Development of a Tag/Catcher-mediated capsid virus-like particle vaccine presenting the conserved Neisseria gonorrhoeae SliC antigen that blocks human lysozyme.

Virus-like particles (VLPs) are promising nanotools for the development of subunit vaccines due to high immunogenicity and safety. Herein, we explored the versatile and effective Tag/Catcher-AP205 capsid VLP (cVLP) vaccine platform to address the urgent need for the development of an effective and safe vaccine against gonorrhea. The benefits of this clinically validated cVLP platform include its ability to facilitate unidirectional, high-density display of complex/full-length antigens through an effective split-protein Tag/Catcher conjugation system. To assess this modular approach for making cVLP vaccines, we used a conserved surface lipoprotein, SliC, that contributes to the Neisseria gonorrhoeae defense against human lysozyme, as a model antigen. This protein was genetically fused at the N- or C-terminus to the small peptide Tag enabling their conjugation to AP205 cVLP, displaying the complementary Catcher. We determined that SliC with the N-terminal SpyTag, N-SliC, retained lysozyme-blocking activity and could be displayed at high density on cVLPs without causing aggregation. In mice, the N-SliC-VLP vaccines, adjuvanted with AddaVax or CpG, induced significantly higher antibody titers compared to controls. In contrast, similar vaccine formulations containing monomeric SliC were non-immunogenic. Accordingly, sera from N-SliC-VLP-immunized mice also had significantly higher human complement-dependent serum bactericidal activity. Furthermore, the N-SliC-VLP vaccines administered subcutaneously with an intranasal boost elicited systemic and vaginal IgG and IgA, whereas subcutaneous delivery alone failed to induce vaginal IgA. The N-SliC-VLP with CpG (10 µg/dose) induced the most significant increase in total serum IgG and IgG3 titers, vaginal IgG and IgA, and bactericidal antibodies.

Leaf surface traits contributing to wettability, water interception and uptake of above-ground water sources in shrubs of Patagonian arid ecosystems.

BACKGROUND AND AIMS: The ecohydrological significance of leaf wetting due to atmospheric water in arid and semiarid ecosystems is not well understood. In these environments, the inputs of precipitation or dew formation resulting in leaf wetting have positive effects on plant functioning. However, its impact on plant water relations may depend on the degree of leaf surface wettability. In this study we evaluated leaf wettability and other leaf traits and its effects on foliar water uptake and canopy interception in plant species of a Patagonian steppe. We also studied how leaf traits affecting wettability vary seasonally from growing to dry season. METHODS: Contact angle of a water droplet with the leaf surface, water adhesion, droplet retention angle, stomatal density, cuticular conductance, canopy interception and maximum foliar water uptake were determined in six dominant shrub species. KEY RESULTS: All species increased leaf wettability during the dry season and most species were considered highly wettable. The leaf surface had very high capacity to store and retain water. We found a negative correlation between foliar water uptake and leaf hydrophilia. CONCLUSIONS: Despite the diversity of life forms, including cushion shrubs and tall shrubs, as well as phenological variability, all species converged in similar seasonal changes in leaf traits that favour wettability. Intercepted water by crowns and the extremely high capacity of retention of droplets on leaf surfaces can have a significant impact on eco-hydrological process in water limited ecosystems where most of water sources during the growing and the dry season may be small rainfall events or dew, which do not always increase soil water availability.

Immature stages of the limnephilid caddisfly Verger lutzi (Navás 1918) (Trichoptera: Limnephilidae): description and larval life-history traits in seasonal forested wetlands of Northwestern Patagonia.

The genus Verger Navás 1918 (Trichoptera: Limnephilidae), is a Neotropical genus exclusive to the Andean region, with most of its species distributed from Tierra del Fuego to north central Chile and Argentina. Currently, 20 species of the genus have been described from adults and only six larvae have been associated and diagnosed. The ecology of the species is completely unknown. In this work, we describe and illustrate the immature stages of Verger lutzi (Navás 1918) and study its breeding phenology, larval growth and adult emergence. The main characters that enable the separation of this species are the coloration the body, shape of the anterior ventral apotome, shape and distribution of metanotal setal areas, distribution of tracheal gills and number of accessory teeth in the anal prolegs. Reproduction occurs during the summer and females lay their eggs on the wetland basin formed by humid leaf litter and organic debris, covered by herbaceous vegetation. Larvae hatch after flooding and overwinter in the wetland. Larvae develop fast during spring and emergence begins in December before the wetland dries up. Description of the immature stages is helpful for use of macroinvertebrates biomonitoring, ecological studies and understanding their ecosystem services in seasonal-lentic habitats.

