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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. PbZrO

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., eLife digest Tens of trillions of microbes living in the gut help humans and other animals digest their food. In the process, the microbes provide necessary nutrients for themselves and the animal. Learning more about the interaction of food components and gut bacteria could help scientists to better understand how different diets affect human health. Currently, studying these complex interactions is challenging, but new technologies that measure microbial nutrient processing in the gut could help. Now, Wesener et al. show that swallowable microscopic biosensors can measure how gut bacteria break down nutrients from food. To make the biosensors, Wesener et al. attached complex carbohydrates extracted from peas and fluorescent tags to microscopic beads. In the experiments, mice colonized with human gut microbes were fed the beads along with a traditional low fiber, Western diet. Some of the animals also received fiber supplements. The microscopic beads were then recovered from the intestines after digestion and the remaining carbohydrates on the beads were measured. The genetic makeup of the gut microbiome and the expression of microbial genes was also examined. The experiments revealed which pea carbohydrates the gut microbes consumed and showed that pairing certain carbohydrates together on the microbead surface increased their digestion in mice that received fiber supplements. If future studies prove that the microbead biosensors created by Wesener et al. are safe for humans to ingest, they could be used to help diagnose how well a person’s gut microbiota can process different foods. Studies using the microbead sensors may also help scientists develop more nutritious foods or supplements that promote the growth of microbes important for health.

Loss-of-function mutations in K

Development of microbiota-directed foods (MDFs) that selectively increase the abundance of beneficial human gut microbes, and their expressed functions, requires knowledge of both the bioactive components of MDFs and the mechanisms underlying microbe-microbe interactions. Here, gnotobiotic mice were colonized with a defined consortium of human-gut-derived bacterial strains and fed different combinations of 34 food-grade fibers added to a representative low-fiber diet consumed in the United States. Bioactive carbohydrates in fiber preparations targeting particular Bacteroides species were identified using community-wide quantitative proteomic analyses of bacterial gene expression coupled with forward genetic screens. Deliberate manipulation of community membership combined with administration of retrievable artificial food particles, consisting of paramagnetic microscopic beads coated with dietary polysaccharides, disclosed the contributions of targeted species to fiber degradation. Our approach, including the use of bead-based biosensors, defines nutrient-harvesting strategies that underlie, as well as alleviate, competition between Bacteroides and control the selectivity of MDF components.

Background Successful cannulation is an important prerequisite for a functional arteriovenous fistula (AVF). Reasons for unsuccessful cannulation of an AVF are multifactorial and poorly evaluated. In our experience, a needle access segment (NAS) with a length of 10 cm, 6 mm diameter assessed objectively using duplex Doppler ultrasound (DDUS) imaging, in a fistula with brachial artery flow >500 mL/min, permits consistent cannulation. This report provides observational data on the NAS of the outflow veins after fistula creation and a detailed long-term outcome on AVFs that needed superficialization of the NAS using minimal incision superficialization technique (MIST) to make them suitable for cannulation. This report is based on prospectively collected data with a longitudinal follow-up in a large patient cohort. Methods A prospective database was used to analyze consecutive patients undergoing AVF until the study end point. All patients underwent a protocol-based maturation evaluation using color DDUS imaging. Unsuitable NAS were surgically corrected using superficialization (by MIST or lipectomy) of deeply situated veins or NAS reconstruction. Results Between February 1, 2007, and May 31, 2013, 617 new AVF surgeries were performed. Outflow vein superficialization (MIST or lipectomy) or NAS reconstruction was necessary in 226 of 585 procedures (38.6%) included in this analysis. Of these, 162 (72%) were performed using MIST, 50 (22%) with a single long incision, and 14 (6%) using lipectomy technique. Technical success for MIST was 100%, and only two fistulae failed to mature. The vein depth of 9.2 ± 3.2 mm during initial vessel mapping was similar to the pre-MIST depth of 9.1 ± 3.8 mm. Depth of NAS improved to 3.1 ± 1.0 mm after MIST. The secondary patency after MIST at 6, 12, 24, 48, and 60 months was 98%, 93.3%, 88.1%, 83.3%, and 80.9%. During the 400.8 post-MIST functional fistula-years, only 0.63 procedures per year were required to maintain AVF patency. Conclusions 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.

