SummaryTwo-pore domain (K2P) K+ channels are major regulators of excitability that endow cells with an outwardly rectifying background “leak” conductance. In some K2P channels, strong voltage-dependent activation has been observed, but the mechanism remains unresolved because they lack a canonical voltage-sensing domain. Here, we show voltage-dependent gating is common to most K2P channels and that this voltage sensitivity originates from the movement of three to four ions into the high electric field of an inactive selectivity filter. Overall, this ion-flux gating mechanism generates a one-way “check valve” within the filter because outward movement of K+ induces filter opening, whereas inward movement promotes inactivation. Furthermore, many physiological stimuli switch off this flux gating mode to convert K2P channels into a leak conductance. These findings provide insight into the functional plasticity of a K+-selective filter and also refine our understanding of K2P channels and the mechanisms by which ion channels can sense voltage.

Recent X-ray crystal structures of the two-pore domain (K2P) family of potassium channels have revealed a unique structural architecture at the point where the cytoplasmic bundle-crossing gate is found in most other tetrameric K+ channels. However, despite the apparently open nature of the inner pore in the TWIK-1 (K2P1/KCNK1) crystal structure, the reasons underlying its low levels of functional activity remain unclear. In this study, we use a combination of molecular dynamics simulations and functional validation to demonstrate that TWIK-1 possesses a hydrophobic barrier deep within the inner pore, and that stochastic dewetting of this hydrophobic constriction acts as a major barrier to ion conduction. These results not only provide an important insight into the mechanisms which control TWIK-1 channel activity, but also have important implications for our understanding of how ion permeation may be controlled in similar ion channels and pores.

A combination of experimental measurements and numerical simulations are used to characterize the mechanical and electrochemical response of thin film amorphous Si electrodes during cyclic lithiation. Parameters extracted from the experiment include the variation of elastic modulus and the flow stress as functions of Li concentration; the strain rate sensitivity; the diffusion coefficient for Li transport in the electrode; the free energy of mixing as a function of Li concentration in the electrode; the exchange current density for the Lithium insertion reaction; as well as reaction rates and diffusion coefficients characterizing the rate of formation of solid-electrolyte interphase layer at the electrode surface. Model predictions are compared with experimental measurements; and the implications for practical Si based electrodes are discussed.

This is the first quantitative analysis of mechanical reliability of all-solid state batteries. Mechanical degradation of the solid electrolyte (SE) is caused by intercalation-induced expansion of the electrode particles, within the constrains of a dense microstructure. A coupled electro-chemo-mechanical model was implemented to quantify the material properties that cause a SE to fracture. The treatment of microstructural details is essential to the understanding of stresslocalization phenomena and fracture. A cohesive zone model is employed to simulate the evolution of damage. In the numerical tests, fracture is prevented when electrode-particle's expansion is lower than 7.5% (typical for most Li-intercalating compounds) and the solid-electrolyte's fracture energy higher than G c = 4 J m −2 . Perhaps counterintuitively, the analyses show that compliant solid electrolytes (with Young's modulus in the order of E SE = 15 GPa) are more prone to micro-cracking. This result, captured by our non-linear kinematics model, contradicts the speculation that sulfide SEs are more suitable for the design of bulk-type batteries than oxide SEs. Mechanical degradation is linked to the battery power-density. Fracture in solid Li-ion conductors represents a barrier for Li transport, and accelerates the decay of rate performance.

