Hyperbaric oxygen rapidly produces intracellular bioenergetics dysfunction in human pulmonary cells.

Hyperoxic exposure lasting days alters mitochondrial bioenergetic and dynamic functions in pulmonary cells as indices of oxygen toxicity. The aim of this study was to examine effects of short duration hyperbaric and hyperoxic exposures to induce oxygen toxicity similarly. Cultured human lung microvascular endothelial cells, human pulmonary artery endothelial cells and A549 cells were exposed to hyperoxia (∼5 % CO equivalent, balance O) under hyperbaric conditions (4.

RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in the development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health, and the small GTPase RAB7 regulates many functions of this system.

Hyperoxic exposure alters intracellular bioenergetics distribution in human pulmonary cells.

Aims: Pulmonary oxygen toxicity is caused by exposure to a high fraction of inspired oxygen, which damages multiple cell types within the lung. The cellular basis for pulmonary oxygen toxicity includes mitochondrial dysfunction. The aim of this study was to identify the effects of hyperoxic exposure on mitochondrial bioenergetic and dynamic functions in pulmonary cells.

RAB7 deficiency impairs pulmonary artery endothelial function and promotes pulmonary hypertension.

Pulmonary arterial hypertension (PAH) is a devastating and progressive disease with limited treatment options. Endothelial dysfunction plays a central role in development and progression of PAH, yet the underlying mechanisms are incompletely understood. The endosome-lysosome system is important to maintain cellular health and the small GTPase RAB7 regulates many functions of this system.

Mitochondrial dynamics involves molecular and mechanical events in motility, fusion and fission.

Mitochondria are cell organelles that play pivotal roles in maintaining cell survival, cellular metabolic homeostasis, and cell death. Mitochondria are highly dynamic entities which undergo fusion and fission, and have been shown to be very motile in neurons and in multiple cell lines. Fusion and fission are essential for maintaining mitochondrial homeostasis through control of morphology, content exchange, inheritance of mitochondria, maintenance of mitochondrial DNA, and removal of damaged mitochondria by autophagy.

Biophysical Considerations in the Rational Design and Cellular Targeting of Flexible Polymeric Nanoparticles.

How nanoparticle (NP) mechanical properties impact multivalent ligand-receptor-mediated binding to cell surfaces, the avidity, propensity for internalization, and effects due to crowding remains unknown or unquantified. Through computational analyses, the effects of NP composition from soft, deformable NPs to rigid spheres, effect of tethers, the crowding of NPs at the membrane surface, and the cell membrane properties such as cytoskeletal interactions are addressed. Analyses of binding mechanisms of three distinct NPs that differ in type and rigidity (core-corona flexible NP, rigid NP, and rigid-tethered NP) but are otherwise similar in size and ligand surface density are reported; moreover, for the case of flexible NP, NP stiffness is tuned by varying the internal crosslinking density.

Hyperbaric oxygen alters intracellular bioenergetics distribution in human dermal fibroblasts.

Aims: Hyperbaric oxygen therapy (HBOT), used to promote wound healing, has limited efficacy in many clinical conditions. Wound healing exerts bioenergetic demands on cells that can exceed their intrinsic bioenergetic capacity to proliferate and migrate. The aim of this investigation was to quantify the effects of HBOT on mitochondrial dynamics and bioenergetics functions in cells relevant to wound healing.

Difficulty in Advancing Flexible Epidural Catheters When Establishing Labor Analgesia: An Observational Open-Label Randomized Trial.

Background: While flexible epidural catheters reduce the risk of paresthesia and intravascular cannulation, they may be more challenging to advance beyond the tip of a Tuohy needle. This may increase placement time, number of attempts, and possibly complications when establishing labor analgesia. This study investigated the ability to advance flexible epidural catheters through different epidural needles from 2 commonly used, commercially available, epidural kits.

In vitro comparison of hydroxocobalamin (B12a) and the mitochondrial directed therapy by a succinate prodrug in a cellular model of cyanide poisoning.

