Low-temperature synthesis of cation-ordered bulk Zn3WN4 semiconductor via heterovalent solid-state metathesis.

Metathesis reactions are widely used in synthetic chemistry. While state-of-the-art organic metathesis involves highly controlled processes where specific bonds are broken and formed, inorganic metathesis reactions are often extremely exothermic and, consequently, poorly controlled. Ternary nitrides offer a technologically relevant platform for expanding synthetic control of inorganic metathesis reactions. Here, we show that energy-controlled metathesis reactions involving a heterovalent exchange are possible in inorganic nitrides. We synthesized Zn3WN4 by swapping Zn2+ and Li+ between Li6WN4 and ZnX2 (X = Br, Cl, F) precursors. The in situ synchrotron powder X-ray diffraction and differential scanning calorimetry show that the reaction onset is correlated with the ZnX2 melting point and that product purity is inversely correlated with the reaction's exothermicity. Therefore, careful choice of the halide counterion (i.e., ZnBr2) allows the synthesis to proceed in a swift but controlled manner at a surprisingly low temperature for an inorganic nitride (300 °C). High resolution synchrotron powder X-ray diffraction and diffuse reflectance spectroscopy confirm the synthesis of a cation-ordered Zn3WN4 semiconducting material. We hypothesize that this synthesis strategy is generalizable because many Li-M-N phases are known (where M is a metal) and could therefore serve as precursors for metathesis reactions targeting new ternary nitrides. This work expands the synthetic control of inorganic metathesis reactions in a way that will accelerate the discovery of novel functional ternary nitrides and other currently inaccessible materials.

Adaptive Pore Opening to Form Tailored Adsorption Sites in a Cooperatively Flexible Framework Enables Record Inverse Propane/Propylene Separation.

A proposed low-energy alternative to the separation of alkanes from alkenes by energy-intensive cryogenic distillation is separation by porous adsorbents. Unfortunately, most adsorbents preferentially take up the desired, high-value major component alkene, requiring frequent regeneration. Adsorbents with inverse selectivity for the minor component alkane would enable the direct production of purified, reagent-grade alkene, greatly reducing global energy consumption. However, such materials are exceedingly rare, especially for propane/propylene separation. Here, we report that through adaptive and spontaneous pore size and shape adaptation to optimize an ensemble of weak noncovalent interactions, the structurally responsive metal-organic framework CdIF-13 (sod-Cd(benzimidazolate)2) exhibits inverse selectivity for propane over propylene with record-setting separation performance under industrially relevant temperature, pressure, and mixture conditions. Powder synchrotron X-ray diffraction measurements combined with first-principles calculations yield atomic-scale insight and reveal the induced fit mechanism of adsorbate-specific pore adaptation and ensemble interactions between ligands and adsorbates. Dynamic column breakthrough measurements confirm that CdIF-13 displays selectivity under mixed-component conditions of varying ratios, with a record measured selectivity factor of α ≈ 3 at 95:5 propylene:propane at 298 K and 1 bar. When sequenced with a low-cost rigid adsorbent, we demonstrated the direct purification of propylene under ambient conditions. This combined atomic-level structural characterization and performance testing firmly establishes how cooperatively flexible materials can be capable of unprecedented separation factors.

Multivariate Flexible Framework with High Usable Hydrogen Capacity in a Reduced Pressure Swing Process.

