Density Gradient Research Articles

Multifaceted investigation of Sulfamerazine: Insights from computational methods, experimental techniques, and molecular simulations

The powerful sulfonamide antibiotic Sulfamerazine has been the subject of in-depth study to clarify its complex molecular interactions. In order to understand Sulfamerazine's pharmacological behaviour and interactions with biological components, this comprehensive study uses computational tools such as Density Functional Theory (DFT) calculations, spectroscopic analyses, and molecular docking simulations. Exploitation B3LYP/6-311++G(d,p) basis set, DFT simulations have provided important new understandings of the structure, vibrational properties, and binding mechanisms of this system. Vibrational assignments have been conducted by analyzing individual vibrational modes and comparing them to experimental data. The molecule's weak interactions have been identified grounded on electron density using Reduced Density Gradient Analysis. Fukui and MEP plot analyses have been employed to pinpoint the molecule's electrophilic and nucleophilic sites. Frontier molecular orbital analysis supported the observation of charge transfer within the molecule. Sulfamerazine is a viable option for further pharmaceutical development, as shown by drug-likeness and ADME (absorption, distribution, metabolism, and excretion) studies. In docking analysis, the inhibitor 6qzh stood out as particularly potent, capable of forming up to three hydrogen bonds, resulting in a binding energy of -8.2 kcal/mol. Molecular dynamics simulations have also shed light on the stability, solubility, and possible interactions of Sulfamerazine in diverse settings. This all-encompassing strategy promises to increase our understanding of the mechanism of action of Sulfamerazine, creating new opportunities for the logical development of more potent pharmaceuticals.

Electron Precipitation Driven by EMIC Waves: Two Types of Energy Dispersion

AbstractElectromagnetic ion cyclotron (EMIC) waves can very rapidly and effectively scatter relativistic electrons into the atmosphere. EMIC‐driven precipitation bursts can be detected by low‐altitude spacecraft, and analysis of the fine structure of such bursts may reveal unique information about the near‐equatorial EMIC source region. In this study, we report, for the first time, observations of EMIC‐driven electron precipitation exhibiting energy, E, dispersion as a function of latitude (and hence L‐shell): two predominant categories exhibit dE/dL > 0 and dE/dL < 0. We interpret precipitation with dE/dL < 0 as due to the typical inward radial gradient of cold plasma density and equatorial magnetic field (∼65% of the statistics). Precipitation with dE/dL > 0 is interpreted as due to an outward radial gradient of the equatorial magnetic field, likely produced by energetic ions freshly injected into the ring current (∼35% of the statistics). The observed energy dispersion of EMIC‐driven electron precipitation was reproduced in simulations.

Exploring the structure and dynamics of a fluorescent schiff base (1E,1′E)-1,1′-(1,4-phenylene) bis(N-(4-chlorophenyl) methamine: Synthesis, spectroscopic analysis, thermal, electronic and crystallographic study with biological applications

Schiff bases have emerged as attractive biological agents with a wide range of uses due to the extraordinary physical, chemical, and pharmacological characteristics that they possess. This study focuses on the effective synthesis of a Schiff base that is produced from 4-chloroaniline and terephthaldehyde. The success of this synthesis is supported by a variety of spectroscopic methods and Single crystal XRD analysis. The chemical that was synthesised had significant fluorescence qualities, with measured values at 457.13, 481.49, and 524.15 nm, highlighting the fact that it has the potential to be utilised in a variety of applications within the field. Using thermogravimetric analysis, the thermal stability of the compound was studied, which revealed an excellent stability at 399 °C. Thermal stability is an essential component of compound usefulness. Molecular insights were obtained by the utilisation of Density Functional Theory, which revealed an energy gap of 1.70 electron volts (eV) and electrophilic behaviour in certain atoms. The distribution of charges was brought to light through the use of Mulliken charges and molecular electrostatic potential analysis, which brought attention to the distinctive qualities of the subject molecule. An examination of the electron localization function revealed that the electron density inside carbon, nitrogen, and chlorine atoms had been delocalized. Additionally, the localised orbital locator wave function and reduced density gradient maps offered vital insights into the non-covalent interactions that were taking place within the system under investigation. In the course of the evaluation of antimicrobial efficacy, it was discovered that the chemical exhibited more powerful antibacterial activity against gram-positive B. subtilis than the conventional antibiotic amoxicillin. The antibacterial findings were further supported by molecular docking tests, which involved using particular proteins from the target species. These investigations showed that B. subtilis had a higher affinity for binding. These findings were further validated by molecular dynamic simulations. The synthesised chemical was subjected to in silico toxicity assessment using seven models, which demonstrated its non-irritating properties on the skin and eyes. The extensive analysis that is given here lays the groundwork for more targeted research on novel antibacterial drugs, with a particular focus on the safety, molecular interactions, and effectiveness of these compounds. As a result of the compound's potential applicability in biocompatible antimicrobial formulations, it is a viable candidate for improving the development of antibacterial medicines that are both effective and safe.

