Gating and modulation of a hetero-octameric AMPA glutamate receptor.

AMPA receptors (AMPARs) mediate the majority of excitatory transmission in the brain and enable the synaptic plasticity that underlies learning1. A diverse array of AMPAR signalling complexes are established by receptor auxiliary subunits, which associate with the AMPAR in various combinations to modulate trafficking, gating and synaptic strength2. However, their mechanisms of action are poorly understood. Here we determine cryo-electron microscopy structures of the heteromeric GluA1-GluA2 receptor assembled with both TARP-γ8 and CNIH2, the predominant AMPAR complex in the forebrain, in both resting and active states. Two TARP-γ8 and two CNIH2 subunits insert at distinct sites beneath the ligand-binding domains of the receptor, with site-specific lipids shaping each interaction and affecting the gating regulation of the AMPARs. Activation of the receptor leads to asymmetry between GluA1 and GluA2 along the ion conduction path and an outward expansion of the channel triggers counter-rotations of both auxiliary subunit pairs, promoting the active-state conformation. In addition, both TARP-γ8 and CNIH2 pivot towards the pore exit upon activation, extending their reach for cytoplasmic receptor elements. CNIH2 achieves this through its uniquely extended M2 helix, which has transformed this endoplasmic reticulum-export factor into a powerful AMPAR modulator that is capable of providing hippocampal pyramidal neurons with their integrative synaptic properties.

Juggling Optoelectronics and Catalysis: The Dual Talents of Bench Stable 1,4-Azaborinines.

Boron- and nitrogen-doped polycyclic aromatic hydrocarbons (B-PAHs) have established a strong foothold in the realm of organic electronics. However, their catalytic potential remains largely untapped. In this study, we synthesise and characterise two bench stable B,N-doped PAH derivatives based on a 1,4-azaborinine motif. Most importantly, the anthracene derived structure is an efficient catalyst in the reduction of various carbonyls and imines. These results underscore the potential of B,N-PAHs in catalytic transformations, setting the stage for deeper exploration in this chemical space.

Thromboembolic events after major bleeding events in patients with mechanical heart valves: a 13-year analysis.

Anticoagulation in patients with mechanical heart valves (MHV) is associated with a risk of major bleeding episodes (MBE). In case of MBE, anticoagulant interruption is advocated. However, there is lack of data regarding the thrombo-embolic events (TE) risk associated with anticoagulant interruption. The main objective of the study was to evaluate the rate and risk factors of 6-months of TEs in patients with MHV experiencing MBE. This observational study was conducted over a 13-year period. Adult patients with a MHV presenting with a MBE were included. The main study endpoint was 6-month TEs, defined by clinical TEs or an echocardiographic documented thrombosis, occurring during an ICU stay or within 6-months. Thromboembolic events were recorded at ICU discharge, and 6 months after discharge. Seventy-nine MBEs were analysed, the rate of TEs at 6-months was 19% CI [11-29%]. The only difference of presentation and management between 6-month TEs and free-TE patients was the time without effective anticoagulation (TWA). The Receiver Operator Characteristic curve identified the value of 122 h of TWA as a cut-off. The multivariate analysis identified early bleeding recurrences (OR 3.62, 95% CI [1.07-12.25], p = 0.039), and TWA longer than 122 h (OR 4.24, 95% CI [1.24-14.5], p = 0.021), as independent risk factors for 6-month TEs. A higher rate of TE was associated with anticoagulation interruption longer than 5 days and early bleeding recurrences. However, the management should still be personalized and discussed for each case given the heterogeneity of causes of MBE and possibilities of haemostatic procedures.

Early tropical crop production in marginal subtropical and temperate Polynesia.