Summary Dramatic increases in processed food consumption represent a global health threat. Maillard reaction products (MRPs), which are common in processed foods, form upon heat-induced reaction of amino acids with reducing sugars and include advanced glycation end products with deleterious health effects. To examine how processed foods affect the microbiota, we fed gnotobiotic mice, colonized with 54 phylogenetically diverse human gut bacterial strains, defined sugar-rich diets containing whey as the protein source or a matched amino acid mixture. Whey or ϵ-fructoselysine, an MRP in whey and many processed foods, selectively increases Collinsella intestinalis absolute abundance and induces Collinsella expression of genomic loci directing import and metabolism of ϵ-fructoselysine to innocuous products. This locus is repressed by glucose in C. aerofaciens, whose abundance decreases with whey, but is not repressed in C. intestinalis. Identifying gut organisms responding to and degrading potentially harmful processed food components has implications for food science, microbiome science, and public health.

The IKs current controls action potential duration in the heart, and abnormal function of this current causes cardiac arrhythmias. The IKs current is carried by the voltage activated KCNQ1 potassium channel associated with KCNE1 β-subunits. 18 years of study have shown that KCNE1 drastically modulates every characteristic of KCNQ1, such that it would appear as if KCNQ1 and KCNQ1+ KCNE1 were completely unrelated channels. However, no coherent mechanism has been provided that can explain all these drastic changes, which are essential for the physiological role of IKs. Here we show that KCNE1 alters the state-dependent interactions (coupling) between the voltage-sensing and pore-gate domains of KCNQ1 and that this sole mechanism is sufficient to explain all these changes. Contrary to conventional belief that the voltage-sensing domain must reach the fully-activated state before promoting pore-opening, we found that the KCNQ1 channels can open when the voltage-sensing domain is at intermediate and fully-activated states. Importantly, the intermediate-open and activated-open channels differ in voltage-dependence, ion-permeation, pharmacology and dependence on PIP2, a cofactor for coupling between the voltage-sensing and pore-gate domains. By changing the coupling, KCNE1 prevents the intermediate-open state and changes the properties of the activated-open state, thereby bringing about the characteristics of the IKs current. These results indicate that, during voltage-dependent ion channel gating, every-state of the voltage-sensing domain along its activation pathway is coupled to the conformation of the pore domain through a unique set of protein-protein and protein-lipid interactions. These interactions determine both the open-probability and the open-pore properties.

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, eLife digest Cells are surrounded by a membrane that prevents charged molecules from flowing directly into or out of the cell. Instead ions move through channel proteins within the cell membrane. Most ion channel proteins are selective and only allow one or a few types of ion to cross. Ion channels can also be ‘gated’, and have a central pore that can open or close to allow or stop the flow of selected ions. This gating can be affected by the channel sensing changes in conditions, such as changes in the voltage across the cell membrane. Research conducted more than half a century ago—before the discovery of channel proteins—led to a mathematical model of the flow of potassium ions across a membrane in response to changes in voltage. This model made a number of assumptions, many of which are still widely accepted. However, Zaydman et al. have now called into question some of the assumptions of this model. Based on the original model, it has been long assumed that the voltage-sensing domains that open or close the central pore in response to changes in voltage must be fully activated to allow the channel to open. It had also been assumed that the voltage-sensing domains do not affect the flow of ions once the channel is open. Zaydman et al. have now shown that these assumptions are not valid for a specific voltage-gated potassium channel called KCNQ1. Instead, this ion channel opens when its voltage-sensing domains are either partially or fully activated. Zaydman found that the intermediate-open and activated-open states had different preferences for passing various types of ion; therefore, the gating of the channel and the flow of ions through the open channel are both dependent on the state of the voltage-sensing domains. This is in direct contrast to what had previously been assumed. The original model cannot reproduce the gating of KCNQ1, nor can any other established model. Therefore, Zaydman et al. devised a new model to understand how the interactions between different states of the voltage-sensing domains and the pore lead to gating. Zaydman et al. then used their model to address how another protein called KCNE1 is able to alter properties of the KCNQ1 channel. KCNE1 is a protein that is expressed in the heart muscle cell and mutations affecting KCNQ1 or KCNE1 have been associated with potentially fatal heart conditions. Based on the assumptions of the original model, it had been difficult to understand how KCNE1 was able to affect different properties of the KCNQ1 channel. Thus, for nearly 20 years it has been debated whether KCNE1 primarily affects the activation of the voltage-sensing domains or the opening of the pore. Zaydman et al. found instead that KCNE1 alters the interactions between the voltage-sensing domains and the pore, which prevented the intermediate-open state and modified the properties of the activated-open state. This mechanism provides one of the most complete explanations for the action of the KCNE1 protein. DOI: http://dx.doi.org/10.7554/eLife.03606.002

