The ClC-1 chloride channel inhibitor NMD670 improves skeletal muscle function in rat models and patients with myasthenia gravis.

Myasthenia gravis (MG) is a neuromuscular disease that results in compromised transmission of electrical signals at the neuromuscular junction (NMJ) from motor neurons to skeletal muscle fibers. As a result, patients with MG have reduced skeletal muscle function and present with symptoms of severe muscle weakness and fatigue. ClC-1 is a skeletal muscle specific chloride (Cl-) ion channel that plays important roles in regulating neuromuscular transmission and muscle fiber excitability during intense exercise. Here, we show that partial inhibition of ClC-1 with an orally bioavailable small molecule (NMD670) can restore muscle function in rat models of MG and in patients with MG. In severely affected MG rats, ClC-1 inhibition enhanced neuromuscular transmission, restored muscle function, and improved mobility after both single and prolonged administrations of NMD670. On this basis, NMD670 was progressed through nonclinical safety pharmacology and toxicology studies, leading to approval for testing in clinical studies. After successfully completing phase 1 single ascending dose in healthy volunteers, NMD670 was tested in patients with MG in a randomized, placebo-controlled, single-dose, three-way crossover clinical trial. The clinical trial evaluated safety, pharmacokinetics, and pharmacodynamics of NMD670 in 12 patients with mild MG. NMD670 had a favorable safety profile and led to clinically relevant improvements in the quantitative myasthenia gravis (QMG) total score. This translational study spanning from single muscle fiber recordings to patients provides proof of mechanism for ClC-1 inhibition as a potential therapeutic approach in MG and supports further development of NMD670.

Ruthenium Nanoparticles Stabilized with Methoxy-Functionalized Ionic Liquids: Synthesis and Structure-Performance Relations in Styrene Hydrogenation.

A series of ruthenium nanoparticles (RuNPs) were synthesized by the organometallic approach in different functionalized imidazolium ionic liquids (FILs). Transmission electron microscopy (TEM) showed well-dispersed and narrow-sized RuNPs ranging from 1.3 to 2.2 nm, depending on the IL functionalization. Thermal gravimetric analysis (TGA) and X-ray photoelectron spectroscopy (XPS) allowed the interaction between the RuNPs and the ILs to be studied. The RuNPs stabilized by methoxy-based FILs (MEM and MME) displayed a good balance between catalytic activity and stability when evaluated in the hydrogenation of styrene (S) under mild reaction conditions. Moreover, the catalysts showed total selectivity towards ethylbenzene (EB) under milder reaction conditions (5 bar, 30 °C) than reported in the literature for other RuNP catalysts.

Versatile CO2 Hydrogenation-Dehydrogenation Catalysis with a Ru-PNP/Ionic Liquid System.

High catalytic activities of Ru-PNP [Ru = ruthenium; PNP = bis alkyl- or aryl ethylphosphinoamine complexes in ionic liquids (ILs) were obtained for the reversible hydrogenation of CO2 and dehydrogenation of formic acid (FA) under exceedingly mild conditions and without sacrificial additives. The novel catalytic system relies on the synergic combination of Ru-PNP and IL and proceeds with CO2 hydrogenation already at 25 °C under a continuous flow of 1 bar of CO2/H2 (1:5), leading to 14 mol % FA with respect to the IL. A pressure of 40 bar of CO2/H2 (1:1) provides 126 mol % of FA/IL corresponding to a space-time yield (STY) of FA of 0.15 mol L-1 h-1. The conversion of CO2 contained in imitated biogas was also achieved at 25 °C. Furthermore, the Ru-PNP/IL system catalyzes FA dehydrogenation with average turnover frequencies up to 11,000 h-1 under heat-integrated conditions for proton-exchange membrane fuel cell applications (<100 °C). Thus, 4 mL of a 0.005 M Ru-PNP/IL system converted 14.5 L FA over 4 months with a turnover number exceeding 18,000,000 and a STY of CO2 and H2 of 35.7 mol L-1 h-1. Finally, 13 hydrogenation/dehydrogenation cycles were achieved with no sign of deactivation. These results demonstrate the potential of the Ru-PNP/IL system to serve as a FA/CO2 battery, a H2 releaser, and a hydrogenative CO2 converter.

