Thioamides antithyroid‐drugs (ATDs) are important in hyperthyroid disease management. Identification of the susceptibility locus of ATD‐induced agranulocytosis is important for clinical management. ...We performed a genome‐wide association study (GWAS) involving 20 patients with ATD‐induced agranulocytosis and 775 healthy controls. The top finding was further replicated. A single‐nucleotide polymorphism (SNP), rs185386680, showed the strongest association with ATD‐induced agranulocytosis in GWAS (odds ratio (OR) = 36.4; 95% confidence interval (CI) = 12.8–103.7; P = 1.3 × 10‐24) and replication (OR = 37; 95% CI = 3.7–367.4; P = 9.6 × 10‐7). HLA‐B*38:02:01 was in complete linkage disequilibrium with rs185386680. High‐resolution HLA typing confirmed that HLA‐B*38:02:01 was associated with carbimazole (CMZ)/methimazole (MMI)‐induced agranulocytosis (OR = 265.5; 95% CI = 27.9–2528.0; P = 2.5 × 10‐14), but not associated with propylthiouracil (PTU). The positive and negative predictive values of HLA‐B*38:02:01 in predicting CMZ/MMI‐induced agranulocytosis were 0.07 and 0.999. Approximately 211 cases need to be screened to prevent one case. Screening for the risk allele will be useful in preventing agranulocytosis in populations in which the frequency of the risk allele is high.
•Thermal diodes with various heat transfer mechanisms are summarized;•Existing application studies of thermal diodes are discussed;•Potential for further study and application directions of thermal ...diodes are presented.
Thermal management is an essential aspect of various applications, especially in the area of electronic miniaturization. Thermal diodes, which exhibit asymmetric heat transfer characteristics along an axial direction, are one of the vital components for use in thermal management systems. This review summarizes both theoretical and experimental studies of various types of thermal diodes introduced in recent years. The thermal diodes discussed in this review are classified based on their primary heat transfer mechanisms and the materials from which they are constructed. After gaining an understanding of the thermal rectification mechanisms of these thermal diodes, we also discuss several applications of thermal diodes, including solar power systems, caloric refrigeration systems, and thermal computing. Lastly, we present the application potential of the thermal diodes in several thermal systems that have not been investigated before, such as temperature controllers, micro-electronic cooling, space technologies, atomic clocks, and bio-technologies.
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Development of biomaterial-based bioinks is critical for replacement and/or regeneration of tissues and organs by three-dimensional (3D) printing techniques. However, the number of 3D-printable ...biomaterials in practical use remains limited despite the rapid development of 3D printing techniques. Controlling the flow properties of bioinks and mechanical properties of the resultant printed objects is key considerations in the design of biomaterial-based bioinks for practical applications. In this study, a printable hydrogel comprising biocompatible polysaccharides that has potential for cartilage regeneration via tissue engineering approaches was designed. Self-healing hydrogels were prepared from partially oxidized hyaluronate (OHA) and glycol chitosan (GC) in the presence of adipic acid dihydrazide (ADH). The self-healing ability of OHA/GC/ADH hydrogels was attributed to the combination of two dynamic bonds in the gels, including imine bonds obtained via a Schiff base reaction between OHA and GC, as well as acylhydrazone bonds formed by the reaction between OHA and ADH. The OHA/GC/ADH hydrogels did not require any postgelation or additional cross-linking processes for use in the fabrication of 3D constructs using an extrusion-based 3D printer. The concentrations and molecular weights of the constituent polymers were found to be critical parameters affecting the flow and mechanical properties of the self-healing hydrogels, which showed great potential as bioinks for fabricating cell-laden structures using a 3D printer. The expression of chondrogenic marker genes such as SOX-9 and collagen type II of ATDC5 cells encapsulated in the OHA/GC/ADH hydrogel was not significantly affected by the printing process. This self-healing hydrogel system may have the potential in tissue engineering applications, including cartilage regeneration.
Polymer photovoltaic cells with power conversion efficiencies approaching 5 % have been fabricated using titanium oxide (TiOx) as an optical spacer (see Figure). Solar cells with a TiOx layer ...(deposited via a sol–gel process) between the active layer and the electron‐collecting aluminum electrode exhibit approximately a 50 % enhancement in short‐circuit current compared to similar devices without the optical spacer, as a result of modification of the spatial distribution of the light intensity inside the device.
