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Programmable C−N Bond Formation through Radical‐Mediated Chemistry in Plasma‐Microdroplet Fusion

AbstractNon‐thermal plasma discharge produced in the wake of charged microdroplets is found to facilitate catalyst‐free radical mediated hydrazine cross‐coupling reactions without the use of external light source, heat, precious metal complex, or trapping agents. A plasma‐microdroplet fusion platform is utilized for introduction of hydrazine reagent that undergoes homolytic cleavage forming radical intermediate species. The non‐thermal plasma discharge that causes the cleavage originates from a chemically etched silica capillary. The coupling of the radical intermediates gives various products. Plasma‐microdroplet fusion occurs online in a programmable reaction platform allowing direct process optimization and product validation via mass spectrometry. The platform is applied herein with a variety of hydrazine substrates, enabling i) self‐coupling to form secondary amines with identical N‐substitutions, ii) cross‐coupling to afford secondary amine with different N‐substituents, iii) cross‐coupling followed by in situ dehydrogenation to give the corresponding aryl‐aldimines with two unique N‐substitutions, and iv) cascade heterocyclic carbazole derivatives formation. These unique reactions were made possible in the charged microdroplet environment through our ability to program conditions such as reagent concentration (i. e., flow rate), microdroplet reactivity (i. e., presence or absence of plasma), and reaction timescale (i. e., operational mode of the source). The selected program is implemented in a co‐axial spray format, which is found to be advantageous over the conventional one‐pot single emitter electrospray‐based microdroplet reactions.

Programmable C-N Bond Formation through Radical-Mediated Chemistry in Plasma-Microdroplet Fusion.

Non-thermal plasma discharge produced in the wake of charged microdroplets is found to facilitate catalyst-free radical mediated hydrazine cross-coupling reactions without the use of external light source, heat, precious metal complex, or trapping agents. A plasma-microdroplet fusion platform is utilized for introduction of hydrazine reagent that undergoes homolytic cleavage forming radical intermediate species. The non-thermal plasma discharge that causes the cleavage originates from a chemically etched silica capillary. The coupling of the radical intermediates gives various products. Plasma-microdroplet fusion occurs online in a programmable reaction platform allowing direct process optimization and product validation via mass spectrometry. The platform is applied herein with a variety of hydrazine substrates, enabling i) self-coupling to form secondary amines with identical N-substitutions, ii) cross-coupling to afford secondary amine with different N-substituents, iii) cross-coupling followed by in-situ dehydrogenation to give the corresponding aryl-aldimines with two unique N-substitutions, and iv) cascade heterocyclic carbazole derivatives formation. These unique reactions were made possible in the charged microdroplet environment through our ability to program conditions such as reagent concentration (i.e., flowrate), microdroplet reactivity (i.e., presence or absence of plasma), and reaction timescale (i.e., operational mode source). The selected program is implemented in a co-axial spray format.

The Internalization Pathways of Liposomes, PLGA, and Magnetic Nanoparticles in Neutrophils.

Neutrophils are emerging as promising candidates for cell-based nanodrug delivery to tumors due to their unique biological properties. This study aims to investigate the mechanisms of nanoparticle internalization by neutrophils, specifically focusing on liposomes, poly(lactic-co-glycolic acid) (PLGA), and magnetite nanoparticles. Understanding these mechanisms could enhance the efficiency of neutrophil-based nanodrug delivery for cancer treatment. Neutrophils were isolated from the peripheral blood of mice bearing 4T1 mammary adenocarcinoma. Confocal microscopy, transmission electron microscopy, and flow cytometry were employed to evaluate the uptake of liposomes, PLGA, and magnetite nanoparticles by neutrophils. The effects of cultivation conditions, such as the presence or absence of plasma in the growth medium, were also examined. Additionally, the roles of immunoglobulins (IgG/IgM) and cell surface receptors (Fc and scavenger receptors) in nanoparticle internalization were explored. All types of nanoparticles were successfully internalized by neutrophils, though the mechanisms of uptake varied. Plasma presence in the medium significantly influenced nanoparticle binding, particularly for PLGA nanoparticles. Internalization of PLGA nanoparticles was found to depend on the presence of IgG/IgM in the medium and Fc receptors on neutrophil surfaces, while scavenger receptors were not involved. Understanding the distinct endocytosis pathways for different nanoparticles can improve the efficacy of neutrophil loading with nanodrugs, potentially advancing the development of neutrophil-based cancer therapies. The findings underscore the importance of the extracellular environment in modulating nanoparticle uptake.