Step-shaped adsorption-desorption of gaseous payloads by flexible metal-organic frameworks can facilitate the delivery of large usable capacities with significantly reduced energetic penalties. This is desirable for the storage, transport, and delivery of H2, as prototypical adsorbents require large swings in pressure and temperature to achieve usable capacities approaching their total capacities. However, the weak physisorption of H2 typically necessitates undesirably high pressures to induce the framework phase change. As de novo design of flexible frameworks is exceedingly challenging, the ability to intuitively adapt known frameworks is required. We demonstrate that the multivariate linker approach is a powerful tool for tuning the phase change behavior of flexible frameworks. In this work, 2-methyl-5,6-difluorobenzimidazolate was solvothermally incorporated into the known framework CdIF-13 (sod-Cd(benzimidazolate)2), resulting in the multivariate framework sod-Cd(benzimidazolate)1.87(2-methyl-5,6-difluorobenzimidazolate)0.13 (ratio = 14:1), which exhibited a considerably reduced stepped adsorption threshold pressure while maintaining the desirable adsorption-desorption profile and capacity of CdIF-13. At 77 K, the multivariate framework exhibits stepped H2 adsorption with saturation below 50 bar and minimal desorption hysteresis at 5 bar. At 87 K, saturation of step-shaped adsorption occurs by 90 bar, with hysteresis closing at 30 bar. These adsorption-desorption profiles enable usable capacities in a mild pressure swing process above 1 mass %, representing 85-92% of the total capacities. This work demonstrates that the desirable performance of flexible frameworks can be readily adapted through the multivariate approach to enable efficient storage and delivery of weakly physisorbing species.

Multivariate zeolitic imidazolate frameworks with an inverting trend in flexibility.

Through systematic linker substitution in a flexible zeolitic imidazolate framework (ZIF) with step-shaped adsorption-desorption, structural intermediates between the known open and closed phases were isolated. Reflecting this, modulative sorption behaviour with an inverting adsorption pressure trend-in which the step pressure decreases and then increases again with increasing mixed linker concentration-is observed, highlighting how linker substitution modifies the energetic landscape of framework flexibility.

Magnetic structure, excitations and short-range order in honeycomb Na2Ni2TeO6.

Na2Ni2TeO6has a layered hexagonal structure with a honeycomb lattice constituted by Ni2+and a chiral charge distribution of Na+that resides between the Ni layers. In the present work, the antiferromagnetic (AFM) transition temperature of Na2Ni2TeO6is confirmed atTN≈ 27 K, and further, it is found to be robust up to 8 T magnetic field and 1.2 GPa external pressure; and, without any frequency-dependence. Slight deviations from nominal Na-content (up to 5%) does not seem to influence the magnetic transition temperature,TN. Isothermal magnetization curves remain almost linear up to 13 T. Our analysis of neutron diffraction data shows that the magnetic structure of Na2Ni2TeO6is faithfully described by a model consisting of two phases described by the commensurate wave vectorsk→c,0.500and0.500.5, with an additional short-range order component incorporated in to the latter phase. Consequently, a zig-zag long-range ordered magnetic phase of Ni2+results in the compound, mixed with a short-range ordered phase, which is supported by our specific heat data. Theoretical computations based on density functional theory predict predominantly in-plane magnetic exchange interactions that conform to aJ1-J2-J3model with a strongJ3term. The computationally predicted parameters lead to a reliable estimate forTNand the experimentally observed zig-zag magnetic structure. A spin wave excitation in Na2Ni2TeO6atE≈ 5 meV atT= 5 K is mapped out through inelastic neutron scattering experiments, which is reproduced by linear spin wave theory calculations using theJvalues from our computations. Our specific heat data and inelastic neutron scattering data strongly indicate the presence of short-range spin correlations, atT>TN, stemming from incipient AFM clusters.

Chemical Bonding Governs Complex Magnetism in MnPt5P.

