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Neuronal nicotinic acetylcholine receptors (nAChRs) are prototypical cation-selective, ligand-gated ion channels that mediate fast neurotransmission in the central and peripheral nervous systems. nAChRs are involved in a range of physiological and pathological functions and hence are important therapeutic targets. Their subunit homology and diverse pentameric assembly contribute to their challenging pharmacology and limit their drug development potential. Toxins produced by an extensive range of algae, plants and animals target nAChRs, with many proving pivotal in elucidating receptor pharmacology and biochemistry, as well as providing templates for structure-based drug design. The crystal structures of these toxins with diverse chemical profiles in complex with acetylcholine binding protein (AChBP), a soluble homolog of the extracellular ligand-binding domain of the nAChRs and more recently the extracellular domain of human α9 nAChRs, have been reported. These studies have shed light on the diverse molecular mechanisms of ligand-binding at neuronal nAChR subtypes and uncovered critical insights useful for rational drug design. This review provides a comprehensive overview and perspectives obtained from structure and function studies of diverse plant and animal toxins and their associated inhibitory mechanisms at neuronal nAChRs.

\"More so than any war in history, World War II was a woman's war. Women, motivated by patriotism, the opportunity for new experiences, and the desire to serve, participated widely in the global conflict. Within the Allied countries, women of all ages proved to be invaluable in the fight for victory. Rosie the Riveter became the most enduring image of women's involvement in World War II. What Rosie represented, however, is only a small portion of a complex story. As wartime production workers, enlistees in auxiliary military units, members of voluntary organizations or resistance groups, wives and mothers on the home front, journalists, and USO performers, American women found ways to challenge traditional gender roles and stereotypes. Beyond Rosie offers readers an opportunity to see the numerous contributions women made to the fight against the Axis powers and how American women's roles changed during the war. The primary documents (newspapers, propaganda posters, cartoons, excerpts from oral histories and memoirs, speeches, photographs, and editorials) collected here represent cultural, political, economic, and social perspectives on the diverse roles women played during World War II.\"--Page 4 of cover.

Marine cone snails are a large family of gastropods that have evolved highly potent venoms for predation and defense. The cone snail venom has exceptional molecular diversity in neuropharmacologically active compounds, targeting a range of receptors, ion channels, and transporters. These conotoxins have helped to dissect the structure and function of many of these therapeutically significant targets in the central and peripheral nervous systems, as well as unravelling the complex cellular mechanisms modulated by these receptors and ion channels. This review provides an overview of α-conotoxins targeting neuronal nicotinic acetylcholine receptors. The structure and activity of both classical and non-classical α-conotoxins are discussed, along with their contributions towards understanding nicotinic acetylcholine receptor (nAChR) structure and function.

Published data were used to model the transfer of ciguatoxins (CTX) across three trophic levels of a marine food chain on the Great Barrier Reef (GBR), Australia, to produce a mildly toxic common coral trout (Plectropomus leopardus), one of the most targeted food fishes on the GBR. Our model generated a 1.6 kg grouper with a flesh concentration of 0.1 µg/kg of Pacific-ciguatoxin-1 (P-CTX-1 = CTX1B) from 1.1 to 4.3 µg of P-CTX-1 equivalents (eq.) entering the food chain from 0.7 to 2.7 million benthic dinoflagellates (Gambierdiscus sp.) producing 1.6 pg/cell of the P-CTX-1 precursor, P-CTX-4B (CTX4B). We simulated the food chain transfer of ciguatoxins via surgeonfishes by modelling Ctenochaetus striatus feeding on turf algae. A C. striatus feeding on ≥1000 Gambierdiscus/cm2 of turf algae accumulates sufficient toxin in <2 days that when preyed on, produces a 1.6 kg common coral trout with a flesh concentration of 0.1 µg/kg P-CTX-1. Our model shows that even transient blooms of highly ciguatoxic Gambierdiscus can generate ciguateric fishes. In contrast, sparse cell densities of ≤10 Gambierdiscus/cm2 are unlikely to pose a significant risk, at least in areas where the P-CTX-1 family of ciguatoxins predominate. The ciguatera risk from intermediate Gambierdiscus densities (~100 cells/cm2) is more difficult to assess, as it requires feeding times for surgeonfish (~4–14 days) that overlap with turnover rates of turf algae that are grazed by herbivorous fishes, at least in regions such as the GBR, where stocks of herbivorous fishes are not impacted by fishing. We use our model to explore how the duration of ciguatoxic Gambierdiscus blooms, the type of ciguatoxins they produce, and fish feeding behaviours can produce differences in relative toxicities between trophic levels. Our simple model indicates thresholds for the design of risk and mitigation strategies for ciguatera and the variables that can be manipulated to explore alternate scenarios for the accumulation and transfer of P-CTX-1 analogues through marine food chains and, potentially, for other ciguatoxins in other regions, as more data become available.

