Voltage-gated ion channels generate electrical currents that control muscle
contraction, encode neuronal information, and trigger hormonal release.
Tissue-specific expression of accessory (β) subunits causes these channels to
generate currents with distinct properties. In the heart, KCNQ1 voltage-gated
potassium channels coassemble with KCNE1 β-subunits to generate the
IKs current (Barhanin et al.,
1996; Sanguinetti et al., 1996),
an important current for maintenance of stable heart rhythms. KCNE1 significantly
modulates the gating, permeation, and pharmacology of KCNQ1 (Wrobel et al., 2012; Sun et
al., 2012; Abbott, 2014). These
changes are essential for the physiological role of IKs (Silva and Rudy, 2005); however, after 18 years
of study, no coherent mechanism explaining how KCNE1 affects KCNQ1 has emerged. Here
we provide evidence of such a mechanism, whereby, KCNE1 alters the state-dependent
interactions that functionally couple the voltage-sensing domains (VSDs) to the
pore.DOI:
http://dx.doi.org/10.7554/eLife.03606.001
Highlights d In vivo screen for fibers targeting specific human gut taxa in a defined community d Proteomics and forward genetics identify bioactive nutrients and their utilization d Interspecies competition controls the outcome of fiberbased microbiota manipulation d Artificial food particles as biosensors of community-wide glycan degradation
Our data suggest that maturation of AVFs using objective criteria based on DDUS provides an opportunity to identify NAS problems in outflow veins before cannulation. Most of the of the AVF outflow veins (71.7%) could be transposed or superficialized using MIST, with excellent long-term outcomes.
Highlights d Fructoselysine (FL) is a common Maillard reaction product (MRP) in whey protein d FL selectively increases fitness of Collinsella intestinalis in gnotobiotic mice d C. intestinalis metabolizes FL via regulated transcription of a FL utilization locus d Gut bacteria may affect food safety through MRP degradation to harmless products
Antiferroelectric materials, where the transition between antipolar and polar phase is controlled by external electric fields, offer exceptional energy storage capacity with high efficiencies, giant electrocaloric effect, and superb electromechanical response. PbZrO3 is the first discovered and the archetypal antiferroelectric material. Nonetheless, substantial challenges in processing phase pure PbZrO3 have limited studies of the undoped composition, hindering understanding of the phase transitions in this material or unraveling the controversial origins of a low‐field ferroelectric phase observed in lead zirconate thin films. Leveraging highly oriented PbZrO3 thin films, a room‐temperature ferrielectric phase is observed in the absence of external electric fields, with modulations of amplitude and direction of the spontaneous polarization and large anisotropy for critical electric fields required for phase transition. The ferrielectric state observations are qualitatively consistent with theoretical predictions, and correlate with very high dielectric tunability, and ultrahigh strains (up to 1.1%). This work suggests a need for re‐evaluation of the fundamental science of antiferroelectricity in this archetypal material.
Loss-of-function mutations in Kv7.1 often lead to long QT syndrome (LQTS), a cardiac repolarization disorder associated with arrhythmia and subsequent sudden cardiac death. The discovery of agonistic IKs modulators may offer a new potential strategy in pharmacological treatment of this disorder. The benzodiazepine derivative (R)-L3 potently activates Kv7.1 channels and shortens action potential duration, thus may represent a starting point for drug development. However, the molecular mechanisms underlying modulation by (R)-L3 are still unknown. By combining alanine scanning mutagenesis, non-canonical amino acid incorporation, voltage-clamp electrophysiology and fluorometry, and in silico protein modelling, we show that (R)-L3 not only stimulates currents by allosteric modulation of the pore domain but also alters the kinetics independently from the pore domain effects. We identify novel (R)-L3-interacting key residues in the lower S4-segment of Kv7.1 and observed an uncoupling of the outer S4 segment with the inner S5, S6 and selectivity filter segments.
Methods for measuring gut microbiota biochemical activities in vivo are needed to characterize its functional states in health and disease. To illustrate one approach, an arabinan-containing polysaccharide was isolated from pea fiber, its structure defined, and forward genetic and proteomic analyses used to compare its effects, versus unfractionated pea fiber and sugar beet arabinan, on a human gut bacterial strain consortium in gnotobiotic mice. We produced ‘Microbiota Functional Activity Biosensors’ (MFABs) consisting of glycans covalently linked to the surface of fluorescent paramagnetic microscopic glass beads. Three MFABs, each containing a unique glycan/fluorophore combination, were simultaneously orally gavaged into gnotobiotic mice, recovered from their intestines, and analyzed to directly quantify bacterial metabolism of structurally distinct arabinans in different human diet contexts. Colocalizing pea-fiber arabinan and another polysaccharide (glucomannan) on the bead surface enhanced in vivo degradation of glucomannan. MFABs represent a potentially versatile platform for developing new prebiotics and more nutritious foods.
Voltage-dependent potassium channels are crucial for electrical excitability and cellular signaling; however, the molecular machinery that the channel employs, to relay the state of the voltage sensor to the pore, is not well understood. To gain insight into this voltage-transduction pathway, interacting networks need to be reliably mapped. Here we present a methodology to estimate the strength of site specific interactions called the Generalized Interaction-energy Analysis (or GIA). Our approach involves combining thermodynamic cycle analysis with information from the gating charge verses voltage curves of putative interactors. This methodology was benchmarked against well established kinetic models of Shaker potassium channels and BK channels using Monte Carlo like sampling. Our simulations show that GIA can provide free energy estimates in a selfconsistent manner that will be useful to identify site-specific interactors that contribute to gating transitions. Implementing this approach on the Shaker potassium channel, we identify a cluster of highly conserved residues, located in the intracellular side of the channel pore, by the gate, that are energetically coupled.Specifically, it appears that tyrosine 485, on the S6 helix, is critical for maintaining the flexibility of an important hinge in the electromechanical coupling pathway.
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