On the Oxidative Valorization of Lignin to High-Value Chemicals: A Critical Review of Opportunities and Challenges.

The efficient valorization of lignin is crucial if we are to replace current petroleum-based feedstock and establish more sustainable and competitive lignocellulosic biorefineries. Pulp and paper mills and second-generation biorefineries produce large quantities of low-value technical lignin as a by-product, which is often combusted on-site for energy recovery. This Review focuses on the conversion of technical lignins by oxidative depolymerization employing heterogeneous catalysts. It scrutinizes the current literature describing the use of various heterogeneous catalysts in the oxidative depolymerization of lignin and includes a comparison of the methods, catalyst loadings, reaction media, and types of catalyst applied, as well as the reaction products and yields. Furthermore, current techniques for the determination of product yields and product recovery are discussed. Finally, challenges and suggestions for future approaches are outlined.

Copper Supported on Ceria Mesocellular Foam Silica as an Effective Catalyst for Reductive Condensation of Acetone to Methyl Isobutyl Ketone.

Copper-containing materials based on Ce- and Ca-Nb-mesocellular foam (MCF) silica supports are prepared, characterized and applied as catalysts for gas-phase reductive condensation of acetone to produce methyl isobutyl ketone (MIBK). The properties of the materials, the interaction of metal species, and their role in the catalytic process are examined by nitrogen physisorption, XRD, XPS, CO2 -TPD, H2 -TPR, and chemisorption of NO and pyridine combined with FTIR spectroscopy. A synergistic interaction of Cu2+ , Cu0 , and CeO2 species incorporated in the MCF support enable the Cu/Ce-MCF catalyst to yield 34 % of acetone conversion with over 90 % MIBK selectivity at 250 °C. Moreover, this high catalyst selectivity is maintained during operation for 24 h despite a decline in catalyst activity. The catalytic performance is superior to that of hydroxyapatite-supported Cu and similar previously reported Pd-containing catalysts.

Alterations in fast-twitch muscle membrane conductance regulation do not explain decreased muscle function of SOD1G93A rats.

INTRODUCTION/AIMS: Both neuromuscular junction (NMJ) dysfunction and altered electrophysiological properties of muscle fibers have been reported in amyotrophic lateral sclerosis (ALS) patients. ALS-related preclinical studies typically use rodent SOD1G93A overexpression models, but translation to the human disease has been challenged. The present work explored NMJ function and cellular electrophysiological properties of muscles fibers in SOD1G93A overexpression rats. METHODS: Longitudinal studies of compound muscle action potentials (CMAPs) were performed in SOD1G93A rats. Cellular studies were performed to evaluate electrophysiological properties of muscle fibers, including the resting membrane conductance (Gm ) and its regulation during prolonged action potential (AP) firing. RESULTS: SOD1G93A rats showed a substantial loss of gastrocnemius CMAP amplitude (35.8 mV, P < .001) and a minor increase in CMAP decrement (8.5%, P = .002) at 25 weeks. In addition, SOD1G93A EDL muscle fibers showed a lower baseline Gm (wild-type, 1325 µS/cm2 ; SOD1G93A , 1137 µS/cm2 ; P < .001) and minor alterations in Gm regulation during repeated firing of APs as compared with wild-type rats. DISCUSSION: The current data suggest that loss of CMAP amplitude is largely explained by defects in either lower motor neuron or skeletal muscle with only minor indications of a role for neuromuscular transmission defects in SOD1G93A rats. Electrophysiological properties of muscle fibers were not markedly affected, and an elevated Gm , as has been reported in motor neuron disease (MND) patients, was not replicated in SOD1G93A muscles. Collectively, the neuromuscular pathology of SOD1G93A rats appears to differ from that of ALS/MND patients with respect to neuromuscular transmission defects and electrophysiological properties of muscle fibers.

Depletion of ATP Limits Membrane Excitability of Skeletal Muscle by Increasing Both ClC1-Open Probability and Membrane Conductance.