Subtle changes in chemical bonds may result in dramatic revolutions in magnetic properties in solid-state materials. MnPt5P, a derivative of the rare-earth-free ferromagnetic MnPt5As, was discovered and is presented in this work. MnPt5P was synthesized, and its crystal structure and chemical composition were characterized by X-ray diffraction as well as energy-dispersive X-ray spectroscopy. Accordingly, MnPt5P crystallizes in the layered tetragonal structure with the space group P4/mmm (No. 123), in which the face-shared Mn@Pt12 polyhedral layers are separated by P layers. In contrast to the ferromagnetism observed in MnPt5As, the magnetic properties measurements on MnPt5P show antiferromagnetic ordering occurs at ∼188 K with a strong magnetic anisotropy in and out of the ab-plane. Moreover, a spin-flop transition appears when a high magnetic field is applied. An A-type antiferromagnetic structure was obtained from the analysis of powder neutron diffraction (PND) patterns collected at 150 and 9 K. Calculated electronic structures imply that hybridization of Mn-3d and Pt-5d orbitals is critical for both the structural stability and observed magnetic properties. Semiempirical molecular orbitals calculations on both MnPt5P and MnPt5As indicate that the lack of 4p character on the P atoms at the highest occupied molecular orbital (HOMO) in MnPt5P may cause the different magnetic behavior in MnPt5P compared to MnPt5As. The discovery of MnPt5P, along with our previously reported MnPt5As, parametrizes the end points of a tunable system to study the chemical bonding which tunes the magnetic ordering from ferromagnetism to antiferromagnetism with the strong spin-orbit coupling (SOC) effect.

Structural resolution and mechanistic insight into hydrogen adsorption in flexible ZIF-7.

Flexible metal-organic frameworks offer a route towards high useable hydrogen storage capacities with minimal swings in pressure and temperature via step-shaped adsorption and desorption profiles. Yet, the understanding of hydrogen-induced flexibility in candidate storage materials remains incomplete. Here, we investigate the hydrogen storage properties of a quintessential flexible metal-organic framework, ZIF-7. We use high-pressure isothermal hydrogen adsorption measurements to identify the pressure-temperature conditions of the hydrogen-induced structural transition in ZIF-7. The material displays narrow hysteresis and has a shallow adsorption slope between 100 K and 125 K. To gain mechanistic insight into the cause of the phase transition correlating with stepped adsorption and desorption, we conduct powder neutron diffraction measurements of the D2 gas-dosed structures at conditions across the phase change. Rietveld refinements of the powder neutron diffraction patterns yield the structures of activated ZIF-7 and of the gas-dosed material in the dense and open phases. The structure of the activated phase of ZIF-7 is corroborated by the structure of the activated phase of the Cd congener, CdIF-13, which we report here for the first time based on single crystal X-ray diffraction measurements. Subsequent Rietveld refinements of the powder patterns for the gas-dosed structure reveal that the primary D2 adsorption sites in the dense phase form D2-arene interactions between adjacent ligands in a sandwich-like adsorption motif. These sites are prevalent in both the dense and the open structure for ZIF-7, and we hypothesize that they play an important role in templating the structure of the open phase. We discuss the implications of our findings for future approaches to rationally tune step-shaped adsorption in ZIF-7, its congeners, and flexible porous adsorbents in general. Lastly, important to the application of flexible frameworks, we show that pelletization of ZIF-7 produces minimal variation in performance.

Self-adjusting binding pockets enhance H2 and CH4 adsorption in a uranium-based metal-organic framework.

A new, air-stable, permanently porous uranium(iv) metal-organic framework U(bdc)2 (1, bdc2- = 1,4-benzenedicarboxylate) was synthesized and its H2 and CH4 adsorption properties were investigated. Low temperature adsorption isotherms confirm strong adsorption of both gases in the framework at low pressures. In situ gas-dosed neutron diffraction experiments with different D2 loadings revealed a rare example of cooperative framework contraction (ΔV = -7.8%), triggered by D2 adsorption at low pressures. This deformation creates two optimized binding pockets for hydrogen (Q st = -8.6 kJ mol-1) per pore, in agreement with H2 adsorption data. Analogous experiments with CD4 (Q st = -24.8 kJ mol-1) and N,N-dimethylformamide as guests revealed that the binding pockets in 1 adjust by selective framework contractions that are unique for each adsorbent, augmenting individual host-guest interactions. Our results suggest that the strategic combination of binding pockets and structural flexibility in metal-organic frameworks holds great potential for the development of new adsorbents with an enhanced substrate affinity.

Developing a Health Impact Model for Adult Lead Exposure and Cardiovascular Disease Mortality.

