Biophysical Modelling for Insight into Oxygen Diffusion, Distribution, and Measurement.

Building on an extensive history of physiological and systems-oriented modelling, my group and others have recently used molecular simulation studies to understand oxygen (O) transport and localisation. Molecular simulations enable biophysical insight into processes difficult to study with experiments alone and are sometimes described as a "computational microscope." Our work has emphasised lipid membrane contributions to oxygen diffusion and uptake, suggesting that lipid-based pathways along membranes and lipid deposits are likely to accelerate diffusive transport through cells and tissues.

Understanding the Role of Caveolae in Oxygen Buffering: The Effect of Membrane Curvature.

The "oxygen paradox" can be explained as two opposing biological processes with oxygen (O) as a reactant. On the one hand, oxygen is essential to aerobic metabolism, powering oxidative phosphorylation in mitochondria. On the other hand, an excess supply of oxygen will generate reactive species which are harmful for the cell.

Correction to: Atomistic Simulations Modify Interpretation of Spin-Label Oximetry Data. Part 1: Intensified Water-Lipid Interfacial Resistances.

[This corrects the article PMC10249954.].

On the pursuitworthiness of qualitative methods in empirical philosophy of science.

While the pursuitworthiness of philosophical ideas has changed over time, philosophical practice and methodology have not kept pace. The worthiness of a philosophical pursuit includes not only the ideas and objectives one pursues but also the methods with which one pursues them. In this paper, we articulate how empirical approaches benefit philosophy of science, particularly advocating for the use of qualitative methods for understanding the social and normative aspects of scientific inquiry.

Still no pill for men? Double standards & demarcating values in biomedical research.

Double standards are widespread throughout biomedicine, especially in research on reproductive health. One of the clearest cases of double standards involves the feminine gendering of reproductive responsibility for contraception and the continued lack of highly effective, reversible methods for cisgender men. While the biomedical establishment accepts diversity and inclusion as important social values for clinical trials, their continued use of inequitable standards undermines their ability to challenge unfair social hierarchies by developing male contraception.

The FDA ought to change Plan B's label.

This commentary defends 3 arguments for changing the label of levonorgestrel-based emergency contraception (LNG EC) so that it no longer supports the possibility of a mechanism of action after fertilization. First, there is no direct scientific evidence confirming any postfertilization mechanisms. Second, despite the weight of evidence, there is still widespread public misunderstanding over the mechanism of LNG EC.

Discerning Membrane Steady-State Oxygen Flux by Monte Carlo Markov Chain Modeling.

Molecular oxygen (O) permeability coefficients for lipid bilayers have previously been estimated using both electron paramagnetic resonance (EPR) oximetry and molecular dynamics simulation data. Yet, neither technique captures the fluxes that exist physiologically. Here, the dynamic steady state is modeled using a stochastic approach built on atomic resolution molecular dynamics simulation data.

Updated Evaluation of Cholesterol's Influence on Membrane Oxygen Permeability.

There is a surprising gap in knowledge regarding the mechanism of oxygen (O) diffusional delivery at the level of tissues and cells. Yet, the effectiveness of tumor radiotherapy, the success of tissue engineering, and healthy metabolism all require ample intracellular oxygen. Tissue-level diffusion takes place in a complex and crowded macromolecular environment.

Simulation Study of Breast Cancer Lipid Changes Affecting Membrane Oxygen Permeability: Effects of Chain Length and Cholesterol.

Tumor radiotherapy relies on intracellular oxygen (O) to generate reactive species that trigger cell death, yet hypoxia is common in cancers of the breast. De novo lipid synthesis in tumors supports cell proliferation but also may lead to unusually high levels of the 16:1 palmitoleoyl (Y) phospholipid tail, which is two carbons shorter than the 18:1 oleoyl (O) tail abundant in normal breast tissue. Here, we use atomic resolution molecular dynamics simulations to test two hypotheses: (1) the shorter, 16:1 Y, tail of the de novo lipid biosynthesis product 1-palmitoyl,2-palmitoleoyl-phosphatidylcholine (PYPC) promotes lower membrane permeability relative to the more common lipid 1-palmitoyl,2-oleoylphosphatidylcholine (POPC), by reducing oxygen solubility in the interleaflet region, and (2) cholesterol further lessens the permeability of PYPC by reducing overall O solubility and promoting PYPC tail order adjacent to the rigid cholesterol ring system.

How does oxygen diffuse from capillaries to tissue mitochondria? Barriers and pathways.

Timely delivery of oxygen (O ) to tissue mitochondria is so essential that elaborate circulatory systems have evolved to minimize diffusion distances within tissue. Yet, knowledge is surprisingly limited regarding the diffusion pathway between blood capillaries and tissue mitochondria. An established and growing body of work examines the influence cellular and extracellular structures may have on subcellular oxygen availability.

Pathways of Oxygen Diffusion in Cells and Tissues : Hydrophobic Channeling via Networked Lipids.

Oxygen delivery to tissue mitochondria relies on simple diffusion in the target cells and tissues. As such, intracellular availability of O in tissue depends on its solubility and diffusivity in complex and heterogeneous macromolecular environments. The path of oxygen diffusion is key to its rate of transfer, especially where pathways of differing favorability are present.

Reduced Oxygen Permeability upon Protein Incorporation Within Phospholipid Bilayers.

Intracellular oxygenation is key to energy metabolism as well as tumor radiation therapy. Although integral proteins are ubiquitous in membranes, few studies have considered their effects on molecular oxygen permeability. Published experimental work with rhodopsin and bacteriorhodopsin has led to the hypothesis that integral proteins lessen membrane oxygen permeability, as well as the permeability of the lipid region.

The Role of Fault-Zone Architectural Elements on Pore Pressure Propagation and Induced Seismicity.

We used hydrogeologic models to assess how fault-zone properties promote or inhibit the downward propagation of fluid overpressures from a basal reservoir injection well (150 m from fault zone, Q = 5000 m /day) into the underlying crystalline basement rocks. We varied the permeability of the fault-zone architectural components and a crystalline basement weathered layer as part of a numerical sensitivity study. Realistic conduit-barrier style fault zones effectively transmit elevated pore pressures associated with 4 years of continuous injection to depths of approximately 2.

Influence of Cholesterol on the Oxygen Permeability of Membranes: Insight from Atomistic Simulations.

Cholesterol is widely known to alter the physical properties and permeability of membranes. Several prior works have implicated cell membrane cholesterol as a barrier to tissue oxygenation, yet a good deal remains to be explained with regard to the mechanism and magnitude of the effect. We use molecular dynamics simulations to provide atomic-resolution insight into the influence of cholesterol on oxygen diffusion across and within the membrane.

Magnification of Cholesterol-Induced Membrane Resistance on the Tissue Level: Implications for Hypoxia.

High cellular membrane cholesterol is known to generate membrane resistance and reduce oxygen (O2) permeability. As such, cholesterol may contribute to the Warburg effect in tumor cells by stimulating intracellular hypoxia that cannot be detected from extracellular oxygen measurements. We probe the tissue-level impact of the phenomenon, asking whether layering of cells can magnify the influence of cholesterol, to modulate hypoxia in relation to capillary proximity.