Oligodendrocyte‐formed myelin sheaths play important roles in the neuronal functions in the central nervous system. In demyelinating diseases, such as Multiple Sclerosis, the myelin sheaths are ...damaged and the remyelinating process is somehow hindered. Restoration of the myelin sheaths requires the differentiation of the oligodendrocyte precursor cells (OPCs) into mature oligodendrocytes (OLs). To discover small molecule compounds that might promote the OPC to OL differentiation, a high‐throughput screening system is established and L‐ascorbyl‐2‐phosphate (As‐2P), a stable form of Vitamin C (Vc), is found to greatly enhance the OPC to OL differentiation. As‐2P promotes gradual expression of OL lineage markers, including O4, CNPase and MBP, in a dose‐ and time‐dependent manner. It also facilitates the formation of myelin sheaths in OPC‐neuron co‐culture. As‐2P also promotes the repair of the myelin sheaths in vivo and provides significant therapeutic effect in a cuprizone‐mediated demyelination animal model. Interestingly, As‐2P's function in promoting OPC differentiation is not related to its antioxidant activity. And an intracellular rather than an extracellular mechanism might be involved. Considering the safe use of Vc as a dietary supplement for many years, it might also be used as an alternative medicine for CNS demyelinating diseases.
Main Points
As‐2P, a stable form of Vitamin C, promotes oligodendrocyte differentiation.
As‐2P promotes myelin formation both in vitro and in vivo.
SVCT2 mediates As‐2P's effect in oligodendrocyte differentiation.
The optimal perioperative chemotherapeutic regimen for locally advanced gastric cancer remains undefined. We evaluated the efficacy and safety of perioperative and postoperative S-1 and oxaliplatin ...(SOX) compared with postoperative capecitabine and oxaliplatin (CapOx) in patients with locally advanced gastric cancer undergoing D2 gastrectomy.
We did this open-label, phase 3, superiority and non-inferiority, randomised trial at 27 hospitals in China. We recruited antitumour treatment-naive patients aged 18 years or older with historically confirmed cT4a N+ M0 or cT4b Nany M0 gastric or gastro-oesophageal junction adenocarcinoma, with Karnofsky performance score of 70 or more. Patients undergoing D2 gastrectomy were randomly assigned (1:1:1) via an interactive web response system, stratified by participating centres and Lauren classification, to receive adjuvant CapOx (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral capecitabine 1000 mg/m2 twice a day), adjuvant SOX (eight postoperative cycles of intravenous oxaliplatin 130 mg/m2 on day one of each 21 day cycle plus oral S-1 40–60 mg twice a day), or perioperative SOX (intravenous oxaliplatin 130 mg/m2 on day one of each 21 day plus oral S-1 40–60 mg twice a day for three cycles preoperatively and five cycles postoperatively followed by three cycles of S-1 monotherapy). The primary endpoint, assessed in the modified intention-to-treat population, 3-year disease-free survival to assess the superiority of perioperative-SOX compared with adjuvant-SOX and the non-inferiority (hazard ratio non-inferiority margin of 1·33) of adjuvant-SOX compared with adjuvant-CapOx. Safety analysis were done in patients who received at least one dose of the assigned treatment. This study is registered with ClinicalTrials.gov, NCT01534546.
Between Aug 15, 2012, and Feb 28, 2017, 1094 patients were screened and 1022 (93%) were included in the modified intention-to-treat population, of whom 345 (34%) patients were assigned to the adjuvant-CapOx, 340 (33%) patients to the adjuvant-SOX group, and 337 (33%) patients to the perioperative-SOX group. 3-year disease-free survival was 51·1% (95% CI 45·5–56·3) in the adjuvant-CapOx group, 56·5% (51·0–61·7) in the adjuvant-SOX group, and 59·4% (53·8–64·6) in the perioperative-SOX group. The hazard ratio (HR) was 0·77 (95% CI 0·61–0·97; Wald p=0·028) for the perioperative-SOX group compared with the adjuvant-CapOx group and 0·86 (0·68–1·07; Wald p=0·17) for the adjuvant-SOX group compared with the adjuvant-CapOx group. The most common grade 3–4 adverse events was neutropenia (32 12% of 258 patients in the adjuvant-CapOx group, 21 8% of 249 patients in the adjuvant-SOX group, and 30 10% of 310 patients in the perioperative-SOX group). Serious adverse events were reported in seven (3%) of 258 patients in adjuvant-CapOx group, two of which were related to treatment; eight (3%) of 249 patients in adjuvant-SOX group, two of which were related to treatment; and seven (2%) of 310 patients in perioperative-SOX group, four of which were related to treatment. No treatment-related deaths were reported.
