ADC189 is a novel drug of cap-dependent endonuclease inhibitor. In our study, its antiviral efficacy was evaluated in vitro and in vivo, and compared with baloxavir marboxil and oseltamivir. A first-in-human phase I study in healthy volunteers included single ascending dose (SAD) and food effect (FE) parts. In the preclinical study, ADC189 showed potent antiviral activity against various types of influenza viruses, including H1N1, H3N2, influenza B virus, and highly pathogenic avian influenza, comparable to baloxavir marboxil. Additionally, ADC189 exhibited much better antiviral efficacy than oseltamivir in H1N1 infected mice. In the phase I study, ADC189 was rapidly metabolized to ADC189-I07, and its exposure increased proportionally with the dose. The terminal elimination half-life (T_1/2) ranged from 76.69 to 98.28 hours. Of note, food had no effect on the concentration, clearance, and exposure of ADC189. It was well tolerated, with few treatment-emergent adverse events (TEAEs) reported and no serious adverse events (SAEs). ADC189 demonstrated excellent antiviral efficacy both in vitro and in vivo. It was safe, well-tolerated, and had favorable pharmacokinetic characteristics in healthy volunteers, supporting its potential for single oral dosing in clinical practice.
Humans ; Antiviral Agents/therapeutic use* ; Animals ; Male ; Adult ; Mice ; Female ; Endonucleases/antagonists & inhibitors* ; Influenza, Human/drug therapy* ; Young Adult ; Dibenzothiepins/pharmacology* ; Oseltamivir/pharmacology* ; Middle Aged ; Triazines/pharmacology* ; Thiepins/pharmacology* ; Influenza B virus/drug effects* ; Influenza A Virus, H1N1 Subtype/drug effects* ; Pyridines/pharmacology* ; Morpholines ; Pyridones

Objective To explore the effects of EEG biofeedback on the sleep quality and autonomic nervous function in the patients with depression sleep disorder.Methods A total of 98 inpatients with depres-sive sleep disorder treated in this hospital from January 2020 to August 2021were selected as the study sub-jects and divided into the study group and control group according to the random number table method,49 ca-ses in each group.The control group adopted the escitalopram treatment,and the study group was combined with EEG biofeedback on this basis.The Hamilton Depression Scale(HAMD)score,Pittsburgh Sleep Quality Index(PSQI)score,subjective insomnia symptom score,heart rate variability(HRV)index,serum neuropep-tide Y(NPY)and 5-hydroxytryptamine(5-HT)levels and the incidence rate of adverse reactions before treat-ment and in 3 months of treatment were compared between the two groups.Results The total effective rate of the study group was significantly higher than that of the control group(95.92％vs.81.63％),and the difference was statistically significant(P＜0.05).After 3 months of treatment,the HAMD,PSQI,subjective insomnia symptom score and PNN50 in both groups were decreased compared with those before treatment,moreover the study group was lower than the control;the levels of SDNN,SDANN,LF,HF and serum NPY and 5-HT were increased compared with those before treatment,moreover the study group was higher than the control group,and the differences were statistically significant(P＜0.05).There was no statistically sig-nificant difference in the incidence rate of adverse reactions between the two groups(14.29％vs.10.20％,P＞0.05).Conclusion EEG biofeedback combined with escitalopram could significantly improve the depres-sive symptoms and sleep quality in the patients with depression,regulate the autonomic nervous function and increase serum NPY and 5-HT levels.

Sialyllactose is one of the most abundant sialylated oligosaccharides in human milk oligosaccharides (HMOs), which plays an important role in the healthy development of infants and young children. However, its efficient and cheap production technology is still lacking presently. This study developed a two-step process employing multiple-strains for the production of sialyllactose. In the first step, two engineered strains, E. coli JM109(DE3)/ pET28a-BT0453 and JM109(DE3)/pET28a-nanA, were constructed to synthesize the intermediate N-acetylneuraminic acid. When the ratio of the biomass of the two engineered strains was 1:1 and the reaction time was 32 hours, the maximum yield of N-acetylneuraminic acid was 20.4 g/L. In the second step, E. coli JM109(DE3)/ pET28a-neuA, JM109(DE3)/ pET28a-nst and Baker's yeast were added to the above fermentation broth to synthesize 3'-sialyllactose (3'-SL). Using optimal conditions including 200 mmol/L N-acetyl-glucosamine and lactose, 150 g/L Baker's yeast, 20 mmol/L Mg²⁺, the maximum yield of 3'-SL in the fermentation broth reached 55.04 g/L after 24 hours of fermentation and the conversion rate of the substrate N-acetyl-glucosamine was 43.47%. This research provides an alternative technical route for economical production of 3'-SL.
Child ; Humans ; Child, Preschool ; N-Acetylneuraminic Acid ; Escherichia coli/genetics* ; Lactose ; Fermentation ; Saccharomyces cerevisiae ; Oligosaccharides ; Glucosamine

