concentration-matched H2O2-treated proteins did not recapitulate the effects of gas plasma, suggesting sufficiently short diffusion distances for the short-lived reactive species to modify proteins. Our data provide evidence of dendric cell maturation and activation upon exposure to gas plasma- but not H2O2-modified model proteins. The biological consequences of these findings need to be elucidated in future inflammation and cancer disease models

Of Animal Husbandry and Food Production—A First Step towards a Modular Agent-Based Modelling Platform for Socio-Ecological Dynamics

Agent-based models provide detailed, bottom-up approaches to investigate complex socio-ecological systems. This study presents a first step towards a modular agent-based simulation that is based upon empirical data, as well as environmental suitability maps and an assessment of livestock units. To illustrate the capabilities of our simulation, we use a geographically explicit approach to simulate a component of the production of animal products of a rural settlement in the lower Bakırçay catchment, western Turkey. The model structurally couples various agent types representing several elements and processes of the animal husbandry and food production value chain, such as sedentary herders—practising daily, short-distance pastoralism—and their flocks of goats and sheep, as well as milking and slaughtering. The modelling tool captures the fundamental socio-ecological dynamics of animal husbandry and food production in rural settlements. Therefore, the tool is valuable as a basis to discuss hypotheses regarding the number of animals that are needed to cover the requirements of different growing populations

Of Animal Husbandry and Food Production - A First Step towards a Modular Agent-Based Modelling Platform for Socio-Ecological Dynamics

Agent-based models provide detailed, bottom-up approaches to investigate complex socio-ecological systems. This study presents a first step towards a modular agent-based simulation that is based upon empirical data, as well as environmental suitability maps and an assessment of livestock units. To illustrate the capabilities of our simulation, we use a geographically explicit approach to simulate a component of the production of animal products of a rural settlement in the lower Bakırçay catchment, western Turkey. The model structurally couples various agent types representing several elements and processes of the animal husbandry and food production value chain, such as sedentary herders—practising daily, short-distance pastoralism - and their flocks of goats and sheep, as well as milking and slaughtering. The modelling tool captures the fundamental socio-ecological dynamics of animal husbandry and food production in rural settlements. Therefore, the tool is valuable as a basis to discuss hypotheses regarding the number of animals that are needed to cover the requirements of different growing populations

Oxidized Proteins Differentially Affect Maturation and Activation of Human Monocyte-Derived Cells

In cancer, antigen-presenting cells (APC), including dendritic cells (DCs), take up and process proteins to mount adaptive antitumor immune responses. This often happens in the context of inflamed cancer, where reactive oxygen species (ROS) are ubiquitous to modify proteins. However, the inflammatory consequences of oxidized protein uptake in DCs are understudied. To this end, we investigated human monocyte-derived cell surface marker expression and cytokine release profiles when exposed to oxidized and native proteins. Seventeen proteins were analyzed, including viral proteins (e.g., CMV and HBV), inflammation-related proteins (e.g., HO1 and HMGB1), matrix proteins (e.g., Vim and Coll), and vastly in the laboratory used proteins (e.g., BSA and Ova). The multifaceted nature of inflammation-associated ROS was mimicked using gas plasma technology, generating reactive species cocktails for protein oxidation. Fourteen oxidized proteins led to elevated surface marker expression levels of CD25, CD40, CD80, CD86, and MHC-II as well as strongly modified release of IL6, IL8, IL10, IL12, IL23, MCP-1, and TNFα compared to their native counterparts. Especially IL8, heme oxygenase 2, and vimentin oxidation gave pronounced effects. Furthermore, protein kinase phospho-array studies in monocyte-derived cells pulsed with native vs. oxidized IL8 and insulin showed enhanced AKT and RSK2 phosphorylation. In summary, our data provide for the first time an overview of the functional consequences of oxidized protein uptake by human monocyte-derived cells and could therefore be a starting point for exploiting such principle in anticancer therapy in the future

Argon Plasma Exposure Augments Costimulatory Ligands and Cytokine Release in Human Monocyte-Derived Dendritic Cells

Cold physical plasma is a partially ionized gas expelling many reactive oxygen and nitrogen species (ROS/RNS). Several plasma devices have been licensed for medical use in dermatology, and recent experimental studies suggest their putative role in cancer treatment. In cancer therapies with an immunological dimension, successful antigen presentation and inflammation modulation is a key hallmark to elicit antitumor immunity. Dendritic cells (DCs) are critical for this task. However, the inflammatory consequences of DCs following plasma exposure are unknown. To this end, human monocyte-derived DCs (moDCs) were expanded from isolated human primary monocytes; exposed to plasma; and their metabolic activity, surface marker expression, and cytokine profiles were analyzed. As controls, hydrogen peroxide, hypochlorous acid, and peroxynitrite were used. Among all types of ROS/RNS-mediated treatments, plasma exposure exerted the most notable increase of activation markers at 24 h such as CD25, CD40, and CD83 known to be crucial for T cell costimulation. Moreover, the treatments increased interleukin (IL)-1α, IL-6, and IL-23. Altogether, this study suggests plasma treatment augmenting costimulatory ligand and cytokine expression in human moDCs, which might exert beneficial effects in the tumor microenvironment

Review of Importance of Weather and Environmental Variables in Agent-Based Arbovirus Models