Polynesians introduced the tropical crop taro (Colocasia esculenta) to temperate New Zealand after 1280 CE, but evidence for its cultivation is limited. This contrasts with the abundant evidence for big game hunting, raising longstanding questions of the initial economic and ecological importance of crop production. Here we compare fossil data from wetland sedimentary deposits indicative of taro and leaf vegetable (including Sonchus and Rorippa spp.) cultivation from Ahuahu, a northern New Zealand offshore island, with Raivavae and Rapa, both subtropical islands in French Polynesia. Preservation of taro pollen on all islands between 1300 CE and 1550 CE indicates perennial cultivation over multiple growing seasons, as plants rarely flower when frequently harvested. The pollen cooccurs with previously undetected fossil remains of extinct trees, as well as many weeds and commensal invertebrates common to tropical Polynesian gardens. Sedimentary charcoal and charred plant remains show that fire use rapidly reduced forest cover, particularly on Ahuahu. Fires were less frequent by 1500 CE on all islands as forest cover diminished, and short-lived plants increased, indicating higher-intensity production. The northern offshore islands of New Zealand were likely preferred sites for early gardens where taro production was briefly attempted, before being supplanted by sweet potato (Ipomoea batatas), a more temperate climate-adapted crop, which was later established in large-scale cultivation systems on the mainland after 1500 CE.

Chloroplast genome evolution in the Dracunculus clade (Aroideae, Araceae).

Chloroplast (cp) genomes are considered important for the study of lineage-specific molecular evolution, population genetics, and phylogenetics. Our aim here was to elucidate the molecular evolution in cp genomes of species in the Dracunculus clade (Aroideae, Araceae). We report de novo assembled cp genomes for eight species from eight genera and also retrieved cp genomes of four species from the National Center for Biotechnology Information (NCBI). The cp genomes varied in size from 162,424 bp to 176,835 bp. Large Single Copy (LSC) region ranged in size from 87,141 bp to 95,475 bp; Small Single Copy (SSC) from 14,338 bp to 23,981 bp; and Inverted Repeats (IRa and IRb) from 25,131 bp to 32,708 bp. The expansion in inverted repeats led to duplication of ycf1 genes in four species. The genera showed high similarity in gene content and yielded 113 unique genes (79 protein-coding, 4 rRNA, and 30 tRNA genes). Codon usage, amino acid frequency, RNA editing sites, microsatellites repeats, transition and transversion substitutions, and synonymous and non-synonymous substitutions were also similar across the clade. A previous study reported deletion of ycf1, accD, psbE, trnL-CAA, and trnG-GCC genes in four Amorphophallus species. Our study supports conservative structure of cp genomes in the Dracunculus clade including Amorphophallus species and does not support gene deletion mentioned above. We also report suitable polymorphic loci based on comparative analyses of Dracunculus clade species, which could be useful for phylogenetic inference. Overall, the current study broad our knowledge about the molecular evolution of chloroplast genome in aroids.

Initiation and slow propagation of epileptiform activity from ventral to dorsal medial entorhinal cortex is constrained by an inhibitory gradient.