Plastics are one of the most important polymers with huge global demand. However, the downsides of this polymer are that it is difficult to degrade, which causes huge pollution. The environmental-friendly bio-degradable plastics therefore could be an alternative and eventually fulfill the ever-growing demand from every aspect of the society. One of the building blocks of bio-degradable plastics is dicarboxylic acids, which have excellent biodegradability and numerous industrial applications. More importantly, dicarboxylic acid can be biologically synthesized. Herein, this review discusses the recent advance on the biosynthesis routes and metabolic engineering strategies of some of the typical dicarboxylic acids, in hope that it will help to provide inspiration to further efforts on the biosynthesis of dicarboxylic acids.
Biodegradable Plastics ; Dicarboxylic Acids ; Polymers/metabolism* ; Biodegradation, Environmental ; Metabolic Engineering

As an important dicarboxylic acids existing in nature, glucaric acid has been widely used in medical, health, and polymer materials industry, therefore it is considered as one of the "top value-added chemicals from biomass". In this study, using Saccharomyces cerevisiae as a chassis microorganism, the effects of overexpression of myo-inositol transporter Itr1, fusional expression of inositol oxygenase MIOX4 and uronate dehydrogenase Udh, and down-expression of glucose-6-phosphate dehydrogenase gene ZWF1 on the glucaric acid production were investigated. The results showed that the yield of glucaric acid was increased by 26% compared with the original strain Bga-3 under shake flask fermentation after overexpressing myo-inositol transporter Itr1. The yield of glucaric acid was increased by 40% compared with Bga-3 strain by expressing the MIOX4-Udh fusion protein. On these basis, the production of glucaric acid reached 5.5 g/L, which was 60% higher than that of Bga-3 strain. In a 5 L fermenter, the highest yield of glucaric acid was 10.85 g/L, which was increased 80% compared with that of Bga-3 strain. The application of the above metabolic engineering strategy improved the pathway efficiency and the yield of glucaric acid, which may serve as a reference for engineering S. cerevisiae to produce other chemicals.
Fermentation ; Glucaric Acid/metabolism* ; Inositol Oxygenase/genetics* ; Metabolic Engineering ; Saccharomyces cerevisiae/metabolism*

Objective:To explore the relationship between soft markers found in the first trimester (11-13 + 6 gestational weeks) ultrasound screening and fetal adverse pregnancy outcomes. Methods:Single pregnancy fetuses were selected from the Multicenter Clinical Study of First Trimester Screening in China during August 2017 to August 2020. The types and detection rate of soft markers during the first trimester were compared. The correlation between positive soft markers and adverse pregnancy outcomes was analyzed by binary Logistics regression.Results:A total of 16 625 fetuses with complete follow-up outcomes were included in the group. Six hundred and seven ultrasonic soft markers were detected in 556 fetuses with positive soft markers during the first trimester, and the first four most frequently occurred were increased nuchal translucency (NT) (2.08%, 345/16 625), echogenic intracardiac focus (EIF) (0.94%, 156/16 625), hypoplasia of fetal nasal bone (0.20%, 34/16 625), single umbilical artery (SUA) (0.19%, 31/16 625). Among 556 fetuses, the incidence of adverse pregnancy outcome in fetuses with two or more positive soft markers was 32.50% (13/40), which was significantly higher than fetuses with single positive soft marker (11.05%, 57/516), and the difference was statistically significant (χ 2=5.055, P<0.001). The incidence of adverse pregnancy outcome in positive soft markers fetus associated with structural abnormalities was 80.77% (21/26), which was significantly higher than fetuses with isolated positive soft marker (12.08%, 64/530), and the difference was statistically significant (χ 2=90.310, P<0.001). Binary logistic regression analysis showed choroid plexus cyst (CPC), SUA, echogenic bowel (EB), absent/reversed a-wave of ductus venosus, hypoplasia of fetal nasal bone, increased NT, and EIF were closely related to the adverse pregnancy outcomes (all P<0.05). However, there were no significant correlations between tricuspid regurgitation (TR), pyelectasis (PYE) and fetal adverse pregnancy outcomes (all P>0.05). Conclusions:The ultrasonic soft markers during the first trimester are of great significance in predicting fetal adverse pregnancy outcomes. For multiple positive soft markers or positive soft markers combined with structural abnormalities, more attention should be paid to them and comprehensive evaluation is required to be carried out.

Denitrification is an indispensable part of most sewage treatment systems. The biological denitrification process has attracted much attention in the past decades due to the advantages such as cost-effectiveness, process simplicity, and absence of secondary pollution. This review summarized the advances on biological denitrification processes in recent years according to the different physiological characteristics and denitrification mechanisms of denitrification microorganisms. The pros and cons of different biological denitrification processes developed based on nitrifying bacteria, denitrifying bacteria, and anaerobic ammonia-oxidizing bacteria were compared with the aim to identify the best strategy for denitrification in a complex wastewater environment. The rapid development of synthetic biology provides possibilities to develop highly-efficient denitrifying strains based on mechanistic understandings. Combined with the applications of automatic simulation to obtain the optimal denitrification conditions, cost-effective and highly-efficient denitrification processed can be envisioned in the foreseeable future.
Aerobiosis ; Denitrification ; Nitrification ; Nitrogen ; Waste Water