Predicting the vertical density structure of oceanic gravity current intrusions

Understanding the dynamics and structures in the deep ocean is one of the remaining challenges in oceanography and climate sciences. We present results from large-scale laboratory experiments of rotating down-slope gravity currents intruding into a two-layer stratified ambient, performed in the largest rotating tank in the world, the Coriolis Rotating Platform in Grenoble. By means of velocity and density measurements, we show that no mixing occurs once the current has detached from the boundary. The shape of the vertical density profile in the stratified receiving ambient enables to identify two distinct regimes: the first issued by laminar transport through Ekman dynamics, the second by turbulent transport due to intermittent dense water cascading. Vertical density gradients reveal a piece-wise linear dependence on the density anomaly for the turbulent transport, suggesting an advection-diffusion process. For the turbulent regime, the scale height is deduced and an analytical model based on the critical Froude number is proposed to predict its value. Results show that the total thickness of the intruding current is on average 2.5 times the scale height. For laminar intrusions the scale height diverges whereas the thickness of the intrusion is a few times the Ekman layer thickness. Comparing the intrusion scale height with its measured vertical extension has led to a criteria to distinguish between laminar and turbulent regimes, which is corroborated by two additional independent criteria, one based on the sign of the local vorticity and the other based on the local maxima of the vertical density gradient. The model allows us to connect laboratory experiments to deep sea observations, gravity currents and Meddies and emphasizes the importance of laboratory experiments in understanding climate dynamics.

Hybrid modeling of an ultracentrifugation process for separation of full and empty adeno-associated virus particles

Ultracentrifugation is an attractive method for separating full and empty capsids, exploiting their density difference. Changes of the serotype/capsid, density of loading material, or the genetic information contained in the adeno-associated viruses (AAVs) require the adaptation of the harvesting parameters and the density gradient loaded onto the centrifuge. To streamline these adaptations, a mathematical model could support the design and testing of operating conditions.Here, hybrid models, which combine empirical functions with artificial neural networks, are proposed to describe the separation of full and empty capsids as a function of material and operational parameters, i.e., the harvest model. In addition, critical quality attributes are estimated by a quality model which is operating on top of the harvest model. The performance of these models was evaluated using test data and two additional blind runs. Also, a “what-if” analysis was conducted to investigate whether the models’ predictions align with expectations.It is concluded that the models are sufficiently accurate to support the design of operating conditions, though the accuracy and applicability of the models can further be increased by training them on more specific data with higher variability.

Investigation of effects of initial interface conditions on the two-dimensional single-mode compressible Rayleigh–Taylor instability: Based on the discrete Boltzmann method

The Rayleigh–Taylor (RT) instability in inertial confinement fusion implosions evolves at the unstable interface of two fluids when the light fluid is pushing the heavy one. The effects of the initial amplitude and transition layer on the compressible RT instability are investigated numerically by using the discrete Boltzmann method. On the one hand, during the RT evolution, higher initial amplitudes initially increase the global density gradient and non-equilibrium area, with a subsequent reversal. The increasing initial amplitude leads to an initial rise followed by a decline in the system’s maximum Mach number. On the other hand, the impact of the transition layer is generally opposite to the one of initial amplitude in the RT process. These findings offer significant insights into controlling and understanding RT instability in fusion implosion scenarios, emphasizing novel aspects relative to existing literature.

