"Toxicity Testing in the 21st Century—A Vision and Strategy"proposed by the National Research Council of US has brought innovative directives and objectives for toxicity evaluation and risk assessment,pushing forward the next generation of toxicity testing and risk assessment.In this initiative,the concept of adverse outcome pathways(AOPs)has emerged as a prominent methodology,capturing the attention of toxicologists and researchers due to its promising applications in recent years.The quantitative AOP(qAOP)is an extension of the adverse outcome pathway,which is built upon the foundational qualitative adverse outcome pathway model and leverages mathematical frame-works to depict dose-response and/or response-response relationships.This article reviews the princi-ples and advancement surrounding qAOP,introduceds two prevalent methodologies for constructing qAOP,Bayesian network models and regression models,and demonstrates diverse applications of qAOP.Actual cases are used to underscore the transformative role of qAOP in contemporary toxicology and risk assessment practices.

Endosomal TLRs (TLR3/7/8/9) are highly analogous innate immunity sensors for various viral or bacterial RNA/DNA molecular patterns. Among them, TLR7, in particular, has been suggested to be a target for various inflammatory disorders and autoimmune diseases including systemic lupus erythematosus (SLE); but few small-molecule inhibitors with elaborated mechanism have been reported in literature. Here, we reported a well-characterized human TLR7-specific small-molecule inhibitor, TH-407b, with promising potency and negligible cytotoxicity through a novel binding mechanism. Notably, TH-407b not only effectively inhibited TLR7-mediated pro-inflammatory signaling in a variety of cultured cell lines but also demonstrated potent inflammation suppressing activities in primary peripheral blood mononuclear cells (PBMCs) derived from SLE patients. Furthermore, TH-407b showed prominent efficacy in vivo, improved survival rate and ameliorated symptoms of SLE model mice. To obtain molecular insights into the TH-407b derivatives' inhibition mechanism, we performed the structural analysis of TLR7/TH-407b complex using cryogenic electron microscopy (cryo-EM) method. As an atomistic resolution cryo-EM structure of the TLR family, it not only of value to facilitate structure-based drug design, but also shed light to methodology development of small proteins using EM. Significantly, TH-407b has unveiled an inhibition strategy for TLR7 via stabilizing its resting/inactivated state. Such a resting state could be generally applicable to all TLRs, rendering a useful method for targeting this group of important immunological receptors.

Abstract The popularization of the use of electronic has become a global trend, and children are exposed to devices at younger ages. A large proportion of children and adolescents spend on screen time more than 2 h which is recommended in most guidelines. The paper reviews possible effects of screen time on physical and mental health, as well as mental disorders in children and adolescents. It is found that excessive screen time showed negative impacts on mental health, including depression, anxiety, mood disorder, social adaptational problems, behavioral disorders, self injurious behaviors, and health risk behaviors. Much attention has been paid on the association between excessive screen time and mental health of children and adolescents, while possible mechanisms and influencing factors are lacking. Effective intervention studies are needed to provide a basis for child and adolescent health promotion.

Objective:To explore the safety and efficiency of a novel bipolar electric knife for endoscopic submucosal dissection.Methods:The thermal damage on tissue caused by the new bipolar knife and traditional monopolar knife were compared by finite element analysis. The vertical thermal damage to the porcine gastric wall caused by the two types of electric knife were analyzed in vitro animal experiments. In vivo animal experiments were used to compare operation related indexes of two types of electric knife, including en bloc resection rate and cutting efficiency in porcine digestive tract submucosal dissection. Results:Through overcoming deviation of experimental individuals and operator experience, the finite element model showed that the length, width and depth of thermal damage on tissue caused by the monopolar knife was 1.08 times, 1.12 times, and 1.23 times of that of the bipolar knife, respectively. Additionally, the bipolar knife caused less vertical thermal damage to the porcine gastric wall than the monopolar knife (433.25±42.58 μm VS 898.03±111.59 μm, t=6.740, P=0.003) in vitro animal experiments when charged for 1 s at the same power. Finally, in vivo animal experiments showed that the en bloc resection rates of the two kinds of electric knife systems were both 100.0%. In addition, the cutting area and cutting time of the bipolar knife was 229.58±185.29 mm 2 and 164.37±96.27 s, respectively. The corresponding indicators of the monopolar knife was 209.70±167.35 mm 2 and 162.65±69.97 s, respectively, and there was no significant difference (all P>0.05). Conclusion:The novel bipolar knife not only ensures the cutting efficiency but also reduces the thermal damage during endoscopic submucosal dissection in simulating experiment and animal experiment, which needs further verification in clinical trial.