Electron trapping efficiency of a magnetron sputtering cathode

A common feature of all types of magnetron sputtering (MS) assemblies is an effective confinement of electrons by an appropriate combination of electric and magnetic fields. Therefore, studying the motions of electrons in the fields of magnetron assemblies is of particular importance. Here, we systematically analyze the electrons motions in front of a typical DC MS cathode. We first calculate the profiles of the magnetron’s magnetic field for balanced and two types of unbalanced configurations. Then, we compute the profiles of the cathode’s electric field before the gas discharge and after the plasma formation. A semi-analytical model is utilized to compute the plasma potential. We then track the motions of electrons released from the target and electrons produced through impact ionization of the background gas in the prescribed fields. A Monte Carlo model is implemented to consider electron-gas collisions and a mixed boundary condition is employed to account for electron-wall interactions. The study analyzes the impact of field profiles on the cathode’s efficiency in trapping electron by examining electron escape from the magnetic trap and electron recapture at the target surface. It is shown that the presence of plasma in all configurations leads to a significant increase in the trapping efficiency and the ionization performance, as well as a decrease in the recapture probability. These effects are attributed to the high electric field developed in the cathode sheath. Moreover, we statistically analyze the trapping efficiency by illustrating the spatial distributions of electrons locations in both axial and radial dimensions. It is demonstrated that during their azimuthal drift motion, the electrons released from the middle region at the target surface have the smallest range of axial and radial locations, in all configurations in the absence of plasma. Finally, the impact of field profiles on the average energies of electrons is discussed.

Phase and Morphology of Water-ice Grains Formed in a Cryogenic Laboratory Plasma

Grains of ice are formed spontaneously when water vapor is injected into a weakly ionized laboratory plasma in which the background gas has been cooled to cryogenic temperatures comparable to those of deep space. These ice grains are levitated indefinitely within the plasma so that their time evolution can be observed under free-floating conditions. Using microscope imaging, ice grains are shown to have a spindle-like fractal structure and grow over time. Both crystalline and amorphous phases of ice are observed using Fourier transform infrared spectroscopy. A mix of crystalline and amorphous grains coexists under certain thermal conditions, and a linear mixing model is used on the ice absorption band surrounding 3.2 μm to examine the ice phase composition and its temporal stability. The extinction spectrum is also affected by inelastic scattering as grains grow, and characteristic grain radii are obtained from Mie scattering theory and compared to size measurements from direct imaging. Observations are used to compare possible ice nucleation mechanisms, and it is concluded that nucleation is likely catalyzed by ions, as ice does not nucleate in the absence of plasma and impurities are not detected. Ice grain properties and infrared extinction spectra show similarity to observations of some astrophysical ices observed in protoplanetary disks, implying that the fractal morphology of the ice and observed processes of homogeneous ice nucleation could occur as well in such astrophysical environments with weakly ionized conditions.

Transient Binding Dynamics of Complement System Pattern Recognition Molecules on Pathogens.

Previous studies of pattern recognition molecules (PRMs) of the complement system have revealed difficulties in observing binding on pathogens such as Aspergillus fumigatus and Escherichia coli, despite complement deposition indicative of classical and lectin pathway activation. Thus, we investigated the binding dynamics of PRMs of the complement system, specifically C1q of the classical pathway and mannose-binding lectin (MBL) of the lectin pathway. We observed consistently increasing deposition of essential complement components such as C4b, C3b, and the terminal complement complex on A. fumigatus and E. coli. However, C1q and MBL binding to the surface rapidly declined during incubation after just 2-4 min in 10% plasma. The detachment of C1q and MBL can be linked to complement cascade activation, as the PRMs remain bound in the absence of plasma. The dissociation and the fate of C1q and MBL seem to have different mechanistic functions. Notably, C1q dynamics were associated with local C1 complex activation. When C1s was inhibited in plasma, C1q binding not only remained high but further increased over time. In contrast, MBL binding was inversely correlated with total and early complement activation due to MBL binding being partially retained by complement inhibition. Results indicate that detached MBL might be able to functionally rebind to A. fumigatus. In conclusion, these results reveal a (to our knowledge) novel "hit-and-run" complement-dependent PRM dynamic mechanism on pathogens. These dynamics may have profound implications for host defense and may help increase the functionality and longevity of complement-dependent PRMs in circulation.