BACKGROUND: Lead (Pb) is a highly toxic pollutant. Evidence suggests it is associated with cardiovascular disease (CVD)-related mortality. OBJECTIVES: We present a rigorous approach for identifying concentration-response functions that relate adult Pb exposures to CVD mortality to inform a health impact model (HIM). We then use the model in a proof-of-concept example. METHODS: Building on previously conducted government literature reviews and a de novo supplemental literature review, we compiled and evaluated the available data on Pb and CVD mortality in humans. We applied a set of predefined selection criteria to identify studies that would be most useful in understanding the impact of Pb exposure on CVD mortality risk in adults. Once we identified the studies, we derived a HIM and used each study's concentration-response function in a proof-of-concept example. RESULTS: Our literature search identified 15 studies for full-text review. Of those 15 studies, 4 fit our criteria for use in the HIM. Using population and CVD mortality rates for 40- to 80-y-olds in 2014, we estimated that 34,000-99,000 deaths have been avoided due to the lowering of blood Pb levels from 1999 to 2014. Based on these values we estimated that approximately 16%-46% of the decreased CVD-related death rate from 1999 to 2014 may be attributable to decreased blood Pb levels. CONCLUSION: Our results demonstrate that decreases in Pb exposure can result in large benefits for the adult population. We have provided a HIM that can be used in a variety of applications from burden-of-disease estimates to regulatory impact assessments and have demonstrated its sensitivity to the choice of concentration-response function. https://doi.org/10.1289/EHP6552.

Pressure-Induced Collapse of Magnetic Order in Jarosite.

We report a pressure-induced phase transition in the frustrated kagomé material jarosite at ∼45 GPa, which leads to the disappearance of magnetic order. Using a suite of experimental techniques, we characterize the structural, electronic, and magnetic changes in jarosite through this phase transition. Synchrotron powder x-ray diffraction and Fourier transform infrared spectroscopy experiments, analyzed in aggregate with the results from density functional theory calculations, indicate that the material changes from a R3[over ¯]m structure to a structure with a R3[over ¯]c space group. The resulting phase features a rare twisted kagomé lattice in which the integrity of the equilateral Fe^{3+} triangles persists. Based on symmetry arguments we hypothesize that the resulting structural changes alter the magnetic interactions to favor a possible quantum paramagnetic phase at high pressure.

Orbital energy mismatch engenders high-spin ground states in heterobimetallic complexes.

The spin state in heterobimetallic complexes heavily influences both reactivity and magnetism. Exerting control over spin states in main group-based heterobimetallics requires a different approach as the orbital interactions can differ substantially from that of classic coordination complexes. By deliberately engendering an energetic mismatch within the two metals in a bimetallic complex we can mimic the electronic structure of lanthanides. Towards this end, we report a new family of complexes, [Ph,MeTpMSnPh3] where M = Mn (3), Fe (4), Co (5), Ni (6), Zn (7), featuring unsupported bonding between a transition metal and Sn which represent an unusual high spin electronic structure. Analysis of the frontier orbitals reveal the desired orbital mismatch with Sn 5s/5p primarily interacting with 4s/4p M orbitals yielding localized, non-bonding d orbitals. This approach offers a mechanism to design and control spin states in bimetallic complexes.

Morningness-eveningness scores predict outcomes differentially for depressed patients attending morning vs. afternoon day treatment streams.

