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Living systems carry out the reduction of N 2 to ammonia (NH 3 ) through a series of protonation and electron transfer steps under ambient conditions using the enzyme nitrogenase. In the chemical industry, the Haber-Bosch process hydrogenates N 2 but requires high temperatures and pressures. Both processes rely on iron-based catalysts, but molecular iron complexes that promote the formation of NH 3 on addition of H 2 to N 2 have remained difficult to devise. Here, we isolate the tri(iron)bis(nitrido) complex [(Cp'Fe) 3 (μ 3 -N) 2 ] (in which Cp' = η 5 -1,2,4-(Me 3 C) 3 C 5 H 2 ), which is prepared by reduction of [Cp'Fe(μ-I)] 2 under an N 2 atmosphere and comprises three iron centres bridged by two μ 3 -nitrido ligands. In solution, this complex reacts with H 2 at ambient temperature (22 °C) and low pressure (1 or 4 bar) to form NH 3 . In the solid state, it is converted into the tri(iron)bis(imido) species, [(Cp'Fe) 3 (μ 3 -NH) 2 ], by addition of H 2 (10 bar) through an unusual solid-gas, single-crystal-to-single-crystal transformation. In solution, [(Cp'Fe) 3 (μ 3 -NH) 2 ] further reacts with H 2 or H + to form NH 3 .

The coordination chemistry of the sterically encumbered pentadienyl ligand pdl' (pdl' = 2,4-(Me3C)2C5H5) towards a series of rare-earth metals was systematically explored and the resulting metal complexes were fully characterized by several techniques including X-ray diffraction, elemental analysis, NMR spectroscopy and solid-state magnetic susceptibility studies. Three different reaction products were isolated depending on the redox-potentials and ionic radii of the metal atoms. They can be classified as (a) salt-metathesis, (b) metal reduction-ligand oxidation and (c) ligand deprotonation products. While for the larger and difficult to reduce metal ions, M = La, Ce, Pr and Nd, trivalent compounds [(η5-pdl')3M] (1-M) were isolated, for the more readily reduced metal ions the corresponding divalent compounds [[(η5-pdl')2M(thf)n] (2-M; with M = Sm (n = 2); Eu, Yb (n = 1)) were formed. A more complex structural motif was observed for the smaller and also difficult to reduce metal ions, M = Sc, Y, Gd, Tb, Dy, Ho, Er, Tm and Lu, which yielded the bimetallic complexes of the type [(pdl')(pdl'-1H)(pdl'-2H)M2(thf)2] (3-M). In these dimeric complexes the pdl' ligand acts as a result of deprotonation reactions not only as a monoanionic [pdl']-, but also as a dianionic [pdl'-1H]2- and a trianionic [pdl'-2H]3- ligand scaffold, which form unusual structural motifs including a six-membered metallacycle. Solid-state magnetic susceptibility studies revealed the expected free-ion magnetic moments at T = 300 K for all investigated compounds, whereas at lower temperatures crystal-field effects dominate. Furthermore, for 3-Gd, 3-Tb, 3-Dy and 3-Er weak ferromagnetic exchange interactions were observed at low temperature.

Acid-sensing ion channel 3 (ASIC3) is a proton-gated Na + channel with important roles in pain. ASIC3 quickly desensitizes in less than a second, limiting its capacity to sense sustained acidosis during pain. RFamide neuropeptides are modulators of ASIC3 that slow its desensitization and induce a variable sustained current. The molecular mechanism of slowed desensitization and the RFamide binding site on ASIC3 are unknown. RPRFamide, a RFamide from the venom of a cone snail, has a comparatively high affinity for ASIC3 and strongly slows its desensitization. Here we show that covalent binding of a UV-sensitive RPRFamide variant to ASIC3 prevents desensitization, suggesting that RPRFamide has to unbind from ASIC3 before it can desensitize. Moreover, we show by in silico docking to a homology model of ASIC3 that a cavity in the lower palm domain, which is also known as the nonproton ligand-sensing domain, is a potential binding site of RPRFamide. Finally, using extensive mutagenesis of residues lining the nonproton ligand-sensing domain, we confirm that this domain is essential for RPRFamide modulation of ASIC3. As comparative analysis of ASIC crystal structures in the open and in the desensitized conformation suggests that the lower palm domain contracts during desensitization, our results collectively suggest that RPRFamide, and probably also other RFamide neuropeptides, bind to the nonproton ligand-sensing domain to stabilize the open conformation of ASIC3., (Copyright © 2018 by The American Society for Pharmacology and Experimental Therapeutics.)