Improving In Vitro-In Vivo Extrapolation of Clearance Using Rat Liver Microsomes for Highly Plasma Protein-Bound Molecules.

It is common practice in drug discovery and development to predict in vivo hepatic clearance from in vitro incubations with liver microsomes or hepatocytes using the well-stirred model (WSM). When applying the WSM to a set of approximately 3000 Novartis research compounds, 73% of neutral and basic compounds (extended clearance classification system [ECCS] class 2) were well-predicted within 3-fold. In contrast, only 44% (ECCS class 1A) or 34% (ECCS class 1B) of acids were predicted within 3-fold. To explore the hypothesis whether the higher degree of plasma protein binding for acids contributes to the in vitro-in vivo correlation (IVIVC) disconnect, 68 proprietary compounds were incubated with rat liver microsomes in the presence and absence of 5% plasma. A minor impact of plasma on clearance IVIVC was found for moderately bound compounds (fraction unbound in plasma [fup] ≥1%). However, addition of plasma significantly improved the IVIVC for highly bound compounds (fup <1%) as indicated by an increase of the average fold error from 0.10 to 0.36. Correlating fup with the scaled unbound intrinsic clearance ratio in the presence or absence of plasma allowed the establishment of an empirical, nonlinear correction equation that depends on fup Taken together, estimation of the metabolic clearance of highly bound compounds was enhanced by the addition of plasma to microsomal incubations. For standard incubations in buffer only, application of an empirical correction provided improved clearance predictions. SIGNIFICANCE STATEMENT: Application of the well-stirred liver model for clearance in vitro-in vivo extrapolation (IVIVE) in rat generally underpredicts the clearance of acids and the strong protein binding of acids is suspected to be one responsible factor. Unbound intrinsic in vitro clearance (CLint,u) determinations using rat liver microsomes supplemented with 5% plasma resulted in an improved IVIVE. An empirical equation was derived that can be applied to correct CLint,u-values in dependance of fraction unbound in plasma (fup) and measured CLint in buffer.

Managing the Scaling Relationship for Plasma-Activated Electrolysis Toward Nitrogen Fixation

To substitute fossil feedstock, storing renewable electricity in chemical bonds has become one of the tremendous and attractive approaches. This approach enables the transformation of base molecules (i.e., H2O, N2, CO2) into energy or chemical-rich molecules. The energy stored in the nitrogen-based compound is a critical biogeochemical cycle in nature due to its essential nutrient for living organisms in the forms of ammonia, nitrates, urea, amino acids, and DNA/RNA nucleotides as well as the high atmospheric volume of 78%. Artificial nitrogen fixation via a catalytic approach powered by sustainable renewables (e.g. wind, solar) provides an alternative as well as promising route to resource the value-added chemicals.N2 is a nonreactive base molecule due to its non-polarity and a strong triple bond between the atoms. Subsequently, even with an active catalyst, a substantial amount of energy is needed to activate N2 [1]. This Account covers our group’s recent advances in solid oxide electrolysis cells (SOECs) for providing reacting species on catalysts in a controllable manner while a radio frequency (RF) plasma is used to increase the reactivity of nitrogen [2,3]. Using oxygen ion or proton conducting SOECs we can produce either ammonia or nitric oxide (via reacting with plasma-activated N2) by suppressing oxygen or hydrogen evolution, respectively. The spatial separation of nitrogen dissociation and catalytic formation of the target molecules provides true independent parameters to optimize the electrocatalytic reactions. In both cases, the concentration of products is orders of magnitude higher than equilibrium (in the absence of plasma) while very high selectivity to nitrogen fixation is observed.To date most of the studies have focused on the material axis, however, recent theoretical studies have revealed that large-scale N2 fixation necessitates the rational design of the reactor, catalyst selectivity, reaction kinetics, and fluid dynamics and thus it keeps the processes far from the optimum performance. In this contribution, we investigate several aspects including flow dynamics, nature of the catalyst, activation energy of the catalytic process, catalyst surface-to-volume ratio, catalyst selectivity, and residence time of plasma-activated nitrogen to reach the catalyst surface, toward solving the aforementioned limitations.