Activation of skeletal muscle contractions require that action potentials can be excited and propagated along the muscle fibers. Recent studies have revealed that muscle fiber excitability is regulated during repeated firing of action potentials by cellular signaling systems that control the function of ion channel that determine the resting membrane conductance (G m ). In fast-twitch muscle, prolonged firing of action potentials triggers a marked increase in G m , reducing muscle fiber excitability and causing action potential failure. Both ClC-1 and KATP ion channels contribute to this G m rise, but the exact molecular regulation underlying their activation remains unclear. Studies in expression systems have revealed that ClC-1 is able to bind adenosine nucleotides, and that low adenosine nucleotide levels result in ClC-1 activation. In three series of experiments, this study aimed to explore whether ClC-1 is also regulated by adenosine nucleotides in native skeletal muscle fibers, and whether the adenosine nucleotide sensitivity of ClC-1 could explain the rise in G m muscle fibers during prolonged action potential firing. First, whole cell patch clamping of mouse muscle fibers demonstrated that ClC-1 activation shifted in the hyperpolarized direction when clamping pipette solution contained 0 mM ATP compared with 5 mM ATP. Second, three-electrode G m measurement during muscle fiber stimulation showed that glycolysis inhibition, with 2-deoxy-glucose or iodoacetate, resulted in an accelerated and rapid >400% G m rise during short periods of repeated action potential firing in both fast-twitch and slow-twitch rat, and in human muscle fibers. Moreover, ClC-1 inhibition with 9-anthracenecarboxylic acid resulted in either an absence or blunted G m rise during action potential firing in human muscle fibers. Third, G m measurement during repeated action potential firing in muscle fibers from a murine McArdle disease model suggest that the rise in G m was accelerated in a subset of fibers. Together, these results are compatible with ClC-1 function being regulated by the level of adenosine nucleotides in native tissue, and that the channel operates as a sensor of skeletal muscle metabolic state, limiting muscle excitability when energy status is low.

Pd-Catalyzed Cyclocarbonylation of Allylic Alcohol under Benign Conditions with Ionic Liquid as Stabilizer.

Homogeneous palladium-catalyzed (Pd-catalyzed) cyclocarbonylation of unsaturated allylic alcohols and alkynols in the presence of hydrogen forms lactone products with important applications in the food, perfume, and polymer industry. In this work, the cyclocarbonylation of 2-methyl-3-buten-2-ol was studied for the first time using a very active Pd-DPEphos (bis[(2-diphenylphosphino)phenyl]ether) catalyst in the presence of the ionic liquid (IL) [BMIM]Cl (1-butyl-3-methylimidazolium chloride) in dichloromethane to selectively produce 4,4-dimethyl-γ-butyrolactone. The effect of different parameters such as temperature, gas partial pressures, time of reaction, substrate and ligand concentrations were investigated and found to provide optimal conditions for lactonization (95 °C, 28 bar (CO/H2/N2: 20/5/3)), 18 h, 0.1 M substrate, and 16 mol% DPEphos), which were significantly milder than previously reported systems for cyclocarbonylation. Importantly, the study further showed that presence of the IL in the reaction mixture provided stabilization of the catalyst system and prevented formation of Pd-black, which allowed reuse of the catalytic system in consecutive reactions after intermediate extraction of the lactone product.

Synthesis of Nixantphos Core-Functionalized Amphiphilic Nanoreactors and Application to Rhodium-Catalyzed Aqueous Biphasic 1-Octene Hydroformylation.

A latex of amphiphilic star polymer particles, functionalized in the hydrophobic core with nixantphos and containing P(MAA-co-PEOMA) linear chains in the hydrophilic shell (nixantphos-functionalized core-crosslinked micelles, or nixantphos@CCM), has been prepared in a one-pot three-step convergent synthesis using reversible addition-fragmentation chain transfer (RAFT) polymerization in water. The synthesis involves polymerization-induced self-assembly (PISA) in the second step and chain crosslinking with di(ethylene glycol) dimethacrylate (DEGDMA) in the final step. The core consists of a functionalized polystyrene, obtained by incorporation of a new nixantphos-functionalized styrene monomer (nixantphos-styrene), which is limited to 1 mol%. The nixantphos-styrene monomer was synthesized in one step by nucleophilic substitution of the chloride of 4-chloromethylstyrene by deprotonated nixantphos in DMF at 60 °C, without interference of either phosphine attack or self-induced styrene polymerization. The polymer particles, after loading with the [Rh(acac)(CO)2] precatalyst to yield Rh-nixantphos@CCM, function as catalytic nanoreactors under aqueous biphasic conditions for the hydroformylation of 1-octene to yield n-nonanal selectively, with no significant amounts of the branched product 2-methyl-octanal.

