AhR activation promotes Treg cell generation by enhancing Lkb1-mediated fatty acid oxidation via the Skp2/K63-ubiquitination pathway.

Several aryl hydrocarbon receptor (AhR) agonists have been reported to promote the generation of regulatory T cells (Treg cells), and the action mechanisms need to be identified. In this study, we addressed the underlying mechanism of AhR activation to induce the generation of Treg cells in the view of cellular metabolism. Naïve CD4+ T cells were purified with mouse CD4+ CD62L+ T Cells Isolation Kits. The proportions of Treg cells were detected by flow cytometry. The value of oxygen consumption rate (OCR) of CD4+ T cells was detected by the Seahorse XFe 96 analyzer. The activation of fatty acid oxidation (FAO)-related metabolic pathways was detected by Western blotting. Intracellular localization of Lkb1 was detected by immunofluorescence. The Strad-Mo25-Lkb1 complex formation and K63 chain ubiquitination modification of Lkb1 were detected by co-immunoprecipitation. The binding of AhR to the Skp2 promoter was detected by constructing luciferase reporter gene. AhR or carnitine palmitoyltransferases 1 was knockdown in dextran sulphate sodium (DSS)-induced colitis or collagen-induced arthritis (CIA) mice by infecting mice with adeno-associated virus via the tail vein injection. Compared to the control group, exogenous and endogenous AhR agonists 3,3'-diindolylmethane (DIM) and 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) were shown to preferentially upregulate the mRNA expression of FAO-related enzymes and the value of OCR. Consistently, pharmacological or genetic inhibition of FAO markedly diminished the induction of DIM and ITE on the differentiation of Treg cells. DIM and ITE functioned mainly through activating the liver kinase B1 (Lkb1)-AMPK pathway via promotion of Lkb1-Strad-Mo25 complex formation and Lkb1 K63 ubiquitination. DIM and ITE were also shown to upregulate the mRNA expression of Skp2, a ubiquitination-related enzyme, and facilitate the binding of AhR to the xenobiotic responsive element of Skp2 promoter region by luciferase reporter gene assay. Furthermore, the contribution of Skp2/K63 ubiquitination/Lkb1/FAO axis was verified in (DSS)-induced colitis or CIA mice. In summary, these findings indicate that AhR activation promotes Treg cell generation by enhancing Lkb1-mediated FAO via the Skp2/K63-ubiquitination pathway, and AhR agonists may be used as inducers of Treg cells to prevent and treat autoimmune diseases.

Real-time neural network scheduling of emergency medical mask production during COVID-19.

During the outbreak of the novel coronavirus pneumonia (COVID-19), there is a huge demand for medical masks. A mask manufacturer often receives a large amount of orders that must be processed within a short response time. It is of critical importance for the manufacturer to schedule and reschedule mask production tasks as efficiently as possible. However, when the number of tasks is large, most existing scheduling algorithms require very long computational time and, therefore, cannot meet the needs of emergency response. In this paper, we propose an end-to-end neural network, which takes a sequence of production tasks as inputs and produces a schedule of tasks in a real-time manner. The network is trained by reinforcement learning using the negative total tardiness as the reward signal. We applied the proposed approach to schedule emergency production tasks for a medical mask manufacturer during the peak of COVID-19 in China. Computational results show that the neural network scheduler can solve problem instances with hundreds of tasks within seconds. The objective function value obtained by the neural network scheduler is significantly better than those of existing constructive heuristics, and is close to those of the state-of-the-art metaheuristics whose computational time is unaffordable in practice.

Honokiol Exerts Antidepressant Effects in Rats Exposed to Chronic Unpredictable Mild Stress by Regulating Brain Derived Neurotrophic Factor Level and Hypothalamus-Pituitary-Adrenal Axis Activity.

Honokiol (HNK), the main active component of Magnolia officinalis, has shown a variety of pharmacological activities. In the present study, we measured the antidepressant-like effects of HNK in a rat model of chronic unpredictable mild stress (CUMS) and explored its possible mechanisms. The antidepressant-like effects of HNK were assessed in rats by an open field test (OFT), sucrose preference test (SPT) and forced swimming test (FST). Then, serum levels of corticotrophin-releasing hormone (CRH), adrenocorticotropic hormone (ACTH) and corticosterone (CORT) and hippocampal brain-derived neurotrophic factor (BDNF) and glucocorticoid receptor α (GRα) levels were assessed to explore the possible mechanisms. We identified that HNK treatment (2, 4, and 8 mg/kg) alleviated the CUMS-induced behavioural deficits. Treatment with HNK also normalized the CUMS-induced hyperactivity of the limbic hypothalamic-pituitary-adrenal (HPA) axis, as indicated by reduced CRH, ACTH and CORT serum levels. In addition, HNK increased the expression of GRα (mRNA and protein) and BDNF (mRNA and protein) in the hippocampus. These data confirmed the antidepressant-like effects of HNK, which may be related to its normalizing the function of the HPA axis and increasing the BDNF level in the hippocampus.