An Optimized Human Erythroblast Differentiation System Reveals Cholesterol-Dependency of Robust Production of Cultured Red Blood Cells Ex Vivo

The generation of cultured red blood cells (cRBCs) ex vivo represents a potentially unlimited source for RBC transfusion and other cell therapies. However, efficient differentiation and terminal maturation (symbolized by enucleation) into cRBCs ex vivo highly depend on replenishing human plasma. In addition to cost, this requirement results in variable potency across donors or batches and complicates consistent cRBC production required for clinical translations. Thus, exploration of key factor(s) in plasma and development of a compositionally defined medium would be in need. To investigate the role of human plasma in erythroblast terminal maturation, we first optimized a widely-used differentiation system that we and other have used in the past decade. We found that culture of erythroblasts in a newly developed medium called human plasma like medium (HPLM) greatly improves the yield and consistence of erythrocyte maturation. However, human serum (1-2%) was indispensable for efficient terminal maturation in the absence of plasma. The serum-derived factor or factors (likely a protein or complex) is essential for erythroblast growth assessed at day 3 after induction of terminal differentiation. We used size exclusion chromatography (SEC) and other protein biochemistry approaches to fractionate human serum and assessed the biological effect of each fraction. We found that the activity is fractions containing proteins or complexes of &amp;gt;100K Da. Proteomics revealed that the fractions with biological activities are enriched for low density lipoproteins (LDL)-containing proteins such as apolipoprotein B-100. In addition, we performed RNA-sequencing (RNA-seq) analysis on cultured erythroblasts with or without serum. Transcriptomic data revealed that the genes associated with de novo biosynthesis of steroids and cholesterol are upregulated in the absence of serum, although production of enzymes encoded by these genes alone is insufficient to provide cholesterol required for erythroblast differentiation and maturation. Hence, we hypothesize that cholesterol-carrying LDL that are naturally present in blood is sufficient to replace human serum for erythroblast survival and terminal differentiation ex vivo. We next examined directly whether LDL purified from human blood is sufficient for erythroid commitment and enucleation. Through LDL binding and uptake assays, we confirmed that LDL binds to erythroblasts that expressed the LDL receptor and is transported intracellularly. Furthermore, LDL purified from human plasma can essentially replace 2% unfractionated serum for efficient generation of erythrocytes in culture. In addition to using human erythroblasts derived from peripheral blood mononuclear cells (PBMCs), we also extended this optimized protocol to human erythroblasts from various sources, including cord blood-derived mononuclear cells, CD34+ HSPCs, and extensively expanded erythroblasts after BMI1 gene transduction. After induction of terminal differentiation for 8 days, erythroblasts from all these sources effectively enucleated (&amp;gt;50%) and stably produced reticulocytes with no significant difference compared to the serum-containing system. We are also in progress to substitute LDL by chemical synthetic cholesterol. In sum, we developed a compositionally defined culture medium (LDL-containing Optimized Maturation Medium, LOAM) enabling robust generation of cRBCs from multiple sources of erythroblasts with high enucleation efficiency and higher reticulocyte yield compared to culture in traditional media supplemented with human plasma or serum. Using this advanced human erythroblast differentiation model, we further revealed that cholesterol carried by LDL is critical to erythroblast terminal maturation.

Helicobacter pylori extract induces purified neutrophils to produce reactive oxygen species only in the presence of plasma.

