This article has been retracted: please see Elsevier Policy on Article Withdrawal (https://www.elsevier.com/about/policies/article-withdrawal). This article has been retracted at the request of the Editor-in-Chief. Concerns raised by Dr. Sander Kersten in PubPeer pointed out that Figs. 6.1B and 6.2B of this paper were different figures but the legends and Western blots were identical; the quantification was also seen to be different between the two figures. Shortly afterwards, the authors asked to publish a corrigendum for part B of Fig. 6.1, including images of western blots and associated bar plots. Subsequently, the journal conducted an investigation and found evidence that there had been improper manipulation and duplication of images in Fig. 2 E, 6.2 B, 5 A and and 6.2 D, as shown by the reuse of several western blot bands with approximately 180° rotation in each case. After raising the complaint with the authors, the corresponding author agreed that the paper should be retracted. The authors apologise to the readers of the journal.

ABSTRACT Monoclonal antibodies (mAbs) and the post-exposure prophylaxis (PEP) with mAbs represent a very important public health strategy against coronavirus disease 2019 (COVID-19). This study has assessed a new Anti-SARS-COV-2 mAb (SA58) Nasal Spray for PEP against COVID-19 in healthy adults aged 18 years and older within three days of exposure to a SARS-CoV-2 infected individual. Recruited participants were randomized in a ratio of 3:1 to receive SA58 or placebo. Primary endpoints were laboratory-confirmed symptomatic COVID-19 within the study period. A total of 1222 participants were randomized and dosed (SA58, n = 901; placebo, n = 321). Median of follow-up was 2.25 and 2.79 days for SA58 and placebo, respectively. Adverse events occurred in 221 of 901 (25%) and 72 of 321 (22%) participants with SA58 and placebo, respectively. All adverse events were mild in severity. Laboratory-confirmed symptomatic COVID-19 developed in 7 of 824 participants (0.22 per 100 person-days) in the SA58 group vs. 14 of 299 (1.17 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 80.82% (95%CI 52.41%−92.27%). There were 32 SARS-CoV-2 reverse transcriptase polymerase chain reaction (RT–PCR) positives (1.04 per 100 person-days) in the SA58 group vs. 32 (2.80 per 100 person-days) in the placebo group, resulting in an estimated efficacy of 61.83% (95%CI 37.50%−76.69%). A total of 21 RT–PCR positive samples were sequenced and all were the Omicron variant BF.7. In conclusion, SA58 Nasal Spray showed favourable efficacy and safety in preventing symptomatic COVID-19 or SARS-CoV-2 infection in adults who had exposure to SARS-CoV-2 within 72 h.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron sublineages have escaped most receptor-binding domain (RBD)-targeting therapeutic neutralizing antibodies (NAbs), which proves that previous NAb drug screening strategies are deficient against the fast-evolving SARS-CoV-2. Better broad NAb drug candidate selection methods are needed. Here, we describe a rational approach for identifying RBD-targeting broad SARS-CoV-2 NAb cocktails. Based on high-throughput epitope determination, we propose that broad NAb drugs should target non-immunodominant RBD epitopes to avoid herd-immunity-directed escape mutations. Also, their interacting antigen residues should focus on sarbecovirus conserved sites and associate with critical viral functions, making the antibody-escaping mutations less likely to appear. Following these criteria, a featured non-competing antibody cocktail, SA55+SA58, is identified from a large collection of broad sarbecovirus NAbs isolated from SARS-CoV-2-vaccinated SARS convalescents. SA55+SA58 potently neutralizes ACE2-utilizing sarbecoviruses, including circulating Omicron variants, and could serve as broad SARS-CoV-2 prophylactics to offer long-term protection, especially for individuals who are immunocompromised or with high-risk comorbidities.

