Redox-induced controllable engineering of MnO2-MnxCo3-xO4 interface to boost catalytic oxidation of ethane.

Multicomponent oxides are intriguing materials in heterogeneous catalysis, and the interface between various components often plays an essential role in oxidations. However, the underlying principles of how the hetero-interface affects the catalytic process remain largely unexplored. Here we report a unique structure design of MnCoOx catalysts by chemical reduction, specifically for ethane oxidation. Part of the Mn ions incorporates with Co oxides to form spinel MnxCo3-xO4, while the rests stay as MnO2 domains to create the MnO2-MnxCo3-xO4 interface. MnCoOx with Mn/Co ratio of 0.5 exhibits an excellent activity and stability up to 1000 h under humid conditions. The synergistic effects between MnO2 and MnxCo3-xO4 are elucidated, in which the C2H6 tends to be adsorbed on the interfacial Co sites and subsequently break the C-H bonds on the reactive lattice O of MnO2 layer. Findings from this study provide valuable insights for the rational design of efficient catalysts for alkane combustion.

Fluoroscopy-guided high-intensity focused ultrasound neurotomy of the lumbar zygapophyseal joints: a prospective, open-label study.

OBJECTIVE: The objective of this study is to investigate safety and effectiveness of a fluoroscopy-guided high-intensity focused ultrasound (HIFU) system for thermal ablation of the lumbar medial branch nerves. METHODS: This dual center prospective cohort study enrolled 30 participants with lumbar zygapophyseal joint syndrome. Each participant previously had a positive response to either a single diagnostic analgesic block or radiofrequency ablation (RFA). The primary effectiveness outcome was individual responder rate, defined as a reduction of two points or more on the pain intensity numerical rating scale without an increase in opioid intake, or a reduction in opioid intake without an increase in pain at 6 months after the intervention. The primary safety outcome was procedure-related or device-related adverse events (AEs). Secondary outcome variables included MRI evidence of tissue ablation, Oswestry Disability Index, 12-Item Short Form Health Survey, Brief Pain Inventory, and Patient Global Impression of Change. RESULTS: The individual responder rate was 89.7% at 2 days, 89.7% at 7 days, 72.4% at 14 days, 82.1% at 30 days, 59.3% at 90 days and 82.6% at 180 days. The average Numeric Rating Scale for pain severity decreased from 7.1 at baseline to 3.0 (N=29) after 2 days, 3.0 (N=29) after 7 days, 3.1 (N=29) after 14 days, 3.2 (N=28) after 30 days, 4.3 (N=27) after 90 days, and 3.3 (N=23) after 180 days. All participants tolerated the procedure well with no significant side effects or complications. CONCLUSIONS: Fluoroscopy-guided HIFU neurotomy achieved clinical responses comparable with RFA, and there were no significant device-related or procedure-related AEs. TRIAL REGISTRATION NUMBER: NCT04129034.

New molten metal catalysts for CO2 and CH4 conversion to 2 : 1 H2 : CO syngas.

Activity trends for 22 metals and metal alloys are reported for the conversion of CO2 and CH4 to 2 : 1 H2 : CO syngas and carbon. A correlation is observed between CO2 conversion and the free energy of oxidation by CO2 on pure metal catalysts. Indium and indium alloys activate CO2 at the highest rates. We identify a new bifunctional 20 : 80 mol% Sn-In alloy that activates both CO2 and CH4 while catalyzing both reactions.

Electrocatalytic Hydrogenation of Guaiacol in Diverse Electrolytes Using a Stirred Slurry Reactor.

Electrocatalytic hydrogenation (ECH) of guaiacol was performed in a stirred slurry electrochemical reactor (SSER) using 5 wt % Pt/C catalyst in the cathode compartment. Different pairs of acid (H2 SO4 ), neutral (NaCl), and alkaline (NaOH) catholyte-anolyte combinations separated by a Nafion® 117 cation exchange membrane, were investigated by galvanostatic and potentiostatic electrolysis to probe the electrolyte and proton concentration effect on guaiacol conversion, product distribution, and Faradaic efficiency. The acid-acid and neutral-acid pairs were found to be the most effective. In the case of the neutral-acid pair, proton diffusion and migration through the membrane from the anolyte to the catholyte supplies the protons required for ECH. Typically, the two major hydrogenation products were cyclohexanol and 2-methoxycyclohexanol. However, ECH at constant cathode superficial current density (-182 mA cm-2 ) and higher temperature (i.e., 60 °C) favored a pathway leading mainly to cyclohexanone. The guaiacol conversion routes were affected by temperature- and cathode potential-dependent surface coverage of adsorbed hydrogen radicals generated through electroreduction of protons.