At the Center for Addiction and Mental Health (CAMH) Integrated Day Treatment (IDT) program, each patient attends either a morning stream or an afternoon stream, but not both. We examined whether subjective chronotype, or the time of day an individual prefers to be most active and alert, predicted treatment outcomes differentially in depressed patients attending the morning vs. afternoon IDT streams. The Horne-Östberg Morningness-Eveningness Questionnaire (MEQ) was administered before IDT treatment to 203 consecutive patients experiencing a major depressive episode. Multiple regression was used to predict change in depression and quality of life scores based on treatment stream (morning or afternoon), baseline MEQ scores and the treatment stream by MEQ interaction. The treatment stream by MEQ interaction was a highly significant predictor of both depression and quality of life change scores. Post-hoc analyses based on established MEQ categories revealed that definite evening chronotypes had significantly better responses in the morning stream than did morning chronotypes, and significantly worse responses in the afternoon stream relative to moderate evening or neutral chronotypes. There were insufficient morning chronotypes in the afternoon stream to assess clinical responses for this subgroup. In the morning stream only, there was a significant positive correlation between the change in MEQ scores after four weeks of IDT treatment (i.e. a shift to greater morningness) and the decrease in depression scores (r = .36, p = .003), consistent with a therapeutic phase advance in circadian rhythms. In sum, these preliminary data suggest that definite evening chronotypes may have the greatest relative benefit from attending the morning vs. afternoon IDT stream. As patients currently select which IDT stream they will attend, future work based on randomized treatment assignment and using passive actigraphy to assess circadian phase is currently planned to extend these preliminary findings.

Impact of Pressure on Magnetic Order in Jarosite.

Jarosite, a mineral with a kagomé lattice, displays magnetic frustration yet orders magnetically below 65 K. As magnetic frustration can engender exotic physical properties, understanding the complex magnetism of jarosite comprises a multidecade interdisciplinary challenge. Unraveling the nature of the disparate magnetic coupling interactions that lead to magnetic order in jarosite remains an open question. Specifically, there is no observed trend in the interlayer spacing with magnetic order. Similarly, the relationship between metal-ligand bond distance and magnetic order remains uninvestigated. Here, we use applied pressure to smoothly vary jarosite's structure without manipulating the chemical composition, enabling a chemically invariant structure-function study. Using single-crystal and powder X-ray diffraction, we show that high applied pressures alter both the interlayer spacing and the metal-ligand bond distances. By harnessing a suite of magnetic techniques under pressure, including SQUID-based magnetometry, time-resolved synchrotron Mössbauer spectroscopy, and X-ray magnetic circular dichroism, we construct the magnetic phase diagram for jarosite up to 40 GPa. Notably, we demonstrate that the magnetic ordering temperature increases dramatically to 240 K at the highest pressures. Additionally, we conduct X-ray emission spectroscopy, Mössbauer spectroscopy, and UV-visible absorption spectroscopy experiments to comprehensively map the magnetic and electronic structures of jarosite at high pressure. We use these maps to construct chemically pure magnetostructural correlations which fully explain the nature and role of the disparate magnetic coupling interactions in jarosite.

Efinaconazole 10% and Tavaborole 5% Penetrate Across Poly-ureaurethane 16%: Results of In Vitro Release Testing and Clinical Implications of Onychodystrophy in Onychomycosis.

