Bjerrum pairing correlations at charged interfaces

Electrostatic correlations play a fundamental role in aqueous solutions. In this letter, we identify transverse and lateral correlations as two mutually exclusive regimes. We show that the transverse regime leads to binding by generalization of Bjerrum pair formation theory, yielding binding constants from first-principle statistical-mechanical calculations. We compare our theoretical predictions with experiments on charged membranes and Langmuir monolayers and find good agreement. We contrast our approach with existing theories in the strong-coupling limit and on charged modulated interfaces, and discuss different scenarios that lead to charge reversal and equal-sign attraction by macro-ions.Comment: 7 pages, 4 figure

CBS domains form energy-sensing modules whose binding of adenosine ligands is disrupted by disease mutations

CBS domains are defined as sequence motifs that occur in several different proteins in all kingdoms of life. Although thought to be regulatory, their exact functions have been unknown. However, their importance was underlined by findings that mutations in conserved residues within them cause a variety of human hereditary diseases, including (with the gene mutated in parentheses): Wolff-Parkinson-White syndrome (γ2 subunit of AMP-activated protein kinase); retinitis pigmentosa (IMP dehydrogenase-1); congenital myotonia, idiopathic generalized epilepsy, hypercalciuric nephrolithiasis, and classic Bartter syndrome (CLC chloride channel family members); and homocystinuria (cystathionine β-synthase). AMP-activated protein kinase is a sensor of cellular energy status that is activated by AMP and inhibited by ATP, but the location of the regulatory nucleotide-binding sites (which are prime targets for drugs to treat obesity and diabetes) was not characterized. We now show that tandem pairs of CBS domains from AMP-activated protein kinase, IMP dehydrogenase-2, the chloride channel CLC2, and cystathionine β-synthase bind AMP, ATP, or S-adenosyl methionine,while mutations that cause hereditary diseases impair this binding. This shows that tandem pairs of CBS domains act, in most cases, as sensors of cellular energy status and, as such, represent a newly identified class of binding domain for adenosine derivatives

Phase field modeling of electrochemistry II: Kinetics

The kinetic behavior of a phase field model of electrochemistry is explored for advancing (electrodeposition) and receding (electrodissolution) conditions in one dimension. We described the equilibrium behavior of this model in [J. E. Guyer, W. J. Boettinger, J.A. Warren, and G. B. McFadden, ``Phase field modeling of electrochemistry I: Equilibrium'', cond-mat/0308173]. We examine the relationship between the parameters of the phase field method and the more typical parameters of electrochemistry. We demonstrate ohmic conduction in the electrode and ionic conduction in the electrolyte. We find that, despite making simple, linear dynamic postulates, we obtain the nonlinear relationship between current and overpotential predicted by the classical ``Butler-Volmer'' equation and observed in electrochemical experiments. The charge distribution in the interfacial double layer changes with the passage of current and, at sufficiently high currents, we find that the diffusion limited deposition of a more noble cation leads to alloy deposition with less noble species.Comment: v3: To be published in Phys. Rev. E v2: Attempt to work around turnpage bug. Replaced color Fig. 4a with grayscale 13 pages, 7 figures in 10 files, REVTeX 4, SIunits.sty, follows cond-mat/030817

The LKB1-AMPK-α1 signaling pathway triggers hypoxic pulmonary vasoconstriction downstream of mitochondria