BackgroundA vaccine against COVID-19 is urgently needed for older adults, in whom morbidity and mortality due to the disease are increased. We aimed to assess the safety, tolerability, and immunogenicity of a candidate COVID-19 vaccine, CoronaVac, containing inactivated SARS-CoV-2, in adults aged 60 years and older.MethodsWe did a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial of CoronaVac in healthy adults aged 60 years and older in Renqiu (Hebei, China). Vaccine or placebo was given by intramuscular injection in two doses (days 0 and 28). Phase 1 comprised a dose-escalation study, in which participants were allocated to two blocks: block 1 (3 μg inactivated virus in 0·5 mL of aluminium hydroxide solution per injection) and block 2 (6 μg per injection). Within each block, participants were randomly assigned (2:1) using block randomisation to receive CoronaVac or placebo (aluminium hydroxide solution only). In phase 2, participants were randomly assigned (2:2:2:1) using block randomisation to receive either CoronaVac at 1·5 μg, 3 μg, or 6 μg per dose, or placebo. All participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after each injection in all participants who received at least one dose. The primary immunogenicity endpoint was seroconversion rate at 28 days after the second injection (which was assessed in all participants who had received the two doses of vaccine according to their random assignment, had antibody results available, and did not violate the trial protocol). Seroconversion was defined as a change from seronegative at baseline to seropositive for neutralising antibodies to live SARS-CoV-2 (positive cutoff titre 1/8), or a four-fold titre increase if the participant was seropositive at baseline. This study is ongoing and is registered with ClinicalTrials.gov (NCT04383574).FindingsBetween May 22 and June 1, 2020, 72 participants (24 in each intervention group and 24 in the placebo group; mean age 65·8 years [SD 4·8]) were enrolled in phase 1, and between June 12 and June 15, 2020, 350 participants were enrolled in phase 2 (100 in each intervention group and 50 in the placebo group; mean age 66·6 years [SD 4·7] in 349 participants). In the safety populations from both phases, any adverse reaction within 28 days after injection occurred in 20 (20%) of 100 participants in the 1·5 μg group, 25 (20%) of 125 in the 3 μg group, 27 (22%) of 123 in the 6 μg group, and 15 (21%) of 73 in the placebo group. All adverse reactions were mild or moderate in severity and injection site pain (39 [9%] of 421 participants) was the most frequently reported event. As of Aug 28, 2020, eight serious adverse events, considered unrelated to vaccination, have been reported by seven (2%) participants. In phase 1, seroconversion after the second dose was observed in 24 of 24 participants (100·0% [95% CI 85·8–100·0]) in the 3 μg group and 22 of 23 (95·7% [78·1–99·9]) in the 6 μg group. In phase 2, seroconversion was seen in 88 of 97 participants in the 1·5 μg group (90·7% [83·1–95·7]), 96 of 98 in the 3 μg group (98·0% [92·8–99·8]), and 97 of 98 (99·0% [94·5–100·0]) in the 6 μg group. There were no detectable antibody responses in the placebo groups.InterpretationCoronaVac is safe and well tolerated in older adults. Neutralising antibody titres induced by the 3 μg dose were similar to those of the 6 μg dose, and higher than those of the 1·5 μg dose, supporting the use of the 3 μg dose CoronaVac in phase 3 trials to assess protection against COVID-19.FundingChinese National Key Research and Development Program and Beijing Science and Technology Program.

Importance: Whether herd immunity through mass vaccination is sufficient to curb SARS-CoV-2 transmission requires an understanding of the duration of vaccine-induced immunity, and the necessity and timing of booster doses. Objective: To evaluate immune persistence of two priming doses of CoronaVac, and immunogenicity and safety of a third dose in healthy adults [≥]60 years. Design, setting, and participants: We conducted a vaccine booster study built on a single-center, randomized, double-blind phase 1/2 trial of the two-dose schedule of CoronaVac among healthy adults[≥]60 years in Hebei, China. We examined neutralizing antibody titres six months or more after the second dose in all participants. We provided a third dose to 303 participants recruited in phase 2 trial to assess their immune responses. Interventions: Two formulations (3 g, and 6 g) were used in phase 1 trial, and an additional formulation of 1.5 g was used in phase 2 trial. All participants were given two doses 28 days apart and followed up 6 months after the second dose. Participants in phase 2 received a third dose 8 months after the second dose. Main outcomes and measures: Geometric mean titres (GMT) of neutralizing antibodies to live SARS-CoV-2 and adverse events were assessed at multiple time points following vaccination. Results: Neutralizing antibody titres dropped below the seropositive cutoff of 8 at 6 months after the primary vaccination in all vaccine groups in the phase 1/2 trial. A third dose given 8 months or more after the second dose significantly increased neutralizing antibody levels. In the 3 g group (the licensed formulation), GMT increased to 305 [95%CI 215.3-432.0] on day 7 following the third dose, an approximately 7-fold increase compared with the GMT 28 days after the second dose. All solicited adverse reactions reported within 28 days after a booster dose were of grade 1 or 2 severity. Conclusion and relevance: Neutralizing antibody titres declined substantially six months after two doses of CoronaVac among older adults. A booster dose rapidly induces robust immune responses. This evidence could help policymakers determine the necessity and the timing of a booster dose for older adults. Trial registration: ClinicalTrials.gov (NCT04383574).