Evaluation of Radiographic Features Including Metatarsus Primus Elevatus in Hallux Rigidus.

The etiology of hallux rigidus remains a controversial issue in foot and ankle surgery, i.e., the relationship between metatarsus primus elevatus (MPE) and hallux rigidus. The purpose of this study was to evaluate several radiographic parameters including first metatarsal elevation in patients with hallux rigidus compared to a matched control group. A retrospective case control study was performed including 50 feet, 25 feet with and 25 feet without hallux rigidus. In the patients with hallux rigidus, the first metatarsal was more elevated than in the control group (8.3 ± 1.7 mm vs 3.0 ± 2.0 mm, p < .001) and in 60% of patients with hallux rigidus MPE was diagnosed, compared to zero patients in the control group (p < .001). The lateral 1 to 2 intermetatarsal angle was higher in patients with hallux rigidus (3.6 ± 2.5 vs -0.7 ± 2.8; p < .001). The first metatarsal declination angle was not different between the 2 groups. Intraclass correlation coefficient between 2 observers for measuring the first metatarsal elevation was 0.929 (p < .001). In the current study, increased elevation of the first metatarsal, a higher incidence of MPE and increased lateral 1 to 2 intermetatarsal angle were found in patients with hallux rigidus compared to the control group. These findings support the theory of an association between MPE and hallux rigidus. Further high reliability of first metatarsal elevation measurement was found in our study.

A multi-biomarker study on Atlantic salmon (Salmo salar L.) affected by the emerging Red Skin Disease in the Baltic Sea.

For half a decade, the Atlantic salmon in the Baltic Sea has been facing severe health issues. Clinical signs like haemorrhage, erosions and ulcerative/necrotic skin conditions in returning adults have been reported from different Swedish rivers. These primary disease signs precede a secondary, terminal fungal infection. As initial investigations of the disease did not provide conclusive answers regarding the pathogenesis, this study was initiated to gain insight into a possible link between this so-called Red Skin Disease and anthropogenic influences. Therefore, returning salmon were caught in rivers along the Swedish coast and different tissues were sampled. The focus was put on the measurements of a battery of biomarkers as well as biochemical and haematological parameters, which were analysed using multivariate statistics. The main findings were a severe osmotic haemodilution, an immune response and an alteration of the carbohydrate metabolism in diseased fish. Furthermore, oxidative stress does not seem to be a likely factor in the pathogenesis. Concluding, certain changes in physiological parameters were shown to be indicative for the disease patterns, while others were ruled out as significant factors. Thus, this study contributes to the understanding of the Red Skin Disease and may act as a hypothesis generator for future studies.

From Perviousness to Plaque Imaging in Acute Basilar Occlusions: The Impact of Underlying Stenosis and How to Detect It.

Background and Purpose- Recent studies show that mechanical thrombectomy of acute basilar artery occlusions (BAO) results in high rates of successful recanalization and good outcomes, but predictors are not completely established yet. Varying occlusion types may benefit differently, and especially, an underlying basilar stenosis (BS) seems to have an impact. Aim of this study was to investigate angiographic and clinical differences in BAO subtypes and to test the potential of perviousness measures for a preinterventional identification of clinically relevant different occlusion types. Methods- All consecutive patients with acute BAO, endovascular treated at a single comprehensive stroke center, were included. Different occlusion patterns, especially underlying BS, were identified and analyzed in respect of angiographic and clinical (National Institutes of Health Stroke Scale/modified Rankin Scale) outcome parameters (N=115). Thrombus perviousness measures (change in thrombus attenuation Δt and corrected void fraction ε) were assessed in admission computed tomography imaging and correlated to different etiological subgroups. Results- Despite comparable rates of successful recanalization (87% for BAO with BS versus 95% without BS), the BS group showed worse clinical outcome with higher National Institutes of Health Stroke Scale/modified Rankin Scale values (P=0.002/0.003). The group of BS turned out to have lower thrombus density values in unenhanced scans (mean, 42.0 Hounsfield units) and higher perviousness measures Δt (mean, 34.6 Hounsfield units) and ε (mean, 0.23) than thrombi without an underlying BS (mean, 53.6 Hounsfield units/13.1 Hounsfield units/0.08, P=0.01/ 0.004/ 0.001). Conclusions- In agreement with previous studies, outcome of mechanical thrombectomy of BAO seems to depend on pathogenesis with less clinical benefit for underlying BS, raising the question of early identification of this subgroup. Perviousness showed a high potential to differentiate acute BAO with and without BS, possibly usable as an admission imaging marker for BS.