International audienceHypoxic pulmonary vasoconstriction (HPV), which aids ventilation-perfusion matching in the lungs, is triggered by mechanisms intrinsic to pulmonary arterial smooth muscles. The unique sensitivity of these muscles to hypoxia is conferred by mitochondrial cytochrome c oxidase subunit 4 isoform 2, the inhibition of which has been proposed to trigger HPV through increased generation of mitochondrial reactive oxygen species. Contrary to this model, we have shown that the LKB1-AMPK-α1 signaling pathway is critical to HPV. Spectral Doppler ultrasound revealed that deletion of the AMPK-α1 catalytic subunit blocked HPV in mice during mild (8% O2) and severe (5% O2) hypoxia, whereas AMPK-α2 deletion attenuated HPV only during severe hypoxia. By contrast, neither of these genetic manipulations affected serotonin-induced reductions in pulmonary vascular flow. HPV was also attenuated by reduced expression of LKB1, a kinase that activates AMPK during energy stress, but not after deletion of CaMKK2, a kinase that activates AMPK in response to increases in cytoplasmic Ca2+ Fluorescence imaging of acutely isolated pulmonary arterial myocytes revealed that AMPK-α1 or AMPK-α2 deletion did not affect mitochondrial membrane potential during normoxia or hypoxia. However, deletion of AMPK-α1, but not of AMPK-α2, blocked hypoxia from inhibiting KV1.5, the classical "oxygen-sensing" K+ channel in pulmonary arterial myocytes. We conclude that LKB1-AMPK-α1 signaling pathways downstream of mitochondria are critical for the induction of HPV, in a manner also supported by AMPK-α2 during severe hypoxia

How does iron interact with sporopollenin exine capsules? An X-ray absorption study including microfocus XANES and XRF imaging

Sporopollenin exine capsules (SECs) derived from plant spores and pollen grains have been proposed as adsorption, remediation and drug delivery agents. Despite many studies there is scant structural data available. This X-ray absorption investigation represents the first direct structural data on the interaction of metals with SECs and allows elucidation of their structure–property relationships. Fe K-edge XANES and EXAFS data have shown that the iron local environment in SECs (derived from Lycopodium clavatum) reacted with aqueous ferric chloride solutions is similar to that of ferrihydrite (FeOOH) and by implication ferritin. Fe Kα XRF micro-focus experiments show that there is a poor correlation between the iron distribution and the underlying SEC structure indicating that the SEC is coated in the FeOOH material. In contrast, the Fe Kα XRF micro-focus experiments on SECs reacted with aqueous ferrous chloride solutions show that there is a very high correlation between the iron distribution and the SEC structure, indicating a much more specific form of interaction of the iron with the SEC surface functional groups. Fe K-edge XANES and EXAFS data show that the FeII can be easily oxidised to give a structure similar to, but not identical to that in the FeIII case, and that even if anaerobic conditions are used there is still partial oxidation to FeIII

Genotoxic Damage Activates the AMPK-α1 Isoform in the Nucleus via Ca2+/CaMKK2 Signaling to Enhance Tumor Cell Survival

2017 American Association for Cancer Research. Many genotoxic cancer treatments activate AMP-activated protein kinase (AMPK), but the mechanisms of AMPK activation in response to DNA damage, and its downstream consequences, have been unclear. In this study, etoposide activates the a1 but not the a2 isoform of AMPK, primarily within the nucleus. AMPK activation is independent of ataxia-telangiectasia mutated (ATM), a DNA damage-activated kinase, and the principal upstream kinase for AMPK, LKB1, but correlates with increased nuclear Ca2þ and requires the Ca2þ/calmodulin-dependent kinase, CaMKK2. Intriguingly, Ca2þ-dependent activation of AMPK in two different LKB1-null cancer cell lines caused G1-phase cell-cycle arrest, and enhanced cell viability/ survival after etoposide treatment, with both effects being abolished by knockout of AMPK-a1 and a2. The CDK4/6 inhibitor palbociclib also caused G1 arrest in G361 but not HeLa cells and, consistent with this, enhanced cell survival after etoposide treatment only in G361 cells. These results suggest that AMPK activation protects cells against etoposide by limiting entry into S-phase, where cells would be more vulnerable to genotoxic stress. Implications: These results reveal that the a1 isoform of AMPK promotes tumorigenesis by protecting cells against genotoxic stress, which may explain findings that the gene encoding AMPK-a1 (but not -a2) is amplified in some human cancers. Furthermore, a1-selective inhibitors might enhance the anticancer effects of genotoxic-based therapies