目的 探讨白术多糖(AMP)对高糖诱导的肾小球足细胞(HPC)损伤的影响及作用机制.方法 HPC分为对照组(NG组)、高糖组(HG组)、HG+25 mg/L AMP组(HG+AMP-L组)、HG+50 mg/L AMP组(HG+AMP-M组)和HG+100 mg/L AMP组(HG+AMP-H组),Annexin V-FITC/PI双染实验检测细胞凋亡率,Western印迹检测Synaptopodin、desmin、B淋巴细胞瘤(Bcl)-2、Bcl-2相关X蛋白(Bax)和ADIPOR1蛋白表达水平,实时荧光定量-聚合酶链反应(qRT-PCR)检测miR-320c和ADIPOR1 mRNA表达水平.高糖诱导miR-320c表达抑制或过表达ADIPOR1的HPC细胞,同时使用100 mg/L的AMP作用于高糖诱导的过表达miR-320c的HPC,相同方法检测HPC凋亡率、Synaptopodin、desmin、Bcl-2、Bax和ADIPOR1蛋白表达的影响.双荧光素酶报告基因实验验证miR-320c与ADIPOR1之间靶向关系.结果 高糖诱导可使HPC凋亡率、desmin和Bax蛋白及miR-320c表达升高(P<0.05),Synaptopodin和Bcl-2蛋白及ADIPOR1 mRNA和蛋白表达降低(P<0.05).AMP可使高糖诱导的HPC凋亡率、desmin和Bax蛋白及miR-320c表达降低(P<0.05),Synaptopodin和Bcl-2蛋白及ADIPOR1 mRNA和蛋白表达升高(P<0.05),且呈浓度依赖性.抑制miR-320c表达或过表达ADIPOR1可使高糖诱导的HPC凋亡率、desmin和Bax蛋白表达降低(P<0.05),Synaptopodin和Bcl-2蛋白及ADIPOR1 mRNA和蛋白表达升高(P<0.05).miR-320c靶向负调控ADIPOR1表达.miR-320c过表达逆转了AMP(100 mg/L)对高糖诱导的HPC凋亡率、desmin、Synaptopodin、Bax和Bcl-2蛋白表达的影响.结论 AMD可保护高糖诱导的HPC损伤,其作用机制与下调miR-320c上调ADIPOR1表达有关.

Background Large-scale vaccination is being implemented globally with CoronaVac, an inactivated vaccine against coronavirus disease 2019 (COVID-19). Immunogenicity and safety profiles of homologous two-dose schedules have been published. We report interim results of immune persistence, and the immunogenicity and safety of a third dose of CoronaVac. Methods In this ongoing, placebo-controlled, double-blind phase 2 trial in 18-to-59-year-olds, we randomly assigned subjects, 1:1:1:1, to one of four schedules to receive a third dose, 28 days or 6 months after two two-dose regimens (14-day or 28-day apart): schedule 1: days 0, 14, 42; schedule 2: days 0, 14, 194; schedule 3: days 0, 28, 56; schedule 4: days 0, 28, 208. For each schedule, participants were randomly assigned to either a medium-dose group (3 g per 0.5 mL of aluminum hydroxide diluent per dose), a high-dose group (6 g), or a placebo group (2:2:1). The primary outcome was geometric mean titers (GMTs) of neutralizing antibody to live SARS-CoV-2. Results Overall, 540 participants received a third dose. In the 3 g group, neutralizing antibody titers induced by the first two doses declined after 6-8 months to below the seropositive cutoff (GMT: 4.1 [95%CI 3.3-5.2] for Schedule 2 and 6.7 [95%CI 5.2-8.6] for Schedule 4). When a third dose was given 6-8 months after a second dose, GMTs assessed 14 days later increased to 137.9 [95%CI 99.9-190.4] for Schedule 2, and 143.1 [95%CI 110.8-184.7] for Schedule 4, approximately 3-fold above Schedule 1 and Schedule 3 GMTs after third doses. Similar patterns were observed for the 6 g group. The severity of solicited local and systemic adverse reactions reported within 28 days after the third dose were grade 1 to grade 2 in all vaccination cohorts. None of the fourteen serious adverse events were considered to be related to vaccination. Conclusions A third dose of CoronaVac administered 6 or more months after a second dose effectively recalled specific immune response to SARS-CoV-2, resulting in a remarkable increase in antibody levels, and indicating that a two-dose schedule generates good immune memory. Optimizing the timing of a booster dose should take into account immunogenicity, vaccine efficacy/effectiveness, local epidemic situation, infection risk, and vaccine supply. (Funded by the National Key Research and Development Program, Beijing Science and Technology Program and National Science Fund for Distinguished Young Scholars; ClinicalTrials.gov number, NCT04352608.)