The objective of this study was to compare the use of hydroxocobalamin (B12a) and a succinate prodrug to evaluate for improvement in mitochondrial function in an model of cyanide poisoning. Peripheral blood mononuclear cells (PBMC) and human aortic smooth muscle cells (HASMC) incubated with 50 mM of sodium cyanide (CN) for five minutes serving as the CN group compared to controls. We investigated the following: (1) Mitochondrial respiration; (2) Superoxide and mitochondrial membrane potential with microscopy; (3) Citrate synthase protein expression.

Multiscale modeling of protein membrane interactions for nanoparticle targeting in drug delivery.

Nanoparticle (NP)-based imaging and drug delivery systems for systemic (e.g. intravenous) therapeutic and diagnostic applications are inherently a complex integration of biology and engineering.

Ex vivo use of cell-permeable succinate prodrug attenuates mitochondrial dysfunction in blood cells obtained from carbon monoxide-poisoned individuals.

The purpose of this study was to evaluate a new pharmacological strategy using a first-generation succinate prodrug, NV118, in peripheral blood mononuclear cells (PBMCs) obtained from subjects with carbon monoxide (CO) poisoning and healthy controls. We obtained human blood cells from subjects with CO poisoning and healthy control subjects. Intact PBMCs from subjects in the CO and Control group were analyzed with high-resolution respirometry measured in pmol O per second per 10 PBMCs.

Prophylaxis of mitochondrial dysfunction caused by cellular decompression from hyperbaric exposure.

Mitochondrial dysfunction occurring in response to cellular perturbations can include altered mitochondrial motility and bioenergetic function having intracellular heterogeneity. Exogenous mitochondrial directed therapy may correct these dysfunctions. Using in vitro approaches, we find that cell perturbations induced by rapid decompression from hyperbaric conditions with specific gas exposures has differential effects on mitochondrial motility, inner membrane potential, cellular respiration, reactive oxygen species production, impaired maintenance of cell shape and altered intracellular distribution of bioenergetic capacity in perinuclear and cell peripheral domains.

Nanoparticle transport phenomena in confined flows.

Nanoparticles submerged in confined flow fields occur in several technological applications involving heat and mass transfer in nanoscale systems. Describing the transport with nanoparticles in confined flows poses additional challenges due to the coupling between the thermal effects and fluid forces. Here, we focus on the relevant literature related to Brownian motion, hydrodynamic interactions and transport associated with nanoparticles in confined flows.

Cross-linker-Modulated Nanogel Flexibility Correlates with Tunable Targeting to a Sterically Impeded Endothelial Marker.

Deformability of injectable nanocarriers impacts rheological behavior, drug loading, and affinity target adhesion. Here, we present atomic force microscopy (AFM) and spectroscopy measurements of nanocarrier Young's moduli, tune the moduli of deformable nanocarriers with cross-linkers, and demonstrate vascular targeting behavior that correlates with Young's modulus. Homobifunctional cross-linkers were introduced into lysozyme-dextran nanogels (NGs).

Nanofluid Dynamics of Flexible Polymeric Nanoparticles Under Wall Confinement.

Describing the hydrodynamics of nanoparticles in fluid media poses interesting challenges due to the coupling between the Brownian and hydrodynamic forces at the nanoscale. We focus on multiscale formulations of Brownian motion and hydrodynamic interactions (HI) of a single flexible polymeric nanoparticle in confining flows using the Brownian Dynamics method. The nanoparticle is modeled as a self-avoiding freely jointed polymer chain that is subject to Brownian forces, hydrodynamics forces, and repulsive interactions with the confining wall.

Stiffness can mediate balance between hydrodynamic forces and avidity to impact the targeting of flexible polymeric nanoparticles in flow.

We report computational investigations of deformable polymeric nanoparticles (NPs) under colloidal suspension flow and adhesive environment. We employ a coarse-grained model for the polymeric NP and perform Brownian dynamics (BD) simulations with hydrodynamic interactions and in the presence of wall-confinement, particulate margination, and wall-adhesion for obtaining NP microstructure, shape, and anisotropic and inhomogeneous transport properties for different NP stiffness. These microscopic properties are utilized in solving the Fokker-Planck equation to obtain the spatial distribution of NP subject to shear, margination due to colloidal microparticles, and confinement due to a vessel wall.