BACKGROUND: Poly-ureaurethane has been previously described for the management of dry, brittle, and in general, dystrophic nails. The polymer yields a waterproof, breathable barrier to protect the nail plate and prevent further damage to the nail, while regulating transonychial water loss (TOWL). Because nail dystrophy and dessication are contributing factors to onychomycosis, a barrier that protects the nail but also allows a topical antifungal to permeate its shield is potentially an advantageous combination. Oral antifungals such as terbinafine, itraconazole, and fluconazole, as well as the newer topical antifungals efinaconazole and tavaborole (although formulated to penetrate the nail unit and work with the porosity and inherent electrical charge of the nail plate), do not take into account nail damage that has been created from years of harboring a dermatophyte infection. Up to 50% of cases presumed to be onychomycosis are in fact onychodystrophy without fungal infection, and laboratory testing for fungus should be obtained prior to initiating antifungal treatment. Whether a nail has onychomycosis, or onychodystrophy due to other causes, barrier function and structural integrity are compromised in diseased nails, and should be addressed. A poly-ureaurethane barrier that protects against wetting/drying, fungal reservoirs, and microtrauma, followed by the addition of oral or topical antifungals after laboratory fungal confirmation may optimize outcomes in the treatment of onychomycosis.
OBJECTIVE: The purpose of this work was to determine through in vitro release testing (IVRT) whether poly-ureaurethane 16% allows for penetration of efinaconazole 10% or tavaborole 5%. Results could spur subsequent clinical studies which would have implications for the addition of an antifungal based on fungal confirmation, after addresssing the underlying nail dystrophy primarily.
METHODS: A vertical diffusion cell system was used to evaluate the ability of efinaconazole 10% and tavaborole 5% to penetrate across poly-ureaurethane 16%. The diffusion cells had a 1.0 cm2 surface area and approximately 8 mL receptor volume. Poly-ureaurethane 16% was applied to a 0.45 μm nylon membrane and allowed to dry before use. Efinaconazole 10% or tavaborole 5% was then applied to the poly-ureaurethane 16% coated membrane, and samples were pulled from the receptor chamber at various times. Reverse phase chromatography was then used to assess the penetration of each active ingredient across the membrane.
RESULTS: The flux and permeability of efinaconazole or tavaborole across poly-ureaurethane 16% were determined from efinaconazole 10% or tavaborole 5%, respectively. The flux and permeability of efinaconazole were determined to be 503.9 +/- 31.9 μg/cm2/hr and 14.0 +/- 0.9 nm/sec. The flux and permeability of tavaborole were determined to be 755.5 +/- 290.4 μg/cm2/hr and 42.0 +/- 16.1 nm/sec.
CONCLUSION: In addition to the treatment of onychoschizia, onychorrhexis, and other signs of severe dessication of the nail plate, a barrier that regulates TOWL should be considered in the management onychomycosis to address barrier dysfunction and to promote stabilization of the damaged nail. Previously published flux values across the nail are reported to be 1.4 μg/cm2/day for efinaconazole and 204 μg/cm2/day for tavaborole. These values are substantially lower than the herein determined flux for both molecules across poly-ureaurethane 16%. A comparison of the data suggests that poly-ureaurethane 16%, if used prior to efinaconazole or tavaborole, would not limit the ability of either active ingredient to access the nail, and therefore, would be unlikely to reduce their antifungal effect. Onychodystrophy is inherent in, and often precedes onychomycosis, and consideration should be given for initiation of treatment in the same sequence: stabilizing and protecting the nail plate barrier primarily, and subsequently adding oral or topical antifungals after laboratory confirmation. Future clinical studies will be needed to determine combination efficacy for in vivo use.

J Drugs Dermatol. 2016;15(9):1116-1120.

Randomized Trial of Once-Daily Fluticasone Furoate in Children with Inadequately Controlled Asthma.

OBJECTIVE: To evaluate the dose-response, efficacy, and safety of fluticasone furoate (FF; 25 µg, 50 µg, and 100 µg), administered once daily in the evening during a 12-week treatment period to children with inadequately controlled asthma. STUDY DESIGN: This was a Phase IIb, multicenter, stratified, randomized, double-blind, double-dummy, parallel-group, placebo- and active-controlled study in children aged 5-11 years with inadequately controlled asthma. The study comprised a 4-week run-in period, 12-week treatment period, and 1-week follow-up period. Children were randomized to receive either placebo once daily, fluticasone propionate (FP) 100 µg twice daily, FF 25 µg, FF 50 µg, or FF 100 µg each once daily in the evening. Primary endpoint was the mean change from baseline in daily morning peak expiratory flow (PEF) averaged over weeks 1-12. Adverse events (AEs) also were investigated. RESULTS: In total, 593 children were included in the intent-to-treat population. The difference vs placebo in change from baseline daily morning PEF averaged over weeks 1-12 was statistically significant for the FF 25, FF 50, FF 100, and FP 100 groups (18.6 L/min, 19.5 L/min, 12.5 L/min, and 14.0 L/min, respectively; P < .001 for all). The incidence of AEs was greater in the FF groups (32%-36%) than in the placebo group (29%); the most frequent AE was cough. CONCLUSION: FF and FP resulted in significant improvements in morning PEF compared with placebo, suggesting that they are effective treatments for children with inadequately controlled asthma. All treatments were well tolerated; no new safety concerns were identified. TRIAL REGISTRATION: ClinicalTrials.gov:NCT01563029.

