Coherent phasic excitation during hippocampal ripples

High-frequency hippocampal network oscillations, or "ripples," are thought to be involved in episodic memory. According to current theories, memory traces are represented by assemblies of principal neurons that are activated during ripple-associated network states. Here we performed in?vivo and in?vitro experiments to investigate the synaptic mechanisms during ripples. We discovered postsynaptic currents that are phase-locked to ripples and coherent among even distant CA1 pyramidal neurons. These fast currents are consistent with excitatory postsynaptic currents (EPSCs) as they are observed at the equilibrium potential of Cl(-), and they display kinetics characteristic of EPSCs. Furthermore, they survived after intracellular blockade of GABAergic transmission and are effective to regulate the timing of action potentials. In addition, our data show a progressive synchronization of phasic excitation and inhibition during the course of ripples. Together, our results demonstrate the presence of phasic excitation during ripples reflecting an exquisite temporal coordination of assemblies of active pyramidal cells.     

The channel-kinase TRPM7 regulates phosphorylation of the translational factor eEF2 via eEF2-k

Protein translation is an essential but energetically expensive process, which is carefully regulated in accordance to the cellular nutritional and energy status. Eukaryotic elongation factor 2 (eEF2) is a central regulation point since it mediates ribosomal translocation and can be inhibited by phosphorylation at Thr56. TRPM7 is the unique fusion of an ion channel with a functional Ser/Thr-kinase. While TRPM7's channel function has been implicated in regulating vertebrate Mg²⁺ uptake required for cell growth, the function of its kinase domain remains unclear. Here, we show that under conditions where cell growth is limited by Mg²⁺ availability, TRPM7 via its kinase mediates enhanced Thr56 phosphorylation of eEF2. TRPM7-kinase does not appear to directly phosphorylate eEF2, but rather to influence the amount of eEF2's cognate kinase eEF2-k, involving its phosphorylation at Ser77. These findings suggest that TRPM7's structural duality ensures ideal positioning of its kinase in close proximity to channel-mediated Mg²⁺ uptake, allowing for the adjustment of protein translational rates to the availability of Mg²⁺.     

Convergence of trophic interaction strengths in grassland food webs through metabolic scaling of herbivore biomass

1. Food web theory hypothesizes that trophic interaction strengths of consumers should vary with consumer metabolic body mass (mass(0·75) ) rather than simply with consumer body mass (mass(1·0) ) owing to constraints on consumption imposed by metabolic demand for and metabolic capacity to process nutrients and energy. Accordingly, species with similar metabolic body masses should have similar trophic interaction strengths. 2. We experimentally tested this hypothesis by assembling food webs comprised of species of arthropod predators, small sap-feeding and large leaf-chewing insect herbivores and herbaceous plants in a New England, USA meadow grassland. The experiment comprised of a density-matching treatment where herbivore species were stocked into field mesocosms at equal densities to quantify baseline species identity and metabolic body mass effects. The experiment also comprised of a metabolic biomass-matching treatment where smaller sap-feeding herbivore (SH) species were stocked into mesocosms such that the product of their density and metabolic body mass (metabolic biomass) was equal to the large herbivore (LH) species. We compared the magnitude of the direct effects of herbivore species on plants in the different treatments. We also compared the magnitude of indirect effects between predators and plants mediated by herbivores in the different treatments. 3. Consistent with the hypothesis, we found that increasing metabolic biomass translated into a 9-14-fold increase in magnitude of herbivore direct effects and up to a fivefold increase in indirect effects on plants. Moreover, metabolic biomass matching caused interaction strengths among herbivore species to converge. This result came about through increases in the herbivore mean effects as well as decreases in variation in effects among treatment replicates as herbivore metabolic biomass increased. 4. We found, however, that herbivore feeding mode rather than herbivore metabolic biomass explained differences in the sign of indirect effects in the different food webs. 5. We conclude that increasing herbivore metabolic biomass not only strengthened the direct and indirect effects on plants but also made those effects more consistent across space. Nevertheless, metabolic biomass alone could not completely explain variation in the nature of indirect effects in the food web, suggesting that additional consideration of consumer traits like feeding mode will provide a more nuanced understanding of trophic interaction strengths in food webs.     

Structure and mechanism of human UDP-glucose 6-dehydrogenase

Elevated production of the matrix glycosaminoglycan hyaluronan is strongly implicated in epithelial tumor progression. Inhibition of synthesis of the hyaluronan precursor UDP-glucuronic acid (UDP-GlcUA) therefore presents an emerging target for cancer therapy. Human UDP-glucose 6-dehydrogenase (hUGDH) catalyzes, in two NAD(+)-dependent steps without release of intermediate aldehyde, the biosynthetic oxidation of UDP-glucose (UDP-Glc) to UDP-GlcUA. Here, we present a structural characterization of the hUGDH reaction coordinate using crystal structures of the apoenzyme and ternary complexes of the enzyme bound with UDP-Glc/NADH and UDP-GlcUA/NAD(+). The quaternary structure of hUGDH is a disc-shaped trimer of homodimers whose subunits consist of two discrete α/β domains with the active site located in the interdomain cleft. Ternary complex formation is accompanied by rigid-body and restrained movement of the N-terminal NAD(+) binding domain, sequestering substrate and coenzyme in their reactive positions through interdomain closure. By alternating between conformations in and out of the active site during domain motion, Tyr(14), Glu(161), and Glu(165) participate in control of coenzyme binding and release during 2-fold oxidation. The proposed mechanism of hUGDH involves formation and breakdown of thiohemiacetal and thioester intermediates whereby Cys(276) functions as the catalytic nucleophile. Stopped-flow kinetic data capture the essential deprotonation of Cys(276) in the course of the first oxidation step, allowing the thiolate side chain to act as a trap of the incipient aldehyde. Because thiohemiacetal intermediate accumulates at steady state under physiological reaction conditions, hUGDH inhibition might best explore ligand binding to the NAD(+) binding domain.     