KEY POINTS: The medial entorhinal cortex (mEC) has an important role in initiation and propagation of seizure activity. Several anatomical relationships exist in neurophysiological properties of mEC neurons; however, in the context of hyperexcitability, previous studies often considered it as a homogeneous structure. Using multi-site extracellular recording techniques, ictal-like activity was observed along the dorso-ventral axis of the mEC in vitro in response to various ictogenic stimuli. This originated predominantly from ventral areas, spreading to dorsal mEC with a surprisingly slow velocity. Modulation of inhibitory tone was capable of changing the slope of ictal initiation, suggesting seizure propagation behaviours are highly dependent on levels of GABAergic function in this region. A distinct disinhibition model also showed, in the absence of inhibition, a prevalence for interictal-like initiation in ventral mEC, reflecting the intrinsic differences in mEC neurons. These findings suggest the ventral mEC is more prone to hyperexcitable discharge than the dorsal mEC, which may be relevant under pathological conditions. ABSTRACT: The medial entorhinal cortex (mEC) has an important role in the generation and propagation of seizure activity. The organization of the mEC is such that a number of dorso-ventral relationships exist in neurophysiological properties of neurons. These range from intrinsic and synaptic properties to density of inhibitory connectivity. We examined the influence of these gradients on generation and propagation of epileptiform activity in the mEC. Using a 16-shank silicon probe array to record along the dorso-ventral axis of the mEC in vitro, we found 4-aminopyridine application produces ictal-like activity originating predominantly in ventral areas. This activity spreads to dorsal mEC at a surprisingly slow velocity (138 µm s-1 ), while cross-site interictal-like activity appeared relatively synchronous. We propose that ictal propagation is constrained by differential levels of GABAergic control since increasing (diazepam) or decreasing (Ro19-4603) GABAA receptor activation, respectively, reduced or increased the slope of ictal initiation. The observation that ictal activity is predominately generated in ventral mEC was replicated using a separate 0-Mg2+ model of epileptiform activity in vitro. By using a distinct disinhibition model (co-application of kainate and picrotoxin) we show that additional physiological features (for example intrinsic properties of mEC neurons) still produce a prevalence for interictal-like initiation in ventral mEC. These findings suggest that the ventral mEC is more likely to initiate hyperexcitable discharges than the dorsal mEC, and that seizure propagation is highly dependent on levels of GABAergic expression across the mEC.

Applying the ARRIVE Guidelines to an In Vivo Database.

The Animal Research: Reporting of In Vivo Experiments (ARRIVE) guidelines were developed to address the lack of reproducibility in biomedical animal studies and improve the communication of research findings. While intended to guide the preparation of peer-reviewed manuscripts, the principles of transparent reporting are also fundamental for in vivo databases. Here, we describe the benefits and challenges of applying the guidelines for the International Mouse Phenotyping Consortium (IMPC), whose goal is to produce and phenotype 20,000 knockout mouse strains in a reproducible manner across ten research centres. In addition to ensuring the transparency and reproducibility of the IMPC, the solutions to the challenges of applying the ARRIVE guidelines in the context of IMPC will provide a resource to help guide similar initiatives in the future.

Novel Xanthate Complexes for the Size-Controlled Synthesis of Copper Sulfide Nanorods.

We present a simple, easily scalable route to monodisperse copper sulfide nanocrystals by the hot injection of a series of novel copper(I) xanthate single-source precursors [(PPh3)2Cu(S2COR)] (R = isobutyl, 2-methoxyethyl, 2-ethoxyethyl, 1-methoxy-2-propyl, 3-methoxy-1-butyl, and 3-methoxy-3-methyl-1-butyl), whose crystal structures are also reported. We show that the width of the obtained rods is dependent on the length of the xanthate chain, which we rationalize through a computational study, where we show that there is a relationship between the ground-state energy of the precursor and the copper sulfide rod width.

"Hot spots" of N and C impact nitric oxide, nitrous oxide and nitrogen gas emissions from a UK grassland soil.

Agricultural soils are a major source of nitric- (NO) and nitrous oxide (N2O), which are produced and consumed by biotic and abiotic soil processes. The dominant sources of NO and N2O are microbial nitrification and denitrification, and emissions of NO and N2O generally increase after fertiliser application. The present study investigated the impact of N-source distribution on emissions of NO and N2O from soil and the significance of denitrification, rather than nitrification, as a source of NO emissions. To eliminate spatial variability and changing environmental factors which impact processes and results, the experiment was conducted under highly controlled conditions. A laboratory incubation system (DENIS) was used, allowing simultaneous measurement of three N-gases (NO, N2O, N2) emitted from a repacked soil core, which was combined with 15N-enrichment isotopic techniques to determine the source of N emissions. It was found that the areal distribution of N and C significantly affected the quantity and timing of gaseous emissions and 15N-analysis showed that N2O emissions resulted almost exclusively from the added amendments. Localised higher concentrations, so-called hot spots, resulted in a delay in N2O and N2 emissions causing a longer residence time of the applied N-source in the soil, therefore minimising NO emissions while at the same time being potentially advantageous for plant-uptake of nutrients. If such effects are also observed for a wider range of soils and conditions, then this will have major implications for fertiliser application protocols to minimise gaseous N emissions while maintaining fertilisation efficiency.