The KCNQ1 K+ channel α subunit and the auxiliary subunit KCNE1 form the IKs channel in the heart that is important in controlling heart rhythm. In response to membrane depolarization, the KCNQ1 channel undergoes intermediate open (IO) and activated open (AO) states that correspond to the stepwise movement of the voltage sensor to the intermediate and full activation. IO and AO states showed different properties in voltage dependence of gating, permeation, and pharmacology. The association of KCNE1 suppresses IO but enhances AO, thereby radically alters properties of the channel to suit the physiological role of IKs in terminating the action potential.

Rate adaptation is the physiological shortening of the cardiac action potential duration as heart rate increases. Rate adaptation protects the diastolic interval and maintains electrical stability of the cardiac myocyte. Inherited mutations that decrease the cardiac IKs current predispose patients to arrythmias that manifest during stress or exercise, suggesting that IKs plays a prominent role in limiting action potential duration under conditions where heart rate is fast and beta-adrenergic tone is elevated. Using computational models of IKs, Silva et al. were able to reproduce rate adaptive behavior. In their model, IKs channel can occupy readily recruitable- (shallow) or functionally silent- (deep) closed states at rest. However, the molecular basis of the deep-closed states was unknown, and it was empirically modeled as an additional, slow voltage-sensor transition. In a recent study of Kv7.1, the principal subunit of the IKs channel, we found that binding of the lipid phosphatidylinositol 4,5-bisphosphate (PIP2) is required to couple voltage-sensor activation to pore-opening. Here we study the properties of PIP2 interaction with hIKs channels and describe three phenomena: a large reserve of PIP2 unbound channels that exists in biological membranes, the kinetics of PIP2 binding and unbinding are slow, and the activated-open state has a much greater apparent affinity for PIP2 compared to other gating states. Based on these experimentally observed properties we propose that PIP2 binding is the molecular basis for the mode switching behavior in the model by Silva et al., and it underlies spontaneous adaptation of IKs current to changes in cycle length. We test these hypotheses using kinetic and cellular computational models and experimental protocols simulating fast heart rates.

Coupling between the voltage-sensing domain (VSD) and pore-gate domain (PGD) is required for the voltage-dependent gating of ion channels, but the molecular mechanisms of coupling are unclear. Previous studies have identified protein-protein interactions that are important for coupling, while structural and recent functional data demonstrate that membrane lipids also play a role. In a recent study of Kv7.1, we found that phosphatidylinositol 4,5-bisphosphate (PIP2) binding at the VSD-PD interface is required to couple the activated-state of the VSD to the open-state of the PD. We devised a method to directly measure PIP2 mediated coupling and an allosteric framework for describing such coupling. These advances provide new tools to investigate the mechanisms of VSD-PGD coupling. We also identified a putative PIP2 binding site and found that mutations of residues within this site reduce PIP2-mediated coupling. Paradoxically, a set of mutations near the PIP2 binding site increased the macroscopic current. Using a combined computational and experimental approach to study these gain of function mutations, we now identify a PIP2-interaction that is preferred by the resting-closed channel. Using the KCNE1 accessory subunit as an experimental tool, we are able to resolve the functional effects of this resting-closed state interaction. These results allow us to propose a novel mechanism for voltage-dependent gating in which repositioning of cofactor lipids at the VSD-PD represents a critical step in the transitions between resting-closed and activated-open states. This model can be used to explain the phenomena of cooperativity and concerted motion in voltage-gated channels.