O2 Activation by Non-Heme Thiolate-Based Dinuclear Fe Complexes.

Iron centers featuring thiolates in their metal coordination sphere (as ligands or substrates) are well-known to activate dioxygen. Both heme and non-heme centers that contain iron-thiolate bonds are found in nature. Investigating the ability of iron-thiolate model complexes to activate O2 is expected to improve the understanding of the key factors that direct reactivity to either iron or sulfur. We report here the structural and redox properties of a thiolate-based dinuclear Fe complex, [FeII2(LS)2] (LS2- = 2,2'-(2,2'-bipyridine-6,6'-iyl)bis(1,1-diphenylethanethiolate)), and its reactivity with dioxygen, in comparison with its previously reported protonated counterpart, [FeII2(LS)(LSH)]+. When reaction with O2 occurs in the absence of protons or in the presence of 1 equiv of proton (i.e., from [FeII2(LS)(LSH)]+), unsupported µ-oxo or µ-hydroxo FeIII dinuclear complexes ([FeIII2(LS)2O] and [FeIII2(LS)2(OH)]+, respectively) are generated. [FeIII2(LS)2O], reported previously but isolated here for the first time from O2 activation, is characterized by single crystal X-ray diffraction and Mössbauer, resonance Raman, and NMR spectroscopies. The addition of protons leads to the release of water and the generation of a mixture of two Fe-based "oxygen-free" species. Density functional theory calculations provide insight into the formation of the µ-oxo or µ-hydroxo FeIII dimers, suggesting that a dinuclear µ-peroxo FeIII intermediate is key to reactivity, and the structure of which changes as a function of protonation state. Compared to previously reported Mn-thiolate analogues, the evolution of the peroxo intermediates to the final products is different and involves a comproportionation vs a dismutation process for the Mn and Fe derivate, respectively.

Foliar water uptake in arid ecosystems: seasonal variability and ecophysiological consequences.

Foliar water uptake (FWU) has been reported for different species across several ecosystems types. However, little attention has been given to arid ecosystems, where FWU during dew formation or small rain events could ameliorate water deficits. FWU and their effects on leaf water potential (ΨLeaf) were evaluated in grasses and shrubs exploring different soil water sources in a Patagonian steppe. Also, seasonal variability in FWU and the role of cell wall elasticity in determining the effects on ΨLeaf were assessed. Eleven small rain events (< 8 mm) and 45 days with dew formation were recorded during the study period. All species exhibited FWU after experimental wetting. There was a large variability in FWU across species, from 0.04 mmol m-2 s-1 in species with deep roots to 0.75 mmol m-2 s-1 in species with shallow roots. Species-specific mean FWU rates were positively correlated with mean transpiration rates. The increase in ΨLeaf after leaf wetting varied between 0.65 MPa and 1.67 MPa across species and seasons. The effects of FWU on ΨLeaf were inversely correlated with cell wall elasticity. FWU integrated over both seasons varied between 28 mol m-2 in species with deep roots to 361 mol m-2 in species with shallow roots. Taking into account the percentage of coverage of each species, accumulated FWU represented 1.6% of the total annual transpiration of grasses and shrubs in this ecosystem. Despite this low FWU integrated over time compared to transpiration, wetting leaves surfaces can help to avoid larger water deficit during the dry season.

Bioengineering of Cytochrome P450 OleTJE: How Does Substrate Positioning Affect the Product Distributions?