Background Although COVID-19 vaccines are currently under use in pregnant and postpartum women, there is still lack of evidence regarding safety and effectiveness in these populations. This study aims to describe the safety profile of COVID-19 vaccines in pregnant and postpartum women in the early stage of vaccination campaign in Brazil. Methods This is an observational cross-sectional study using data from the Brazilian surveillance information system for adverse events (SI-EAPV) to characterize the safety of COVID-19 vaccines available (Sinovac/Butantan, Pfizer/BioNTech, AstraZeneca and Janssen) in Brazilian pregnant and postpartum women after receiving it from April to August 2021. A descriptive analysis was performed to assess the frequency and incidence rate of the adverse events (AE) for COVID-19 vaccines. Results A total of 3,333 adverse events following COVID-19 immunization were reported for the study population in the SIEAPV. The incidence of AE found was 309.4/100,000 doses (95% CI 297.23, 321.51). Regarding the four vaccines available in the country, Sinovac/Butantan had the lowest incidence (74.08/100,000 doses; 95% CI 63.47, 84.69). Systemic events were the most frequent notified for the group (82.07%), followed by local (11.93%) and maternal (4.74%), being most of them classified as non-severe (90.65%). Conclusion A similar pattern of AE as stated in other studies was found, with even better results for non-viral vector vaccines, corroborating to the recommendation of vaccination for these groups. Even though, further studies appraising a longer observation time are still needed to provide a broader safety aspect for the vaccines currently under use for this population.

目的 探究驱动蛋白超家族成员16B(KIF16B)在低密度脂蛋白受体诱导降解蛋白(IDOL)调节肝细胞摄取低密度脂蛋白胆固醇(LD LC)中的作用.方法 干扰/过表达IDOL (RNAi/OE-IDOL)的慢病毒感染HepG2和LO2细胞,通过倒置荧光显微镜来观测病毒感染效果;油红O染色观察细胞内脂质蓄积水平;DiI荧光染料标记的LDL(DiI-LDL)摄取实验检测肝细胞对LDLC的摄取能力,流式细胞术检测肝细胞表面低密度脂蛋白受体(LDLR)丰度;Western blot检测IDOL、KIF16B及LDLR蛋白的表达变化,并免疫共沉淀进一步检测蛋白之间的相互作用.结果 两种感染慢病毒的肝细胞内均显示绿色荧光,提示RNAi/OE-IDOL的慢病毒已感染HepG2和LO2细胞;与无慢病毒感染的Control组比较,OE-IDOL组的细胞内脂质含量显著减少(P＜0.05),LDLC的摄取显著减弱(P＜0.05),且肝细胞表面LDLR丰度显著降低(P＜0.01);RNAi-IDOL组的细胞内脂滴含量显著增加(P＜0.01),LDLC摄取增强,且肝细胞表面LDLR丰度显著增高(P＜0.01);与慢病毒载体的Control组比较,RNAi-IDOL组LDLR蛋白和KIF16B蛋白的表达升高(P＜0.01),且KIF16B与LDLR的相互作用增强;OE-IDOL组LDLR蛋白和KIF16B蛋白的表达降低(P＜0.05),LDLR与KIF16B相互作用随之减弱.结论 IDOL调节的肝细胞摄取LDLC的过程可能与KIF16B跟LDLR之间存在相互作用有关.

