Background and purpose: Apremilast is an orally administered phosphodiesterase‐4 inhibitor, currently in phase 2 clinical studies of psoriasis and other chronic inflammatory diseases. The inhibitory ...effects of apremilast on pro‐inflammatory responses of human primary peripheral blood mononuclear cells (PBMC), polymorphonuclear cells, natural killer (NK) cells and epidermal keratinocytes were explored in vitro, and in a preclinical model of psoriasis.
Experimental approach: Apremilast was tested in vitro against endotoxin‐ and superantigen‐stimulated PBMC, bacterial peptide and zymosan‐stimulated polymorphonuclear cells, immunonoglobulin and cytokine‐stimulated NK cells, and ultraviolet B light‐activated keratinocytes. Apremilast was orally administered to beige‐severe combined immunodeficient mice, xenotransplanted with normal human skin and triggered with human psoriatic NK cells. Epidermal skin thickness, proliferation index and inflammation markers were analysed.
Key results: Apremilast inhibited PBMC production of the chemokines CXCL9 and CXCL10, cytokines interferon‐γ and tumour necrosis factor (TNF)‐α, and interleukins (IL)‐2, IL‐12 and IL‐23. Production of TNF‐α by NK cells and keratinocytes was also inhibited. In vivo, apremilast significantly reduced epidermal thickness and proliferation, decreased the general histopathological appearance of psoriasiform features and reduced expression of TNF‐α, human leukocyte antigen‐DR and intercellular adhesion molecule‐1 in the lesioned skin.
Conclusions and implications: Apremilast displayed a broad pattern of anti‐inflammatory activity in a variety of cell types and decreased the incidence and severity of a psoriasiform response in vivo. Inhibition of TNF‐α, IL‐12 and IL‐23 production, as well as NK and keratinocyte responses by this phosphodiesterase‐4 inhibitor suggests a novel approach to the treatment of psoriasis.
Alloys with ultra-high strength and sufficient ductility are highly desired for modern engineering applications but difficult to develop. Here we report that, by a careful controlling alloy ...composition, thermomechanical process, and microstructural feature, a Co-Cr-Ni-based medium-entropy alloy (MEA) with a dual heterogeneous structure of both matrix and precipitates can be designed to provide an ultra-high tensile strength of 2.2 GPa and uniform elongation of 13% at ambient temperature, properties that are much improved over their counterparts without the heterogeneous structure. Electron microscopy characterizations reveal that the dual heterogeneous structures are composed of a heterogeneous matrix with both coarse grains (10∼30 μm) and ultra-fine grains (0.5∼2 μm), together with heterogeneous L1
-structured nanoprecipitates ranging from several to hundreds of nanometers. The heterogeneous L1
nanoprecipitates are fully coherent with the matrix, minimizing the elastic misfit strain of interfaces, relieving the stress concentration during deformation, and playing an active role in enhanced ductility.
The deformation responses of NiCoCrFe high-entropy alloy (HEA) under quasi-static (1 × 10−4-1 × 10−1/s) and dynamic (1,000–6,000/s) tension were investigated. A good combination of high strength and ...ductility is obtained under dynamic tension. The yield strength and true ultimate tensile strength is increased from 217 to 830 MPa at 1 × 10−4/s to 440 MPa and more than 1,000 MPa at 6,000/s, respectively. In addition, the engineering fracture strains maintain 60%–85% over a wide range of strain rates. The enhancements of strength and ductility originate from (1) the significant strain-rate sensitivity (SRS) mainly due to the presence of short-range orders/clusters (SROs/SRCs) as well as phonon drag effect of dislocations, and (2) the extraordinary work-hardening capacity due to dynamically formed nanoscale twins upon high strain-rate tension. The temperature and strain-rate dependence of the yield strength of the alloy are well modeled based on the thermally activated mechanism. Additionally, considering nanoscale twin boundaries as local sites for nucleating and accommodating dislocations, the dislocation density evolution model is modified and subsequently introduced into Taylor hardening model to accurately capture the hardening behavior of the current NiCoCrFe HEA. Hence, the distinguished work-hardening capacity under dynamic tension can be mainly ascribed to the low dislocation recovery rate and remarkable twin-induced dislocation generation.
