Note: When clicking on a Digital Object Identifier (DOI) number, you will be taken to an external site maintained by the publisher.
Some full text articles may not yet be available without a charge during the embargo (administrative interval).
What is a DOI Number?
Some links on this page may take you to non-federal websites. Their policies may differ from this site.
-
We developed a computational model of sodium fluorescein (SF) biliary excretion in ex vivo machine perfusion and used this model to assess changes in model parameters associated with the activity of MRP2, a hepatocyte membrane transporter, in response to increasing warm ischemia time. We found a significant decrease in the parameter value describing MRP2 activity, consistent with a role of decreased MRP2 function in ischemia-reperfusion injury leading to decreased secretion of SF into bile.more » « lessFree, publicly-accessible full text available September 1, 2025
-
We assessed lung tissue mitochondrial bioenergetics in rats with tolerance (H-T) or susceptibility (H-S) to hyperoxia-induced ARDS. Results from studies in isolated mitochondria, tissue homogenate, and isolated perfused lungs show that mitochondrial bioenergetics are differentially altered in H-T and H-S lungs suggesting a potential role for mitochondrial bioenergetics in hyperoxia-induced ARDS. Results are clinically relevant since hyperoxia exposure is a primary therapy for patients with ARDS, and differential sensitivity to hyperoxia surely occurs in humans.more » « lessFree, publicly-accessible full text available August 1, 2025
-
The suprachiasmatic nucleus (SCN) sets the phase of oscillation throughout the brain and body. Anatomical evidence reveals a portal system linking the SCN and the organum vasculosum of the lamina terminalis (OVLT), begging the question of the direction of blood flow and the nature of diffusible signals that flow in this specialized vasculature. Using a combination of anatomical and in vivo two-photon imaging approaches, we unequivocally show that blood flows unidirectionally from the SCN to the OVLT, that blood flow rate displays daily oscillations with a higher rate at night than in the day, and that circulating vasopressin can access portal vessels. These findings highlight a previously unknown central nervous system communication pathway, which, like that of the pituitary portal system, could allow neurosecretions to reach nearby target sites in OVLT, avoiding dilution in the systemic blood. In both of these brain portal pathways, the target sites relay signals broadly to both the brain and the rest of the body.more » « less
-
Abstract A key open question in the study of layered superconducting nickelate films is the role that hydrogen incorporation into the lattice plays in the appearance of the superconducting state. Due to the challenges of stabilizing highly crystalline square planar nickelate films, films are prepared by the deposition of a more stable parent compound which is then transformed into the target phaseviaa topotactic reaction with a strongly reducing agent such as CaH2. Recent studies, both experimental and theoretical, have introduced the possibility that the incorporation of hydrogen from the reducing agent into the nickelate lattice may be critical for the superconductivity. In this work, we use secondary ion mass spectrometry to examine superconducting La1−xXxNiO2/ SrTiO3(X= Ca and Sr) and Nd6Ni5O12/ NdGaO3films, along with non-superconducting NdNiO2/ SrTiO3and (Nd,Sr)NiO2/ SrTiO3. We find no evidence for extensive hydrogen incorporation across a broad range of samples, including both superconducting and non-superconducting films. Theoretical calculations indicate that hydrogen incorporation is broadly energetically unfavorable in these systems, supporting our conclusion that extensive hydrogen incorporation is not generally required to achieve a superconducting state in layered square-planar nickelates.more » « lessFree, publicly-accessible full text available December 1, 2025
-
Abstract SummaryMolecular mechanisms of biological functions and disease processes are exceptionally complex, and our ability to interrogate and understand relationships is becoming increasingly dependent on the use of computational modeling. We have developed “BioModME,” a standalone R-based web application package, providing an intuitive and comprehensive graphical user interface to help investigators build, solve, visualize, and analyze computational models of complex biological systems. Some important features of the application package include multi-region system modeling, custom reaction rate laws and equations, unit conversion, model parameter estimation utilizing experimental data, and import and export of model information in the Systems Biology Matkup Language format. The users can also export models to MATLAB, R, and Python languages and the equations to LaTeX and Mathematical Markup Language formats. Other important features include an online model development platform, multi-modality visualization tool, and efficient numerical solvers for differential-algebraic equations and optimization. Availability and implementationAll relevant software information including documentation and tutorials can be found at https://mcw.marquette.edu/biomedical-engineering/computational-systems-biology-lab/biomodme.php. Deployed software can be accessed at https://biomodme.ctsi.mcw.edu/. Source code is freely available for download at https://github.com/MCWComputationalBiologyLab/BioModME.more » « less
-
Mitochondria are major sources of reactive oxygen species (ROS), which play important roles in both physiological and pathological processes. However, the specific contributions of different ROS production and scavenging components in the mitochondria of metabolically active tissues such as heart and kidney cortex and outer medulla (OM) are not well understood. Therefore, the goal of this study was to determine contributions of different ROS production and scavenging components and provide detailed comparisons of mitochondrial respiration, bioenergetics, ROS emission between the heart and kidney cortex and OM using tissues obtained from the same Sprague-Dawley rat under identical conditions and perturbations. Specifically, data were obtained using both NADH-linked substrate pyruvate + malate and FADH2-linked substrate succinate followed by additions of inhibitors of different components of the electron transport chain (ETC) and oxidative phosphorylation (OxPhos) and other ROS production and scavenging systems. Currently, there is limited data available for the mitochondria of kidney cortex and OM, the two major energy-consuming tissues in the body only next to the heart, and scarce quantitative information on the interplay between mitochondrial ROS production and scavenging systems in the three tissues. The findings from this study demonstrate significant differences in mitochondrial respiratory and bioenergetic functions and ROS emission among the three tissues. The results quantify the rates of ROS production from different complexes of the ETC, identify the complexes responsible for variations in mitochondrial membrane depolarization and regulations of ROS production, and quantify the contributions of ROS scavenging enzymes towards overall mitochondrial ROS emission. These findings advance our fundamental knowledge of tissue-specific and substrate-dependent mitochondrial respiratory and bioenergetic functions and ROS emission. This is important given the critical role that excess ROS production, oxidative stress, and mitochondrial dysfunction in the heart and kidney cortex and OM play in the pathogenesis of cardiovascular and renal diseases, including salt-sensitive hypertension. Keywords: Forward and reverse electron transfer; Mitochondrial metabolism; NADPH oxidase; Oxidative stress; ROS emission; ROS production and scavenging; Respiration and bioenergetics.more » « less