Analgesic and Respiratory Depressant Effects of R-dihydroetorphine: A Pharmacokinetic-Pharmacodynamic Analysis in Healthy Male Volunteers.

BACKGROUND: There is an ongoing need for potent opioids with less adverse effects than commonly used opioids. R-dihydroetorphine is a full opioid receptor agonist with relatively high affinity at the µ-, δ- and κ-opioid receptors and low affinity at the nociception/orphanin FQ receptor. The authors quantified its antinociceptive and respiratory effects in healthy volunteers. The authors hypothesized that given its receptor profile, R-dihydroetorphine will exhibit an apparent plateau in respiratory depression, but not in antinociception. METHODS: The authors performed a population pharmacokinetic-pharmacodynamic study (Eudract registration No. 2009-010880-17). Four intravenous R-dihydroetorphine doses were studied: 12.5, 75, 125, and 150 ng/kg (infused more than 10 min) in 4 of 4, 6 of 6, 6 of 6, and 4 of 4 male subjects in pain and respiratory studies, respectively. The authors measured isohypercapnic ventilation, pain threshold, and tolerance responses to electrical noxious stimulation and arterial blood samples for pharmacokinetic analysis. RESULTS: R-dihydroetorphine displayed a dose-dependent increase in peak plasma concentrations at the end of the infusion. Concentration-effect relationships differed significantly between endpoints. R-dihydroetorphine produced respiratory depression best described by a sigmoid EMAX-model. A 50% reduction in ventilation in between baseline and minimum ventilation was observed at an R-dihydroetorphine concentration of 17 ± 4 pg/ml (median ± standard error of the estimate). The maximum reduction in ventilation observed was at 33% of baseline. In contrast, over the dose range studied, R-dihydroetorphine produced dose-dependent analgesia best described by a linear model. A 50% increase in stimulus intensity was observed at 34 ± 11 pg/ml. CONCLUSIONS: Over the dose range studied, R-dihydroetorphine exhibited a plateau in respiratory depression, but not in analgesia. Whether these experimental advantages extrapolate to the clinical setting and whether analgesia has no plateau at higher concentrations than investigated requires further studies.

Esterification over Acid-Treated Mesoporous Carbon Derived from Petroleum Coke.

Multistep activation of a Canadian oilsands petroleum coke that yields an acidified mesoporous carbon catalyst is reported. Microporous-activated carbon (APC; ∼2000 m2/g), obtained by thermochemical activation of petroleum coke using KOH, was impregnated with ammonium heptamolybdate and activated by carbothermal hydrogen reduction (CHR). The resulting Mo2C, supported on high-mesopore volume (V meso ∼0.4 cm3/g) carbon, yields the desired mesoporous carbon catalyst (V meso ∼0.7 cm3/g) following acid washing. The effect of CHR temperature and the benefit of Mo2C loading on mesopore development is reported, and pore development models are discussed. The mesoporous carbons are active for the esterification of acetic acid and 1-butanol at 77 °C, and the butanol conversion correlates with the catalyst acidity, as measured by NH3-TPD.

Mesoporous Silica-Supported Nanostructured PdO/CeO2 Catalysts for Low-Temperature Methane Oxidation.

Nanostructured PdO/CeO2 supported on mesoporous SBA-15 silica was synthesized using a combination of incipient wetness impregnation and surface-assisted reduction. After calcination, the materials showed good activity as catalysts for the low-temperature oxidation of methane, with a sample having 5 wt % Pd loading showing 50% conversion to CO2 at ∼290 °C and complete conversion below 360 °C. The stability of catalysts in the presence of water was studied. The formation of Pd(0) during the methane oxidation reaction increases the oxygen vacancies on the surface of catalysts, improving the catalytic activity.