Randomised trial of once-daily vilanterol in children with asthma on inhaled corticosteroid therapy.

BACKGROUND: Inhaled corticosteroids (ICS) are effective maintenance treatments for childhood asthma; however, many children remain uncontrolled. Vilanterol (VI) is an inhaled long-acting beta-2 agonist which, in combination with the ICS fluticasone furoate, is being explored as a once-daily treatment for asthma in children. We evaluated the dose-response, efficacy, and safety of once-daily VI (6.25 µg, 12.5 µg and 25 µg) administered in the evening over 4 weeks, on background fluticasone propionate (FP) in children with asthma inadequately controlled on ICS. METHODS: This was a Phase IIb, multicentre, randomised, double-blind, parallel-group, placebo-controlled study in children ages 5-11 years with persistent asthma on ICS and as-needed short-acting beta-agonist. The study comprised a 4-week run-in, 4-week treatment period, and 1-week follow-up. From study start, children replaced their current ICS with open-label FP 100 µg twice daily. Children were randomised to receive placebo, VI 6.25 µg, VI 12.5 µg or VI 25 µg once daily. Primary endpoint was treatment difference between VI 25 and placebo groups in mean change from baseline in evening peak expiratory flow averaged over the 4-week treatment. Secondary endpoints included change from baseline in trough forced expiratory volume in one second (FEV1) at Week 4 and change from baseline in percentage of rescue-free and symptom-free 24-h periods. Safety assessments included incidence of adverse events (AEs) and asthma exacerbations. RESULTS: In total, 456 children comprised the intention-to-treat population. The adjusted treatment difference between VI 25 and placebo groups for the primary endpoint was not statistically significant (p = 0.227) so no statistical inference was made for other VI dose comparisons or other endpoints. No difference in change from baseline in trough FEV1 was observed for any VI treatments versus placebo; however, VI 25 resulted in an additional 0.6 rescue-free days and 0.7 symptom-free days per week versus placebo. The incidence of AEs was slightly higher in the VI groups (28-33 %) versus placebo (22 %). Nine children experienced asthma exacerbations during the treatment period. CONCLUSION: VI plus FP did not result in significant improvements in lung function versus placebo plus FP, but was well tolerated at all doses assessed. TRIAL REGISTRATION: NCT01573767 (ClinicalTrials.gov).

Chirality-selected phase behaviour in ionic polypeptide complexes.

Polyelectrolyte complexes present new opportunities for self-assembled soft matter. Factors determining whether the phase of the complex is solid or liquid remain unclear. Ionic polypeptides enable examination of the effects of stereochemistry on complex formation. Here we demonstrate that chirality determines the state of polyelectrolyte complexes, formed from mixing dilute solutions of oppositely charged polypeptides, via a combination of electrostatic and hydrogen-bonding interactions. Fluid complexes occur when at least one of the polypeptides in the mixture is racemic, which disrupts backbone hydrogen-bonding networks. Pairs of purely chiral polypeptides, of any sense, form compact, fibrillar solids with a ß-sheet structure. Analogous behaviour occurs in micelles formed from polypeptide block copolymers with polyethylene oxide, where assembly into aggregates with either solid or fluid cores, and eventually into ordered phases at high concentrations, is possible. Chirality is an exploitable tool for manipulating material properties in polyelectrolyte complexation.

Discovery of a highly potent, nonabsorbable apical sodium-dependent bile acid transporter inhibitor (GSK2330672) for treatment of type 2 diabetes.