The cytochromes P450 are versatile enzymes found in all forms of life. Most P450s use dioxygen on a heme center to activate substrates, but one class of P450s utilizes hydrogen peroxide instead. Within the class of P450 peroxygenases, the P450 OleTJE isozyme binds fatty acid substrates and converts them into a range of products through the α-hydroxylation, ß-hydroxylation and decarboxylation of the substrate. The latter produces hydrocarbon products and hence can be used as biofuels. The origin of these product distributions is unclear, and, as such, we decided to investigate substrate positioning in the active site and find out what the effect is on the chemoselectivity of the reaction. In this work we present a detailed computational study on the wild-type and engineered structures of P450 OleTJE using a combination of density functional theory and quantum mechanics/molecular mechanics methods. We initially explore the wild-type structure with a variety of methods and models and show that various substrate activation transition states are close in energy and hence small perturbations as through the protein may affect product distributions. We then engineered the protein by generating an in silico model of the double mutant Asn242Arg/Arg245Asn that moves the position of an active site Arg residue in the substrate-binding pocket that is known to form a salt-bridge with the substrate. The substrate activation by the iron(IV)-oxo heme cation radical species (Compound I) was again studied using quantum mechanics/molecular mechanics (QM/MM) methods. Dramatic differences in reactivity patterns, barrier heights and structure are seen, which shows the importance of correct substrate positioning in the protein and the effect of the second-coordination sphere on the selectivity and activity of enzymes.

A Non-Heme Diiron Complex for (Electro)catalytic Reduction of Dioxygen: Tuning the Selectivity through Electron Delivery.

In the oxygen reduction reaction (ORR) domain, the investigation of new homogeneous catalysts is a crucial step toward the full comprehension of the key structural and/or electronic factors that control catalytic efficiency and selectivity. Herein, we report a unique non-heme diiron complex that can act as a homogeneous ORR catalyst in acetonitrile solution. This iron(II) thiolate dinuclear complex, [FeII2(LS)(LSH)] ([Fe2SH]+) (LS2- = 2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate)) contains a thiol group in the metal coordination sphere. [Fe2SH]+ is an efficient ORR catalyst both in the presence of a one-electron reducing agent and under electrochemically assisted conditions. However, its selectivity is dependent on the electron delivery pathway; in particular, the process is selective for H2O2 production under chemical conditions (up to ∼95%), whereas H2O is the main product during electrocatalysis (less than ∼10% H2O2). Based on computational work alongside the experimental data, a mechanistic proposal is discussed that rationalizes the selective and tunable reduction of dioxygen.

Functional relationships between hydraulic traits and the timing of diurnal depression of photosynthesis.

The hydraulic coordination along the water transport pathway helps trees provide adequate water supply to the canopy, ensuring that water deficits are minimized and that stomata remain open for CO2 uptake. We evaluated the stem and leaf hydraulic coordination and the linkages between hydraulic traits and the timing of diurnal depression of photosynthesis across seven evergreen tree species in the southern Andes. There was a positive correlation between stem hydraulic conductivity (ks ) and leaf hydraulic conductance (KLeaf ) across species. All species had similar maximum photosynthetic rates (Amax ). The species with higher ks and KLeaf attained Amax in the morning, whereas the species with lower ks and KLeaf exhibited their Amax in the early afternoon concurrently with turgor loss. These latter species had very negative leaf water potentials, but far from the pressure at which the 88% of leaf hydraulic conductance is lost. Our results suggest that diurnal gas exchange dynamics may be determined by leaf hydraulic vulnerability such that a species more vulnerable to drought restrict water loss and carbon assimilation earlier than species less vulnerable. However, under stronger drought, species with earlier CO2 uptake depression may increase the risk of hydraulic failure, as their safety margins are relatively narrow.

The Equatorial Ligand Effect on the Properties and Reactivity of Iron(V) Oxo Intermediates.