为探讨褪黑素受体激动剂Neu-P11(Piromelatine)对急性高血压大鼠血压的影响及其相关机制,本实验采用Trendelenburg(头低脚高80°位置)卧位法建立急性高血压SD大鼠模型.将40只SD大鼠分为正常对照组10例和模型组30例,30只模型组大鼠建模成功后又分为高血压组,Mel治疗组,Neu-P11治疗组(n=10).实验末心脏取血检测大鼠血清氧化应激水平.结果显示,与高血压组相比,Neu-P11治疗后能显著降低急性高血压大鼠血压和血清过氧化物丙二醛(MDA)水平,升高抗氧化物酶超氧化物歧化酶(SOD)和谷胱甘肽过氧化物酶(GSH-Px)血清水平(P<0.05).提示Neu-P11可能通过抑制氧化应激降低急性高血压大鼠血压.

It is well-recognized that hyperlipidemia and lipid peroxidation contribute to the progression of diabetic nephropathy (DN), which is associated with oxidative stress (OS) and fibrotic lesions. Ibrolipim, a specific lipoprotein lipase activator, has been proved to reduce hyperglycemia and hyperlipidemia, suppress renal lipid deposition, and also protect renal damage. However, the underlying mechanisms of its renoprotective effect are not clearly elaborated. Herein, the present study was to identify whether the putative mechanism of Ibrolipim was related to OS and fibrogenesis in diabetic minipigs fed by high-sucrose and high-fat diet (HSFD) with or without Ibrolipim for 5 months. Compared with the normal control diet, nutrient stress induced by HSFD caused moderate glomerulosclerosis and tubulointerstitial fibrosis, and promoted renal ultrastructural and functional abnormalities. These abnormalities were correlated with renal OS and fibrogenesis characterized by the increased levels of reactive oxygen species (ROS), malondialdehyde, hydroxyproline, collagen type Ⅳ alpha 1 and fibronectin, and decreased contents of reduced glutathione and total antioxidant capacity in kidneys. Ibrolipim significantly ameliorated these abnormalities in HSFD-fed minipigs. In addition, Ibrolipim diminished HSFD-induced nicotinamide-adenine dinucleotide phosphate oxidase-4 activation to reduce ROS production, and enhanced the expression and activity of antioxidant enzymes (i.e. superoxide dismutase 1, catalase and glutathione peroxidase 1) to increase ROS elimination, resulting in obvious suppression of renal OS. Meanwhile, Ibrolipim not only inhibited the upregulation of transforming growth factor-β1 but also partially reversed the downregulation of matrix metalloproteinase 2, and then prevented extracellular matrix (ECM) accumulation. Taken together, Ibrolipim exhibits anti-oxidative and anti-fibrotic effects via modulating the rebalance of renal ROS and ECM metabolism, and ultimately attenuates the progression of nephropathy in diet-induced diabetic minipigs.

Trimethylamine N-oxide (TMAO) is produced from the phosphatidylcholine metabolism of gut flora and acts as a risk factor of cardiovascular disease. However, the underlying mechanisms for its proatherogenic action remain unclear. This study aimed to observe the effect of TMAO on endothelial cell pyroptosis and explore the underlying mechanisms. Our results showed that TMAO promoted the progression of atherosclerotic lesions in apolipoprotein E-deficient (apoE(-/-)) mice fed a high-fat diet. Pyroptosis and succinate dehydrogenase complex subunit B (SDHB) upregulation were detected in the vascular endothelial cells of apoE(-/-) mice and in cultured human umbilical vein endothelial cells (HUVECs) treated with TMAO. Overexpression of SDHB in HUVECs enhanced pyroptosis and impaired mitochondria and high reactive oxygen species (ROS) level. Pyroptosis in the SDHB overexpression of endothelial cells was inhibited by the ROS scavenger NAC. In summary, TMAO promotes vascular endothelial cell pyroptosis via ROS induced through SDHB upregulation, thereby contributing to the progression of atherosclerotic lesions.

