Background and Aim
Remimazolam tosilate (RT) is a new short‐acting GABA(A) receptor agonist, having potential to be an effective option for procedural sedation. Here, we aimed to compare the efficacy ...and safety of RT with propofol in patients undergoing upper gastrointestinal endoscopy.
Methods
This positive‐controlled, non‐inferiority, phase III trial recruited patients at 17 centers, between September 2017 and November 2017. A total of 384 patients scheduled to undergo upper gastrointestinal endoscopy were randomly assigned to receive RT or propofol. Primary endpoint was the success rate of sedation. Adverse events (AEs) were recorded to evaluate safety.
Results
The success rate of sedation in the RT group was non‐inferior to that in the propofol group (97.34% vs 100.00%; difference in rate −2.66%, 95% CI −4.96 to −0.36, meeting criteria for non‐inferiority). Patients in the RT group had longer time to adequate sedation (P < 0.0001) but shorter time to fully alert (P < 0.0001) than that in the propofol group. The incidences of hypotension (13.04% vs 42.86%, P < 0.0001), treatment‐related hypotension (0.54% vs 5.82%, P < 0.0001), and respiratory depression (1.09% vs 6.88%, P = 0.0064) were significantly lower in the RT group. AEs were reported in 74 (39.15%) patients in the RT group and 114 (60.32%) patients in the propofol group, with significant difference (P < 0.0001).
Conclusion
This trial established non‐inferior sedation success rate of RT compared with propofol. RT allows faster recovery from sedation compared with propofol. The safety profile is favorable and appears to be superior to propofol, indicating that it was feasible and well tolerated for patients.
Midnight and post‐midnight ionospheric irregularities are observed over Brazil sector during the June solstice of solar inactive years. The prevailing nighttime winds in the magnetic meridional plane ...(magnetic meridional winds) are experimentally described as a trans‐equatorial wind, and superposed a convergent/equatorward component that emerges after 03 LT. Further computation of the growth rate of the generalized Rayleigh‐Taylor (GRT) instability well explains the local time dependent irregularities observed. Our analysis indicates that the trans‐equatorial wind before midnight uplifts the ionosphere in the upwind (northern) hemisphere, whereas the expected downwelling in the conjugate hemisphere is almost unseen. The wind hence decreases the field‐line integrated Pedersen conductivity and promotes the midnight instability, instead of suppressing it as conventionally known. After 03 LT, the convergent/equatorward component also provides an unstable condition, consistent with the theory that a meridional wind profile with a negative latitudinal gradient will destabilize the ionosphere. The growth rate gets lower as the neutral winds weakened with increasing solar activity, but seemingly insufficient to explain the much fewer instabilities observed in 2012 than in 2009. Other solar activity dependent factors need to be taken into account in addition to the growing process of the GRT instability in the F region.
Key Points
Local time variations of the neutral winds in Brazil sector are reconstructed by combining the SAMI2 model and ionospheric hmF2 data
Equatorward winds superposed on a trans‐equatorial wind well explain the occurrence of copious midnight/post‐midnight irregularities
Either of the two components effectively uplifts the ionosphere and contributes to the growth rate of the generalized Rayleigh‐Taylor instability
We performed a meta-analysis of randomized controlled trials (RCT) and observational studies to answer the two following questions: (i) whether low maternal circulating 25 hydroxyvitamin D (25-OHD) ...is associated with an increased risk of preterm birth (PTB) or spontaneous PTB (sPTB); and (ii) whether vitamin D supplementation alone during pregnancy can reduce the risk of PTB.
Literature search was carried out using Pubmed, Web of Science and Embase databases up to June 2016. Pooled OR or relative risk (RR) with 95%CI were computed using fixed or random effects models depending on the size of heterogeneity. Subgroup analysis was used to explore potential sources of between-study heterogeneity. Publication bias was evaluated using Egger's test and Begg's test.
Twenty-four articles (six RCT and 18 observational studies) were identified. Maternal circulating 25-OHD deficiency (pooled OR, 1.25; 95%CI: 1.13-1.38) rather than insufficiency (pooled OR, 1.09; 95%CI: 0.89-1.35) was associated with an increased risk of PTB, and vitamin D supplementation alone during pregnancy could reduce the risk of PTB (pooled RR, 0.57; 95%CI: 0.36-0.91). This was also the case for the sPTB subgroup (circulating 25-OHD <50 vs >50 nmol/L; pooled OR, 1.45; 95%CI: 1.20-1.75).
Maternal circulating 25-OHD deficiency could increase PTB risk and vitamin D supplementation alone during pregnancy could reduce PTB risk. Extrapolation of the results, however, must be done with caution, and there is urgent need for larger, better-designed RCT to confirm this effect.