High-valent metal oxo oxidants are common catalytic-cycle intermediates in enzymes and known to be highly reactive. To understand which features of these oxidants affect their reactivity, a series of biomimetic iron(V) oxo oxidants with peripherally substituted biuret-modified tetraamido macrocyclic ligands were synthesized and characterized. Major shifts in the UV/Vis absorption as a result of replacing a group in the equatorial plane of the iron(V) oxo species were found. Further characterization by EPR spectroscopy, ESI-MS, and resonance Raman spectroscopy revealed differences in structure and the electronic configuration of these complexes. A systematic reactivity study with a range of substrates was performed and showed that the reactions are affected by electron-withdrawing substituents in the equatorial ligand, which enhance the reaction rate by almost 1016 orders of magnitude. Thus, the long-range electrostatic perturbations have a major influence on the rate constant. Finally, computational studies identified the various electronic contributions to the rate-determining reaction step and explained how the equatorial ligand periphery affects the properties of the oxidant.

Warming-induced shifts in amphibian phenology and behavior lead to altered predator-prey dynamics.

Climate change-induced phenological variation in amphibians can disrupt time-sensitive processes such as breeding, hatching, and metamorphosis, and can consequently alter size-dependent interactions such as predation. Temperature can further alter size-dependent, predator-prey relationships through changes in species' behavior. We thus hypothesized that phenological shifts due to climate warming would alter the predator-prey dynamic in a larval amphibian community through changes in body size and behavior of both the predator and prey. We utilized an amphibian predator-prey system common to the montane wetlands of the U.S. Pacific Northwest: the long-toed salamander (Ambystoma macrodactylum) and its anuran prey, the Pacific chorus frog (Pseudacris regilla). We conducted predation trials to test if changes in predator phenology and environmental temperature influence predation success. We simulated predator phenological shifts using different size classes of the long-toed salamander representing an earlier onset of breeding while using spring temperatures corresponding to early and mid-season larval rearing conditions. Our results indicated that the predator-prey dynamic was highly dependent upon predator phenology and temperature, and both acted synergistically. Increased size asymmetry resulted in higher tadpole predation rates and tadpole tail damage. Both predators and prey altered activity and locomotor performance in warmer treatments. Consequently, behavioral modifications resulted in decreased survival rates of tadpoles in the presence of large salamander larvae. If predators shift to breed disproportionately earlier than prey due to climate warming, this has the potential to negatively impact tadpole populations in high-elevation amphibian assemblages through changes in predation rates mediated by behavior.

Joint contact areas after radial head arthroplasty: a comparative study of 3 prostheses.

BACKGROUND: Contact stresses of radial head prostheses remain a concern, potentially leading to early capitellar cartilage wear and erosion. In particular, point contact or edge loading could have a detrimental effect. The purpose of this study was to compare 3 different types of radial head prostheses in terms of joint contact areas with each other and with the native situation. The hypothesis was that the joint contact areas would be lower after monopolar arthroplasty. METHODS: Seven fresh-frozen cadaveric upper limbs were used. Radiocapitellar contact areas of a monopolar design, a straight-neck bipolar design, and an angled-neck bipolar design were compared with each other and with the native joint. After standardized preparation, polysiloxane was injected into the loaded radiocapitellar joint to create a cast from which the joint contact area was measured. Measurements were performed at 3 angles of elbow flexion and in 3 different forearm positions. RESULTS: In the native elbow, contact areas were highest in supination. Elbow flexion had no significant effect on native and prosthetic joint contact areas. Contact areas were decreased for all types of arthroplasties compared with the native joint (from 11% to 53%). No significant contact area difference was found between the 3 designs. However, bipolar prostheses showed lateral subluxation in neutral forearm rotation, resulting in a significant decrease in the contact areas from pronation to the neutral position. CONCLUSIONS: All types of radial head prostheses tested showed a significant decrease in radiocapitellar contact area compared with the native joint. Bipolar designs led to subluxation of the radial head, further decreasing radiocapitellar contact.

Hydrogen by Deuterium Substitution in an Aldehyde Tunes the Regioselectivity by a Nonheme Manganese(III)-Peroxo Complex.