Synthesis, characterization, and comprehensive computational analysis of aromatic hydrazone compounds: Unveiling quantum parameters, evaluating antioxidant activity, and investigating molecular docking interactions

This study presents a synergistic approach encompassing experimental synthesis, computational analysis, and antioxidant activity evaluation of two aromatic hydrazone compounds, namely 4-[(2E)-2-(2-nitrobenzylidene) hydrazinyl] benzoic acid (NBHZ) and 4-[(2E)-2-(2-hydroxybenzylidene) hydrazinyl] benzoic acid (HBHZ). Efficient synthesis yielded impressive quantities (70 % and 58 %, respectively), and structural characterization employed IR, UV–Vis, and NMR spectroscopy. Antioxidant potential was assessed using the DPPH free radical scavenging assay, revealing distinct capabilities of NBHZ and HBHZ, each featuring a nitro (NO2) and a hydroxy (OH) group, respectively, at the ortho position. HBHZ exhibited superior efficacy (IC50 = 1.15 μg/mL) compared to NBHZ (IC50 = 2.1 μg/mL) and the standard antioxidant BHT (IC50 = 1.83 μg/mL). Computational analyses using Gaussian 09 at the B3LYP/6–311 G(d,p) level elucidated electronic characteristics, molecular electrostatic potential (MEP), HOMO-LUMO energies, and global reactivity descriptors. VEDA 4 further investigated vibrational behavior and potential energy distribution (PED), topological analyses electron localization function (ELF), localized orbital locator (LOL), average localized ionization energy (ALIE), and reduced density gradient (RDG) were identified to evaluate their interactions. Thermochemical parameters explored antioxidant mechanisms (hydrogen atom transfer (HAT), single electron transfer–proton transfer (SET–PT), and sequential proton loss electron transfer (SPLET)). Molecular docking via iGEMDOCK revealed binding interactions with the target NADPH oxidase. These findings not only provide insights into the compounds' antioxidant potential but also underscore the impact of specific molecular features on their properties. This integrated approach contributes to advancing the understanding of hydrazone compounds, guiding the design of materials with tailored functionalities for applications in oxidative stress mitigation.

Bifonazole caffeate: The first molecular salt of bifonazole with enhanced biopharmaceutical property based on experiments and quantum chemistry research

In order to make novel breakthroughs in molecular salt studies of BCS class-IV antifungal medication bifonazole (BIF), a salification-driven strategy towards ameliorating attributes and aiding augment efficiency is raised. This strategy fully harnesses structural characters together attributes and benefits of caffeic acid (CAF) to concurrently enhance dissolvability and permeability of BIF by introducing the two ingredients into the identical molecular salt lattice through the salification reaction, which, coupled with the aroused potential activity of CAF significantly amplifies the antifungal efficacy of BIF. Guided by this route, the first BIF-organic molecular salt, BIF-CAF, is directionally designed and synthesized with satisfactorily structural characterizations and integrated theoretical and experimental explorations on the pharmaceutical properties. Single-crystal X-ray diffraction resolving confirms that there is a lipid-water amphiphilic sandwich structure constructed by robust charge-assistant hydrogen bonds in the salt crystal, endowing the molecular salt with the potential to enhance both dissolvability and permeability relative to the parent drug, which is validated by experimental evaluations. Remarkably, the comprehensive DFT-based theoretical investigations covering frontier molecular orbital, molecular electrostatic potential, Hirshfeld surface analysis, reduced density gradient, topology, sphericity and planarity analysis strongly support these observations, thereby allowing some positive relationships between macroscopic properties and microstructures of the molecular salt can be made. Intriguingly, the optimal properties, together with the stimulated activity of CAF markedly augment in vitro antifungal ability of the molecular salt, with magnifying inhibition zones and reducing minimum inhibitory concentrations. These findings fill in the gaps on researches of BIF-organic molecular salt, and adequately exemplify the feasibility and validity by integrating theoretical and experimental approaches to resolve BIF’s problems via the salification-driven tactic.

Comprehensive Analysis of CXCR4, JUNB, and PD-L1 Expression in Circulating Tumor Cells (CTCs) from Prostate Cancer Patients.