Perioperative-SOX showed a clinically meaningful improvement compared with adjuvant-CapOx in patients with locally advanced gastric cancer who had D2 gastrectomy; adjuvant-SOX was non-inferior to adjuvant-CapOx in these patients. Perioperative-SOX could be considered a new treatment option for patients with locally advanced gastric cancer.
National Key Research and Development Program of China, Beijing Scholars Program 2018–2024, Peking University Clinical Scientist Program, Taiho, Sanofi-Aventis, and Hengrui Pharmaceutical.
For the Chinese translation of the abstract see Supplementary Materials section.
Although some ratiometric fluorescent sensors have been reported to detect tetracyclines, most of ratiometric fluorescent sensors were established based on europium ion with a narrow linear range. In ...this work, a ratiometric fluorescent sensor for tetracyclines detection was established based on the dual-emission lanthanum-doped carbon dots (La-CDs) as probes combining with the characteristic pH-response of tetracyclines. The fluorescence intensity of tetracyclines will be enhanced in high pH, and the emission peak of tetracyclines overlapped with the peak of probes. The superposition effect of tetracyclines and probes at 515 nm greatly improved the sensitivity of the ratiometric fluorescent sensor and widened the detection range, and linear ranges for oxytetracycline (OTC) and tetracycline (TC) were respectively 0.00–805.20 μM and 0.00–1039.50 μM. Moreover, the preparation procedure of the La-CDs was simple and time saving and the coupling agent was not required. A comparison of La-CDs with undoped carbon dots (un-CDs) showed that the optical performance and sensing performance of La-CDs were improved. In addition, a portable paper sensor with La-CDs as probes was preliminarily explored in this work, and the sensor has been applied to detect OTC and TC in pork and fish with satisfactory results.
Graphical abstract
Three novel isostructural lanthanide(III) coordination polymers (LnCPs), {Ln3(bidc)4(phen)2(NO3)·2H2O} n (Ln = Gd (1), Eu (2), Tb (3); H2bidc = benzimidazole-5,6-dicarboxylic acid, and phen = ...1,10-phenanthroline), were synthesized via hydrothermal reaction and characterized. The complexes crystallize in the chiral space group P212121. They possess 1D structures based on lanthanide trinuclear clusters containing Ln(1)O9, Ln(2)O6N2, and Ln(3)O6N2 polyhedra by bidc linkers, and phen and nitrate act as terminal ligands. The bidc and phen ligands provide efficient energy transfer for the sensitization of Eu(III) and Tb(III) complexes. The complexes 2 and 3 emit red and green light, respectively. Lifetimes and quantum yields of luminescence are 0.86 ms and 13.20% for 2 and 0.32 ms and 2.08% for 3. Tuning of white-light emission by adjusting the doping concentration of Eu(III) and Tb(III) ions in the Gd(III) complex was achieved.
Hepatoid adenocarcinoma of the stomach (HAS), a rare subtype of gastric cancer (GC), has a low incidence but a high mortality rate. Little is known about the molecular features of HAS. Here we ...applied whole-exome sequencing (WES) on 58 tumours and the matched normal controls from 54 HAS patients, transcriptome sequencing on 30 HAS tumours, and single-cell RNA sequencing (scRNA-seq) on one HAS tumour. Our results reveal that the adenocarcinomatous component and hepatocellular-like component of the same HAS tumour originate monoclonally, and HAS is likely to initiate from pluripotent precursor cells. HAS has high stemness and high methionine cycle activity compared to classical GC. Two genes in the methionine cycle, MAT2A, and AHCY are potential targets for HAS treatments. We provide the first integrative genomic profiles of HAS, which may facilitate its diagnosis, prognosis, and treatment.
Clinical studies have shown that electroacupuncture (EA) alleviates chronic itch. Gastrin-releasing peptide receptor (GRPR) and dynorphin (DYN) in the spinal dorsal horn positively or negatively ...regulate itch, respectively. However, which frequency of EA is effective on relieving chronic itch and reducing the expression of GRPR, whether DYN-A in the spinal cord is involved in the underlying mechanism of the antipruritus effect of EA remains unknown.