Key interactions by conserved polar amino acids located at the transmembrane helical boundaries in Class B GPCRs modulate activation, effector specificity and biased signalling in the glucagon-like peptide-1 receptor.

Class B GPCRs can activate multiple signalling effectors with the potential to exhibit biased agonism in response to ligand stimulation. Previously, we highlighted key TM domain polar amino acids that were crucial for the function of the GLP-1 receptor, a key therapeutic target for diabetes and obesity. Using a combination of mutagenesis, pharmacological characterisation, mathematical and computational molecular modelling, this study identifies additional highly conserved polar residues located towards the TM helical boundaries of Class B GPCRs that are important for GLP-1 receptor stability and/or controlling signalling specificity and biased agonism. This includes (i) three positively charged residues (R3.30227, K4.64288, R5.40310) located at the extracellular boundaries of TMs 3, 4 and 5 that are predicted in molecular models to stabilise extracellular loop 2, a crucial domain for ligand affinity and receptor activation; (ii) a predicted hydrogen bond network between residues located in TMs 2 (R2.46176), 6 (R6.37348) and 7 (N7.61406 and E7.63408) at the cytoplasmic face of the receptor that is important for stabilising the inactive receptor and directing signalling specificity, (iii) residues at the bottom of TM 5 (R5.56326) and TM6 (K6.35346 and K6.40351) that are crucial for receptor activation and downstream signalling; (iv) residues predicted to be involved in stabilisation of TM4 (N2.52182 and Y3.52250) that also influence cell signalling. Collectively, this work expands our understanding of peptide-mediated signalling by the GLP-1 receptor.

The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism.

Ligand-directed signal bias offers opportunities for sculpting molecular events, with the promise of better, safer therapeutics. Critical to the exploitation of signal bias is an understanding of the molecular events coupling ligand binding to intracellular signaling. Activation of class B G protein-coupled receptors is driven by interaction of the peptide N terminus with the receptor core. To understand how this drives signaling, we have used advanced analytical methods that enable separation of effects on pathway-specific signaling from those that modify agonist affinity and mapped the functional consequence of receptor modification onto three-dimensional models of a receptor-ligand complex. This yields molecular insights into the initiation of receptor activation and the mechanistic basis for biased agonism. Our data reveal that peptide agonists can engage different elements of the receptor extracellular face to achieve effector coupling and biased signaling providing a foundation for rational design of biased agonists.

A Hydrogen-Bonded Polar Network in the Core of the Glucagon-Like Peptide-1 Receptor Is a Fulcrum for Biased Agonism: Lessons from Class B Crystal Structures.

The glucagon-like peptide 1 (GLP-1) receptor is a class B G protein-coupled receptor (GPCR) that is a key target for treatments for type II diabetes and obesity. This receptor, like other class B GPCRs, displays biased agonism, though the physiologic significance of this is yet to be elucidated. Previous work has implicated R2.60(190), N3.43(240), Q7.49(394), and H6.52(363) as key residues involved in peptide-mediated biased agonism, with R2.60(190), N3.43(240), and Q7.49(394) predicted to form a polar interaction network. In this study, we used novel insight gained from recent crystal structures of the transmembrane domains of the glucagon and corticotropin releasing factor 1 (CRF1) receptors to develop improved models of the GLP-1 receptor that predict additional key molecular interactions with these amino acids. We have introduced E6.53(364)A, N3.43(240)Q, Q7.49(394)N, and N3.43(240)Q/Q7.49(394)N mutations to probe the role of predicted H-bonding and charge-charge interactions in driving cAMP, calcium, or extracellular signal-regulated kinase (ERK) signaling. A polar interaction between E6.53(364) and R2.60(190) was predicted to be important for GLP-1- and exendin-4-, but not oxyntomodulin-mediated cAMP formation and also ERK1/2 phosphorylation. In contrast, Q7.49(394), but not R2.60(190)/E6.53(364) was critical for calcium mobilization for all three peptides. Mutation of N3.43(240) and Q7.49(394) had differential effects on individual peptides, providing evidence for molecular differences in activation transition. Collectively, this work expands our understanding of peptide-mediated signaling from the GLP-1 receptor and the key role that the central polar network plays in these events.