BackgroundWith the unprecedented morbidity and mortality associated with the COVID-19 pandemic, a vaccine against COVID-19 is urgently needed. We investigated CoronaVac (Sinovac Life Sciences, Beijing, China), an inactivated vaccine candidate against COVID-19, containing inactivated severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), for its safety, tolerability and immunogenicity.MethodsIn this randomised, double-blind, placebo-controlled, phase 1/2 clinical trial, healthy adults aged 18–59 years were recruited from the community in Suining County of Jiangsu province, China. Adults with SARS-CoV-2 exposure or infection history, with axillary temperature above 37·0°C, or an allergic reaction to any vaccine component were excluded. The experimental vaccine for the phase 1 trial was manufactured using a cell factory process (CellSTACK Cell Culture Chamber 10, Corning, Wujiang, China), whereas those for the phase 2 trial were produced through a bioreactor process (ReadyToProcess WAVE 25, GE, Umea, Sweden). The phase 1 trial was done in a dose-escalating manner. At screening, participants were initially separated (1:1), with no specific randomisation, into two vaccination schedule cohorts, the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and within each cohort the first 36 participants were assigned to block 1 (low dose CoronaVac [3 μg per 0·5 mL of aluminium hydroxide diluent per dose) then another 36 were assigned to block 2 (high-dose Coronavc [6 μg per 0·5 mL of aluminium hydroxide diluent per dse]). Within each block, participants were randomly assigned (2:1), using block randomisation with a block size of six, to either two doses of CoronaVac or two doses of placebo. In the phase 2 trial, at screening, participants were initially separated (1:1), with no specific randomisation, into the days 0 and 14 vaccination cohort and the days 0 and 28 vaccination cohort, and participants were randomly assigned (2:2:1), using block randomisation with a block size of five, to receive two doses of either low-dose CoronaVac, high-dose CoronaVac, or placebo. Participants, investigators, and laboratory staff were masked to treatment allocation. The primary safety endpoint was adverse reactions within 28 days after injection in all participants who were given at least one dose of study drug (safety population). The primary immunogenic outcome was seroconversion rates of neutralising antibodies to live SARS-CoV-2 at day 14 after the last dose in the days 0 and 14 cohort, and at day 28 after the last dose in the days 0 and 28 cohort in participants who completed their allocated two-dose vaccination schedule (per-protocol population). This trial is registered with ClinicalTrials.gov, NCT04352608, and is closed to accrual.FindingsBetween April 16 and April 25, 2020, 144 participants were enrolled in the phase 1 trial, and between May 3 and May 5, 2020, 600 participants were enrolled in the phase 2 trial. 743 participants received at least one dose of investigational product (n=143 for phase 1 and n=600 for phase 2; safety population). In the phase 1 trial, the incidence of adverse reactions for the days 0 and 14 cohort was seven (29%) of 24 participants in the 3 ug group, nine (38%) of 24 in the 6 μg group, and two (8%) of 24 in the placebo group, and for the days 0 and 28 cohort was three (13%) of 24 in the 3 μg group, four (17%) of 24 in the 6 μg group, and three (13%) of 23 in the placebo group. The seroconversion of neutralising antibodies on day 14 after the days 0 and 14 vaccination schedule was seen in 11 (46%) of 24 participants in the 3 μg group, 12 (50%) of 24 in the 6 μg group, and none (0%) of 24 in the placebo group; whereas at day 28 after the days 0 and 28 vaccination schedule, seroconversion was seen in 20 (83%) of 24 in the 3 μg group, 19 (79%) of 24 in the 6 μg group, and one (4%) of 24 in the placebo group. In the phase 2 trial, the incidence of adverse reactions for the days 0 and 14 cohort was 40 (33%) of 120 participants in the 3 μg group, 42 (35%) of 120 in the 6 μg group, and 13 (22%) of 60 in the placebo group, and for the days 0 and 28 cohort was 23 (19%) of 120 in the 3 μg group, 23 (19%) of 120 in the 6 μg group, and 11 (18%) of 60 for the placebo group. Seroconversion of neutralising antibodies was seen for 109 (92%) of 118 participants in the 3 μg group, 117 (98%) of 119 in the 6 μg group, and two (3%) of 60 in the placebo group at day 14 after the days 0 and 14 schedule; whereas at day 28 after the days 0 and 28 schedule, seroconversion was seen in 114 (97%) of 117 in the 3 μg group, 118 (100%) of 118 in the 6 μg group, and none (0%) of 59 in the placebo group.InterpretationTaking safety, immunogenicity, and production capacity into account, the 3 μg dose of CoronaVac is the suggested dose for efficacy assessment in future phase 3 trials.FundingChinese National Key Research and Development Program and Beijing Science and Technology Program.