CXCR4, JUNB and PD-L1 are implicated in cancer progression and metastasis. The current study investigated these biomarkers in CTCs isolated from metastatic prostate cancer (mPCa) patients at the RNA and protein levels. CTCs were isolated from 48 mPCa patients using the Ficoll density gradient and ISET system (17 out of 48). The (CK/PD-L1/CD45) and (CK/CXCR4/JUNB) phenotypes were identified using two triple immunofluorescence stainings followed by VyCAP platform analysis. Molecular analysis was conducted with an EpCAM-dependent method for 25/48 patients. CK-8, CK-18, CK-19, JUNB, CXCR4, PD-L1, and B2M (reference gene) were analyzed with RT-qPCR. The (CK+/PD-L1+/CD45-) and the (CK+/CXCR4+/JUNB+) were the most frequent phenotypes (61.1% and 62.5%, respectively). Furthermore, the (CK+/CXCR4+/JUNB-) phenotype was correlated with poorer progression-free survival [(PFS), HR: 2.5, p = 0.049], while the (CK+/PD-L1+/CD45-) phenotype was linked to decreased overall survival [(OS), HR: 262.7, p = 0.007]. Molecular analysis revealed that 76.0% of the samples were positive for CK-8,18, and 19, while 28.0% were positive for JUNB, 44.0% for CXCR4, and 48.0% for PD-L1. Conclusively, CXCR4, JUNB, and PD-L1 were highly expressed in CTCs from mPCa patients. The CXCR4 protein expression was associated with poorer PFS, while PD-L1 was correlated with decreased OS, providing new biomarkers with potential clinical relevance.

Contribution of high turbidity to tidal dynamics in a curved channel in Zhoushan Islands, China

The curved tidal channel, Luotou Deep-water Navigational Channel, is the main channel of the Ningbo Zhoushan Port, which is ranked first in the world. Tidal dynamics in the channel are spatially and temporally asymmetric. In this study, the three-dimensional tidal dynamics in the channel were analyzed using field data and simulated using FVCOM. The results show that the tides in the channel flood/ebb along the northern/southern bank near the bottom/surface layer and these asymmetries are due to the imbalanced Coriolis force, centrifugal force, sea-level gradient, and density gradient. Residual current velocity peaks (0.7 m/s) in the middle of the channel as the same distribution as sediment flux. There are two high turbidity zones (>4 kg/m3) which are northern at flood than at an ebb in the channel. The drag reduction effect of fluid mud enhances the lateral circulation, which is strong near the Chuanshan Peninsula and frictional dissipation plays an important role in it. The presence of suspended sediment changes the contribution of acceleration terms through impacting density and bottom friction, and the centrifugal force term has the largest increases. This study provides the foundation for the morphology evolution and harbor management of macro-tidal turbid coastal zones. Highlights A baroclinic model was built to study the tidal dynamics in macro-tidal turbid Zhoushan Islands. Asymmetric tides and lateral circulation occur in the Luotou Deep-water Navigational Channel (DNC). Mechanism of lateral circulation depends on tidal phases and locations in the DNC. Sediment impacts water density and drag coefficient, and then changes currents and sediment fluxes in the DNC.

Investigations on Growth, Characterization, NCI-RDG, AIM, Molecular Docking and In-Silico ADME Properties of 1,2-Benzene Dicarboxylic Acid Anhydride

Superior single crystal of 1,2-benzene dicarboxylic acid anhydride additionally called Phthalic anhydride (PAN) was developed via solution growth at low temperatures. Single crystal X-ray diffraction investigation revealed the crystal system and unit cell characteristics. The phase stability and crystalline nature were uncovered by powder X-ray diffraction analysis. FT-IR examination was done for the titular material so as to survey the various functional groups. With the use of the VEDA program's relevant resources, vibrational assignments have been made on the concept of Potential Energy Distribution (PED). Density Functional Theory (DFT) was employed to smooth out the molecular structure of PAN and was additionally utilized to consider FT-IR spectrum at molecular level. Non covalent interactions reduced density gradient (NCI-RDG) analysis has been used for the prediction of the weak interaction in the actual space in terms of the electron density along with its derivatives for PAN. Atoms in Molecules (AIM) analysis was carried for out for PAN. The docking research of the small molecule (PAN) with target protein confirmed that this is a great molecule which docks nicely with numerous targets associated with Hypoxia Inducible Factor 1-α. The absorption, distribution, metabolism, excretion (ADME) characteristics have been calculated with the assist of online server preADMET.