A Modular Approach to Inorganic Phosphazane Macrocycles.

Inorganic macrocycles, based on non-carbon backbones, present exciting synthetic challenges in the systematic assembly of inorganic molecules, as well as new avenues in host-guest and supramolecular chemistry. Here we demonstrate a new high-yielding modular approach to a broad range of trimeric and hexameric S- and Se-bridged inorganic macrocycles based on cyclophosphazane frameworks, using the building blocks [S=(H)P(µ-NR)]2 . The method involves the in situ generation of the key intermediate [E....._ (S....._ )P(µ-NR)]22- (E=S, Se) dianion, which can be reacted with electrophilic [ClP(µ-NR)]2 to give PIII /PV hexameric rings or reacted with I2 to give trimeric PV variants. Important issues which are highlighted in this work are the competitive bridging ability of S versus Se in these systems and the synthesis of the first air-stable and chiral inorganic macrocycles.

How Does Substitutional Doping Affect Visible Light Absorption in a Series of Homodisperse Ti11 Polyoxotitanate Nanoparticles--A Comment on the Band Gap Determination of the Fe(II) Cages (Chem. Eur. J. 2015, 21, 11538).

There is no experimental support for the conclusion by Coppens and Chen in a recent paper that the (HOMO-LUMO) band gaps in a series of Fe(II) polyoxotitanate cages are in the range 1.43-1.59 eV.

The International Mouse Phenotyping Consortium Web Portal, a unified point of access for knockout mice and related phenotyping data.

The International Mouse Phenotyping Consortium (IMPC) web portal (http://www.mousephenotype.org) provides the biomedical community with a unified point of access to mutant mice and rich collection of related emerging and existing mouse phenotype data. IMPC mouse clinics worldwide follow rigorous highly structured and standardized protocols for the experimentation, collection and dissemination of data. Dedicated 'data wranglers' work with each phenotyping center to collate data and perform quality control of data. An automated statistical analysis pipeline has been developed to identify knockout strains with a significant change in the phenotype parameters. Annotation with biomedical ontologies allows biologists and clinicians to easily find mouse strains with phenotypic traits relevant to their research. Data integration with other resources will provide insights into mammalian gene function and human disease. As phenotype data become available for every gene in the mouse, the IMPC web portal will become an invaluable tool for researchers studying the genetic contributions of genes to human diseases.

A mouse informatics platform for phenotypic and translational discovery.

The International Mouse Phenotyping Consortium (IMPC) is providing the world's first functional catalogue of a mammalian genome by characterising a knockout mouse strain for every gene. A robust and highly structured informatics platform has been developed to systematically collate, analyse and disseminate the data produced by the IMPC. As the first phase of the project, in which 5000 new knockout strains are being broadly phenotyped, nears completion, the informatics platform is extending and adapting to support the increasing volume and complexity of the data produced as well as addressing a large volume of users and emerging user groups. An intuitive interface helps researchers explore IMPC data by giving overviews and the ability to find and visualise data that support a phenotype assertion. Dedicated disease pages allow researchers to find new mouse models of human diseases, and novel viewers provide high-resolution images of embryonic and adult dysmorphologies. With each monthly release, the informatics platform will continue to evolve to support the increased data volume and to maintain its position as the primary route of access to IMPC data and as an invaluable resource for clinical and non-clinical researchers.

A Si photocathode protected and activated with a Ti and Ni composite film for solar hydrogen production.

