Effects of Internal Stress and Hydrogen Penetration on the Performance of Er2O3 Coatings as Hydrogen Permeation Barriers.

Ceramic coatings that can effectively prevent hydrogen permeation have a wide range of applications in hydrogen energy and nuclear fusion reactors. In this study, for the first time, the internal stress of Er2O3 coatings was found to be a key factor that could determine their hydrogen permeation resistance and lifespan. The internal stress was controlled by designing layered Er2O3 coatings. The internal stress increased with an increasing number of Er2O3 layers. When the number of layers was below 15, the increased internal stress did not adversely affect the coating performance and might help to increase its hydrogen permeation resistance. Although the overall thickness of the 15-layer Er2O3 coating was only 97 nm, its hydrogen permeation reduction factor (PRF) reached the highest value of 626, whereas a further increase in the internal stress detrimentally affected the ability of the coating to reduce hydrogen permeation. In addition, the experimental observations and simulation results revealed that the performance of the Er2O3 coatings was related to the hydrogen atoms that penetrated the coating, which weakened the Er-O bonds and consequently decreased the Er2O3 fracture limit. This study provides insights into the effects of internal stress and hydrogen penetration on the performance of ceramic coatings as hydrogen permeation barriers and will help guide strategies for the structure design of hydrogen permeation barriers possessing high PRFs and long lifespans.

Prescribing practices in opioid agonist treatment and changes in compliance to clinical dosing guidelines in British Columbia, Canada.

BACKGROUND AND AIM: In British Columbia, Canada, clinical guidelines for the treatment of opioid use disorders (OUD) were updated in 2017, during a period in which the potency and composition of the illicit drug supply changed rapidly. We aimed to describe changes in opioid agonist treatment (OAT) prescribing practices at the population level in a setting in which fentanyl and its analogs have become the primary illicit opioid of use. DESIGN, SETTING AND PARTICIPANTS: This was a population-based retrospective cohort study using three linked health administrative databases in British Columbia (BC), Canada. All individuals with at least one OAT dispensation in BC between 1 January 2014 and 31 August 2021 took part. MEASUREMENTS: To assess changes in OAT prescribing practices over time, we calculated initiation doses, dose titration intervals, maintenance doses and take-home dosing intervals stratified by medication [methadone, buprenorphine-naloxone and slow-release oral morphine (SROM)] according to recommended guidelines. FINDINGS: A total of 265 410 OAT episodes (57.5% on methadone, 34.5% on buprenorphine-naloxone and 8.0% on SROM) were initiated during the study period. Compared with the guideline recommendation, observed initiation doses were higher among all medications from 2014 (2017 for SROM) to 2021 (buprenorphine-naloxone: 14-29%; methadone: 53-66%; SROM: 26-55%). Titration intervals were shorter for all medications, consistent with guidelines for buprenorphine-naloxone (26-49%), but shorter than recommended for methadone or SROM (28-51% and 12-41%, respectively). Higher maintenance dosing was observed for methadone (68-78%) and SROM (3-21%). Take-home allowances extending beyond the recommended guideline length increased across medications (buprenorphine-naloxone: 18-35%; methadone: 50-64%; SROM: 34-39%). Changes in prescribing patterns were similar for first-time OAT initiators. CONCLUSION: In British Columbia, Canada, from 2014 to 2021, prescribers of opioid agonist treatment (OAT) appeared to initiate both new and experienced OAT clients at higher doses than guideline recommendations, titrate them more rapidly and maintain clients at higher doses. Take-home dose allowances also gradually increased.

Self-objectification and cosmetic surgery consideration among Chinese young women: The mediating roles of alienation and body image inflexibility.

The behavior of undergoing cosmetic surgery is a coping strategy for body-image threats and challenges. Self-objectification is associated with alienation and body image inflexibility, and all of these are associated with stronger cosmetic surgery considerations. This study evaluated the relationship between self-objectification and cosmetic surgery consideration, and whether this relationship was mediated by alienation and body image inflexibility. The participants were 650 Chinese female college students. Serial mediation analysis indicated that the relationship between self-objectification and cosmetic surgery consideration was significantly mediated by alienation followed by body image inflexibility. The total mediating effect value was 0.424, accounting for 57.5% of the total effects. These results suggest that reducing alienation and improving the flexibility of body image can reduce the influence of self-objectification on young women's willingness to undergo cosmetic surgery. These findings provide a basis for intervening or preventing the self-objectified young women's willingness for cosmetic surgery.