H. pylori is a bacterial pathogen infecting over half of the world's population and induces several gastric and extra-gastric diseases through its various virulence factors, especially cagA. These factors may be released from the bacteria during interactions with host immune cells. Neutrophils play key roles in innate immunity, and their activity is regulated by plasma factors, which can alter how these cells may interact with pathogens. The aim of the present study was to determine whether purified neutrophils could produce reactive oxygen species (ROS), one of the key functions of their anti-microbial functions, in response to extracts of cagA+ and cagA- H. pylori. Extracts from either cagA+ or cagA- H. pylori were co-cultured with human neutrophils in the presence or absence of plasma, and the neutrophil ROS production was measured. In the absence of plasma, extracts from cagA+ and cagA- H. pylori did not induce neutrophil ROS production, whereas in the presence of plasma, extracts from both cagA+ and cagA- H. pylori-induced ROS production. Furthermore, when peripheral blood mononuclear cells (PBMCs) were added to the purified neutrophils in the absence of plasma, there was no neutrophil ROS production after challenging with extracts from either cagA+ or cagA- H. pylori. Thus, it is suggested that plasma contains immunological components that change the responsiveness of neutrophils, such that when neutrophils encounter the bacterial antigens in H. pylori extracts, they become activated and produce ROS. This study also revealed a potential novel immunopathogenic pathway by which cagA activation of neutrophils contributed to inflammatory damage.

PFAS-CTAB Complexation and Its Role on the Removal of PFAS from a Lab-Prepared Water and a Reverse Osmosis Reject Water Using a Plasma Reactor.

Electrical discharge plasma reactors with argon bubbling can effectively treat long-chain perfluoroalkyl acids (PFAAs) in contaminated water, and the addition of a cationic surfactant cetrimonium bromide (CTAB) is known to enhance the removal of short-chain PFAAs. However, the roles of PFAA chain length, functional group, and water matrix properties on PFAA-CTAB complexation are largely unknown. This work investigated the bulk liquid removal of different PFAAs by CTAB in the absence of plasma. Stepwise addition of CTAB was subsequently used to efficiently treat PFAAs in a lab-prepared water and a reverse osmosis (RO) reject water using an enhanced contact plasma reactor. The results show that CTAB inhibited the bulk liquid removal of long-chain PFAAs in the absence of plasma likely due to the formation of hydrophilic CTAB-PFAA mixed micelles and competition for interfacial access between long-chain PFAAs and CTAB. On the contrary, CTAB enhanced the removal of short- and ultrashort-chain PFAAs by forming hydrophobic complexes. After 6 h of treatment in the plasma reactor with CTAB, PFAAs were 86 to >99% removed from the lab-prepared water and 29 to >99% removed from the RO reject water. This study provides important insights for overcoming mass transfer limitations for PFAA treatment technologies.

Neutral – Eradication of As (III) and Congo red (CR) with green iron oxide (GIO) loaded chitosan(C) - (C - GIO) beads by a non – thermal plasma jet via potential study

In this potential – study, the non – thermal atmospheric pressure plasma is utilized for the neutral – eradication of water contaminants. In the air ambient region, plasma induced reactive species, like as OH•, O (O2−), H2O2 (OH•+OH•) & NOx are performed for the oxidative and reductive transformation of AsIII (H3AsO3) to AsV (H2As O4−) & Fe3O4 (Fe3+) (C-GIO) to Fe2O3 (Fe2+). Whereas, the H2O2 & NOx are quantified maximum (max.) in water, which is 144.24 & 111.82 μM, respectively. In the absence of plasma and plasma with C-GIO, the AsIII was more eradicated, which is 64.01 and 100.00%. While, the C – GIO (catalyst) synergistic enhancement was performed and proved by the neutral – degradation of CR. Also, the AsV adsorbed on C-GIO adsorption capacity qmax and redox-adsorption yield were evaluated, which are 1.36 mg/g and 20.80 g/kWh, respectively. In this research, the waste material (GIO) was recycled, modified, and utilized for the neutral – eradication of water contaminates, which are organic (CR) and inorganic (AsIII) toxicants by the controlling of H and OH• under the interaction of plasma with catalyst (C-GIO). However, in this research, plasma can't adopt the acidic, which is controlled by the C-GIO via RONS. Moreover, in this eradicative study, various water pH alignments were performed, from neutral to acidic & neutral & base for toxicants removal. Furthermore, according to WHO norms, the arsenic level was reduced to 0.01 mg/l for environmental safety. The kinetic and isotherm studies were followed by the mono and multi-layer adsorption was performed on the surface of C – GIO beads, which is estimated by the fitting of rate limiting constant R2 ≈ 1. Furthermore, the C-GIO was examined several characterizations alignments, such as crystal, surface, functional, elemental composition, retention time, mass spectrum, and elemental oriented properties. Overall, the suggested hybrid system is an eco-friendly pathway for the natural – eradication of contaminants, such as organic and inorganic compounds via waste material (GIO) recycling, modification, oxidation, reduction, adsorption, degradation, and neutralization phenomenon.