The half-sandwich complex [Cp'Fe(μ-I)] 2 (1; Cp' = η 5 -1,2,4-(Me 3 C) 3 C 5 H 2 ) is cleaved when heated in toluene to form a cation-anion pair [{Cp'Fe(η 6 -toluene)} + {Cp'FeI 2 } - ] (2), in which the two Fe(ii) atoms adopt different spin states, i.e., a low-spin (S = 0) and a high-spin (S = 2) configuration. Upon oxidation of 1 with C 2 H 4 I 2 , the thermally stable 15VE species [Cp'FeI 2 ] (3) can be isolated, in which the Fe(iii) atom adopts an intermediate spin (S = 3/2) configuration. Complex 3 is an excellent starting material for further functionalizations and it reacts with Mg(CH 2 SiMe 3 ) 2 to form the unprecedented Fe(iii) (S = 3/2) bis(alkyl) complex [Cp'Fe(CH 2 SiMe 3 ) 2 ] (4). The respective spin states of complexes 2-4 are confirmed by single-crystal X-ray crystallography, zero-field 57 Fe Mössbauer spectroscopy, and solid-state magnetic susceptibility measurements. In contrast to the related 14VE high-spin (S = 2) Fe(ii) alkyl species [Cp'FeCH(SiMe 3 ) 2 ], which resists the reaction with H 2 as a consequence of a spin-induced reaction barrier, complex 4 reacts cleanly with H 2 (8 bar) in cyclohexane to yield iron hydrides [{Cp'Fe} 2 (μ-H) 3 ] (5) and [Cp'Fe(μ-H) 2 ] 2 (6) in a 1 : 4 ratio. However, when the hydrogenation of 4 is carried out in benzene, a green 19VE [Cp'Fe(η 6 -C 6 H 6 )] (A) intermediate is formed, which dimerizes to the bis(cyclohexadienyl)-bridged product [(Cp'Fe) 2 (μ 2 -η 5 :η 5 -C 12 H 12 )] (7). Further evidence for the intermediacy of [Cp'Fe(η 6 -C 6 H 6 )] (A) was gathered by X-band EPR and UV/vis spectroscopy. Interestingly, attempts to oxidize 7 with AgSbF 6 proceeded via C-C bond cleavage instead of metal oxidation to form [Cp'Fe(C 6 H 6 )][SbF 6 ] (8).

Background: Ebola virus disease (EVD) survivors are at risk for uveitis during convalescence. Vision loss has been observed following uveitis due to cataracts. Since Ebola virus (EBOV) may persist in the ocular fluid of EVD survivors for an unknown duration, there are questions about the safety and feasibility of vision restorative cataract surgery in EVD survivors., Methods: We conducted a cross-sectional study of EVD survivors anticipating cataract surgery and patients with active uveitis to evaluate EBOV RNA persistence in ocular fluid, as well as vision outcomes post cataract surgery. Patients with aqueous humor that tested negative for EBOV RNA were eligible to proceed with manual small incision cataract surgery (MSICS)., Findings: We screened 137 EVD survivors from June 2016 - August 2017 for enrolment. We enrolled 50 EVD survivors; 46 with visually significant cataract, 1 with a subluxated lens, 2 with active uveitis and 1 with a blind painful eye due to uveitis. The median age was 24.0years (IQR 17-35) and 35 patients (70%) were female. The median logMAR visual acuity (VA) was 3.0 (Snellen VA Hand motions; Interquartile Range, IQR: 1.2-3.0, Snellen VA 20/320 - Hand motions). All patients tested negative for EBOV RNA by RT-PCR in aqueous humor/vitreous fluid and conjunctiva at a median of 19months (IQR 18-20) from EVD diagnosis in Phase 1 of ocular fluid sampling and 34months (IQR 32-36) from EVD diagnosis in Phase 2 of ocular fluid sampling. Thirty-four patients underwent MSICS, with a preoperative median VA improvement from hand motions to 20/30 at three-month postoperative follow-up (P<0.001)., Interpretation: EBOV persistence by RT-PCR was not identified in ocular fluid or conjunctivae of fifty EVD survivors with ocular disease. Cataract surgery can be performed safely with vision restorative outcomes in patients who test negative for EBOV RNA in ocular fluid specimens. These findings impact the thousands of West African EVD survivors at-risk for ocular complications who may also require eye surgery during EVD convalescence., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