The study sought to review the works of literature on agent-based modeling and the influence of climatic and environmental factors on disease outbreak, transmission, and surveillance. Thus, drawing the influence of environmental variables such as vegetation index, households, mosquito habitats, breeding sites, and climatic variables including precipitation or rainfall, temperature, wind speed, and relative humidity on dengue disease modeling using the agent-based model in an African context and globally was the aim of the study. A search strategy was developed and used to search for relevant articles from four databases, namely, PubMed, Scopus, Research4Life, and Google Scholar. Inclusion criteria were developed, and 20 articles met the criteria and have been included in the review. From the reviewed works of literature, the study observed that climatic and environmental factors may influence the arbovirus disease outbreak, transmission, and surveillance. Thus, there is a call for further research on the area. To benefit from arbovirus modeling, it is crucial to consider the influence of climatic and environmental factors, especially in Africa, where there are limited studies exploring this phenomenon

Agent-Based Modeling and Simulation for Transmission Dynamics and Surveillance of Dengue: Conceptual and Design Model

African countries need to strengthen surveillance and control of arboviral diseases such as dengue due to increased outbreaks and spread of arboviruses. Climatic, socio-environment, and ecological variables influence the spread of dengue fever in Sub-Saharan Africa. This paper presents an Agent-Based conceptual and design model for dengue fever developed using the Multi-Agent Research and Simulation (MARS) framework. The study analyzes dengue fever's spatial distribution and identifies the causal relationship between the disease and its climatic and environmental variables. Agent-based modeling (ABM) was used to comprehend the spatial patterns of variation to determine the ecological association between the observed spatio-temporal variations in dengue fever. The domain and design model of an ABM for the surveillance of dengue fever is presented based on the Overview, Design Concepts, and Details (ODD) protocol. Model input parameters and input data for the study area are also presented. The dengue ABM can be adopted and reused for modeling other diseases and other complex problems from different domains while ensuring that their unique characteristics and appropriate modifications are considered to ensure the model's validity and relevance to the new context

Singlet-Oxygen-Induced Phospholipase A2 Inhibition: A Major Role for Interfacial Tryptophan Dioxidation

Several studies have revealed that various diseases such as cancer have been associated with elevated phospholipase A2 (PLA2) activity. Therefore, the regulation of PLA2 catalytic activity is undoubtedly vital. In this study, effective inactivation of PLA2 due to reactive species produced from cold physical plasma as a source to model oxidative stress is reported. We found singlet oxygen to be the most relevant active agent in PLA2 inhibition. A more detailed analysis of the plasma-treated PLA2 identified tryptophan 128 as a hot spot, rich in double oxidation. The significant dioxidation of this interfacial tryptophan resulted in an N-formylkynurenine product via the oxidative opening of the tryptophan indole ring. Molecular dynamics simulation indicated that the efficient interactions between the tryptophan residue and phospholipids are eliminated following tryptophan dioxidation. As interfacial tryptophan residues are predominantly involved in the attaching of membrane enzymes to the bilayers, tryptophan dioxidation and indole ring opening leads to the loss of essential interactions for enzyme binding and, consequently, enzyme inactivation. © 2021 The Authors. Chemistry - A European Journal published by Wiley-VCH Gmb

Elastic lever arm model for myosin V

We present a mechanochemical model for myosin V, a two-headed processive motor protein. We derive the properties of a dimer from those of an individual head, which we model both with a 4-state cycle (detached, attached with ADP.Pi, attached with ADP and attached without nucleotide) and alternatively with a 5-state cycle (where the power stroke is not tightly coupled to the phosphate release). In each state the lever arm leaves the head at a different, but fixed, angle. The lever arm itself is described as an elastic rod. The chemical cycles of both heads are coordinated exclusively by the mechanical connection between the two lever arms. The model explains head coordination by showing that the lead head only binds to actin after the power stroke in the trail head and that it only undergoes its power stroke after the trail head unbinds from actin. Both models (4- and 5-state) reproduce the observed hand-over-hand motion and fit the measured force-velocity relations. The main difference between the two models concerns the load dependence of the run length, which is much weaker in the 5-state model. We show how systematic processivity measurement under varying conditions could be used to distinguish between both models and to determine the kinetic parameters.Comment: 15 pages, 15 figures, to appear in Biophys.

Tumor cytotoxicity and immunogenicity of a novel V-jet neon plasma source compared to the kINPen

Recent research indicated the potential of cold physical plasma in cancer therapy. The plethora of plasma-derived reactive oxygen and nitrogen species (ROS/RNS) mediate diverse antitumor effects after eliciting oxidative stress in cancer cells. We aimed at exploiting this principle using a newly designed dual-jet neon plasma source (Vjet) to treat colorectal cancer cells. A treatment time-dependent ROS/RNS generation induced oxidation, growth retardation, and cell death within 3D tumor spheroids were found. In TUM-CAM, a semi in vivo model, the Vjet markedly reduced vascularized tumors' growth, but an increase of tumor cell immunogenicity or uptake by dendritic cells was not observed. By comparison, the argon-driven single jet kINPen, known to mediate anticancer effects in vitro, in vivo, and in patients, generated less ROS/RNS and terminal cell death in spheroids. In the TUM-CAM model, however, the kINPen was equivalently effective and induced a stronger expression of immunogenic cancer cell death (ICD) markers, leading to increased phagocytosis of kINPen but not Vjet plasma-treated tumor cells by dendritic cells. Moreover, the Vjet was characterized according to the requirements of the DIN-SPEC 91315. Our results highlight the plasma device-specific action on cancer cells for evaluating optimal discharges for plasma cancer treatment