The flavonoids quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether were isolated from the ethyl acetate fractions of the fruits and stems of
Opuntia ficus-indica var.
saboten. In the ...present study, we evaluated their protective effects against oxidative neuronal injuries induced in primary cultured rat cortical cells and their antioxidant activities by using three different cell-free bioassays. Quercetin was found to inhibit H
2O
2- or xanthine (X)/xanthine oxidase (XO)-induced oxidative neuronal cell injury, with an estimated IC
50 of 4–5 μg/ml. However, it was no more protective at concentrations of 30 μg/ml and above. (+)-Dihydroquercetin concentration-dependently inhibited oxidative neuronal injuries, but it was less potent than quercetin. On the other hand, quercetin 3-methyl ether potently and dramatically inhibited H
2O
2- and X/XO-induced neuronal injuries, with IC
50 values of 0.6 and 0.7 μg/ml, respectively. All three principles markedly inhibited lipid peroxidation and scavenged 1,1-diphenyl-2-picrylhydrazyl free radicals. In addition, quercetin and quercetin 3-methyl ether were shown to inhibit XO activity in vitro, with respective IC
50 values of 10.67 and 42.01 μg/ml. These results indicate that quercetin, (+)-dihydroquercetin, and quercetin 3-methyl ether are the active antioxidant principles in the fruits and stems of
Opuntia ficus-indica var.
saboten exhibiting neuroprotective actions against the oxidative injuries induced in cortical cell cultures. Furthermore, quercetin 3-methyl ether appears to be the most potent neuroprotectant of the three flavonoids isolated from this plant.
Gouty arthritis is caused by the deposition of uric acid crystals, which induce the activation of NOD-like receptor family, pyrin domain containing 3(NLRP3) inflammasome. The NLRP3 inflammasome, ...composed of NLRP3, the adaptor protein ASC, and caspase-1, is closely linked to the pathogenesis of various metabolic diseases including gouty arthritis. We investigated whether an orally administrable inhibitor of NLRP3 inflammasome was effective for alleviating the pathological symptoms of gouty arthritis and what was the underlying mechanism. In primary mouse macrophages, caffeic acid phenethyl ester(CAPE) blocked caspase-1 activation and IL-1β production induced by MSU crystals, showing that CAPE suppresses NLRP3 inflammasome activation. In mouse gouty arthritis models, oral administration of CAPE suppressed MSU crystals-induced caspase-1 activation and IL-1β production in the air pouch exudates and the foot tissues, correlating with attenuation of inflammatory symptoms. CAPE directly associated with ASC as shown by SPR analysis and co-precipitation, resulting in blockade of NLRP3-ASC interaction induced by MSU crystals. Our findings provide a novel regulatory mechanism by which small molecules harness the activation of NLRP3 inflammasome by presenting ASC as a new target. Furthermore, the results suggest the preventive or therapeutic strategy for NLRP3-related inflammatory diseases such as gouty arthritis using orally available small molecules.
Summary Background The CLASSIC trial was done to compare adjuvant capecitabine plus oxaliplatin versus observation after D2 gastrectomy for patients with stage II or III gastric cancer. The planned ...interim analysis of CLASSIC (median follow-up 34 months) showed that adjuvant capecitabine plus oxaliplatin significantly improved disease-free survival, the primary endpoint, compared with observation after D2 gastrectomy. We report the 5-year follow-up data from the trial. Methods CLASSIC was a phase 3, randomised, open-label study done at 35 cancer centres, medical centres, and hospitals in China, South Korea, and Taiwan. Patients with stage II–IIIB gastric cancer who underwent curative D2 gastrectomy were randomly assigned (1:1) after surgery to receive adjuvant chemotherapy with capecitabine and oxaliplatin (eight 3-week cycles of oral capecitabine 1000 mg/m2 twice daily on days 1–14 plus intravenous oxaliplatin 130 mg/m2 on day 1) for 6 months or observation alone. Randomisation was stratified by country and disease stage with a permuted block (size four) design. Neither patients nor investigators were masked to treatment assignment. The primary outcome was 3-year disease-free survival in the intention-to-treat population. This analysis presents the final preplanned assessment of outcomes after 5 years. The study is registered with ClinicalTrials.gov , NCT00411229. Findings We enrolled 1035 patients: 520 were randomly assigned to adjuvant capecitabine and oxaliplatin, and 515 to observation. Median follow-up for this analysis in the intention-to-treat population was 62·4 months (IQR 54–70). 139 (27%) patients had disease-free survival events in the adjuvant capecitabine and oxaliplatin group versus 203 (39%) patients in the observation group (stratified hazard ratio HR 0·58, 95% CI 0·47–0·72; p<0·0001). Estimated 5-year disease-free survival was 68% (95% CI 63–73) in the adjuvant capecitabine and oxaliplatin group versus 53% (47–58) in the observation alone group. By the clinical cutoff date, 103 patients (20%) had died in the adjuvant capecitabine and oxaliplatin group versus 141 patients (27%) in the observation group (stratified HR 0·66, 95% CI 0·51–0·85; p=0·0015). Estimated 5-year overall survival was 78% (95% CI 74–82) in the adjuvant capecitabine and oxaliplatin group versus 69% (64–73) in the observation group. Adverse event data were not collected after the primary analysis. Interpretation Adjuvant treatment with capecitabine plus oxaliplatin after D2 gastrectomy should be considered for patients with operable stage II or III gastric cancer. Funding F Hoffmann La-Roche and Sanofi.