Deflection angle analysis under the influence of non-plasma medium and plasma medium for regular black hole with cosmic string

By applying the Keeton and Petters technique, we find the deflection angle as a series expansion with a specific factor of mass. We investigate the shadow structure of a regular black hole with cosmic string with a non-magnetized, pressure-free plasma around it. In order to separate the Hamilton equation and locate the photon areas, certain plasma distributions are taken into consideration. Moreover, by utilizing a new ray-tracing technique, we analyze the photon’s path around a regular black hole with cosmic string in the presence of plasma whose density depends on the radius coordinate. We also analyze the plasma effects on the shadow of black hole. We obtain an analytical formula that describes the boundary curve of the shadow for such a black hole in an expanding universe for an observer at any finite location outside the horizon. In the presence and absence of plasma, we detect deviations that are further investigated by analyzing the geometry of shadow angle at a particular value of plasma frequency.

Experimental study on burning velocity, structure, and NOx emission of premixed laminar and swirl NH3/H2/air flames assisted by non-thermal plasma

This paper investigates the effect of dielectric barrier discharge (DBD) plasma on premixed laminar and swirl NH3/H2 flames by applying a coaxial DBD to the unburned gas mixture. We focused on analyzing the flame structure, burning velocity, lean blow-off limit, and NOx emission characteristics of premixed NH3/H2 flames in the presence and absence of plasma. The mechanism of plasma-enhanced burning velocity was revealed through kinetic simulations based on the CHEMKIN software. The results indicate that DBD plasma can reduce the laminar flame height and increase the laminar burning velocity (LBV). The chemical kinetic effect is dominant for the enhancement of LBV, while the effect of hydrogen generated from ammonia dissociation and ozone is relatively weak. DBD plasma can significantly change the structure of the swirl flames, while has a slight effect on extending the lean blow-off limits of the swirl flames. Finally, emission measurements indicate that DBD plasma increases the NOx emissions for both the premixed laminar and swirl NH3/H2 flames. This effect can be attributed to the reaction pathways involving of H and OH radicals for NOx formation. It is assumed that the effect of hydrogen and DBD plasma on stability and burning velocity is synergistic, while the effect of hydrogen and plasma on NOx emissions is competitive.

Plasma-Enhanced Chemical Looping Oxidative Coupling of Methane through Synergy between Metal-Loaded Dielectric Particles and Non-Thermal Plasma