Acid-Assisted Ball Mill Synthesis of Carboxyl-Functional-Group-Modified Prussian Blue as Sodium-Ion Battery Cathode.

Prussian blue attracts the attention of many researchers as a promising candidate for use in sodium-ion battery cathodes due to its open frameworks and high working potential. However, the interstitial water in its crystal structure and its poor electronic conductivity limits its performance in practical sodium-ion batteries. Here, acid-assisted ball milling synthesis was employed as a versatile method for the production of surface-modified Prussian blue. With (CH3COO)2Fe being used as the raw material, the Prussian blue produced using ball milling synthesis was modified by the carboxyl functional group on its surface, which resulted in lower interstitial water content and enhanced electrochemical cycling performance. In addition, ball milling synthesis provided the as-prepared Prussian blue with a large surface area, improving its electrochemical rate performance. When used as the cathode of sodium-ion batteries, as-prepared Prussian blue delivered a specific capacity of 145.3 mAh g-1 at 0.2 C and 113.7 mAh g-1 at 1 C, maintaining 54.5% of the initial capacity after 1000 cycles at 1 C (1 C = 170 mA g-1). Furthermore, a solid-state sodium-ion battery was mounted, with as-prepared Prussian blue being employed as the cathode and Na metal as the anode, which delivered a high specific capacity of 128.7 mAh g-1 at 0.2 C. The present study put forward an effective solution to overcome the limitations of Prussian blue for its commercial application.

From Mo-Si-B to Mo-Ti-Si-B Alloys: A Short Review.

Mo-Si-B alloys have attracted considerable research interest during the last several decades due to their high melting points, excellent high-temperature strength and relatively good oxidation resistance. However, insufficient room-temperature fracture toughness and high-temperature oxidation resistance restrain their further application. Generally, a sufficient volume fraction of BCC-Mo solid-solution phase, providing the ductility, and a high Si content, responsible for the formation of passive oxide scales, is difficult to achieve simultaneously in this ternary system. Recently, macroalloying of Ti has been proposed to establish a novel phase equilibrium with a combination of enough BCC phase and intermetallic compounds that contain a large amount of Si. In this article, the development history from the ternary Mo-Si-B to the quaternary Mo-Ti-Si-B system was reviewed. It was found that the constitution phases could be easily tailored by changing the Ti content. In this regard, better performance of mechanical properties and oxidation resistance can be obtained through proper alloy design. In-depth understanding of the advantages of the quaternary alloys over their ternary ancestors may contribute to bringing about a new concept in designing novel ultra-high-temperature structural materials.

In situ polyaniline coating of Prussian blue as cathode material for sodium-ion battery.

Prussian blue (PB) has great potential for use as a sodium cathode material owing to its high working potential and cube frame structure. Herein, this work reports a two-step method to synthesize PB with ascorbic acid as the ball-milling additive, which improves the electrochemical rate performance of PB during the traditional co-precipitation method. The obtained PB sample exhibited a superior specific capability (113.3 mAh g-1 even at 20 C, 1 C = 170 mA g-1) and a specific capacity retention of 84.8% after 100 cycles at 1 C rate. In order to enhance the cycling performance of the PB, an in situ polyaniline coating strategy was employed in which aniline was added into the electrolyte and polymerized under electrochemical conditions. The coated anode exhibited a high specific capacity retention of 62.7% after 500 cycles, which is significantly higher than that of the non-coated sample, which only remains 40.1% after 500 cycles. This development has shown a great potential as a low-cost, high-performance and environment-friendly technology for large-scale industrial application of PB.

Self-induced cobalt-derived hollow structure Prussian blue as a cathode for sodium-ion batteries.

As advanced electrode materials for sodium ion batteries, Prussian blue and its derivatives have attracted considerable attention due to their low cost, structural stability and facile synthesis process. However, the application of commercially available Prussian blue is limited by its poor electronic conductivity as well as the structural defect induced by crystalline/interstitial water molecules. Herein, to address these drawbacks, an etching-agent free method is developed to synthesize Prussian blue with a hollow structure, and the synthesis mechanism is revealed. Owing to the stability of divalent iron ions, the shorter electron/ion diffusion pathway and fewer defect sites of the hollow structure, the obtained Prussian blue exhibits excellent electrochemical performance (specific capacity of 133.6 mA h g-1 at 1C, 1C = 170 mA g-1), which can put forward a new avenue to engineer advanced electrode materials for sodium ion batteries.

