Modeling transport of charged species in pore networks: solution of the Nernst-Planck equations coupled with fluid flow and charge conservation equations

A pore network modeling (PNM) framework for the simulation of transport of charged species, such as ions, in porous media is presented. It includes the Nernst-Planck (NP) equations for each charged species in the electrolytic solution in addition to a charge conservation equation which relates the species concentration to each other. Moreover, momentum and mass conservation equations are adopted and there solution allows for the calculation of the advective contribution to the transport in the NP equations. The proposed framework is developed by first deriving the numerical model equations (NMEs) corresponding to the partial differential equations (PDEs) based on several different time and space discretization schemes, which are compared to assess solutions accuracy. The derivation also considers various charge conservation scenarios, which also have pros and cons in terms of speed and accuracy. Ion transport problems in arbitrary pore networks were considered and solved using both PNM and finite element method (FEM) solvers. Comparisons showed an average deviation, in terms of ions concentration, between PNM and FEM below $5\%$ with the PNM simulations being over ${10}^{4}$ times faster than the FEM ones for a medium including about ${10}^{4}$ pores. The improved accuracy is achieved by utilizing more accurate discretization schemes for both the advective and migrative terms, adopted from the CFD literature. The NMEs were implemented within the open-source package OpenPNM based on the iterative Gummel algorithm with relaxation. This work presents a comprehensive approach to modeling charged species transport suitable for a wide range of applications from electrochemical devices to nanoparticle movement in the subsurface

A Study of Water Management in Polymer Electrolyte Fuel Cells: Compression Effect on Multiphase Flow

One of the main obstacles to overcome regarding the uptake of renewable energy technologies, specifically wind and solar energy, is their intermittency. Current energy storage techniques are costly and in-efficient. Fuel cells are a promising candidate for future energy storage, as part of an integrated system combining renewable energy with hydrogen production as the storage vector with reconversion. The Polymer Electrolyte Fuel Cell (PEFC) has the greatest potential for use with micro-generated renewable power and is suitable for the widest range of applications. Hence it has received a great deal of attention from research institutions and industry over the last few decades. However, they suffer performance limitations due to flooding by liquid water in the porous components forming the electrodes of the cell. Two numerical investigations utilising different methods to probe multiphase transport in porous media, and one experimental investigation into the flow through partially saturated porous media, are presented. The porous media under investigation are typical materials for PEFC gas diffusion layers (GDLs), and the influence of compression of the material on the multiphase transport is investigated. In addition, a further study assessing the suitability of pore-scale capillary pressure models for predicting multiphase flow behaviour is included as a final research chapter

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2–4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

The Rise and Fall of Ziggy Stardust and Natural Law

In Natural Law and Natural Rights, John Finnis delves into the past, attempting to revitalise the Thomist natural law tradition cut short by opposing philosophers such as David Hume. In this article, Finnis’s efforts at revival are assessed by way of comparison with—and, indeed, contrast to—the life and art of musician David Bowie. In spite of their extravagant differences, there exist significant points of connection that allow Bowie to be used in interpreting Finnis’s natural law. Bowie’s work—for all its appeals to a Nietzschean ground zero for normative values—shares Finnis’s concern with ordering affairs in a way that will realise humanity’s great potential. In presenting enchanted worlds and evolved characters as an antidote to all that is drab and pointless, Bowie has something to tell his audience about how human beings can thrive. Likewise, natural law holds that a legal system should include certain content that guides people towards a life of “flourishing”. Bowie and Finnis look to the past, plundering it for inspiration and using it as fuel to boost humankind forward. The analogy of Natural Law and Natural Rights and Bowie’s magpie-like relationship to various popular music traditions ultimately reveals that natural law theory is not merely an objective and unchanging edict to be followed without question, but a legacy that is to be recreated by those who carry it into the future. Law’s instruments of critique must not forget these transformative qualities.Arts, Education & Law Group, School of LawFull Tex

A systematic study of the solid state and solution phase conformational preferences of beta-peptides derived from transpentacin

The solid state and solution phase conformational preferences of a homologous series of beta-peptides derived from (S,S)-2-aminocyclopentanecarboxylic acid (transpentacin) have been investigated using a variety of spectroscopic and crystallographic techniques. These studies indicate that the hexamer and pentamer persist as a 12-helix in both the solid state and solution phase. Although the conformational traits of a 12-helix are exhibited by oligomers with as few as three residues in the solid state, in solution the trimer exists as an equilibrium of many alternative conformers whilst the tetramer has been shown to predominantly exist in either a 12-helix or a turn-type conformation. (C) 2010 Elsevier Ltd. All rights reserved.</p

Englerin A Agonizes the TRPC4/C5 Cation Channels to Inhibit Tumor Cell Line Proliferation

<div><p>Englerin A is a structurally unique natural product reported to selectively inhibit growth of renal cell carcinoma cell lines. A large scale phenotypic cell profiling experiment (CLiP) of englerin A on ¬over 500 well characterized cancer cell lines showed that englerin A inhibits growth of a subset of tumor cell lines from many lineages, not just renal cell carcinomas. Expression of the TRPC4 cation channel was the cell line feature that best correlated with sensitivity to englerin A, suggesting the hypothesis that TRPC4 is the efficacy target for englerin A. Genetic experiments demonstrate that TRPC4 expression is both necessary and sufficient for englerin A induced growth inhibition. Englerin A induces calcium influx and membrane depolarization in cells expressing high levels of TRPC4 or its close ortholog TRPC5. Electrophysiology experiments confirmed that englerin A is a TRPC4 agonist. Both the englerin A induced current and the englerin A induced growth inhibition can be blocked by the TRPC4/C5 inhibitor ML204. These experiments confirm that activation of TRPC4/C5 channels inhibits tumor cell line proliferation and confirms the TRPC4 target hypothesis generated by the cell line profiling. In selectivity assays englerin A weakly inhibits TRPA1, TRPV3/V4, and TRPM8 which suggests that englerin A may bind a common feature of TRP ion channels. <i>In vivo</i> experiments show that englerin A is lethal in rodents near doses needed to activate the TRPC4 channel. This toxicity suggests that englerin A itself is probably unsuitable for further drug development. However, since englerin A can be synthesized in the laboratory, it may be a useful chemical starting point to identify novel modulators of other TRP family channels.</p></div

Englerin A selectivity against TRP family and non-TRP family ion channels.

<p>Englerin A selectivity against TRP family and non-TRP family ion channels.</p

Englerin A agonizes the TRPC4/C5 ion channels and channel activation is needed for cell growth inhibition.

<p>(<b>A</b>) Calcium flux stimulated by englerin A in HEK293T cells overexpressing different TRPC proteins (mean +/- standard deviation): TRPC5 (closed diamonds), TRPC4beta (closed squares), TRPC4 (closed circles), TRPC6 (open squares), mock transfected cells (open circles). (<b>B</b>) Membrane depolarization stimulated by englerin A in HEK293T cells overexpressing different TRPC proteins (mean +/- standard deviation), markers as above. (<b>C</b>) TRPC4 current evoked by stimulation of 5 μM Englerin A, saline, or 5 μM Englerin A + 10 μM ML204 in 293T cells with Doxycyline-induced TRPC4. Currents were elicited by 200 ms voltage ramps from -100 to +100 mV, applied every 10 s from holding potential of 0 mV. (<b>D</b>) Summary of englerin A, englerin-B and ML-204 activity on membrane currents (mean +/- S.E.M.) (<b>E</b>) A-673 cell viability in the presence or absence of 50 nM englerin A and/or 50 μM ML204, a TRPC4/C5 channel blocker (mean +/- standard deviation).</p