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•NiCoCrFe HEA possesses simultaneous enhancement of strength and ductility at high strain rates (greater than 1,000/s).•Strong strain rate sensitivity originates from short-range orders/clusters and phonon drag effect of dislocation.•Extraordinary strain hardening mainly stems from the dynamically formed nanoscale twins.•A strain rate-dependent model was established to bridge the gap between microstructure and mechanical properties.•Design idea of new alloys serving under cryogenic temperatures and dynamic impacts was given.
The anomalous metallic state in the high-temperature superconducting cuprates is masked by superconductivity near a quantum critical point. Applying high magnetic fields to suppress superconductivity ...has enabled detailed studies of the normal state, yet the direct effect of strong magnetic fields on the metallic state is poorly understood. We report the high-field magnetoresistance of thin-film La
Sr
CuO
cuprate in the vicinity of the critical doping, 0.161 ≤
≤ 0.190. We find that the metallic state exposed by suppressing superconductivity is characterized by magnetoresistance that is linear in magnetic fields up to 80 tesla. The magnitude of the linear-in-field resistivity mirrors the magnitude and doping evolution of the well-known linear-in-temperature resistivity that has been associated with quantum criticality in high-temperature superconductors.
•Metal dissolution kinetics in saturated pit solution were measured for different alloys.•A model for Epit and Erp was established based on pit growth stability.•Both Epit and Erp correspond to the ...critical condition of idiss,max = idiff,crit.•Lower metal dissolution rate in pit solution correlates with higher Epit and Erp.•Strategy for design of corrosion resistant alloys was proposed.
The pitting resistance of SS316L, SS304, SS430, and pure Fe was studied in chloride-containing solution. Among these alloys, SS316L exhibits the highest pit initiation rate, but also the highest pitting potential. To explain this phenomenon, the maximum pit dissolution current density (idiss,max) of the alloys in saturated pit solution was measured using one-dimensional artificial pit electrodes. A lower idiss,max was found to correlate with higher pitting and repassivation potentials. Based on a recently proposed pitting framework, a conceptual model for pitting and repassivation potentials was established, based on which the effect of idiss,max on pitting resistance was discussed.
Maximising patient comfort during and after surgery is a primary concern of anaesthetists and other perioperative clinicians, but objective measures of what constitutes patient comfort in the ...perioperative period remain poorly defined. The Standardised Endpoints in Perioperative Medicine initiative was established to derive a set of standardised endpoints for use in perioperative clinical trials.
We undertook a systematic review to identify measures of patient comfort used in the anaesthetic, surgical, and other perioperative literature. A multi-round Delphi consensus process that included up to 89 clinician researchers was then used to refine a recommended list of outcome measures.
We identified 122 studies in a literature search, which were the basis for a preliminary list of 24 outcome measures and their definitions. The response rates for Delphi Rounds 1, 2, and 3 were 100% (n=22), 90% (n=79), and 100% (n=13), respectively. A final list of six defined endpoints was identified: pain intensity (at rest and during movement) at 24 h postoperatively, nausea and vomiting (0–6 h, 6–24 h, and overall), one of two quality-of-recovery (QoR) scales (QoR score or QoR-15), time to gastrointestinal recovery, time to mobilisation, and sleep quality.
As standardised outcomes will support benchmarking and pooling (meta-analysis) of trials, one or more of these recommended endpoints should be considered for inclusion in clinical trials assessing patient comfort and pain after surgery.
To examine algino-oligosaccharide production by alginase from newly isolated Flavobacterium sp. LXA and its elicitor and antibacterial activity. Algino-oligosaccharide production from alginate was ...carried out using alginase obtained from a newly isolated Flavobacterium sp. LXA. When alginase was partially purified by dual ammonium sulfate precipitation and used for alginate degradation, the viscosity loss correlated well with the release of reducing terminals. The optimal temperature and pH for alginate degradation was 40°C and pH 7·0, respectively. When alginate was added at an initial concentration of more than 0·8%, the maximal degradation rate of alginate was obtained. Under these optimal reaction conditions and with partially purified alginase, the average degrees of polymerization (DP) of alginate-degraded products was about 6·0, which favoured algino-oligosaccharide production. The algino-oligosaccharides showed an elicitor activity stimulating the accumulation of phytoalexin and inducing phenylalanine ammonia lyase in soybean cotyledon, and antimicrobial activity on Pseudomonas aeruginosa. Algino-oligosaccharide could be degraded from alginate by the partially purified alginase and its maximal bioactivity occurred on the oligosaccharide with average DP 6·8. Algino-oligosaccharide was first reported to have elicitor and antibacterial activity and have potential as a biological agent for protection against plant or human disease.