Liver X receptors (LXRs) are transcription factors involved in the regulation of cholesterol homeostasis. LXR ligands have athero-protective properties independent of their effects on cholesterol metabolism. Platelets are involved in the initiation of atherosclerosis and despite being anucleate express nuclear receptors. We hypothesized that the athero-protective effects of LXR ligands could be in part mediated through platelets and therefore explored the potential role of LXR in platelets. Our results show that LXR-␤ is present in human platelets and the LXR ligands, GW3965 and T0901317, modulated nongenomically platelet aggregation stimulated by a range of agonists. GW3965 caused LXR to associate with signaling components proximal to the collagen receptor, GPVI, suggesting a potential mechanism of LXR action in platelets that leads to diminished platelet responses. Activation of platelets at sites of atherosclerotic lesions results in thrombosis preceding myocardial infarction and stroke. Using an in vivo model of thrombosis in mice, we show that GW3965 has antithrombotic effects, reducing the size and the stability of thrombi. The atheroprotective effects of GW3965, together with its novel antiplatelet/thrombotic effects, indicate LXR as a potential target for prevention of athero-thrombotic disease. (Blood. 2011;117(21):5751-5761) IntroductionLiver X receptors (LXRs) belong to the nuclear receptor superfamily, and their natural ligands, oxysterols, are cholesterol derivatives. 1 LXRs play key roles in cholesterol homeostasis by regulating the transcription of genes, such as cytochrome P450 7␣-hydroxylase 1 (Cyp7a1) and apoliprotein E (ApoE), involved in cholesterol catabolism to bile acids 2,3 and cholesterol efflux back to the liver, 4-6 respectively. LXRs have also been shown to have anti-inflammatory 7,8 and athero-protective effects after ligand stimulation. 9,10 Platelets are anucleate blood cells with a central role in hemostasis but are also involved in inflammation and atherosclerosis. [11][12][13][14] Their primary function is to prevent hemorrhage at sites of vascular injury, where exposed extracellular matrix proteins, such as collagen, interact with platelet surface receptors, resulting in platelet activation, aggregation, and thrombus formation. Although platelets are essential for the preservation of vascular integrity, inappropriate platelet activation, for example, at sites of atherosclerotic lesions, causes arterial thrombosis, leading to ischemic stroke and myocardial infarction, 2 of the main causes of morbidity and mortality in the industrialized world. 15 Low-density lipoprotein is the main therapeutic target for the prevention of atherothrombosis, 16 and low-density lipoprotein-lowering medications, such as statins, appear additionally to display antiplatelet actions. 17,18 Platelet function is also affected by cholesterol derivatives, although there is no consensus on whether these molecules have inhibitory or activatory roles. 19 The initial entrapment of platelets on subendothelial c...

Constraint-induced stresses develop during Li-ion battery cycling, because anode and cathode materials expand and contract as they intercalate or de-intercalate Li. We show in this manuscript that these stresses, in turn, can significantly modify the maximum capacity of the device at a given cell voltage. All-solid-state batteries impose an external elastic constraint on electrode particles, promoting the development of large stresses during cycling. We employ an analytic and a finite element model to study this problem, and we predict that the electrode's capacity decreases with increasing matrix stiffness. In the case of lithiation of a silicon composite electrode, we calculate 64% of capacity loss for stresses up to 2 GPa. According to our analysis, increasing the volume ratio of Si beyond 25-30% has the effect of decreasing the total capacity, because of the interaction between neighboring particles. The stress-induced voltage shift depends on the chemical expansion of the active material and on the constraint-induced stress. However, even small voltage changes may result in very large capacity shift if the material is characterized by a nearly flat open-circuit potential curve.

An in situ study of deformation, fracture, and fatigue behavior of silicon as a lithium-ion battery electrode material is presented. Thin films (100-200 nm) of silicon are cycled in a halfcell configuration with lithium metal foil as counter/reference electrode, with 1M lithium hexafluorophosphate in ethylene carbonate, diethylene carbonate, dimethyl carbonate solution (1:1:1, wt.%) as electrolyte.Stress evolution in the Si thin-film electrodes during electrochemical lithiation and delithiation is measured by monitoring the substrate curvature using the multi-beam optical sensing method. The stress measurements have been corrected for contributions from residual stress arising from sputter-deposition. An indirect method for estimating the potential errors due to formation of the solid-electrolyte-interphase layer and surface charge on the stress measurements was presented. The films undergo extensive inelastic deformation during lithiation and delithiation. The peak compressive stress during lithiation was 1.48 GPa. The stress data along with the electron microscopy observations are used to estimate an upper bound fracture resistance of lithiated Si, which is approximately 9-11 J/m 2 . Fracture initiation and crack density evolution as a function of cycle number is also reported.

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