Phenolic analogs of the N,C-coupled naphthylisoquinoline alkaloid ancistrocladinium A, from Ancistrocladus cochinchinensis (Ancistrocladaceae), with improved antiprotozoal activities

The first N,8′-coupled naphthylisoquinoline alkaloids with free phenolic OH groups, 4′-O-demethylancistrocladinium A and 6,4′-O-didemethylancistrocladinium A, have been isolated from the leaves and bark of the Vietnamese liana Ancistrocladus cochinchinensis, along with its known, non-phenolic parent compound, ancistrocladinium A, and four C,C-coupled representatives. The structure elucidation was achieved by chemical, spectroscopic, and chiroptical methods. The mono-phenolic alkaloid showed excellent activities in particular against the pathogen causing Chagas’ disease, Trypanosoma cruzi.     

Betaine aldehyde dehydrogenase genes from <Emphasis Type="Italic">Arabidopsis</Emphasis> with different sub-cellular localization affect stress responses

Arabidopsis thaliana belongs to those plants that do not naturally accumulate glycine betaine (GB), although its genome contains two genes, ALDH10A8 and ALDH10A9 that code for betaine aldehyde dehydrogenases (BADHs). BADHs were initially known to catalyze the last step of the biosynthesis of GB in plants. But they can also oxidize metabolism-derived aminoaldehydes to their corresponding amino acids in some cases. This study was carried out to investigate the functional properties of Arabidopsis BADH genes. Here, we have shown that ALDH10A8 and ALDH10A9 proteins are targeted to leucoplasts and peroxisomes, respectively. The expression patterns of ALDH10A8 and ALDH10A9 genes have been analysed under abiotic stress conditions. Both genes are expressed in the plant and weakly induced by ABA, salt, chilling (4°C), methyl viologen and dehydration. The role of the ALDH10A8 gene was analysed using T-DNA insertion mutants. There was no phenotypic difference between wild-type and mutant plants in the absence of stress. But ALDH10A8 seedlings and 4-week-old plants were more sensitive to dehydration and salt stress than wild-type plants. The recombinant ALDH10A9 enzyme was shown to oxidize betaine aldehyde, 4-aminobutyraldehyde and 3-aminopropionaldehyde to their corresponding carboxylic acids. We hypothesize that ALDH10A8 or ALDH10A9 may serve as detoxification enzymes controlling the level of aminoaldehydes, which are produced in cellular metabolism under stress conditions.     

Subretinal electronic chips allow blind patients to read letters and combine them to words

A light-sensitive, externally powered microchip was surgically implanted subretinally near the macular region of volunteers blind from hereditary retinal dystrophy. The implant contains an array of 1500 active microphotodiodes ('chip'), each with its own amplifier and local stimulation electrode. At the implant's tip, another array of 16 wire-connected electrodes allows light-independent direct stimulation and testing of the neuron-electrode interface. Visual scenes are projected naturally through the eye's lens onto the chip under the transparent retina. The chip generates a corresponding pattern of 38 × 40 pixels, each releasing light-intensity-dependent electric stimulation pulses. Subsequently, three previously blind persons could locate bright objects on a dark table, two of whom could discern grating patterns. One of these patients was able to correctly describe and name objects like a fork or knife on a table, geometric patterns, different kinds of fruit and discern shades of grey with only 15 per cent contrast. Without a training period, the regained visual functions enabled him to localize and approach persons in a room freely and to read large letters as complete words after several years of blindness. These results demonstrate for the first time that subretinal micro-electrode arrays with 1500 photodiodes can create detailed meaningful visual perception in previously blind individuals.     

Forest tree growth is linked to mycorrhizal fungal composition and function across Europe

Most trees form symbioses with ectomycorrhizal fungi (EMF) which influence access to growth-limiting soil resources. Mesocosm experiments repeatedly show that EMF species differentially affect plant development, yet whether these effects ripple up to influence the growth of entire forests remains unknown. Here we tested the effects of EMF composition and functional genes relative to variation in well-known drivers of tree growth by combining paired molecular EMF surveys with high-resolution forest inventory data across 15 European countries. We show that EMF composition was linked to a three-fold difference in tree growth rate even when controlling for the primary abiotic drivers of tree growth. Fast tree growth was associated with EMF communities harboring high inorganic but low organic nitrogen acquisition gene proportions and EMF which form contact versus medium-distance fringe exploration types. These findings suggest that EMF composition is a strong bio-indicator of underlying drivers of tree growth and/or that variation of forest EMF communities causes differences in tree growth. While it may be too early to assign causality or directionality, our study is one of the first to link fine-scale variation within a key component of the forest microbiome to ecosystem functioning at a continental scale.Subject terms: Microbial ecology, Forest ecology, Fungal ecology, Biogeochemistry