An efficient, stable and scalable hybrid photoelectrode for visible-light-driven H2 generation in an aqueous pH 9.2 electrolyte solution is reported. The photocathode consists of a p-type Si substrate layered with a Ti and Ni-containing composite film, which acts as both a protection and electrocatalyst layer on the Si substrate. The film is prepared by the simple drop casting of the molecular single-source precursor, [{Ti2(OEt)9(NiCl)}2] (TiNipre), onto the p-Si surface at room temperature, followed by cathodic in situ activation to form the catalytically active TiNi film (TiNicat). The p-Si|TiNicat photocathode exhibits prolonged hydrogen generation with a stable photocurrent of approximately -5 mA cm(-2) at 0 V vs. RHE in an aqueous pH 9.2 borate solution for several hours, and serves as a benchmark non-noble photocathode for solar H2 evolution that operates efficiently under neutral-alkaline conditions.

Selective lability of ruthenium(II) arene amino acid complexes.

A series of organometallic complexes of the form [(PhH)Ru(amino acid)](+) have been synthesized using amino acids able to act as tridentate ligands. The straightforward syntheses gave enantiomerically pure complexes with two stereogenic centers due to the enantiopurity of the chelating ligands. Complexes were characterized in the solid-state and/or solution-state where the stability of the complex allowed. The propensity toward labilization of the coordinatively saturated complexes was investigated. The links between complex stability and structural features are very subtle. Nonetheless, H/D exchange rates of coordinated amino groups reveal more significant differences in reactivity linked to metallocycle ring size resulting in decreasing stability of the metallocycle as the amino acid side-chain length increases. The behavior of these systems in acid is unusual, apparently labilizing the carboxylate residue of the amino acid. This acid-catalyzed hemilability in an organometallic is relevant to the use of Ru(II) arenes in medicinal contexts due to the relatively low pH of cancerous cells.

Theory and practice: bulk synthesis of C3B and its H2- and Li-storage capacity.

Previous theoretical studies of C3B have suggested that boron-doped graphite is a promising H2- and Li-storage material, with large maximum capacities. These characteristics could lead to exciting applications as a lightweight H2-storage material for automotive engines and as an anode in a new generation of batteries. However, for these applications to be realized a synthetic route to bulk C3B must be developed. Here we show the thermolysis of a single-source precursor (1,3-(BBr2)2C6H4) to produce graphitic C3B, thus allowing the characteristics of this elusive material to be tested for the first time. C3B was found to be compositionally uniform but turbostratically disordered. Contrary to theoretical expectations, the H2- and Li-storage capacities are lower than anticipated, results that can partially be explained by the disordered nature of the material. This work suggests that to model the properties of graphitic materials more realistically, the possibility of disorder must be considered.

Ab initio structure search and in situ 7Li NMR studies of discharge products in the Li-S battery system.

The high theoretical gravimetric capacity of the Li-S battery system makes it an attractive candidate for numerous energy storage applications. In practice, cell performance is plagued by low practical capacity and poor cycling. In an effort to explore the mechanism of the discharge with the goal of better understanding performance, we examine the Li-S phase diagram using computational techniques and complement this with an in situ (7)Li NMR study of the cell during discharge. Both the computational and experimental studies are consistent with the suggestion that the only solid product formed in the cell is Li2S, formed soon after cell discharge is initiated. In situ NMR spectroscopy also allows the direct observation of soluble Li(+)-species during cell discharge; species that are known to be highly detrimental to capacity retention. We suggest that during the first discharge plateau, S is reduced to soluble polysulfide species concurrently with the formation of a solid component (Li2S) which forms near the beginning of the first plateau, in the cell configuration studied here. The NMR data suggest that the second plateau is defined by the reduction of the residual soluble species to solid product (Li2S). A ternary diagram is presented to rationalize the phases observed with NMR during the discharge pathway and provide thermodynamic underpinnings for the shape of the discharge profile as a function of cell composition.