Negative Problems Orientation Questionnaire for Chinese Adolescents: Bifactor Model and Measurement Invariance.

The Negative Problem Orientation Questionnaire (NPOQ) is a widely used tool for assessing negative problem orientation (NPO). However, its construct and measurement invariance has not been adequately tested in adolescents. The present study explored the possible construct of the NPOQ and its measurement invariance in a sample of 754 Chinese adolescents (51.6% girls, all 12-18 years old). The results supported a bifactor model of the NPOQ that consists of a general factor NPO and three domain-specific factors including perceived threat, self-inefficacy, and negative outcome expectancy. A multiple-group CFA indicated that the bifactor model showed strict invariance across gender and age. The general and domain factors showed unique variance in indexes of worry, depression, anxiety, and stress, which supported well incremental validity of them. This study confirms for a bifactor conceptualization of the NPOQ and its measurement invariance across gender and age in Chinese adolescents. Additionally, it is recommended that the total score should be used to assess NPO in Chinese adolescents.

Perfectionism and adolescent sleep quality: The mediating role of repetitive negative thinking.

This study explores the mediating effects of repetitive negative thinking in the relationship between perfectionism and adolescent sleep quality. A sample of 1664 Chinese adolescents with a mean age of 15.0 years was recruited, and they completed four measures relating to perfectionism, sleep quality, worry, and rumination. The results showed that maladaptive perfectionism was positively correlated with poor sleep quality in adolescents, which was mediated by both worry and rumination. However, adaptive perfectionism was not significantly associated with adolescent sleep quality, and this relationship was suppressed by rumination (but not worry). The implications of these results are also discussed.

The impact of negative mood state on sleep-related attentional bias in insomnia.

Sleep-related attentional bias is thought to play a role in the maintenance of insomnia. However, this concept has been questioned by several studies that did not show the presence of sleep-related attentional bias in clinical insomnia or poor sleepers. Our goal in the present study was to test whether the mood state of individuals with insomnia affects the presence of sleep-related attentional bias. To this end, 31 individuals with insomnia and 34 good sleepers were randomly assigned to a negative mood-inducing condition or a control condition. They then completed a visual probe task with three types of pictorial stimuli (general threat, sleep-related negative pictures and sleep-related positive pictures). Vigilance, maintenance and the overall bias indexes were calculated based on the reaction time. We found individuals with insomnia only showed a greater overall bias compared with good sleepers following a negative mood induction, regardless of the pictures presented. In addition, we found that a negative mood state was significantly correlated with the overall attentional bias in good sleepers but not in individuals with insomnia. These findings suggest that sleep-related attentional bias in insomnia can be modulated by mood state. This effect may reflect the dysregulation of top-down attentional control in individuals with insomnia.

Novel flexible Fenton-like catalyst: Unique CuO nanowires arrays on copper mesh with high efficiency across a wide pH range.

Free-standing and flexible Cu@CuO nanowires (NWs) mesh as an easily recycled Fenton-like catalyst is developed for the first time. Dense CuO nanowire arrays were uniformly grown on a copper mesh surface simply by wet etching accompanied with thermal dehydration. These dense CuO NWs provide a large specific area and therefore guarantee excellent catalytic performance toward the degradation of rhodamine B (RhB). With a k-value of 0.23 min-1, such a Cu@CuO NWs mesh is able to degrade 100% RhB in only 16 min. This Fenton-like catalyst is also appropriate for degrading other organic dyes, including crystal violet, methylene blue, and rhodamine 6G. Unlike the conventional Fenton catalyst implemented at a pH value around 3, the Cu@CuO NWs mesh could adapt to a wide pH range from 2.1 to 12.0. More intriguingly, the Cu@CuO NWs mesh with excellent flexibility could be easily recycled after catalysis, which is a significant advance compared to the previously reported Fenton catalysts in the form of powders or nanoparticles. In addition, the recycling performance of this Cu@CuO NWs mesh was also assessed. On the basis of electron spin resonance (ESR) results, O2- rather than OH is the main active species for the dye degradation by the Cu@CuO NWs mesh. With a marvelous combination of excellent flexibility, wide pH adaptation, and high efficiency, this easily recycled three dimensional Cu@CuO NWs architecture can afford new ideas for the Fenton chemistry.