Industrial microorganisms and their products are widely used in various fields such as industry, agriculture, and medicine, which play a pivotal role in economy. Efficient industrial strains are the key to improve production efficiency, and advanced fermentation technology as well as instrument platform is also important to develop microbial metabolic potential. In recent years, rapid development has been achieved in research of industrial microorganisms. Artificial intelligence, efficient genome-editing and synthetic biology technologies have been increasingly applied, and related industrial applications are being accomplished. In order to promote utilization of industrial microorganisms in biological manufacturing, we organized this special issue on innovation and breakthrough of industrial microorganisms. Progress including microbial strain diversity and metabolism, strain development technology, fermentation process optimization and scale-up, high-throughput droplet culture system, and applications of industrial microorganisms is summarized in this special issue, and prospects on future studies are proposed.
Artificial Intelligence ; Fermentation ; Industrial Microbiology ; Industry ; Metabolic Engineering ; Synthetic Biology

Transcription factor-based biosensors (TFBs) play an essential role in metabolic engineering and synthetic biology. TFBs sense the metabolite concentration signals and convert them into specific signal output. They hold high sensitivity, strong specificity, brief analysis speed, and are widely used in response to target metabolites. Here we reviewe the principles of TFBs, the application examples, and challenges faced in recent years in microbial cells, including detecting target metabolite concentrations, high-throughput screening, adaptive laboratory evolutionary selection, and dynamic control. Simultaneously, to overcome the challenges in the application, we also focus on reviewing the performance tuning strategies of TFBs, mainly including traditional and computer-aided tuning strategies. We also discuss the opportunities and challenges that TFBs may face in practical applications, and propose the future research trend.
Biosensing Techniques ; Gene Expression Regulation ; Metabolic Engineering ; Synthetic Biology ; Transcription Factors/metabolism*

Objective:It is yet to be clarified whether pylorus-preserving gastrectomy (PPG) for early gastric cancer will bring the risk of radical tumor resection, whether it will increase the incidence of postoperative complications, and how much is the benefit of the quality of life for patients after surgery, these issues are not clear. This meta-analysis aims to evaluate the efficacy and safety of pylorus-preserving gastrectomy (PPG) for early middle gastric cancer.Methods:The Chinese and English literatures about PPG and distal gastrectomy (DG) for early gastric cancer were searched from PubMed, Embase, The Cochrane Library, Web of Science, CNKI net and Wanfang database. Literature inclusion criteria: (1) Prospective or retrospective cohort study of PPG and DG for early middle-third gastric cancer published publicly; (2) Patients with early middle-third gastric cancer; (3) The enrolled literatures include at least one of the following outcome indicators: the efficacy indicators include gallstone, residual gastritis, bile reflux, delayed gastric emptying, dumping syndrome, reflux esophagitis and overall complication; the long-term prognostic indicators include 5-year survival rate and 5-year tumor recurrence. Literature exclusion criteria: (1) Reviews, case reports, conference summaries and other non-control studies; (2) Repeated published studies, incomplete studies and unextractable studies; (3) The depth of tumor invasion exceeding submucosa. The search time ended in July 2020. The basic information and evaluation indicators included in the article were extracted. The retrospective study was evaluated using Newcastle-Ottawa literature quality evaluation scale. The prospective randomized controlled study was evaluated using Jadad modified scale. Meta-analysis was performed using Review Manager 5.3. Publication bias was assessed using funnel map. Publication bias was tested using Egger tools.Results:A total of 717 literatures were retrieved, and 17 literatures were enrolled finally, including 2 randomized controlled trials and 15 retrospective studies. A total of 2427 patients were enrolled, including 948 in PPG group and 1479 in DG group. The meta-analysis of the efficacy indicators showed that there were significant differences in gallstones incidence (OR=0.42, 95% CI: 0.28-0.65, P<0.001), residual gastritis incidence (OR=0.50, 95% CI: 0.32-0.77, P=0.002), bile reflux incidence (OR=0.30, 95% CI: 0.20-0.45, P<0.001), delayed gastric emptying incidence (OR=2.40, 95% CI:1.67-3.45, P<0.001), and postoperative dumping syndrome incidence (OR=0.28, 95% CI: 0.15-0.51, P<0.001), while there were no significant differences in postoperative overall complications (OR=0.97, 95% CI: 0.69-1.35, P=0.840), reflux esophagitis incidence (OR=0.79, 95% CI: 0.39-1.61, P=0.520) between the two groups. The meta-analysis of the long-term prognostic indicators showed that no significant differences of 5-year survival (OR=1.02, 95% CI: 0.61-1.71, P=0.940) or 5-year tumor recurrence (OR=0.77, 95% CI: 0.36-1.68, P=0.520) were observed between the two groups. Conclusion:The incidences of gallstone, residual gastritis, dumping syndrome, bile reflux are lower after PPG in early gastric cancer, while the postoperative overall complications and long-term survival are comparable between PPG and DG, indicating that PPG is quite safe and feasible.