Elucidating the ionic liquid distribution in monolithic SILP hydroformylation catalysts by magnetic resonance imaging.

Monolithic silicon carbide supported ionic liquid-phase (SILP) Rh-catalysts have very recently been introduced for gas-phase hydroformylation as an important step toward industrial upscaling. This study investigates the monolithic catalyst system in combination with different impregnation procedures with non-invasive magnetic resonance imaging (MRI). The findings were supported by X-ray microtomography (micro-CT) data of the monolithic pore structure and a catalytic performance test of the catalyst system for 1-butene gas-phase hydroformylation. MRI confirmed a homogeneous impregnation of the liquid phase throughout the full cross-section of the cylindrical monoliths. Consistent impregnations from one side to the other of the monoliths were achieved with a stabilizer in the system that helped preventing inhomogeneous rim formation. External influences relevant for industrial application, such as long-term storage and temperature exposure, did not affect the homogeneous liquid-phase distribution of the catalyst. The work elucidates important parameters to improve liquid-phase catalyst impregnation to obtain efficient monolithic catalysts for industrial exploitation in gas-phase hydroformylation as well as other important industrial processes.

Ru-Doped Wells-Dawson Polyoxometalate as Efficient Catalyst for Glycerol Hydrogenolysis to Propanediols.

A Ru-doped phospho-tungstic Wells-Dawson polyoxometalate (POM) was successfully applied as homogeneous catalyst for glycerol hydrogenolysis in aqueous media. The synthesized compound showed superior catalytic activity compared to classical homogeneous/heterogeneous Ru catalysts like RuCl3 and Ru/C under identical reaction conditions, whereas the analogous POM doped with Pd or Pt proved far less activity. Detailed characterization of the POMs was performed using 31P-NMR to identify characteristic phosphorous peaks of the heteroatoms, infrared spectroscopy (ATR-FTIR) to confirm characteristic P-O and W-O-W vibrations, powder XRD for comparison of crystal structures, and X-ray fluorescence (XRF) and inductive-coupled plasma (ICP) analysis to determine elemental composition. Variation of the reaction parameters for the best performing Ru-doped POM catalyst showed that substrate concentration played an important role for both product selectivity and conversion. Moreover, medium hydrogen pressure and high stirring speed were key factors to obtain highly selective conversion of glycerol to 1,2-propanediol.

Homogeneously-catalysed hydrogen release/storage using the 2-methylindole/2-methylindoline LOHC system in molten salt-organic biphasic reaction systems.

Ir-Complex catalysed hydrogen release/storage using a 2-methylindole/2-methylindoline Liquid Organic Hydrogen Carrier (LOHC) system is shown to be effective in a temperature range of 120 to 140 °C. In the form of a liquid-liquid biphasic reaction system with molten [PPh4][NTf2] as catalyst immobilisation phase, the applied cationic Ir-complex can be easily separated and recycled enabling a small amount of ionic catalyst solution to store/release a large amount of hydrogen.

Selective Hydrodeoxygenation of Alkyl Lactates to Alkyl Propionates with Fe-based Bimetallic Supported Catalysts.

Hydrodeoxygenation (HDO) of methyl lactate (ML) to methyl propionate (MP) was performed with various base-metal supported catalysts. A high yield of 77 % MP was obtained with bimetallic Fe-Ni/ZrO2 in methanol at 220 °C and 50 bar H2 . A synergistic effect of Ni increased the yield of MP significantly when using Fe-Ni/ZrO2 instead of Fe/ZrO2 alone. Moreover, the ZrO2 support contributed to improve the yield as a phase transition of ZrO2 from tetragonal to monoclinic occurred after metal doping giving rise to fine dispersion of the Fe and Ni on the ZrO2 , resulting in a higher catalytic activity of the material. Interestingly, it was observed that Fe-Ni/ZrO2 also effectively catalyzed methanol reforming to produce H2 in situ, followed by HDO of ML, yielding 60 % MP at 220 °C with 50 bar N2 instead of H2 . Fe-Ni/ZrO2 also catalyzed HDO of other short-chain alkyl lactates to the corresponding alkyl propionates in high yields around 70 %. No loss of activity of Fe-Ni/ZrO2 occurred in five consecutive reaction runs demonstrating the high durability of the catalyst system.