Abstract
The tip of the red giant branch (TRGB) provides a luminous standard candle for constructing distance ladders to measure the Hubble constant. In practice, its measurements via edge-detection ...response (EDR) are complicated by the apparent fuzziness of the tip and the multipeak landscape of the EDR. Previously, we optimized an unsupervised algorithm, Comparative Analysis of TRGBs, to minimize the variance among multiple halo fields per host without relying on individualized choices, achieving state-of-the-art ∼<0.05 mag distance measures for optimal data. Here we apply this algorithm to an expanded sample of SN Ia hosts to standardize these to multiple fields in the geometric anchor, NGC 4258. In concert with the Pantheon+ SN Ia sample, this analysis produces a (baseline) result of
H
0
= 73.22 ± 2.06 km s
−1
Mpc
−1
. The largest difference in
H
0
between this and similar studies employing the TRGB derives from corrections for SN survey differences and local flows used in the most recent SN Ia compilations that were absent in earlier studies. The SN-related differences total ∼2.0 km s
−1
Mpc
−1
. A smaller share, ∼1.4 km s
−1
Mpc
−1
, results from the inhomogeneity of the TRGB calibration across the distance ladder. We employ a grid of 108 variants around the optimal TRGB algorithm and find that the median of the variants is 72.94 ± 1.98 km s
−1
Mpc
−1
with an additional uncertainty due to algorithm choices of 0.83 km s
−1
Mpc
−1
. None of these TRGB variants result in an
H
0
of less than 71.6 km s
−1
Mpc
−1
.
While oral antidepressants reach efficacy after weeks, single-dose intravenous (i.v.) ketamine has rapid, yet time-limited antidepressant effects. We aimed to determine the efficacy and safety of ...single-dose i.v. ketamine augmentation of escitalopram in major depressive disorder (MDD).
Thirty outpatients with severe MDD (17-item Hamilton Rating Scale for Depression total score ⩾ 24) were randomized to 4 weeks double-blind treatment with escitalopram 10 mg/day+single-dose i.v. ketamine (0.5 mg/kg over 40 min) or escitalopram 10 mg/day + placebo (0.9% i.v. saline). Depressive symptoms were measured using the Montgomery-Asberg Depression Rating Scale (MADRS) and the Quick Inventory of Depressive Symptomatology - Self-Report (QIDS-SR). Suicidal ideation was evaluated with the QIDS-SR item 12. Adverse psychopathological effects were measured with the Brief Psychiatric Rating Scale (BPRS)-positive symptoms, Young Mania Rating Scale (YMRS) and Clinician Administered Dissociative States Scale (CADSS). Patients were assessed at baseline, 1, 2, 4, 24 and 72 h and 7, 14, 21 and 28 days. Time to response (⩾ 50% MADRS score reduction) was the primary outcome.
By 4 weeks, more escitalopram + ketamine-treated than escitalopram + placebo-treated patients responded (92.3% v. 57.1%, p = 0.04) and remitted (76.9% v. 14.3%, p = 0.001), with significantly shorter time to response hazard ratio (HR) 0.04, 95% confidence interval (CI) 0.01-0.22, p < 0.001 and remission (HR 0.11, 95% CI 0.02-0.63, p = 0.01). Compared to escitalopram + placebo, escitalopram + ketamine was associated with significantly lower MADRS scores from 2 h to 2 weeks (peak = 3 days-2 weeks; effect size (ES) = 1.08-1.18), QIDS-SR scores from 2 h to 2 weeks (maximum ES = 1.27), and QIDS-SR suicidality from 2 to 72 h (maximum ES = 2.24). Only YMRS scores increased significantly with ketamine augmentation (1 and 2 h), without significant BPRS or CADSS elevation.
Single-dose i.v. ketamine augmentation of escitalopram was safe and effective in severe MDD, holding promise for speeding up early oral antidepressant efficacy.
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