-
Doping, or incremental substitution of one element for another, is an effective way to tailor a compound’s structure as well as its physical and chemical properties. Herein, we replaced up to 30% of Ni with Co in members of the family of layered LiNiB compounds, stabilizing the high-temperature polymorph of LiNiB while the room-temperature polymorph does not form. By studying this layered boride with in situ high-temperature powder diffraction, we obtained a distorted variant of LiNi0.7Co0.3B featuring a perfect interlayer placement of [Ni0.7Co0.3B] layers on top of each other─a structural motif not seen before in other borides. Because of the Co doping, LiNi0.7Co0.3B can undergo a nearly complete topochemical Li deintercalation under ambient conditions, resulting in a metastable boride with the formula Li0.04Ni0.7Co0.3B. Heating of Li0.04Ni0.7Co0.3B in anaerobic conditions led to yet another metastable boride, Li0.01Ni0.7Co0.3B, with a CoB-type crystal structure that cannot be obtained by simple annealing of Ni, Co, and B. No significant alterations of magnetic properties were detected upon Co-doping in the temperature-independent paramagnet LiNi0.7Co0.3B or its Li-deintercalated counterparts. Finally, Li0.01Ni0.7Co0.3B stands out as an exceptional catalyst for the selective hydrogenation of the vinyl C═C bond in 3-nitrostyrene, even in the presence of other competing functional groups. This research showcases an innovative approach to heterogeneous catalyst design by meticulously synthesizing metastable compounds.more » « less
-
Abstract— During liver transplantation, ischemia-reperfusion injury (IRI) is inevitable and decreases the overall success of the surgery. While guidelines exist, there is no reliable way to quantitatively assess the degree of IRI present in the liver. Our recent study has shown a correlation between the bile-to-plasma ratio of FDA-approved sodium fluorescein (SF) and the degree of hepatic IRI, presumably due to IRI-induced decrease in the activity of the hepatic multidrug resistance-associated protein 2 (MRP2); however, the contribution of SF blood clearance via the bile is still convoluted with other factors, such as renal clearance. In this work, we sought to computationally model SF blood clearance via the bile. First, we converted extant SF fluorescence data from rat whole blood, plasma, and bile to concentrations using calibration curves. Next, based on these SF concentration data, we generated a “liver-centric”, physiologically-based pharmacokinetic (PBPK) model of SF liver uptake and clearance via the bile. Model simulations show that SF bile concentration is highly sensitive to a change in the activity of hepatic MPR2. These simulations suggest that SF bile clearance along with the PBPK model can be used to quantify the effect of IRI on the activity of MRP2. Clinical Relevance— This study establishes the theory necessary to generate a model for predicting the degree of IRI during liver transplantation.more » « less
-
A map of central nervous system organization based on vascular networks or angiomes1 provides a layer of organization distinct from familiar neural networks or connectomes. As a well-established example, the capillary networks of the pituitary portal system enable a route for small amounts of neurochemical signals to reach local targets by traveling along specialized pathways, thereby avoiding dilution in the systemic circulation. Anatomical studies provided the first evidence of this vascular pathway in the brain. Specifically, Popa and Fielding identified a portal pathway linking the hypothalamus and the pituitary gland. Their anatomical work was based on hematoxylin and eosin-stained sections of the human brain. They also extensively discussed previous studies of this brain region. Based on the available literature and the appearance of India ink in the hypothalamus after it had been injected into the anterior pituitary, they vigorously argued that the direction of blood flow was from the pituitary gland to the hypothalamusmore » « less
-
Abstract Integrated computational modeling provides a mechanistic and quantitative framework to characterize alterations in mitochondrial respiration and bioenergetics in response to different metabolic substrates in-silico. These alterations play critical roles in the pathogenesis of diseases affecting metabolically active organs such as heart and kidney. Therefore, the present study aimed to develop and validate thermodynamically constrained integrated computational models of mitochondrial respiration and bioenergetics in the heart and kidney cortex and outer medulla (OM). The models incorporated the kinetics of major biochemical reactions and transport processes as well as regulatory mechanisms in the mitochondria of these tissues. Intrinsic model parameters such as Michaelis–Menten constants were fixed at previously estimated values, while extrinsic model parameters such as maximal reaction and transport velocities were estimated separately for each tissue. This was achieved by fitting the model solutions to our recently published respirometry data measured in isolated rat heart and kidney cortex and OM mitochondria utilizing various NADH- and FADH2-linked metabolic substrates. The models were validated by predicting additional respirometry and bioenergetics data, which were not used for estimating the extrinsic model parameters. The models were able to predict tissue-specific and substrate-dependent mitochondrial emergent metabolic system properties such as redox states, enzyme and transporter fluxes, metabolite concentrations, membrane potential, and respiratory control index under diverse physiological and pathological conditions. The models were also able to quantitatively characterize differential regulations of NADH- and FADH2-linked metabolic pathways, which contribute differently toward regulations of oxidative phosphorylation and ATP synthesis in the heart and kidney cortex and OM mitochondria.more » « less