The hypothesis that disturbance to coral reefs creates new surfaces that increase the risk of ciguatera is premised upon the increased algal substrates that develop on these surfaces being colonised by high ciguatoxin (CTX)-producing Gambierdiscus species that proliferate and enter the ciguatera food chain. Current evidence indicates that new algal substrates are indeed rapidly colonised by Gambierdiscus. However, the requirement that these Gambierdiscus species include at least one that is a significant (high) CTX-producer is more likely a limiting step. While ambient environmental conditions impact the capacity of Gambierdiscus to bloom, factors that limit the growth of the bloom could influence (typically increase) the flux of CTX entering marine food chains. Additionally, new algal substrates on damaged reefs can be preferentially grazed to funnel ciguatoxins from Gambierdiscus to herbivores in disturbed reef areas. In societies consuming second trophic level species (herbivores, grazers, and detritivores), such funnelling of CTX would increase the risk of ciguatera, although such risk would be partially offset over time by growth (toxin-dilution) and depuration. Here, we review evidence for six potential mechanisms to increase ciguatera risk from disturbance to coral reefs and suggest a hypothesis where ecosystem changes could increase the flux of CTX to groupers through a shift in predation from predominately feeding on planktonic-feeding prey to mostly feeding on benthic-feeding prey, increasing the potential for CTX to accumulate. Evidence for this hypothesis is stronger for the Pacific and Indian Oceans, and it may not apply to the Caribbean Sea/Atlantic Ocean.

Spider venom-derived cysteine knot peptides are a mega-diverse class of molecules that exhibit unique pharmacological properties to modulate key membrane protein targets. Voltage-gated sodium channels (Na ) are often targeted by these peptides to allosterically promote opening or closing of the channel by binding to structural domains outside the channel pore. These effects can result in modified pain responses, muscle paralysis, cardiac arrest, priapism, and numbness. Although such effects are often deleterious, subtype selective spider venom peptides are showing potential to treat a range of neurological disorders, including chronic pain and epilepsy. This review examines the structure-activity relationships of cysteine knot peptides from spider venoms that modulate Na and discusses their potential as leads to novel therapies for neurological disorders.

Continuous low-level supply or in situ generation of hydrogen peroxide (H 2 O 2 ) is essential for the stability of unspecific peroxygenases, which are deemed ideal biocatalysts for the selective activation of C–H bonds. To envisage potential large scale applications of combined catalytic systems the reactions need to be simple, efficient and produce minimal by-products. We show that gold-palladium nanoparticles supported on TiO 2 or carbon have sufficient activity at ambient temperature and pressure to generate H 2 O 2 from H 2 and O 2 and supply the oxidant to the engineered unspecific heme-thiolate peroxygenase PaDa-I. This tandem catalyst combination facilitates efficient oxidation of a range of C-H bonds to hydroxylated products in one reaction vessel with only water as a by-product under conditions that could be easily scaled. Continuous low-level supply or in situ generation of hydrogen peroxide (H 2 O 2 ) is essential for the stability of unspecific peroxygenases. Here, the authors demonstrate that AuPd / TiO 2 can generate sufficient H 2 O 2 for the engineered unspecific heme-thiolate peroxygenase PaDa-I to oxidise a range of C-H bonds.