Mononuclear nonheme MnIII -peroxo complexes are important intermediates in biology, and take part in oxygen activation by photosystem II. Herein, we present work on two isomeric biomimetic side-on MnIII -peroxo intermediates with bispidine ligand system and reactivity patterns with aldehydes. The complexes are characterized with UV/Vis and mass spectrometric techniques and reaction rates with cyclohexane carboxaldehyde (CCA) are measured. The reaction gives an unusual regioselectivity switch from aliphatic to aldehyde hydrogen atom abstraction upon deuteration of the substrate, leading to the corresponding carboxylic acid product for the latter, while the former gives a deformylation reaction. Mechanistic details are established from kinetic isotope effect studies and density functional theory calculations. Thus, replacement of C-H by C-D raises the hydrogen atom abstraction barriers and enables a regioselectivity switch to a competitive pathway that is slightly higher in energy.

Solvent- and Halide-Induced (Inter)conversion between Iron(II)-Disulfide and Iron(III)-Thiolate Complexes.

Disulfide/thiolate interconversion controlled by Cu is proposed to be involved in relevant biological processes. In analogy to Cu, it can be envisaged that Fe also participates in the control of similar biological processes. We describe here Fe complexes that undergo FeIII -thiolate/FeII -disulfide (inter)conversion mediated by halide (de)coordination, and by the nature of the solvent. The dinuclear FeII -disulfide complex [FeII2 (LSSL)]2+ ((LS)2- =2,2'-(2,2'-bipyridine-6,6'-diyl)bis(1,1-diphenylethanethiolate), (LSSL)2- =the corresponding disulfide ligand) shows solvent-dependent properties. Whereas in a non-coordinating solvent (CH2 Cl2 ) the dinuclear FeII -disulfide complex is the only stable form, in the presence of coordinating solvents like MeCN or DMF it is partly or fully converted into mononuclear FeIII -thiolate species having a bound solvent molecule ([FeIII (LS)(Solv)]+ , Solv=DMF, MeCN). Addition of Cl- to a CH2 Cl2 solution containing the FeII -disulfide dinuclear complex leads to the fast and quantitative formation of a mononuclear FeIII -thiolate species with a bound Cl- , that is, ([FeIII (LS)Cl]). The reverse reaction can be achieved by addition of Li[[B(C6 F5 )4 ]. In relation to the metal-sulfur electronic distribution, the comparison between the redox properties of the Fe, Mn and Co complexes involved in these MIII -thiolate/MII -disulfide interconversion processes allow one to rationalize their respective efficiency.

Tillage and Fertilizer Management Effects on Phosphorus Runoff from Minimal Slope Fields.

Phosphorus fertilization can increase P losses in surface runoff, but limited information is available for fields with <2% slopes in the US Midwest. Our objectives were to determine the effects of tillage-fertilizer placement (no-till-broadcast, strip till-broadcast; or strip till-deep placement, -15-cm subsurface band) and fertilizer rate applied in the fall (0, 52, or 90 kg PO ha yr) on runoff P concentrations and loads in fields with <2% slopes near Pesotum, IL, during fall and spring simulation runoff events, and to measure corn ( L.) and soybean [ (L.) Merr.] grain yield. Across four simulated runoff events, deep placement reduced dissolved reactive P (DRP) loads by 69 to 72% compared with the broadcast treatments. A tillage-fertilizer placement × P rate interaction showed that DRP and total P (TP) concentrations remained low when P was deep placed, regardless of P rate, whereas concentrations increased with increasing P rate for the broadcast treatments, but no differences existed for bioavailable P (BAP) (α = 0.05). At one site, rainfall simulation in the spring versus fall increased runoff volumes but sharply decreased BAP concentrations. During fall runoff simulations, deep placement reduced TP loads, and greater TP loads occurred with the 90- than the 52-kg PO ha yr rate. Similarly, when P was broadcast in the fall, DRP and TP concentrations were greater than deep-placed P, but no treatment differences occurred in the spring. Deep banding P and K did not reduce crop yield but reduced runoff losses of P from flat fields compared with broadcast P applications, particularly at high rates of P application.

Keto-Enol Tautomerization Triggers an Electrophilic Aldehyde Deformylation Reaction by a Nonheme Manganese(III)-Peroxo Complex.