Giant Tunability of the Two-Dimensional Electron Gas at the Interface of γ-Al2O3/SrTiO3.

Two-dimensional electron gases (2DEGs) formed at the interface between two oxide insulators provide a rich platform for the next generation of electronic devices. However, their high carrier density makes it rather challenging to control the interface properties under a low electric field through a dielectric solid insulator, that is, in the configuration of conventional field-effect transistors. To surpass this long-standing limit, we used ionic liquids as the dielectric layer for electrostatic gating of oxide interfaces in an electric double layer transistor (EDLT) configuration. Herein, we reported giant tunability of the physical properties of 2DEGs at the spinel/perovskite interface of γ-Al2O3/SrTiO3 (GAO/STO). By modulating the carrier density thus the band filling with ionic-liquid gating, the system experiences a Lifshitz transition at a critical carrier density of 3.0 × 1013 cm-2, where a remarkably strong enhancement of Rashba spin-orbit interaction and an emergence of Kondo effect at low temperatures are observed. Moreover, as the carrier concentration depletes with decreasing gating voltage, the electron mobility is enhanced by more than 6 times in magnitude, leading to the observation of clear quantum oscillations. The great tunability of GAO/STO interface by EDLT gating not only shows promise for design of oxide devices with on-demand properties but also sheds new light on the electronic structure of 2DEG at the nonisostructural spinel/perovskite interface.

Chloride Channels Take Center Stage in Acute Regulation of Excitability in Skeletal Muscle: Implications for Fatigue.

Initiation and propagation of action potentials in muscle fibers is a key element in the transmission of activating motor input from the central nervous system to their contractile apparatus, and maintenance of excitability is therefore paramount for their endurance during work. Here, we review current knowledge about the acute regulation of ClC-1 channels in active muscles and its importance for muscle excitability, function, and fatigue.

Chemoselective hydrogenation of arenes by PVP supported Rh nanoparticles.

Polyvinylpyrrolidone-stabilized Rh nanoparticles (RhNPs/PVP) of ca. 2.2 nm in size were prepared by the hydrogenation of the organometallic complex [Rh(η3-C3H5)3] in the presence of PVP and evaluated as a catalyst in the hydrogenation of a series of arene substrates as well as levulinic acid and methyl levulinate. The catalyst showed excellent activity and selectivity towards aromatic ring hydrogenation compared to other reported transition metal-based catalysts under mild reaction conditions (room temperature and 1 bar H2). Furthermore, it was shown to be a highly promising catalyst for the hydrogenation of levulinic acid and methyl levulinate in water leading to quantitative formation of the fuel additive γ-valerolactone under moderate reaction conditions compared to previously reported catalytic systems.

Mechanism and stereoselectivity of zeolite-catalysed sugar isomerisation in alcohols.

Glucose isomerisation to fructose can occur by different pathways and the mechanism of zeolite-catalysed glucose isomerisation in methanol has remained incompletely understood. Herein, the mechanism is studied using an 1H-13C HSQC NMR assay resolving different fructose isotopomers. We find that zeolite-catalysed glucose isomerisation proceeds predominantly via a hydride shift into the pro-R position of fructose, thus resembling the stereoselectivity of the enzymatic isomerisation process.

Absorption and Oxidation of Nitrogen Oxide in Ionic Liquids.

A new strategy for capturing nitrogen oxide, NO, from the gas phase is presented. Dilute NO gas is removed from the gas phase by ionic liquids under ambient conditions. The nitrate anion of the ionic liquid catalyzes the oxidation of NO to nitric acid by atmospheric oxygen in the presence of water. The nitric acid is absorbed in the ionic liquid up to approximately one mole HNO3 per mole of the ionic liquid due to the formation of hydrogen bonds. The nitric acid can be desorbed by heating, thereby regenerating the ionic liquid with excellent reproducibility. Here, time-resolved in-situ spectroscopic investigations of the reaction and products are presented. The procedure reveals a new vision for removing the pollutant NO by absorption into a non-volatile liquid and converting it into a useful bulk chemical, that is, HNO3 .

Role of physiological ClC-1 Cl- ion channel regulation for the excitability and function of working skeletal muscle.