Objective: To investigate the feasibility and clinic outcome of the turbocharging technique in repairing large defect with free perforator flap. Methods: From January 2017 to December 2018, 6 patients with defect of over length or large size were repaired with free perforator flaps, anterolateral thigh(ALT) flap in 3 cases and deep inferior epigastric artery perforator(DIEP) flap in 3 cases in Department of Hand Surgery, Ningbo No.6 Hospital. There were 4 males and 2 females, aged from 29 to 54 years old, with an average age of 41 years old.It was found that the size of the flap beyond the perforasome, while multiple perforators in the flaps were not from the same pedicle. The turbocharging technique was applied in the operation. The distal perforator of the flap was anastomosed with the proximal pedicle branch. The flap size ranged from 20 cm×8 cm to 25 cm×12 cm. The donor sites were closed directly for 3 cases and skin grafting for 3 cases. Results: All the flaps survived successfully, no distal necrosis occurred. The patients were followed up for 3 to 12 months, with an average of 9 months. All flaps survived well with satisfactory appearance and pliable texture. The healing of skin graft was satisfactory in 3 cases in donor site. No graft skin contracture occurred. The donor sites closed directly in 3 cases had linear scar in donor site, no obvious contracture occurred. The flap sensation returned to S2-S3. Conclusions If the size of the flap is super long or large, beyond the perforasome, while multiple perforators in the flaps were not from the same pedicle, the application of turbocharging technique can avoid partial necrosis of the flap and improve the survival rate of the flap, which is an ideal alternative.

BACKGROUND:A lot of work has been carried out on the development of the primary cultured rat myocardial cel s at home and abroad. The primary culture technology of rat myocardial cel s becomes more mature, but myocardial cel s from neonatal mice are not easy to be obtained under the same experimental conditions. The mouse genome has more similarities with the human genome, which has a higher research value. OBJECTIVE:To improve the primary culture method of neonatal mouse myocardial cel s, and to obtain myocardial cel s with high purity, vitality and original structure and function. METHODS:The mouse cardiac tissues were treated using an enzyme digestion method to isolate isolated single myocardial cel s:first, the cardiac tissues were digested using trypsin, and then col agenous fibers were treated with col agenase to isolate single myocardial cel s. The concentration and action time of trypsin and type II col agenase were adjusted, and the pH values of reagents and temperature of each step were strictly control ed. RESULTS AND CONCLUSION:At 24 hours after inoculation, the myocardial cel s began to be adherent;at 48 hours, independent pulsation of myocardial cel s could be observed;at 72 hours, myocardial cel s were cross-linked;and at 96 hours, myocardial cel s formed cel clusters and presented with consistent beating. The survival rate and purity of myocardial cel s were both over 95%. This modified method could successful y culture myocardial cel s with high purity and viablility from neonatal mice, and the structure and function of myocardial cel s could be retained. Therefore, it is a feasible culture method.

OBJECTIVE:To observe the therapeutic effect of compound glycyrrhizin combining ursodeoxycholic acid in the treatment of chronic hepatitis B.METHODS:87patients with chronic hepatitis B were enrolled to,on whom,the anti-viral therapy proved to be ineffective and who suffered a long-term abnormal liver functions,of the total,47were randomly as?signed to receive compound glycyrrhizin plus ursodeoxycholic acid(treatment group),and40to receive compound glycyrrhizin plus vitamin C(control group).Course of treatment for both groups was8weeks.RESULTS:As compared with the control group,the liver function and immune function for the treatment group had a better amelioration(P