Nanostructured Materials Prepared by Surface-Assisted Reduction: New Catalysts for Methane Oxidation.

Cerium formate hollow spheres and cerium hydroxycarbonate nanorods with residual formate groups are effective for reducing palladium(II) salts onto their surfaces. Calcination of the new materials obtained by this surface-assisted reduction method gives highly active PdO/CeO2 nanostructures with Pd well dispersed on the substrate. Temperature-programmed oxidation experiments showed that these nanomaterials are good catalysts for the low-temperature oxidation of methane, with 50% conversion temperatures (T(50%)) at ∼300 °C.

The unique role of transdermal buprenorphine in the global chronic pain epidemic.

Pain is a global epidemic, exacerbated by barriers to access of opioid analgesics. Regulations about opioids attempt to protect public health from the risks of harmful use of opioids, diversion, and dependence. Transdermal buprenorphine is an effective opioid analgesic agent with unique properties that may make it particularly well suited for more widespread use. It is a versatile analgesic product with demonstrated safety and effectiveness in cancer and noncancer pain populations. Its pharmacological properties make it a first-line opioid analgesic for geriatric patients and patients with renal dysfunction; no dosing adjustments need to be made. The 7-day transdermal delivery system is convenient for patients and promotes compliance. A low dose of buprenorphine can provide effective and well-tolerated pain relief. Although buprenorphine has been associated with certain opioid-related adverse effects, such as dizziness and nausea, it is associated with a lower rate of constipation than many other opioid analgesics. The potential for nonmedical use of buprenorphine is relatively low compared with other opioid agents. Buprenorphine has a relatively low likeability for nonmedical use and the transdermal matrix patch renders the substance particularly difficult to extract for illicit purposes.

Mesoporous Mn- and La-doped cerium oxide/cobalt oxide mixed metal catalysts for methane oxidation.

New precious-metal-free mesoporous materials were investigated as catalysts for the complete oxidation of methane to carbon dioxide. Mesoporous cobalt oxide was first synthesized using KIT-6 mesoporous silica as a hard template. After removal of the silica, the cobalt oxide was itself used as a hard template to construct cerium oxide/cobalt oxide composite materials. Furthermore, cerium oxide/cobalt oxide composite materials doped with manganese and lanthanum were also prepared. All of the new composite materials retained the hierarchical long-range order of the original KIT-6 template. Temperature-programmed oxidation measurements showed that these cerium oxide/cobalt oxide and doped cerium oxide/cobalt oxide materials are effective catalysts for the total oxidation of methane, with a light-off temperature (T50%) of ∼400 °C observed for all of the nanostructured materials.

How absent negativity relates to affect and motivation: an integrative relief model.

The present paper concerns the motivational underpinnings and behavioral correlates of the prevention or stopping of negative stimulation - a situation referred to as relief. Relief is of great theoretical and applied interest. Theoretically, it is tied to theories linking affect, emotion, and motivational systems. Importantly, these theories make different predictions regarding the association between relief and motivational systems. Moreover, relief is a prototypical antecedent of counterfactual emotions, which involve specific cognitive processes compared to factual or mere anticipatory emotions. Practically, relief may be an important motivator of addictive and phobic behaviors, self destructive behaviors, and social influence. In the present paper, we will first provide a review of conflicting conceptualizations of relief. We will then present an integrative relief model (IRMO) that aims at resolving existing theoretical conflicts. We then review evidence relevant to distinctive predictions regarding the moderating role of various procedural features of relief situations. We conclude that our integrated model results in a better understanding of existing evidence on the affective and motivational underpinnings of relief, but that further evidence is needed to come to a more comprehensive evaluation of the viability of IRMO.

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach.

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271-294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.

Validated in vitro/in vivo correlation of prolonged-release oxycodone/naloxone with differing dissolution rates in relation to gastrointestinal transit times.