Modeling Blue Crab (Callinectes sapidus) Larval Transport and Recruitment Dynamics in a Shallow Lagoon‐Inlet‐Coastal Ocean System

AbstractBlue crab (Callinectes sapidus) supports lucrative Mid‐Atlantic crustacean fisheries and plays an important role in estuarine ecology, so their larval transport and recruitment dynamics in the Maryland Coastal Bays system were investigated using simulated and observed surface drifters. Relative contributions of winds, tides, density gradients, and waves to larval recruitment success were identified during the spawning season, particularly under hurricane conditions in 2014. Based on temperature (e.g., 19–29°C) and salinity conditions (e.g., 23–33 PSU), particles representing virtual blue crab larvae were released into the model domain from early June to late October 2014. During the spawning season, variations in the larval recruitment success caused by wind speed and direction, tides (e.g., affecting through inlets), density gradients (e.g., salinity variations), and surface gravity waves were 17%, 4%, −9%, and 17%, respectively. During Hurricane Arthur (2014), variability of self‐recruitment success caused by density gradients are negligible while by other three factors are comparable at 3%–4%. Surface drifter experiments support the modeling results that larval recruitment success is strongly associated with the coastal circulation. The high (low) self‐recruitment success in the Assawoman and Chincoteague Bays (Sinepuxent Bay) is related to the locally weak (strong) circulation; released larvae escape from inlets are likely recruited to southern Fenwick and northern Assateague Islands, and the coastal regions outside the Chincoteague Inlet. Understanding physical factors influencing larval recruitment success helps resource managers make informed decisions about habitat restoration and harvest regulations, in addition to seafood‐related food security.

Simulation of neoclassical heavy impurity transport in ASDEX Upgrade with applied 3D magnetic fields using the nonlinear MHD code JOREK

Accumulation of heavy impurities in the tokamak core is detrimental for its performance and can lead to disruption of the plasma. In small to medium-sized tokamaks the effective neoclassical transport in the pedestal is typically oriented radially inward. In larger tokamaks—e.g., ITER—where the temperature gradient is higher and density gradients are lower due to the need to operate in a radiative divertor regime, the neoclassical transport is predicted to be outwards. The models are derived for axisymmetric quasi-steady-state plasmas. Applied 3D magnetic fields, i.e., Resonant Magnetic Perturbation (RMPs) as they are used to suppress Edge Localized Modes (ELMs), have experimentally been observed in AUG to enhance the outflow of heavy impurities in the pedestal. There is no model that can predict neoclassical heavy impurity transport in these ergodized 3D magnetic fields self-consistently. In this contribution, we present our kinetic tungsten transport simulation for an ASDEX Upgrade plasma with applied RMPs. Our model based on Hoelzl et al. [Nucl. Fusion 61, 065001 (2021)], van Vugt et al. [Phys. Plasmas 26, 042508 (2019)], and Korving et al. [Phys. Plasmas 30, 042509 (2023)] utilizes a full-orbit pusher, ionization, recombination, effective line, and continuum radiation and neoclassical collisions with the background plasma. The effective collisional radiative rates are from the OpenADAS database, the neoclassical collision operator uses the framework of Homma et al. [J. Comput. Phys. 250, 206–223 (2013)] and Homma et al. [Nucl. Fusion 56, 036009 (2016)]. We show that the adopted collision operator produces neoclassical transport within a satisfactory degree of accuracy. A sufficiently high RMP current causes an increase in tungsten diffusion in the pedestal by a factor of 2. We compare the average radial transport between axisymmetric and 3D RMP scenarios in the pedestal region. RMPs enhance the pedestal permeability for impurities, which results in enhanced transport. In addition to the enhanced transport, some of W is found to be trapped in 3D potential wells in the scrape-off layer. Due to the lack of suitable diagnostics for W in the pedestal, we investigate and suggest that argon can be an adequate substitute in experiments for model validation and further understanding impurity transport in scenarios with applied 3D magnetic fields. With the newly developed neutral model [Korving et al., Phys. Plasmas 30, 042509 (2023)], we can combine the interaction in the divertor with the 3D RMPs to model the tungsten transport from the divertor toward the core of the plasma.