Influencing factors on the activity of an enriched Nitrospira culture with granular morphology.

Nitrospira is a common genus of nitrite-oxidising bacteria (NOB) found in wastewater treatment plants (WWTPs). To identify the key factors influencing the composition of NOB communities, research was conducted using both sequencing batch reactor (SBR) and continuous flow reactor under different conditions. High-throughput 16S rRNA gene sequencing revealed that Nitrospira (18.79% in R1 and 25.77% in R3) was the dominant NOB under low dissolved oxygen (DO) and low nitrite (NO2--N) concentrations, while Nitrobacter (21.26% in R2) was the dominant NOB under high DO and high NO2--N concentrations. Flocculent and granule sludge were cultivated with Nitrospira as the dominant genus. Compared to Nitrospira flocculent sludge, Nitrospira granule sludge had higher inhibition threshold concentrations for free ammonia (FA) and free nitrous acid (FNA). It was more likely to resist adverse environmental disturbances. Furthermore, the effects of environmental factors such as temperature, pH, and DO on the activity of Nitrospira granular sludge were also studied. The results showed that the optimum temperature and pH for Nitrospira granular sludge were 36°C and 7.0, respectively. Additionally, Nitrospira granular sludge showed a higher dissolved oxygen half-saturation constant (Ko) of 3.67 ± 0.71 mg/L due to its morphological characteristics. However, the majority of WWTPs conditions do not meet the conditions for the Nitrospira granular sludge. Thus, it can be speculated that future development of aerobic partial nitrification granular sludge may automatically eliminate the influence of Nitrospira. This study provides a theoretical basis for a deeper understanding of Nitrospira and the development of future water treatment processes.

A case of precipitate in intravenous line when general anesthesia implemented with remimazolam.

Adverse reactions caused by drug compatibility are more common in clinical practice, including discoloration, precipitation, crystallization, which can be life-threatening in severe cases. We report a 63-year-old man who developed precipitation during maintenance of general anesthesia with remimazolam tosylate for prostate resection. There were many precipitates in the infusion pipeline and the three-way stopcock, and at that time the infusion liquid was Ringer's acetate solution. Then we investigated the possibility of precipitation with different infusion fluids and remimazolam tosylate. In conclusion, precipitates may not form at a lower remimazolam tosylate concentration and a faster liquid infusion rate and require appropriate attention.

Safety and efficacy of remimazolam compared with propofol in induction of general anesthesia.

BACKGROUND: Remimazolam is a new ultrashort acting benzodiazepine anesthetic which has predictable sedative duration and rapid recovery in gastrointestinal endoscopy. Propofol is a commonly used intravenous anesthetic in clinical work which also has rapid action, short action time and rapid recovery. To date, there have been relatively few articles comparing the two for general anesthesia induction. So, we conducted a randomized trial to evaluate whether remimazolam is superior to propofol during anesthesia induction in terms of efficacy and safety. METHODS: One hundred and eighty nine ASA I or II patients scheduled for elective surgery were divided into four groups: remimazolam 0.2 mg/kg (R1 group), 0.3 mg/kg (R2 group), 0.4 mg/kg (R3 group), and propofol group (P group). All patients were anesthetized with single shots of experimental drugs during induction period. Efficacy was measured by completing the induction of anesthesia without rescue sedation; and safety was defined as no severe adverse events. RESULTS: Success induction rates in remimazolam groups were 89% (R1 group), 94% (R2 group) and 100% (R3 group) while success induction rate in P group was 100%. Hypotension rates during induction were lower in R1 group (13%) and R2 group (24%) compared with P group (44%). Hypotension rate in R3 group (34%) was similar to propofol (44%). Injection site pain in group P was 27% while no pain was observed in remimazolam groups. CONCLUSIONS: Remimazolam is a safe and effective sedative drug during induction with less adverse effects for general anesthesia in ASA I or II patients.

[Start-up of CANON Process and Short-cut Nitrification in a Pilot-scale MBBR Reactor].