The 15-valence electron (VE), high-spin (S = 3/2) half-sandwich complex [Cp'Fe(IiPr 2 Me 2 )] (3; IiPr 2 Me 2 = 1,3-di-iso-propyl-4,5-dimethylimidazol-2-yildene) reversibly coordinates N 2 to form the 17VE, low-spin (S = 1/2) compound [Cp'Fe(IiPr 2 Me 2 )(η 1 -N 2 )] (4).

The iron half-sandwich [Cp'Fe(μ-I)] 2 (Cp' = 1,2,4-(Me 3 C) 3 C 5 H 2 , 1 ) reacts with the pseudohalides NCO - , SCN - , SeCN - and N 3 - to give [Cp'Fe(μ-NCO)] 2 ( 2 ), [Cp'Fe(μ-S)] 2 ( 3 ), [Cp'Fe(μ-Se 2 )] 2 ( 4 ) and [Cp'Fe(μ-N)] 2 ( 5 ), respectively. Various spectroscopic techniques including X-ray diffraction, solid-state magnetic susceptibility studies and 57 Fe Mössbauer spectroscopy were employed in the characterization of these species. Mössbauer spectroscopy shows a decreasing isomer shift with increasing formal oxidation state, ranging from Fe(ii) to Fe(iv), in complexes 1 to 5 . The sulfido-bridged dimer 3 exhibits strong antiferromagnetic coupling between the Fe(iii) centers. This leads to temperature-independent paramagnetism (TIP) at low temperature, from which the energy gap between the ground and the excited state can be estimated to be 2 J = ca. 700 cm -1 . The iron(iv) nitrido complex [Cp'Fe(μ-N)] 2 ( 5 ) shows no reactivity towards H 2 (10 atm), but undergoes clean reactions with CO (5 bar) and XylNC (Xyl = 2,6-Me 2 C 6 H 3 ) to form the diamagnetic isocyanate and carbodiimide complexes [Cp'Fe(CO) 2 (NCO)] ( 7 ) and [Cp'Fe(CNXyl) 2 (NCNXyl)] ( 8 ), respectively. All compounds were fully characterized, and density functional theory (DFT) computations provide useful insights into their formation and the electronic structures of complexes 3 and 5 .

Open-metallocenes of the heavy alkaline-earth metals [(η(5)-Pdl')2M(thf)n] (M = Ca (1), Sr (2), n = 1; M = Ba (3), n = 2; Pdl' = 2,4-tBu2C5H5) are readily prepared by salt-metathesis between MI2 and KPdl' and characterized by NMR spectroscopy and X-ray diffraction studies.

The purpose of this article is to review the suitability of the analytical and statistical techniques that have thus far been developed to assess the dissolution behavior of particles in the respirable aerodynamic size range, as generated by orally inhaled products (OIPs) such as metered-dose inhalers and dry powder inhalers. The review encompasses all analytical techniques publicized to date, namely, those using paddle-over-disk USP 2 dissolution apparatus, flow-through cell dissolution apparatus, and diffusion cell apparatus. The available techniques may have research value for both industry and academia, especially when developing modified-release formulations. The choice of a method should be guided by the question(s) that the research strives to answer, as well as by the strengths and weaknesses of the available techniques. There is still insufficient knowledge, however, for translating the dissolution data into statements about quality, performance, safety, or efficacy of OIPs in general. Any attempts to standardize a dissolution method for compendial inclusion or compendial use would therefore be premature. This review reinforces and expands on the 2008 stimulus article of the USP Inhalation Ad Hoc Advisory Panel, which "could not find compelling evidence suggesting that such dissolution testing is kinetically and/or clinically crucial for currently approved inhalation drug products."