Population density and ranging behaviour of a generalist carnivore varies with human population.

Canid species are highly adaptable, including to urban and peri-urban areas, where they can come into close contact with people. Understanding the mechanisms of wild canid population persistence in these areas is key to managing any negative impacts. The resource dispersion hypothesis predicts that animal density increases and home range size decreases as resource concentration increases, and may help to explain how canids are distributed in environments with an urban-natural gradient. In Australia, dingoes have adapted to human presence, sometimes living in close proximity to towns. Using a targeted camera trap survey and spatial capture-recapture models, we estimated spatial variation in the population density and detection rates of dingoes on Worimi Country in the Great Lakes region of the NSW coast. We tested whether dingo home range and population densities varied across a gradient of human population density, in a mixed-use landscape including, urban, peri-urban, and National Park environs. We found human population density to be a strong driver of dingo density (ranging from 0.025 to 0.433 dingoes/km2 across the natural-urban gradient), and to have a negative effect on dingo home range size. The spatial scale parameter changed depending on survey period, being smaller in the peak tourism period, when human population increases in the area, than in adjacent survey periods, potentially indicating reduced home range size when additional resources are available. Our study highlights the potential value of managing anthropogenic resource availability to manage carnivore densities and potential risk of human-carnivore interactions.

Mixed convection by buoyancy and magnetothermal forces

The magnetic force in the paramagnetic fluid depends on the local gradient of magnetic flux density and the temperature-dependent magnetic susceptibility. In the presence of the gravity, the buoyant force due to the temperature difference additionally overlaps, and the resultant flow becomes a mixed convection. In this study, the effect of the temperature-dependent magnetic force (magnetothermal force) on the natural convection was numerically investigated. The magnetic field formed by the permanent-magnet array was employed and effective one was discussed in terms of the heat transfer. A three-dimensional Rayleigh-Benard convection simulation was conducted with the magnet array below the bottom hot wall. It was found that the magnetothermal force enhances the convection not only where the magnet locates but also away from the magnet due to the force profile.

Directly driven magnetized fast-ignition targets with steep density gradients for inertial fusion energy

The development of advanced targets capable of achieving ignition with improved energy gain at lower driver energies is one of four key technical challenges to be solved in order to realize economical inertial fusion energy. We report the minimum energy necessary for a small hemispherical mass of fast-ignited high-density deuterium–tritium fuel to explosively ignite a significantly larger hemispherical mass of assembled cold fuel with much lower mass density, both with and without a flux-compressed magnetic field connecting the two regions. With the magnetic field, the burn rate improves, and lower energy states become more effective. The imploded fuel reservoir available in the lower-density, larger-mass region of the steep density gradient determines whether the fusion yield is several hundred MJ or up to a few GJ. We report a case wherein the cold reservoir ignited and produced high gain with the assistance of only ∼700 kJ of hotspot yield, an amount that has already been demonstrated as feasible in laboratory experiments using indirect-drive targets.

Extracellular and intracellular inflammatory response of immune cells to radiation exposure