Human pulmonary autograft wall stress at systemic pressures prior to remodeling after the Ross procedure.

BACKGROUND AND AIM OF THE STUDY: Remodeling of the pulmonary autograft upon exposure to systemic pressure can lead to progressive dilatation and aneurysmal pathology. Remodeling is driven by changes in autograft wall stress upon exposure to systemic pressure; however, the magnitude of these changes is unknown. Previously, a porcine autograft finite element model was developed to determine wall stress, but the porcine and human material properties differed significantly. Hence, the study aim was to understand human pulmonary autograft biomechanics that lead to remodeling by determining wall stress magnitudes immediately after the Ross procedure using finite element analysis (FEA). METHODS: Human pulmonary root was scanned by high-resolution microcomputed tomography to construct a realistic three-dimensional geometric mesh. Stress-strain data from biaxial stretch testing was incorporated into an Ogden hyperelastic model to describe autograft mechanical properties for an adult Ross patient. Autograft dilatation and wall stress distribution during pulmonic and systemic pressures prior to remodeling were determined using explicit FEA in LS-DYNA. RESULTS: Human pulmonary autograft demonstrated non-linear material properties, being highly compliant in the low-strain region, and stiffening at high strain. The majority of dilatation occurred with < 20 mmHg pressurization. From pulmonary to systemic pressures, the increases in autograft diameter were up to 17%. Likewise, the maximal wall stress increased approximately 14.6-fold compared to diastolic pressures (from 13.0 to 190.1kPa), and six-fold compared to systolic pressures (from 48.6 to 289.6kPa). CONCLUSION: The first finite element model of the human pulmonary autograft was developed and used to demonstrate how autograft material properties prevent significant dilatation upon initial exposure to systemic pressure. Mild dilatation was noted in the sinuses and sinotubular junction. Autograft wall stress was increased greatly when subjected to systemic pressures, and may trigger biomechanical remodeling of the autograft. Sustained exposure to higher wall stresses, coupled with inadequate remodeling, may lead to future autograft dilatation.

A randomized trial of tigecycline versus ampicillin-sulbactam or amoxicillin-clavulanate for the treatment of complicated skin and skin structure infections.

BACKGROUND: Complicated skin and skin structure infections (cSSSIs) frequently result in hospitalization with significant morbidity and mortality. METHODS: In this phase 3b/4 parallel, randomized, open-label, comparative study, 531 subjects with cSSSI received tigecycline (100 mg initial dose, then 50 mg intravenously every 12 hrs) or ampicillin-sulbactam 1.5-3 g IV every 6 hrs or amoxicillin-clavulanate 1.2 g IV every 6-8 hrs. Vancomycin could be added at the discretion of the investigator to the comparator arm if methicillin-resistant Staphylococcus aureus (MRSA) was confirmed or suspected within 72 hrs of enrollment. The primary endpoint was clinical response in the clinically evaluable (CE) population at the test-of-cure (TOC) visit. Microbiologic response and safety were also assessed. The modified intent-to-treat (mITT) population comprised 531 subjects (tigecycline, n = 268; comparator, n = 263) and 405 were clinically evaluable (tigecycline, n = 209; comparator, n = 196). RESULTS: In the CE population, 162/209 (77.5%) tigecycline-treated subjects and 152/196 (77.6%) comparator-treated subjects were clinically cured (difference 0.0; 95% confidence interval [CI]: -8.7, 8.6). The eradication rates at the subject level for the microbiologically evaluable (ME) population were 79.2% in the tigecycline treatment group and 76.8% in the comparator treatment group (difference 2.4; 95% CI: -9.6, 14.4) at the TOC assessment. Nausea, vomiting, and diarrhea rates were higher in the tigecycline group. CONCLUSIONS: Tigecycline was generally safe and effective in the treatment of cSSSIs. TRIAL REGISTRATION: ClinicalTrials.gov NCT00368537.