OBJECTIVES: To formally establish the relationship between oxycodone dissolution, in vitro, from a prolonged-release, oral, combination of oxycodone and naloxone (OXN PR) tablets with in vivo absorption, by developing a validated Level A in vitro/in vivo correlation (IVIVC) and subsequently ascertaining the temporal absorption of oxycodone during gastrointestinal transit. METHODS: In vitro dissolution data from formulations of OXN PR (20/10 mg) tablets with slow, medium and fast dissolution rates were generated using United States Pharmacopeia I apparatus 2 (paddle at 50 rpm) in simulated gastric fluid, pH 1.2. These batches were administered to healthy volunteers and plasma concentration data were collected during a randomised, open-label, cross-over study. A Level A correlation was established for oxycodone through the determination of in vivo absorption profiles obtained by deconvolution of plasma concentrations with in vitro dissolution data. The IVIVC model was validated using the internal predictability assessment. RESULTS: A Level A correlation between the in vitro and in vivo release data was established. The polynomial function describing the IVIVC produced a goodness of fit (R(2)) of 0.99. CONCLUSIONS: The rate of absorption of oxycodone from OXN PR tablets correlated well with the in vitro release rates, demonstrating that a Level A IVIVC with internal predictability has been successfully developed for OXN PR tablets. In conjunction with a previous gastrointestinal transit study, this report demonstrates that the majority of oxycodone enters the circulation before reaching the colon, thus it is important that naloxone counteracts opioid-induced bowel dysfunction throughout the entire gut.

Heuristic evaluation and usability testing of a computerized patient-reported outcomes survey for headache sufferers.

OBJECTIVE: The aim of this study was to evaluate usability of a prototype tablet PC-administered computerized adaptive test (CAT) of headache impact and patient feedback report, referred to as HEADACHE-CAT. MATERIALS AND METHODS: Heuristic evaluation specialists (n = 2) formed a consensus opinion on the application's strengths and areas for improvement based on general usability principles and human factors research. Usability testing involved structured interviews with headache sufferers (n = 9) to assess how they interacted with and navigated through the application, and to gather input on the survey and report interface, content, visual design, navigation, instructions, and user preferences. RESULTS: Specialists identified the need for improved instructions and text formatting, increased font size, page setup that avoids scrolling, and simplified presentation of feedback reports. Participants found the tool useful, and indicated a willingness to complete it again and recommend it to their healthcare provider. However, some had difficulty using the onscreen keyboard and autoadvance option; understanding the difference between generic and headache-specific questions; and interpreting score reports. CONCLUSIONS: Heuristic evaluation and user testing can help identify usability problems in the early stages of application development, and improve the construct validity of electronic assessments such as the HEADACHE-CAT. An improved computerized HEADACHE-CAT measure can offer headache sufferers an efficient tool to increase patient self-awareness, monitor headaches over time, aid patient-provider communications, and improve quality of life.

A hybrid cohort individual sampling natural history model of age-related macular degeneration: assessing the cost-effectiveness of screening using probabilistic calibration.

BACKGROUND: Age-related macular degeneration (AMD) is a leading cause of visual impairment and blindness. It is likely that treatment of AMD at earlier stages is more effective than later treatment; thus, screening for AMD should be considered. The aim of this study was to develop a natural history model of AMD to estimate the cost-effectiveness of screening. METHODS: A hybrid cohort/individual sampling decision analytic model was developed. Primary data sets, expert elicitation, and data from the literature were used to populate the model. To incorporate joint parameter uncertainty, and to populate unobservable parameters, an innovative form of probabilistic calibration was applied to a range of output parameters. RESULTS: In the reference case, annual screening from age 60 y is the most cost-effective option, although this is subject to high levels of uncertainty. Alternative, age-specific utility values show that screening is predicted to be less cost-effective, assuming interventions that reduce progression to wet AMD moderately improve the cost-effectiveness of screening, whereas the addition of anti-vascular endothelial growth factor therapy for juxtafoveal or subfoveal wet AMD lesions improves the cost-effectiveness of screening significantly. CONCLUSIONS: The extent of the uncertainty around the mean results, and the additional resources and possible reorganization of services required to implement screening, indicate that it may be preferable to reduce the level of uncertainty before implementing screening for AMD. Initial actions may be best targeted at assessing how routine data may be used to describe clinical presentation, a screening pilot study, and a secondary costing study.