Background: Exposure to low doses of ionizing radiation is associated with increased risk of cardiovascular disease (CVD) in a dose-dependent manner. A person exposed to low doses of radiation have a 27-29% risk of developing and dying from CVD. Low doses of radiation initiate an inflammatory process that can increase the risk of developing CVD. Inflammation initiates atherosclerosis via immune cell infiltration subsequent to endothelial cell damage. We hypothesized that CD14+ monocytes will exhibit an amplified inflammatory response, as demonstrated by significant increases in the expression of inflammatory cytokines at 48 and 72 hours post radiation exposure compared to controls which would be magnified by the inflammatory stimulus LPS. Methods: Human venous peripheral blood was collected from 5 healthy young adults (24 ± 3 years, 22 ± 1 BMI, 5 Male) using an institutional review board (IRB)-approved protocol. Women were studied in days 1-5 of menstrual cycle. Peripheral blood mononuclear cells (PBMCs) were harvested by density gradient separation and re-suspended and incubated with anti-human CD14 microbeads. CD14+ immune cells were incubated in plates, exposed to 4 gray (Gy) of x-ray radiation, and then incubated for 48 and 72 hours. CD14+ immune cells were exposed to 1:500 dilution of 0.1 mg/mL of lipopolysaccharide (LPS) for the final 8 hours of incubation. The culture media was recovered, and assayed for secreted factors, specifically for IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, IFN-γ, and TNF-α. Additionally, flow cytometry analysis was performed to quantify intracellular content of IL-10, IL-8, IFN-g, IL-4, receptor for advanced glycation end products (RAGE), and damage-associated molecular pattern (DAMP) molecules (S100A8/9) involved in inflammatory activation. All data were analyzed with two-way repeated measures ANOVA. Results: Secreted Cytokines: Cytokine expression at 48 and 72 hours did not differ between the control, radiation (4Gy), and 4Gy+LPS groups. At 48 and 72 hours, there were no significant differences observed in the expression levels of IFN-γ, IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12p70, IL-13, and TNF-α in control, 4Gy, and 4Gy+LPS cells. Intracellular Content: Compared to control IL-4 content was increased at 48 and 72 hours, after exposure to 4Gy (48h: p=0.013 and 72h: p=0.008) and 4Gy+LPS (48h: p=0.022 and 72h: p=0.002). Furthermore, IL-4 was again increased at 72 hours after exposure to 4Gy+LPS compared to 48 hours (p=0.014). IL-10 content was also increased in after exposure to 4Gy and 4Gy+LPS at 72 hours compared to control (p=0.046 and p=0.007, respectively). S100A8/9 also showed a trending increase at 4Gy compared to control at 72 hours (p=0.11). No other content changed significantly. Conclusion: These data suggest that acute radiation exposure (4 Gy x-ray) has no effect on the secretome of CD14+ immune cells. However, the intracellular content of IL-4 was increased at both 48 and 72 hours, while IL-10 increased at 72 hours, indicating a shift from pro-inflammatory to anti-inflammatory intracellular content the further in time monocytes are from radiation exposure. Future work needs to test increased and repeated doses of radiation, as well as examine both x-ray and proton exposure. TRISH through NASA Cooperative Agreement NNX16AO69A and NIH HL150361. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

A Mitochondrial Targeted Ubiquinol (MitoQ) Improves Immune Cell Bioenergetics in Patients with Heart Failure with Preserved Ejection Fraction

BACKGROUND: Heart failure with preserved ejection fraction (HFpEF) is a proinflammatory syndrome. Mitochondrial dysfunction that is characteristic of HFpEF could alter immunometabolism, attenuating the functional reserve of immune cells. In addition, immune cell mitochondrial respiration is a biomarker of systemic mitochondrial health. The aim of this study was to assess the impact of a chronic oral mitochondrial targeted ubiquinol (MitoQ) on the immune cell bioenergetic profile in patients with HFpEF. We hypothesized that MitoQ administration in patients with HFpEF, would improve mitochondrial respiration in peripheral blood mononuclear cells (PBMC’s). METHODS: In this double-blind, crossover trial 8 patients with a clinical diagnosis of HFpEF (6 female, 2 male; 6 African American/Black, 2 white; mean ± SEM, Age, 58±5 years; BMI, 37±1 kg/m2) received a 4 week oral dose of MitoQ (MTQ, 20 mg/day) and placebo (PLB) in random order separated by a 2 week wash out period. Following completion of each trial arm, a venous blood sample was obtained and PBMCs were isolated using density gradient centrifugation. High resolution respirometry coupled with modulators of cellular respiration was performed to obtain basal respiration, ATP-linked respiration, maximal respiration, and spare respiratory capacity of the immune cells. Paired samples t-tests were used to compare variables between conditions. RESULTS: MitoQ was safe, well tolerated, and compliance was high (MTQ, 99 ± 1%; PLB, 89±4%). Basal respiration (MTQ, 106.4 ± 11.5 pmol/min; PLB, 66.5±5.9 pmol/min; p=0.002), ATP-linked respiration (MTQ, 41.4± 16.9 pmol/min; PLB, 16.3±6.7 pmol/min; p=0.04), maximal respiration (MTQ, 323.9 ± 50.0 pmol/min; PLB, 65.4±23.1 pmol/min; p=0.01), spare respiratory capacity (MTQ, 217.5 ± 39.6 pmol/min; PLB, 149.6 ±18.2 pmol/min; p=0.02), were higher following MTQ compared to PLB. CONCLUSIONS: In patients with HFpEF, administration of a mitochondrial targeted ubiquinol improved the immune cell mitochondrial respiration capacity and effciency. An increase in spare respiratory capacity following MTQ reflects an improvement in functional reserve that would augment the ability to respond to an acute stressor. These findings have positive implications for the ability to target and improve mitochondrial function in patients with HFpEF. Future work should investigate if the observed improvements in immune cell mitochondrial function are mirrored in other tissues. Supported by AHA 19CDA3474002. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Optimization and verification of conditions for induction of neutrophil extracellular traps in vitro