A plasma–catalyst hybrid system has been developed for the direct conversion of methane to C2+ hydrocarbons in dielectric barrier discharge (DBD) plasma. TiO2 presented the highest C2+ yield of 11.63% among different dielectric materials when integrated with DBD plasma, which made us concentrate on the TiO2-based catalyst. It was demonstrated that MnTi catalyst showed the best methane coupling performance of 27.29% C2+ yield with 150 V applied voltage, without additional thermal input. The catalytic performance of MnTi catalyst under various operation parameters was further carried out, and different techniques, such as X-ray diffraction, X-ray photoelectron spectroscopy, transmission electron microscopy, and H2-temperature-programmed reduction were used to explore the effect of Mn loading on methane oxidative coupling (OCM) performance. The results showed that applied voltage and flow rate had a significant effect on methane activation. The dielectric particles of TiO2 loaded with Mn not only synergistically affected the coupling reaction, but also facilitated charge deposition to generate a strong local electric field to activate methane. The synergy effects boosted the OCM performance and the C2+ yield became 1.25 times higher than that of the undoped TiO2 under identical operating conditions in plasma, which was almost impossible to occur even at 850 °C on the MnTi catalyst in the absence of plasma. Moreover, the reaction activity of the catalyst was fully recovered by plasma regeneration at 300 °C and maintained its stability in for at least 30 consecutive cyclic redox tests. This work presents a new opportunity for efficient methane conversion to produce C2+ at low temperatures by plasma assistance.

Metabolite Neu5Ac triggers SLC3A2 degradation promoting vascular endothelial ferroptosis and aggravates atherosclerosis progression in ApoE-/-mice.

Background: Atherosclerosis (AS) is still the major cause of cardiovascular disease (CVD) as well as stroke. Endothelial metabolic disorder has been found to be activated and then promote endothelial cells (ECs) injury, which is regarded to initiate AS progression. N-acetylneuraminic acid (Neu5Ac), a metabolite produced by hexosamine-sialic acid pathway branching from glucose metabolism, was presented as a notable biomarker of CVD and is positively correlated with ECs function. However, few studies explain whether Neu5Ac regulate AS progression by affecting EC function as well as its involved mechanisms are still unknown. Methods: Here, we mimicked an animal model in ApoE-/- mice which displaying similar plasma Neu5Ac levels with AS model to investigate its effect on AS progression. Results: We found that Neu5Ac exacerbated plaques area and increased lipids in plasma in absence of HFD feeding, and ECs inflammatory injury was supposed as the triggering factor upon Neu5Ac treatment with increasing expression of IL-1β, ICAM-1, and promoting ability of monocyte adhesion to ECs. Mechanistic studies showed that Neu5Ac facilitated SLC3A2 binding to ubiquitin and then triggered P62 mediated degradation, further leading to accumulation of lipid peroxidation in ECs. Fer-1 could inhibit ECs injury and reverse AS progression induced by Neu5Ac in ApoE-/- mice. Interestingly, mitochondrial dysfunction was also partly participated in ECs injury after Neu5Ac treatment and been reversed by Fer-1. Conclusions: Together, our study unveils a new mechanism by which evaluated metabolite Neu5Ac could promote SLC3A2 associated endothelial ferroptosis to activate ECs injury and AS plaque progression, thus providing a new insight into the role of Neu5Ac-ferroptosis pathway in AS. Also, our research revealed that pharmacological inhibition of ferroptosis may provide a novel therapeutic strategy for premature AS.

STEM-01. GLIOMA STEM CELLS ACTIVATE PLATELETS BY PLASMA-INDEPENDENT THROMBIN PRODUCTION TO PROMOTE GBM TUMORIGENESIS

Abstract The interaction between platelets and cancer cells has been underexplored in solid tumor models that do not metastasize, for example glioblastoma (GBM) for which metastasis is rare. Histologically, it is known that glioma stem cells (GSCs) are found in perivascular and pseudsopalisading regions of GBM, which are also areas of platelet localization. High platelet counts have been associated with poor clinical outcome in many cancers. While platelets are known to promote progression of other tumors, mechanisms by which platelets influence GBM oncogenesis are unknown. Here, we aimed to understand how the bidirectional interaction between platelets and GSCs drives GBM oncogenesis. Male and female NSG mice were transplanted with patient derived GSC lines and treated with antiplatelet and anti-thrombin inhibitors. Immunofluorescence, qPCR, and Western blots were used to determine expression of coagulation mechanism in GBM tissue and subsequent GSC lines. We demonstrate that GSCs co-opt and activate platelets to promote GBM tumor progression. GSCs endogenously produce all coagulation factors of the intrinsic and extrinsic cascade generating thrombin and activating platelets in the absence of plasma. Conversely, inhibition of platelet activation and of thrombin production by GSCs abrogates platelet-mediated GSC self-renewal and growth (p&amp;lt; 0.0005). Similarly, inhibiting intratumoral thrombin production and function decreases tumor formation in vivo (p&amp;lt; 0.005). These studies challenge and revise the longstanding view that the complete coagulation cascades are found only in the liver and plasma demonstrating that cancer stem cells readily execute a highly liver-specific gene expression program that is mechanistically linked to GBM oncogenesis. We show that cancer cells can co-opt non-cancer cells to promote tumor growth, by uncovering the preferential relationship between platelets and GSCs that drive GBM malignancies and identifies a therapeutically targetable novel interaction.