Flexible 3D Fe@VO2 core-shell mesh: A highly efficient and easy-recycling catalyst for the removal of organic dyes.

Nowadays, it is extremely urgent to search for efficient and effective catalysts for water purification due to the severe worldwide water-contamination crises. Here, 3D Fe@VO2 core-shell mesh, a highly efficient catalyst toward removal of organic dyes with excellent recycling ability in the dark is designed and developed for the first time. This novel core-shell structure is actually 304 stainless steel mesh coated by VO2, fabricated by an electrophoretic deposition method. In such a core-shell structure, Fe as the core allows much easier separation from the water, endowing the catalyst with a flexible property for easy recycling, while VO2 as the shell is highly efficient in degradation of organic dyes with the addition of H2O2. More intriguingly, the 3D Fe@VO2 core-shell mesh exhibits favorable performance across a wide pH range. The 3D Fe@VO2 core-shell mesh can decompose organic dyes both in a light-free condition and under visible irradiation. The possible catalytic oxidation mechanism of Fe@VO2/H2O2 system is also proposed in this work. Considering its facile fabrication, remarkable catalytic efficiency across a wide pH range, and easy recycling characteristic, the 3D Fe@VO2 core-shell mesh is a newly developed high-performance catalyst for addressing the universal water crises.

Identification of novel bifunctional HIV-1 reverse transcriptase inhibitors.

OBJECTIVES: The increasing prevalence of mutations in HIV-1 reverse transcriptase (RT) that confer resistance to existing NRTIs and NNRTIs underscores the need to develop RT inhibitors with novel mode-of-inhibition and distinct resistance profiles. METHODS: Biochemical assays were employed to identify inhibitors of RT activity and characterize their mode of inhibition. The antiviral activity of the inhibitors was assessed by cell-based assays using laboratory HIV-1 isolates and MT4 cells. RT variants were purified via avidin affinity columns. RESULTS: Compound A displayed equal or greater potency against many common NNRTI-resistant RTs (K103N and Y181C RTs) relative to WT RT. Despite possessing certain NNRTI-like properties, such as being unable to inhibit an engineered variant of RT lacking an NNRTI-binding pocket, we found that compound A was dependent on Mg2+ for binding to RT. Optimization of compound A led to more potent analogues, which retained similar activities against WT and K103N mutant viruses with submicromolar potency in a cell-based assay. One of the analogues, compound G, was crystallized in complex with RT and the structure was determined at 2.6 Å resolution. The structure indicated that compound G simultaneously interacts with the active site (Asp186), the highly conserved primer grip region (Leu234 and Trp229) and the NNRTI-binding pocket (Tyr188). CONCLUSIONS: These findings reveal a novel class of RT bifunctional inhibitors that are not sensitive to the most common RT mutations, which can be further developed to address the deficiency of current RT inhibitors.

Parallel patterning of SiO2 wafer via near-field electrospinning of metallic salts and polymeric solution mixtures.

This paper describes a near-field electrospinning technique combined with heat treatment process used to directly align parallel metal oxide and metal nitride fibers on silicon dioxide substrate. The effects of near-field electrospinning parameters (including collector-to-needle distance, applied voltage and the moving speed of the collector) on the morphology of the resulted fibers have been studied. Metallic salt-contained precursor fibers are individually aligned via near-field electrospinning of metallic salts and polymeric solution mixtures. After applying calcination process to these well aligned precursor fibers, patterning by metal oxide and metal nitride fibers such as ZnO, Ga2O3, TiO2, GaN and TiN is successfully obtained. The optical microscope images and the scanning electron microscopy show the presence of fiber patterns, whose crystalline structure is characterized by x-ray diffraction and Raman spectroscopy measurement. The results demonstrate the potential of this approach for assembling ceramic fibers into parallel arrays with controllable orientation and position.

Carboxamide Spleen Tyrosine Kinase (Syk) Inhibitors: Leveraging Ground State Interactions To Accelerate Optimization.