The apical sodium-dependent bile acid transporter (ASBT) transports bile salts from the lumen of the gastrointestinal (GI) tract to the liver via the portal vein. Multiple pharmaceutical companies have exploited the physiological link between ASBT and hepatic cholesterol metabolism, which led to the clinical investigation of ASBT inhibitors as lipid-lowering agents. While modest lipid effects were demonstrated, the potential utility of ASBT inhibitors for treatment of type 2 diabetes has been relatively unexplored. We initiated a lead optimization effort that focused on the identification of a potent, nonabsorbable ASBT inhibitor starting from the first-generation inhibitor 264W94 (1). Extensive SAR studies culminated in the discovery of GSK2330672 (56) as a highly potent, nonabsorbable ASBT inhibitor which lowers glucose in an animal model of type 2 diabetes and shows excellent developability properties for evaluating the potential therapeutic utility of a nonabsorbable ASBT inhibitor for treatment of patients with type 2 diabetes.

Direct activation of human phospholipase C by its well known inhibitor u73122.

Phospholipase C (PLC) enzymes are an important family of regulatory proteins involved in numerous cellular functions, primarily through hydrolysis of the polar head group from inositol-containing membrane phospholipids. U73122 (1-(6-((17ß-3-methoxyestra-1,3,5(10)-trien-17-yl)amino)hexyl)-1H-pyrrole-2,5-dione), one of only a few small molecules reported to inhibit the activity of these enzymes, has been broadly applied as a pharmacological tool to implicate PLCs in diverse experimental phenotypes. The purpose of this study was to develop a better understanding of molecular interactions between U73122 and PLCs. Hence, the effects of U73122 on human PLCß3 (hPLCß3) were evaluated in a cell-free micellar system. Surprisingly, U73122 increased the activity of hPLCß3 in a concentration- and time-dependent manner; up to an 8-fold increase in enzyme activity was observed with an EC50=13.6±5 µm. Activation of hPLCß3 by U73122 required covalent modification of cysteines as evidenced by the observation that enzyme activation was attenuated by thiol-containing nucleophiles, l-cysteine and glutathione. Mass spectrometric analysis confirmed covalent reaction with U73122 at eight cysteines, although maximum activation was achieved without complete alkylation; the modified residues were identified by LC/MS/MS peptide sequencing. Interestingly, U73122 (10 µm) also activated hPLCγ1 (>10-fold) and hPLCß2 (∼2-fold); PLCδ1 was neither activated nor inhibited. Therefore, in contrast to its reported inhibitory potential, U73122 failed to inhibit several purified PLCs. Most of these PLCs were directly activated by U73122, and a simple mechanism for the activation is proposed. These results strongly suggest a need to re-evaluate the use of U73122 as a general inhibitor of PLC isozymes.

Cholestyramine reverses hyperglycemia and enhances glucose-stimulated glucagon-like peptide 1 release in Zucker diabetic fatty rats.

Bile acid sequestrants (BAS) have shown antidiabetic effects in both humans and animals but the underlying mechanism is not clear. In the present study, we evaluated cholestyramine in Zucker diabetic fatty (ZDF) rats. Although control ZDF rats had continuous increases in blood glucose and hemoglobin A1c (HbA1c) and serum glucose and a decrease in serum insulin throughout a 5-week study, the cholestyramine-treated ZDF rats showed a dose-dependent decrease and normalization in serum glucose and HbA1c. An oral glucose tolerance test showed a significant increase in glucose-stimulated glucagon-like peptide 1 (GLP-1), peptide YY (PYY), and insulin release in rats treated with cholestyramine. Quantitative analysis of gene expression indicated that cholestyramine treatment decreased farnesoid X receptor (FXR) activity in the liver and the intestine without liver X receptor (LXR) activation in the liver. Moreover, a combination of an FXR agonist with cholestyramine did not reduce the antihyperglycemic effect over cholestyramine alone, suggesting that the FXR-small heterodimer partner-LXR pathway was not required for the glycemic effects of cholestyramine. In summary, our results demonstrated that cholestyramine could completely reverse hyperglycemia in ZDF rats through improvements in insulin sensitivity and pancreatic beta-cell function. Enhancement in GLP-1 and PYY secretion is an important mechanism for BAS-mediated antidiabetic efficacy.