The mixture of acetone and diethyl ether (1:1) designated as AEW (acetone/diethyl ether and water) treatment was used to induce the dry skin model of chronic itch. EA was applied to Quchi (LI11) and Hegu (LI4). Western blot was used to detect the expression of GRPR and DYN-A. Immunofluorescence was used to detect the expression of DYN-A.
The AEW administration induced remarkable spontaneous scratching, enhanced the expression of GRPR, and reduced the expression of DYN-A. Compared with the sham EA, 2 Hz EA, or 15 Hz EA group, 100 Hz EA was the most effective frequency for relieving chronic itch, reducing the expression of GRPR, and increasing the expression of DYN-A in the cervical dorsal horn. Furthermore, intraperitoneal injection of kappa opioid receptors (KORs) antagonist nor-Binaltorphimine dihydrochloride (nor-BNI) significantly reversed the effect of 100 Hz EA on the inhibition of both itching behavior and GRPR expression.
EA at 100 Hz is the most effective frequency that inhibits chronic itch and GRPR expression through activation of KORs in the spinal dorsal horn, which can effectively guide the clinical treatment and improve the antipruritic effect of acupuncture.
Autophagy is an important protein degradation pathway and a part of the innate immune system that is activated in the brain tissue during animal and human prion diseases. However, the possible ...mechanism by which prion infection triggers autophagy and the significance of activated autophagy on prion accumulation remain unknown. Here, we demonstrated that autophagic flux was enhanced in the persistent prion-infected cell line, SMB-S15. Knockdown of ATG5 and the presence of three autophagic inhibitors resulted in a significant increase of PrP
Sc
. The mammalian target of rapamycin (MTOR) levels in SMB-S15 cells were also markedly decreased, in direct relation to PrP
Sc
accumulation. F-box and WD repeat domain containing 7 (FBXW7) levels in SMB-S15 cells and in the brains of scrapie-agent 263K-infected hamsters were upregulated at the early stage of infection, leading to active ubiquitination and degradation of MTOR. Knockdown of FBXW7 in SMB-S15 cells remarkably inhibited autophagic flux and increased PrP
Sc
accumulation. Thus, we conclude that prion infection induced the expression of FBXW7, which mediated MTOR ubiquitination and degradation, further altering phosphorylation status through cross talk between MTORC1 and AMPK and increasing autophagic flux. Autophagy may serve as innate immunity to degrade PrP
Sc
and maintain prion homeostasis.
Temperature, as a critical abiotic factor, might influence the effectiveness of biological control by parasitoids in host-parasitoid systems. In this study, Neochrysocharis formosa (Westwood), a ...larval endoparasitoid, is used to investigate the efficacy of biological control on a vegetable agriculture pest, Liriomyza sativae Blanchard, reared on kidney bean (Phaseolus vulgaris L.), at four constant temperatures (26, 29, 32, and 35°C) under laboratory conditions. Our results show that high temperatures (29, 32, and 35°C) do not significantly affect lifetime host-killing events of female adults by increased daily host-killing events compared to temperature of 26°C, although their lifespans decrease with an increase in temperatures. Each life-history trait of female adults (lifespan, parasitism, stinging, or non-reproductive host-killing events) present a linear relation with temperatures and host-feeding events, respectively. Our findings contribute to a better understanding of biocontrol efficacy of parasitoid N. formosa against agromyzid leafminers at high-temperature seasons or environments.
•Microgrid optimal dispatch to reduce costs, carbon emissions and power fluctuation.•The multi-objective optimization algorithm based on war strategy.•Pareto frontier sort based on membership ...degree.•Reasonable allocation of new energy and energy storage.
This article introduces a novel metaheuristic multi-objective optimization algorithm to address the complex multi-objective optimization scheduling challenges of the microgrids for the first time. Comparing with common multi-objective optimization algorithms, the proposed Multi-Objective War Strategy Optimization (MOWSO) has the following highlights: 1) MOWSO only needs to set three parameters. The few parameters make the algorithm simple to debug and real-world implement in practical applications. 2) MOWSO avoids the local centralized distribution of Pareto frontier based on a random selection strategy. The selection range of multiple objectives is expanded properly. In addition, a comprehensive multi-objective optimization dispatch model for microgrids is established, concurrently considering operating costs, carbon emissions, and power fluctuations. Furthermore, the impact of new energy proportion and Energy Storage (ES) on microgrid optimal dispatch is thoroughly investigated. Finally, a case study about a village microgrid in North China is presented to validate the effectiveness and the superiority of proposed multi-objective optimization dispatch model and novel MOWSO algorithm.
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