We adapt previous conceptual and numerical models of ciguateric food chains for the bioaccumulation of Pacific-ciguatoxin-1 (P-CTX-1) to a general model for bioaccumulation of P-CTX3C by parrotfish (Scarus frenatus, S. niger, and S. psittacus) that feed by scraping turf algae, and surgeonfish (Naso unicornis) that mostly feed on macroalgae. We also include the Indian Ocean parrotfish Chlorurus sordidus as a model for an excavator feeding parrotfish and include comparisons with the detritivorous surgeonfish Ctenochaetus striatus that brush-feeds on turf algae. Our food chain model suggests that, of the Gambierdiscus and Fukuyoa species so far analysed for ciguatoxin (CTX) production from the Pacific, only G. polynesiensis produces sufficient P-CTX3C to consistently produce parrotfish or N. unicornis with poisonous flesh. Our model suggests that insufficient CTX would accumulate into the flesh of parrotfish or N. unicornis to become poisonous from ingesting benthic dinoflagellates producing ≤0.03 pg P-CTX3C eq./cell, except from extended feeding times on high-density blooms and in the absence of significant depuration of CTX. Apart from G. polynesiensis, only G. belizeanus and possibly G. silvae and G. australes are thought to produce >0.03 pg P-CTX3C eq./cell in the Pacific. However, with relatively low maximum concentrations of ≤0.1 pg P-CTX3C eq./cell it is likely that their contribution is minimal. Our model also suggests that the differences between the area of turf algae grazed by parrotfish and similar sized C. striatus results in greater accumulation of CTX by this surgeonfish. This makes C. striatus a higher ciguatera risk than similar sized parrotfish, either directly for human consumption or as prey for higher trophic level fishes, consistent with poisoning data from Polynesia. It also suggests the possibility that C. striatus could bioaccumulate sufficient CTX to become mildly poisonous from feeding on lower toxicity Gambierdiscus or Fukuyoa species known to produce ≥0.02 P-CTX3C eq./cell. This indicates the potential for at least two food chain pathways to produce ciguateric herbivorous fishes, depending on the CTX concentrations produced by resident Gambierdiscus or Fukuyoa on a reef and the grazing capacity of herbivorous fish. However, only G. polynesiensis appears to produce sufficient P-CTX3C to consistently accumulate in food chains to produce higher trophic level fishes that cause ciguatera in the Pacific. We incorporate CTX depuration into our model to explore scenarios where mildly poisonous parrotfish or N. unicornis ingest CTX at a rate that is balanced by depuration to estimate the Gambierdiscus/Fukuyoa densities and CTX concentrations required for these fish to remain poisonous on a reef.

The selective partial oxidation of methane to methanol using molecular oxygen (O 2 ) represents a long-standing challenge, inspiring extensive study for many decades. However, considerable challenges still prevent low-temperature methane activation via the aerobic route. Here we report a precipitated Pd-containing phosphomolybdate, which, after activation by molecular hydrogen (H 2 ), converts methane and O 2 almost exclusively to methanol at room temperature. The highest activity reaches 67.4 μmol g cat −1  h −1 . Pd enables rapid H 2 activation and H spillover to phosphomolybdate for Mo reduction, while facile O 2 activation and subsequent methane activation occur on the reduced phosphomolybdate sites. Continuous production of methanol from methane was also achieved by concurrently introducing H 2 , O 2 and methane into the system, where H 2 assists in maintaining a moderately reduced state of phosphomolybdate. This work reveals the underexplored potential of such a Mo-based catalyst for aerobic methane oxidation and highlights the importance of regulating the chemical valence state to construct methane active sites. The partial oxidation of methane to methanol is a very attractive yet challenging process. Now, a H 2 -reduced Pd-containing phosphomolybdate catalyst is reported to convert methane and O 2 to methanol with nearly 100% selectivity at room temperature.