Expression of bone morphogenetic protein 4 (BMP4) in adipocytes of white adipose tissue (WAT) produces “white adipocytes” with characteristics of brown fat and leads to a reduction of adiposity and ...its metabolic complications. Although BMP4 is known to induce commitment of pluripotent stem cells to the adipocyte lineage by producing cells that possess the characteristics of preadipocytes, its effects on the mature white adipocyte phenotype and function were unknown. Forced expression of a BMP4 transgene in white adipocytes of mice gives rise to reduced WAT mass and white adipocyte size along with an increased number of a white adipocyte cell types with brown adipocyte characteristics comparable to those of beige or brite adipocytes. These changes correlate closely with increased energy expenditure, improved insulin sensitivity, and protection against diet-induced obesity and diabetes. Conversely, BMP4-deficient mice exhibit enlarged white adipocyte morphology and impaired insulin sensitivity. We identify peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as the target of BMP signaling required for these brown fat-like changes in WAT. This effect of BMP4 on WAT appears to extend to human adipose tissue, because the level of expression of BMP4 in WAT correlates inversely with body mass index. These findings provide a genetic and metabolic basis for BMP4’s role in altering insulin sensitivity by affecting WAT development.
Individual free fatty acids (FAs) play important roles in metabolic homeostasis, many through engagement with more than 40G protein-coupled receptors. Searching for receptors to sense beneficial ...omega-3 FAs of fish oil enabled the identification of GPR120, which is involved in a spectrum of metabolic diseases. Here, we report six cryo-electron microscopy structures of GPR120 in complex with FA hormones or TUG891 and G
or G
trimers. Aromatic residues inside the GPR120 ligand pocket were responsible for recognizing different double-bond positions of these FAs and connect ligand recognition to distinct effector coupling. We also investigated synthetic ligand selectivity and the structural basis of missense single-nucleotide polymorphisms. We reveal how GPR120 differentiates rigid double bonds and flexible single bonds. The knowledge gleaned here may facilitate rational drug design targeting to GPR120.
The present‐day ubiquity of smart devices used under extreme conditions demands robust and more sustainable energy storage. Therefore, lightweight electrodes with both excellent electrochemical and ...mechanical performance to meet these needs are of great importance. Moreover, the recycling of current energy storage devices poses significant environmental concerns, a particularly daunting prospect given the increasing waste volume of metal‐based electrodes. To that end, these challenges of performance and sustainability are addressed by leveraging accessible digital light processing (DLP) technology and tailored post‐process heat treatment to fabricate a metal‐based 3D substrate with ultrahigh precision and hierarchical porosity. Here, a 4‐mm‐thickness metal‐based electrode with NiCo2S4 loading of 18.38 mg cm–2 achieves a high areal capacity of 7.327 mA h cm–2 at 44.85 mA cm–2, providing a promising way to fabricate high‐performance thick electrodes. Most importantly, these electrodes can be fabricated from recyclable metal salt feedstock. The geometric freedom offered by 3D printing supplemented by finite element analyses allows for optimized complex structures to be fabricated. Through rational design realized by 3D printing, a desirable compromise between building density, mechanical properties, electrochemical performances, and environment‐friendly processing cycle can be arrived upon.
A material's performance will be a function of its properties while the structure of it will depend on how it is processed. By utilizing digitization methods enabled by modern technology, 3D metallic electrodes with superior powering performance fabricated in a sustainable loop and excellent mechanical robustness towards end‐use are presented in this work.
Objectives
Coroglaucigenin (CGN), a natural product isolated from Calotropis gigantean by our research group, has been identified as a potential anti‐cancer agent. However, the molecular mechanisms ...involved remain poorly understood.
Materials and methods
Cell viability and cell proliferation were detected by MTT and BrdU assays. Flow cytometry, SA‐β‐gal assay, western blotting and immunofluorescence were performed to determine CGN‐induced apoptosis, senescence and autophagy. Western blotting, siRNA transfection and coimmunoprecipitation were carried out to investigate the mechanisms of CGN‐induced senescence and autophagy. The anti‐tumour activities of combination therapy with CGN and chloroquine were observed in mice tumour models.
Results
We demonstrated that CGN inhibits the proliferation of colorectal cancer cells both in vitro and in vivo. We showed that the inhibition of cell proliferation by CGN is independent of apoptosis, but is associated with cell‐cycle arrest and senescence in colorectal cancer cells. Notably, CGN induces protective autophagy that attenuates CGN‐mediated cell proliferation. Functional studies revealed that CGN disrupts the association of Hsp90 with both CDK4 and Akt, leading to CDK4 degradation and Akt dephosphorylation, eventually resulting in senescence and autophagy, respectively. Combination therapy with CGN and chloroquine resulted in enhanced anti‐tumour effects in vivo.