Electrical membrane properties of skeletal muscle fibers have been thoroughly studied over the last five to six decades. This has shown that muscle fibers from a wide range of species, including fish, amphibians, reptiles, birds, and mammals, are all characterized by high resting membrane permeability for Cl(-) ions. Thus, in resting human muscle, ClC-1 Cl(-) ion channels account for ∼80% of the membrane conductance, and because active Cl(-) transport is limited in muscle fibers, the equilibrium potential for Cl(-) lies close to the resting membrane potential. These conditions-high membrane conductance and passive distribution-enable ClC-1 to conduct membrane current that inhibits muscle excitability. This depressing effect of ClC-1 current on muscle excitability has mostly been associated with skeletal muscle hyperexcitability in myotonia congenita, which arises from loss-of-function mutations in the CLCN1 gene. However, given that ClC-1 must be drastically inhibited (∼80%) before myotonia develops, more recent studies have explored whether acute and more subtle ClC-1 regulation contributes to controlling the excitability of working muscle. Methods were developed to measure ClC-1 function with subsecond temporal resolution in action potential firing muscle fibers. These and other techniques have revealed that ClC-1 function is controlled by multiple cellular signals during muscle activity. Thus, onset of muscle activity triggers ClC-1 inhibition via protein kinase C, intracellular acidosis, and lactate ions. This inhibition is important for preserving excitability of working muscle in the face of activity-induced elevation of extracellular K(+) and accumulating inactivation of voltage-gated sodium channels. Furthermore, during prolonged activity, a marked ClC-1 activation can develop that compromises muscle excitability. Data from ClC-1 expression systems suggest that this ClC-1 activation may arise from loss of regulation by adenosine nucleotides and/or oxidation. The present review summarizes the current knowledge of the physiological factors that control ClC-1 function in active muscle.

Protein kinase C-dependent regulation of ClC-1 channels in active human muscle and its effect on fast and slow gating.

KEY POINTS: Regulation of ion channel function during repeated firing of action potentials is commonly observed in excitable cells. Recently it was shown that muscle activity is associated with rapid, protein kinase C (PKC)-dependent ClC-1 Cl(-) channel inhibition in rodent muscle. While this PKC-dependent ClC-1 inhibition during muscle activity was shown to be important for the maintenance of contractile endurance in rat muscle it is unknown whether a similar regulation exists in human muscle. Also, the molecular mechanisms underlying the observed PKC-dependent ClC-1 inhibition are unclear. Here we present the first demonstration of ClC-1 inhibition in active human muscle fibres, and we determine the changes in ClC-1 gating that underlie the PKC-dependent ClC-1 inhibition in active muscle using human ClC-1 expressed in Xenopus oocytes. This activity-induced ClC-1 inhibition is suggested to represent a mechanism by which human muscle fibres maintain their excitability during sustained activity. ABSTRACT: Repeated firing of action potentials (APs) is known to trigger rapid, protein kinase C (PKC)-dependent inhibition of ClC-1 Cl(-) ion channels in rodent muscle and this inhibition is important for contractile endurance. It is currently unknown whether similar regulation exists in human muscle, and the molecular mechanisms underlying PKC-dependent ClC-1 inhibition are unclear. This study first determined whether PKC-dependent ClC-1 inhibition exists in active human muscle, and second, it clarified how PKC alters the gating of human ClC-1 expressed in Xenopus oocytes. In human abdominal and intercostal muscles, repeated AP firing was associated with 30-60% reduction of ClC-1 function, which could be completely prevented by PKC inhibition (1 µm GF109203X). The role of the PKC-dependent ClC-1 inhibition was evaluated from rheobase currents before and after firing 1000 APs: while rheobase current was well maintained after activity under control conditions it rose dramatically if PKC-dependent ClC-1 inhibition had been prevented with the inhibitor. This demonstrates that the ClC-1 inhibition is important for maintenance of excitability in active human muscle fibres. Oocyte experiments showed that PKC activation lowered the overall open probability of ClC-1 in the voltage range relevant for AP initiation in muscle fibres. More detailed analysis of this reduction showed that PKC mostly affected the slow gate of ClC-1. Indeed, there was no effect of PKC activation in C277S mutated ClC-1 in which the slow gate is effectively locked open. It is concluded that regulation of excitability of active human muscle fibres relies on PKC-dependent ClC-1 inhibition via a gating mechanism.