Oxygen atom transfer by high-valent enzymatic intermediates remains an enigma in chemical catalysis. In particular, manganese is an important first-row metal involved in key biochemical processes, including the biosynthesis of molecular oxygen (through the photosystem II complex) and biodegradation of toxic superoxide to hydrogen peroxide by superoxide dismutase. Biomimetic models of these biological systems have been developed to gain understanding on the structure and properties of short-lived intermediates but also with the aim to create environmentally benign oxidants. In this work, we report a combined spectroscopy, kinetics and computational study on aldehyde deformylation by two side-on manganese(III)-peroxo complexes with bispidine ligands. Both manganese(III)-peroxo complexes are characterized by UV-vis and mass spectrometry techniques, and their reactivity patterns with aldehydes was investigated. We find a novel mechanism for the reaction that is initiated by a hydrogen atom abstraction reaction, which enables a keto-enol tautomerization in the substrate. This is an essential step in the mechanism that makes an electrophilic attack on the olefin bond possible as the attack on the aldehyde carbonyl is too high in energy. Kinetics studies determine a large kinetic isotope effect for the replacement of the transferring hydrogen atom by deuterium, while replacing the transferring hydrogen atom by a methyl group makes the substrate inactive and hence confirm the hypothesized mechanism. Our new mechanism is confirmed with density functional theory modeling on the full mechanism and rationalized through valence bond and thermochemical cycles. Our unprecedented new mechanism may have relevance to biological and biomimetic chemistry processes in general and gives insight into the reactivity patterns of metal-peroxo and metal-hydroperoxo intermediates in general.

Oxygen Atom Transfer Using an Iron(IV)-Oxo Embedded in a Tetracyclic N-Heterocyclic Carbene System: How Does the Reactivity Compare to Cytochrome P450 Compound†I?

N-Heterocyclic carbenes (NHC) are commonly featured as ligands in transition metal catalysis. Recently, a cyclic system containing four NHC groups with a central iron atom was synthesized and its iron(IV)-oxo species, [FeIV (O)(cNHC4 )]2+ , was characterized. This tetracyclic NHC ligand system may give the iron(IV)-oxo species unique catalytic properties as compared to traditional non-heme and heme iron ligand systems. Therefore, we performed a computational study on the structure and reactivity of the [FeIV (O)(cNHC4 )]2+ complex in substrate hydroxylation and epoxidation reactions. The reactivity patterns are compared with cytochrome P450 Compound I and non-heme iron(IV)-oxo models and it is shown that the [FeIV (O)(cNHC4 )]2+ system is an effective oxidant with oxidative power analogous to P450 Compound I. Unfortunately, in polar solvents, a solvent molecule will bind to the sixth ligand position and decrease the catalytic activity of the oxidant. A molecular orbital and valence bond analysis provides insight into the origin of the reactivity differences and makes predictions of how to further exploit these systems in chemical catalysis.

Modulation of Antimalarial Activity at a Putative Bisquinoline Receptor In Vivo Using Fluorinated Bisquinolines.

Antimalarials can interact with heme covalently, by π⋅⋅⋅π interactions or by hydrogen bonding. Consequently, the prototropy of 4-aminoquinolines and quinoline methanols was investigated by using quantum mechanics. Calculations showed mefloquine protonated preferentially at the piperidine and was impeded at the endocyclic nitrogen because of electronic rather than steric factors. In gas-phase calculations, 7-substituted mono- and bis-4-aminoquinolines were preferentially protonated at the endocyclic quinoline nitrogen. By contrast, compounds with a trifluoromethyl substituent on both the 2- and 8-positions, reversed the order of protonation, which now favored the exocyclic secondary amine nitrogen at the 4-position. Loss of antimalarial efficacy by CF3 groups simultaneously occupying the 2- and 8-positions was recovered if the CF3 group occupied the 7-position. Hence, trifluoromethyl groups buttressing the quinolinyl nitrogen shifted binding of antimalarials to hematin, enabling switching from endocyclic to the exocyclic N. Both theoretical calculations (DFT calculations: B3LYP/BS1) and crystal structure of (±)-trans-N1 ,N2 -bis-(2,8-ditrifluoromethylquinolin-4-yl)cyclohexane-1,2-diamine were used to reveal the preferred mode(s) of interaction with hematin. The order of antimalarial activity in vivo followed the capacity for a redox change of the iron(III) state, which has important implications for the future rational design of 4-aminoquinoline antimalarials.