Optimization of a series of highly potent and kinome selective carbon-linked carboxamide spleen tyrosine kinase (Syk) inhibitors with favorable drug-like properties is described. A pervasive Ames liability in an analogous nitrogen-linked carboxamide series was obviated by replacement with a carbon-linked moiety. Initial efforts lacked on-target potency, likely due to strain induced between the hinge binding amide and solvent front heterocycle. Consideration of ground state and bound state energetics allowed rapid realization of improved solvent front substituents affording subnanomolar Syk potency and high kinome selectivity. These molecules were also devoid of mutagenicity risk as assessed via the Ames test using the TA97a Salmonella strain.

Discovery of pyrazolopyrimidine phosphodiesterase 10A inhibitors for the treatment of schizophrenia.

Herein, we present the identification of a novel class of pyrazolopyrimidine phosphodiesterase 10A (PDE10A) inhibitors. Beginning with a lead molecule (1) identified through a fragment-based drug discovery (FBDD) effort, lead optimization was enabled by rational design, X-ray crystallography, metabolic and off-target profiling, and fragment scaffold-hopping. We highlight the discovery of PyP-1, a potent, highly selective, and orally bioavailable pyrazolopyrimidine inhibitor of PDE10A. PyP-1 exhibits sub-nanomolar potency (PDE10A Ki=0.23nM), excellent pharmacokinetic (PK) and physicochemical properties, and a clean off-target profile. It displays dose-dependent efficacy in numerous pharmacodynamic (PD) assays that measure potential for anti-psychotic activity and cognitive improvement. PyP-1 also has a clean preclinical profile with respect to cataleptic potential in rats, prolactin secretion, and weight gain, common adverse events associated with currently marketed therapeutics. Further, PyP-1 displays in vivo preclinical target engagement as measured by PET enzyme occupancy in concert with [(11)C]MK-8193, a novel PDE10A PET tracer.

Structure-activity-relationship of amide and sulfonamide analogs of omarigliptin.

A series of novel substituted-[(3R)-amino-2-(2,5-difluorophenyl)]tetrahydro-2H-pyran analogs have been prepared and evaluated as potent, selective and orally active DPP-4 inhibitors. These efforts lead to the discovery of a long acting DPP-4 inhibitor, omarigliptin (MK-3102), which recently completed phase III clinical development and has been approved in Japan.

Discovery and Optimization of a Series of Pyrimidine-Based Phosphodiesterase 10A (PDE10A) Inhibitors through Fragment Screening, Structure-Based Design, and Parallel Synthesis.

Screening of a fragment library for PDE10A inhibitors identified a low molecular weight pyrimidine hit with PDE10A Ki of 8700 nM and LE of 0.59. Initial optimization by catalog followed by iterative parallel synthesis guided by X-ray cocrystal structures resulted in rapid potency improvements with minimal loss of ligand efficiency. Compound 15 h, with PDE10A Ki of 8.2 pM, LE of 0.49, and >5000-fold selectivity over other PDEs, fully attenuates MK-801-induced hyperlocomotor activity after ip dosing.

Discovery of [¹¹C]MK-8193 as a PET tracer to measure target engagement of phosphodiesterase 10A (PDE10A) inhibitors.

Phosphodiesterase 10A (PDE10A) inhibition has recently been identified as a potential mechanism to treat multiple symptoms that manifest in schizophrenia. In order to facilitate preclinical development and support key proof-of-concept clinical trials of novel PDE10A inhibitors, it is critical to discover positron emission tomography (PET) tracers that enable plasma concentration/PDE10A occupancy relationships to be established across species with structurally diverse PDE10A inhibitors. In this Letter, we describe how a high-throughput screening hit was optimized to provide [(11)C]MK-8193 (8j), a PET tracer that supports the determination of plasma concentration/PDE10A occupancy relationships for structurally diverse series of PDE10A inhibitors in both rat and rhesus monkey.

Omarigliptin (MK-3102): a novel long-acting DPP-4 inhibitor for once-weekly treatment of type 2 diabetes.

In our effort to discover DPP-4 inhibitors with added benefits over currently commercially available DPP-4 inhibitors, MK-3102 (omarigliptin), was identified as a potent and selective dipeptidyl peptidase 4 (DPP-4) inhibitor with an excellent pharmacokinetic profile amenable for once-weekly human dosing and selected as a clinical development candidate. This manuscript summarizes the mechanism of action, scientific rationale, medicinal chemistry, pharmacokinetic properties, and human efficacy data for omarigliptin, which is currently in phase 3 clinical development.