Using a 150 L moving bed biofilm reactor (MBBR), with the temperature controlled at 28℃ and high NH4+-N concentration (average concentration 350 mg·L-1), inorganic wastewater was used as an influent to start the completely autotrophic nitrogen removal over nitrite (CANON) process. Meanwhile, the flocculent sludge was taken into a 5 L sequencing batch reactor, and the influent NH4+-N concentration was maintained at 90-200 mg·L-1 for the recovery of short-cut nitrification. The results showed that in the MBBR reactor, when the average hydraulic retention time (HRT) was 12 h, short-cut nitrification and total nitrogen (TN) removal rate were mutually constrained, the average TN removal rate was 38.2%, and the average δNO3--N/TN value was 0.274; when the HRT dropped to 6 h, the δNO3--N/TN value decreased from 0.347 to 0.146. The sequencing batch reactor (SBR) maintained aeration and anoxic time for 30 min and 20 min, respectively, by intermittent aeration, while the dissolved oxygen concentration during the aerobic process was 0.5 mg·L-1 to 0.6 mg·L-1, the free nitrous acid concentration was higher than 0.18 mg·L-1 at the end of each cycle, NAR increased from 0 to 99.2% after 12 days, NUR decreased to 0 from an initial 24.8 mg·(g·h)-1, and the TN removal rate decreased from 13% to 3%; the system successfully converted to short-range nitrification. High-throughput sequencing results showed that the abundance of Candidatus Kuenenia in the flocculent sludge and biofilm in the MBBR reactor were 7.91% and 17.38% respectively, Nitrosomonas accounted for 27.43% and 2.55%, respectively, while Nitrospira accounted for 0.30% and 0.28%, respectively. After the recovery of short-cut nitrification in the SBR, the abundance of ammonia-oxidizing bacteria and anaerobic ammonia oxidation decreased to 1.18% and 0.01%, respectively, and the abundance of Nitrospira increased to 1.39%.

[Operation Characteristics of the Biofilm CANON Reactor During the Temperature Reduction Process].

The focus of this paper, was low temperature, high ammonia nitrogen wastewater. The operation characteristics of the biofilm CANON process during the temperature reduction process were determined, by continuously adjusting different operating conditions. The aim was to explore the methods needed for the CANON process to obtain stable shortcut nitrification and a good nitrogen removal effect, when the influent NH4+-N concentration is high and the temperature low. The results showed that, ① compared with the biofilm CANON reactor temperature changing from medium to low temperature directly (30℃±1℃→19℃), it was more conducive to adapt the nitrogen-removing bacteria to the low-temperature environment, while the temperature was gradually lowered. Moreover, the extent of each reduction should be minimized. Besides, the operating conditions should be adjusted to ensure the nitrogen removal effect. ② The temperature was gradually reduced to about 19℃ after 25 d, and then decreased to about 15℃ after another 18 d. The NH4+-N and TN removal rates could be respectively stable at 90% and 70% over a long period of time. The TN removal rate and removal load could still reach 72.52% and 0.78 kg·(m3·d)-1, respectively, even when the temperature dropped to 12℃. ③ When adapting biological CANON sludge during the temperature reduction process, shortcut nitrification should be given priority. A stable shortcut nitrification effect should be obtained by maintaining a certain concentration of residual NH4+-N, and by strictly controlling the DO concentration to restrain NOB activity.

[Impact of C/N Ratio on Nitrogen Removal Performance and N2O Release of Granular Sludge CANON Reactor].

To Explore a suitable C/N ratio for efficient nitrogen removal and simultaneously achieving N2O release reduction, ammonia-rich wastewater with sodium acetate as an organic carbon source in a granular sludge completely autotrophic nitrogen removal over nitrite (CANON) reactor under different C/N water conditions were studied to determine the reactor's nitrogen removal performance and N2O release. The results showed that the total nitrogen (TN) removal rate and the removal load tended to increase gradually with the increase of C/N, ranging from 0 to 2.0. When C/N=0, the TN removal rate was 56.50 mg·L-1 in 7 h; the highest TN removal efficiency was 49%. When C/N=2.0, the highest TN removal rate was 71.42 mg·L-1 in 7 h; the highest TN removal efficiency was 59.52%, and the contribution of CANON to nitrogen removal gradually decreased, whereas the denitrification contribution gradually increased. When △NO3--N/△TN=0.086, the contribution of CANON nitrogen removal was only 51.48% and that of denitrification was 48.52%. The N2O release volume and release ratio decreased with increasing C/N. When C/N=0, the N2O release volume and rate were the highest, namely 3.60 mg and 2.13%, respectively. The lowest N2O release volume and rate were 1.61 mg and 0.75%, respectively, when C/N=2.0.