Chlorofluorocarbons (CFCs), used in metered dose inhalers (MDIs), have been identified as being deleterious to the environment leading to a ban on their production. Dry powder inhalers (DPIs) are a widely used alternative to MDIs. One disadvantage of DPIs is that in vivo lung deposition can be influenced by the patient's inspiratory flow rate. The ASTA Medica multi-dose dry powder inhaler (AM-MDPI) has been designed to offer low resistance on inhalation, so that asthmatic patients can achieve inhaled flow rates of approximately 90 L x min(-1). The aim of the study was to evaluate the in vivo deposition of budesonide from the AM-MDPI at different flow rates and to compare this with delivery from a Turbuhaler DPI at a high flow rate. The study was a scintigraphic, randomized, crossover study in which 13 healthy volunteers inhaled a single 200 microg dose of radiolabelled budesonide on four separate occasions with a minimum 44-h washout period between dosings. At the lowest flow rate of 54 L x min(-1), comparable to that for the Turbuhaler (58 L x min(-1)), a similar percentage of the metered dose was delivered to the lung (AM-MDPI median 19.9%; Turbuhaler median 21.4%). At high flow rate (peak inspiratory flow rate 99 L x min(-1)) the AM-MDPI delivered significantly more drug to the lung (median 32.1% of metered dose) than at 65 L x min(-1) or 54 L x min(-1) (median 25.0% and 19.9% of metered dose, respectively), thus demonstrating flow rate dependence. The pattern of regional lung deposition from the AM-MDPI was similar for all three inhalation manoeuvres. It was concluded that the ASTA Medica multi-dose dry powder inhaler achieves at least as much deposition of budesonide in the lungs as a Turbuhaler when used at similar inspiratory flow rates.

Contrast-enhanced MRI in patients with MS shows that increased permeability of the blood-brain barrier (BBB) commonly occurs. The changes in capillary permeability often precede T2-weighted MRI evidence of tissue damage. In animal studies, intracerebral injection of the matrix metalloproteinase (MMP) 72-kDa type IV collagenase (gelatinase A) opens the BBB by disrupting the basal lamina around capillaries. Steroids affect production of endogenous MMPs and tissue inhibitors to metalloproteinases (TIMPs). To determine the role of MMP activity in BBB damage during acute exacerbations of MS, we measured MMPs in the CSF of patients with MS. Patients (n = 7) given steroids to treat an acute episode of MS had CSF sampled before and after 3 days of methylprednisolone (1 g/day). Patients had a graded neurologic examination and gadolinium-enhanced MRI before treatment. CSF studies included total protein, cell count, and a demyelinating profile. We measured levels of MMPs, urokinase-type plasminogen activator (uPA), and TIMPs by zymography, reverse zymography, and Western blots. The MMP, 92-kDa type IV collagenase (gelatinase B), fell from 216 +/- 70 before steroids to 54 +/- 26 relative lysis zone units (p < 0.046) after treatment. Similarly, uPA dropped from 3880 +/- 800 to 2655 +/- 353 (p < 0.03). Four patients with gadolinium enhancement on MRI had the most pronounced drop in gelatinase B and uPA. Western immunoblots showed an increase in a complex of gelatinase B and TIMPs after treatment, suggesting an increase in a TIMP (p < 0.05). Reverse zymography of CSF samples showed that steroids increased a TIMP with a molecular weight similar to that of mouse TIMP-3 (p = 0.053). Our results suggest that increased gelatinase B is associated with an open BBB on MRI. Steroids may improve capillary function by reducing activity of gelatinase B and uPA and increasing levels of TIMPs.