This study aims to optimize the conditions for the formation of neutrophil extracellular traps(NETs) in vitro, so as to establish a relatively stable experimental research platform. Different conditions were compared, including commonly used laboratory animals(rats and mice) and a variety of cell sources(bone marrow neutrophils and peripheral blood neutrophils separated by percoll density gradient centrifugation). Different inducers like lipopolysaccharide(LPS) and phorbol 12-myristate 13-acetate(PMA) were used for induction in vitro. Myeloperoxidase(MPO)/citrullinated histone H3(CitH3)/DAPI immunofluorescence and cell free DNA(cf-DNA) content determination were used for comprehensive evaluation to screen the optimal conditions for the formation of NETs induced in vitro. Furthermore, the stability of the selected conditions for inducing the formation of NETs in vitro was evaluated by tetramethylpyrazine(TMP), an active component in Chinese herbal medicines. The results showed that coated poly-D-lysine(PDL) induced the formation of NETs in bone marrow neutrophils of mice to a certain extent. Both LPS and PMA significantly up-regulated the protein levels of MPO and CitH3 in mouse bone marrow neutrophils and elevated the cfDNA level in the supernatant of rat peripheral blood neutrophils. The cfDNA level in the PMA-induced group increased more significantly than that in the LPS-induced group(P<0.05). The results of immunofluorescence staining showed that the expression of MPO and CitH3 in mouse bone marrow neutrophils, rat bone marrow neutrophils, and rat peripheral blood neutrophils were significantly increased after PMA induction, especially in rat peripheral blood neutrophils. TMP significantly down-regulated the protein levels of MPO, CitH3, and neutrophil elastase(NE) in rat peripheral blood neutrophils induced by PMA. In conclusion, treating the peripheral blood neutrophils of rats with PMA is the optimal condition for inducing the formation of NETs in vitro. This study provides an optimal platform for in vitro studies based on NETs and a basis for studying the effects of traditional Chinese medicines targeting NETs.

Self-similarity of the third type in ultra-relativistic blastwaves

A new type of self-similarity is found in the problem of a plane-parallel, ultra-relativistic blastwave, propagating in a power-law density profile of the form ρ∝z−k. Self-similar solutions of the first kind can be found for k < 7∕4 using dimensional considerations. For steeper density gradients with k > 2, second type solutions are obtained by eliminating a singularity from the equations. However, for intermediate power-law indices 7/4<k<2, the flow does not obey any of the known types of self-similarity. Instead, the solutions belong to a new class in which the self-similar dynamics are dictated by the non-self-similar part of the flow. We obtain an exact solution to the ultra-relativistic fluid equations and find that the non-self-similar flow is described by a relativistic expansion into vacuum, composed of (1) an accelerating piston that contains most of the energy and (2) a leading edge of a fast material that coincides with the interiors of the blastwave and terminates at the shock. The dynamics of the piston itself are self-similar and universal and do not depend on the external medium. The exact solution of the non-self-similar flow is used to solve for the shock in the new class of solutions.