Rheology of colloidal suspensions in confined flow: Treatment of hydrodynamic interactions in particle-based simulations inspired by dynamical density functional theory.

We investigate the microstructure and rheology of a hard-sphere suspension in a Newtonian fluid confined in a cylindrical channel and undergoing pressure-driven flow using Monte Carlo simulations. We develop a hydrodynamic framework inspired by dynamical density functional theory approaches in which the contributions due to various flow-induced hydrodynamic interactions (HI) are included in the form of thermodynamic work done by these HI-derived forces in displacing the hard spheres. Using this framework, we can self-consistently determine the effect of the local microstructure on the average flow field, and vice versa, and coevolve the inhomogeneous density distribution and the flattening velocity profile with increase in the density of suspended particles.

Acute decompression following simulated dive conditions alters mitochondrial respiration and motility.

While barotrauma, decompression sickness, and drowning-related injuries are common morbidities associated with diving and decompression from depth, it remains unclear what impact rapid decompression has on mitochondrial function. In vitro diving simulation was performed with human dermal fibroblast cells subjected to control, air, nitrogen, and oxygen dive conditions. With the exception of the gas mixture, all other related variables, including absolute pressure exposure, dive and decompression rates, and temperature, were held constant.

Flexible Nanoparticles Reach Sterically Obscured Endothelial Targets Inaccessible to Rigid Nanoparticles.

Molecular targeting of nanoparticle drug carriers promises maximized therapeutic impact to sites of disease or injury with minimized systemic effects. Precise targeting demands addressing to subcellular features. Caveolae, invaginations in cell membranes implicated in transcytosis and inflammatory signaling, are appealing subcellular targets.

Alterations in Mitochondrial Function in Blood Cells Obtained From Patients With Sepsis Presenting to an Emergency Department.

Objective: Mitochondrial dysfunction has been implicated as a key cellular event leading to organ dysfunction in sepsis. Our objective is to measure changes in mitochondrial bioenergetics in subjects with early presentation of sepsis to provide insight into the incompletely understood pathophysiology of the dysregulated host response in sepsis.

Design: Prospective observational study.

Translational Application of Measuring Mitochondrial Functions in Blood Cells Obtained from Patients with Acute Poisoning.

It is conservatively estimated that 5,000 deaths per year and 20,000 injuries in the USA are due to poisonings caused by chemical exposures (e.g., carbon monoxide, cyanide, hydrogen sulfide, phosphides) that are cellular inhibitors.

Alterations in mitochondrial respiration and reactive oxygen species in patients poisoned with carbon monoxide treated with hyperbaric oxygen.

Background: Carbon monoxide (CO) poisoning is the leading cause of poisoning mortality and morbidity in the USA. Carboxyhemoglobin (COHb) levels are not predictive of severity or prognosis. At this time, the measurement of mitochondrial respiration may serve as a biomarker in CO poisoning.

Mitochondrial networking in human blood cells with application in acute care illnesses.

Mitochondria are dynamic organelles that adapt in response to environmental stresses or mutations. Dynamic processes involving mitochondria include their locomotion within cells and fusion and fission events in which mitochondrial join together or split apart. Various imaging strategies have been utilized to track mitochondrial dynamics.

Excess area dependent scaling behavior of nano-sized membrane tethers.

Thermal fluctuations in cell membranes manifest as an excess area ([Formula: see text]) which governs a multitude of physical process at the sub-micron scale. We present a theoretical framework, based on an in silico tether pulling method, which may be used to reliably estimate [Formula: see text] in live cells. We perform our simulations in two different thermodynamic ensembles: (i) the constant projected area and (ii) the constant frame tension ensembles and show the equivalence of our results in the two.

Mitochondrial dynamics and respiration within cells with increased open pore cytoskeletal meshes.

The cytoskeletal architecture directly affects the morphology, motility, and tensional homeostasis of the cell. In addition, the cytoskeleton is important for mitosis, intracellular traffic, organelle motility, and even cellular respiration. The organelle responsible for a majority of the energy conversion for the cell, the mitochondrion, has a dependence on the cytoskeleton for mobility and function.