Conclusions
Our results demonstrate that CGN induces senescence and autophagy in colorectal cancer cells and indicate that combining it with an autophagy inhibitor may be a novel strategy suitable for CGN‐mediated anti‐cancer therapy.
The cell membrane exhibits a remarkable complexity of lipids and proteins that dynamically segregate into distinct domains to coordinate various cellular functions. The ability to manipulate the ...partitioning of specific membrane proteins without involving genetic modification is essential for decoding various cellular processes but highly challenging. In this work, by conjugating cholesterols or tocopherols at the three bottom vertices of the DNA tetrahedron, we develop two sets of nanodevices for the selective targeting of lipid-order (Lo) and lipid-disorder (Ld) domains on the live cell membrane. By incorporation of protein-recognition ligands, such as aptamers or antibodies, through toehold-mediated strand displacement, these DNA nanodevices enable dynamic translocation of target proteins between these two domains. We first used PTK7 as a protein model and demonstrated, for the first time, that the accumulation of PTK7 to the Lo domains could promote tumor cell migration, while sequestering it in the Ld domains would inhibit the movement of the cells. Next, based on their modular nature, these DNA nanodevices were extended to regulate the process of T cell activation through manipulating the translocation of CD45 between the Lo and the Ld domains. Thus, our work is expected to provide deep insight into the study of membrane structure and molecular interactions within diverse cell signaling processes.
Owing to its up-conversion photoluminescence, photo-induced electron transfer property, and excellent conductivity, carbon quantum dots (CQDs) have been established as effective sensitizers in ...combination with Fe2O3 nanowires for enhancing the catalytic activity of photoelectrochemical water oxidation. In comparison to pristine Fe2O3 nanowires, Fe2O3 nanowires decorated with CQDs demonstrate 27 orders of magnitude increase in photocurrent density at 0.23 V vs. Ag/AgCl. The mechanism of enhanced photoelectrochemical activity of CQDs/Fe2O3 composite was also investigated. Thereby, it is confirmed that the enhanced optical absorption, accelerated interfacial charge carrier transfer and effective separation of photogenerated electron-hole pairs induced by CQDs decoration account for the enhancement of CQDs/Fe2O3 nanowire arrays in photoelectrochemical application.
Display omitted A photoanode comprised of vertically aligned hematite nanowire arrays decorated with carbon quantum dots was fabricated. The CQDs/Fe2O3 electrode shows high photoelectrochemical response under visible light irradiation.
•Vertically aligned Fe2O3 nanowires were grown on FTO.•The Fe2O3 nanowires were modified by CQDs to construct CQDs/Fe2O3 heterojunction.•CQDs-modified Fe2O3 is active photoanode for water splitting.•The photocurrent of the CQDs/Fe2O3 is 27 times as that of the bare Fe2O3.•Effective separation of photogenerated electron-hole pairs was achieved.
Cardenolides have potential as anticancer drugs. 3'-epi-12β-hydroxyfroside (HyFS) is a new cardenolide structure isolated by our research group, but its molecular mechanisms remain poorly understood. ...This study investigates the relationship between its antitumor activities and autophagy in lung cancer cells.
Cell growth and proliferation were detected by MTT, lactate dehydrogenase (LDH) release, 5-ethynyl-20-deoxyuridine (EDU) and colony formation assays. Cell apoptosis was detected by flow cytometry. Autophagic and signal proteins were detected by Western blotting. Markers of autophagy and autophagy flux were also detected by immunofluorescence, transmission electron microscopy and acridine orange staining. Real time RT-PCR was used to analyze the gene expression of Hsp90. Hsp90 ubiquitination was detected by coimmunoprecipitation. The antitumore activities of HyFS were observed in nude mice.
HyFS treatment inhibited cell proliferation and induced autophagy in A549 and H460 lung cancer cells, but stronger inhibition of cell proliferation and induction of cell apoptosis were shown when HyFS-mediated autophagy was blocked. The Hsp90/Akt/mTOR axis was found to be involved in the activation of HyFS-mediated autophagy. Evidence of direct interaction between Hsp90 and Akt was observed. HyFS treatment resulted in decreased levels of heat shock protein 90 (Hsp90) and phosphorylated Akt, overexpression of Hsp90 increased activation of autophagy, and inhibition of Hsp90 expression decreased autophagy. In addition, ubiquitin-mediated degradation of Hsp90 and subsequent dephosphorylation of its client protein Akt were also found in HyFS-treated lung cancer cells. Moreover, combination treatment with HyFS and chloroquine showed remarkably increased tumor inhibition in both A549- and H460-bearing mice.
Our results demonstrate that HyFS induced cytoprotective autophagy through ubiquitin-mediated degradation of Hsp90, which further blocked the Akt/mTOR pathway in lung cancer cells. Thus, a combination of a HyFS-like cardenolide and an autophagic inhibitor is a potential alternative approach for the treatment of lung cancer.
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