It has been widely reported that ketamine rescues chronic stress-induced depression-like behavior, but the underlying cellular mechanisms of the rapid antidepressant actions of ketamine remain ...largely unclear. Both male and female Sprague-Dawley rats were used and received modified learned helplessness paradigm to induce depression-like behavior. Depression-like behavior was assayed and manipulated using forced swim tests, sucrose preference tests and pharmacological microinjection. We conducted whole-cell patch-clamp electrophysiological recordings in the midbrain ventrolateral periaqueductal gray (vlPAG) neurons. Surface and cytosolic glutamate receptor 1 (GluR1) α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor expression were analyzed using Western blotting. Phosphorylated GluR1 expression was quantified using Western blotting analysis. The results showed that a single systemic administration of a ketamine metabolite (2R,6R)-hydroxynorketamine (2R,6R-HNK) rapidly rescued chronic stress-induced depression-like behavior and persisted for up to 21 days. Consistently, the chronic stress-induced diminished glutamatergic transmission and surface GluR1 expression in the vlPAG were also reversed by a single systemic injection of (2R,6R)-HNK. Furthermore, bath application of (2R,6R)-HNK increased the frequency and amplitude of miniature excitatory postsynaptic currents (mEPSCs) in the vlPAG. Further evidence for the antidepressant action of (2R,6R)-HNK is provided by the finding that microinjection of (2R,6R)-HNK into the vlPAG exhibited a rapid-acting and long-lasting antidepressant effect. This antidepressant effect of (2R,6R)-HNK was prevented by the intra-vlPAG microinjection of AMPA receptor antagonist CNQX. Together, the current results provide evidence that (2R,6R)-HNK rescues chronic stress-induced depression-like behavior with rapid-acting and long-lasting antidepressant effects through enhancement of AMPA receptor-mediated transmission in the vlPAG.
•Both intraperitoneal and intra-vlPAG administration of (2R,6R)-HNK rescue chronic stress-induced depression-like behavior.•(2R,6R)-HNK rapidly rescues chronic stress-induced depression-like behavior.•Antidepressant effects of (2R,6R)-HNK persist for up to 21 days.•(2R,6R)-HNK increases glutamate release presynaptically and surface GluR1 expression postsynaptically in the vlPAG.•Blockage of AMPAR in the vlPAG antagonizes antidepressant effects of (2R,6R)-HNK.
Although a great deal is known biochemically about peroxiredoxins (Prxs), little is known about their real physiological function. We show here that two cytosolic yeast Prxs, cPrxI and II, which ...display diversity in structure and apparent molecular weights (MW), can act alternatively as peroxidases and molecular chaperones. The peroxidase function predominates in the lower MW forms, whereas the chaperone function predominates in the higher MW complexes. Oxidative stress and heat shock exposure of yeasts causes the protein structures of cPrxI and II to shift from low MW species to high MW complexes. This triggers a peroxidase-to-chaperone functional switch. These in vivo changes are primarily guided by the active peroxidase site residue, Cys
47, which serves as an efficient “H
2O
2-sensor” in the cells. The chaperone function of these proteins enhances yeast resistance to heat shock.
•For Al2O3, a ring pattern was formed at low concentration and small particle size.•A uniform pattern was formed at high concentration and larger particle size.•The width of the ring-shaped pattern ...was larger with the small particle size.•The substrate material with a higher contact angle of water showed a greater width.•21nm TiO2 nanofluid formed a greater width than that of 20nm Al2O3 nanofluid.
Nanofluid droplet evaporation has attracted great interest due to its applications such as in painting, coating and patterning. In most studies, either the particle size or the concentration of nanofluid is considered as a factor in the formation of the residue pattern. This work aims to investigate the effect of both particle size and concentration on the residue pattern. A comprehensive study was made of the residue patterns of Al2O3 and TiO2 aqueous nanofluid droplets on different substrates (i.e. glass, stainless steel and Teflon). It was found that a ring-shaped pattern was formed at low concentrations and small particle sizes, while a uniform pattern was formed at high concentrations and large particle sizes for Al2O3 nanofluids. In addition, only ring-shaped residue patterns were observed for all concentrations of TiO2 nanofluids. In the case of different substrates, on a material with a high contact angle with water, it was difficult to form a ring-shaped pattern. The widths of the ring-shaped pattern were analyzed as well. The results showed that the width of the ring-shaped pattern was larger for small particles. The materials of substrate and nanoparticle also influenced the width.
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