Assessment of the safety of the cationic arginine-rich peptides (CARPs) poly-arginine-18 (R18 and R18D) in ex vivo models of mast cell degranulation and red blood cell hemolysis

Our laboratory focuses on the development of novel neuroprotective cationic peptides, such poly-arginine-18 (R18: 18-mer of l-arginine; net charge +18) and its d-enantiomer R18D in stroke and other brain injuries. In the clinical development of R18/R18D, their cationic property raises potential safety concerns on their non-specific effects to induce mast cell degranulation and hemolysis. To address this, we first utilised primary human cultured mast cells (HCMCs) to examine anaphylactoid effects. We also included as controls, the well-characterised neuroprotective TAT-NR2B9c peptide and the widely used heparin reversal peptide, protamine. Degranulation assay based on β-hexosaminidase release demonstrated that R18 and R18D did not induce significant mast cell degranulation in both untreated (naïve) and IgE-sensitised HCMCs in a dose-response study to a maximum peptide concentration of 16 μM. Similarly, TAT-NR2B9c and protamine did not induce significant mast cell degranulation. To examine hemolytic effects, red blood cells (RBCs), were incubated with the peptides at a concentration range of 1–16 μM in the absence or presence of 2% plasma. Measurement of hemoglobin absorbance revealed that only R18 induced a modest, but significant degree of hemolysis at the 16 μM concentration, and only in the absence of plasma. This study addressed the potential safety concern of the application of the cationic neuroprotective peptides, especially, R18D, on anaphylactoid responses and hemolysis. The findings indicate that R18, R18D, TAT-NR2B9c and protamine are unlikely to induce histamine mediated anaphylactoid reactions or RBC hemolysis when administered intravenously to patients.

Shadow analysis for rotating black holes in the presence of plasma for an expanding universe

We explore the structure of shadow for a Kerr-de Sitter black hole with a non-magnetized, pressureless plasma surrounding it. Specific plasma distributions are considered to separate the Hamilton-Jacobi equation and find the photon regions. An analytic formula describing the boundary curve of the shadow for such a black hole in an expanding universe for an observer at any finite point outside the horizon is derived. We observe deviations which are further explored by calculating the curvature radius at a particular point for such structures in the presence and absence of plasma and calculate the diameter of the shadow.

Magnetized particle transport in multi-MA accelerators

Kinetic simulations of Sandia National Laboratories’ Z machine are conducted to understand particle transport in the highly magnetized environment of a multi-MA accelerator. Joule heating leads to the rapid formation of electrode surface plasmas. These plasmas are implicated in reducing accelerator efficiency by diverting current away from the load [M.R. Gomez et al., Phys. Rev. Accel. Beams 20, 010401 (2017), N. Bennett et al., Phys. Rev. Accel. Beams 22, 120401 (2019)]. The fully-relativistic, electromagnetic simulations presented in this paper show that particles emitted in a space-charge-limited manner, in the absence of plasma, are magnetically insulated. However, in the presence of plasma, particles are transported across the magnetic field in spite of being only weakly collisional. The simulated cross-gap currents are well-approximated by the Hall current in the generalized Ohm’s law. The Hall conductivities are calculated using the simulated particle densities and energies, and the parameters that increase the Hall current are related to transmission line inductance. Analogous to the generalized Ohm’s law, we extend the derivation of the magnetized diffusion coefficients to include the coupling of perpendicular components. These yield a Hall diffusion rate, which is equivalent to the empirical Bohm diffusion.