目的 观察Trendelenburg体位SD大鼠眼内压、血压、视网膜组织形态的变化,并探讨其机制.方法 SD大鼠60只,随机分为实验组和正常组各30只.实验组每天上午8:00～9:00将大鼠固定于Trendelenburg体位(头低脚高80°),正常组采取平位.固定体位20 min内每5 min测量眼内压1次、共4次;大鼠固定体位安静5 min后测量尾动脉血压.实验重复1周后处死大鼠,采用HE染色观察大鼠视网膜组织形态变化,检测大鼠血清中的氧化应激指标(MDA含量及GSH-Px、SOD活性).结果 实验1周内实验组每日测得眼内压均高于正常组(P均<0.01);同一实验日内,实验组固定体位后5、10、15、20 min眼内压均高于正常组(P均<0.01),实验组固定体位10 min后眼内压达到最大值.实验组收缩压与舒张压均高于正常组(P均<0.01).实验组视网膜明显增厚、水肿,细胞胞质空亮,层次欠清晰,内层视网膜细胞间隙增大、变厚.实验组血清MDA含量高于对照组,SOD、GSH-Px活性低于对照组(P均<0.01).结论 Trendelenburg体位可升高SD大鼠眼内压和血压,导致视网膜损伤,机制可能与促进氧化应激有关.

Objective: Our previous study showed that Coiled-Coil Domain Containing 80 (CCDC80) accelerates the development of atherosclerosis by decreasing lipoprotein lipase (LPL) expression and activity in apoE knockout mice. However, the regulatory mechanism for CCDC80 expression is unclear. This study was designed to evaluate whether noncoding RNAs involved the regulation of CCDC80 expression in vascular smooth muscle cells. Methods and Results: Bioinformatics prediction and luciferase reporter gene results showed that miR-141-3p/200a-3p bound to the 3 ' UTR of CCDC80. Furthermore, miR-141-3p/200a-3p mimics decreased the expression of CCDC80 but increased LPL expression. Opposite results were observed with miR-141-3p/200a-3p inhibitors. We also found that lncRNA metastasis-associated lung adenocarcinoma transcript-1 (MALAT1) interacted with the sequences of miR-141-3p/200a-3p and decreased their expression. RT-qPCR and western blotting results showed that MALAT1 overexpression increased CCDC80 expression and decreased LPL expression, while MALAT1 knockdown displayed an opposite phenotype. The effects of both MALAT1 overexpression and knockdown were blocked by miR-141-3p/200a-3p mimics or inhibitors. Conclusions: Thus, we demonstrated that lncRNA MALAT1 regulates CCDC80 and LPL expression through miR-141-3p/200a-3p.

ABSTRACTBACKGROUNDThe top priority for the control of COVID-19 pandemic currently is the development of a vaccine. A phase 2 trial conducted to further evaluate the immunogenicity and safety of a SARS-CoV-2 inactivated vaccine (CoronaVac).METHODSWe conducted a randomized, double-blind, placebo-controlled trial to evaluate the optimal dose, immunogenicity and safety of the CoronaVac. A total of 600 healthy adults aged 18-59 years were randomly assigned to receive 2 injections of the trial vaccine at a dose of 3 μg/0.5 mL or 6 μg /0.5mL, or placebo on Day 0,14 schedule or Day 0,28 schedule. For safety evaluation, solicited and unsolicited adverse events were collected after each vaccination within 7 days and 28 days, respectively. Blood samples were taken for antibody assay.RESULTSCoronaVac was well tolerated, and no dose-related safety concerns were observed. Most of the adverse reactions fell in the solicited category and were mild in severity. Pain at injection site was the most frequently reported symptoms. No Grade 3 adverse reaction or vaccine related SAEs were reported. CoronaVac showed good immunogenicity with the lower 3 μg dose eliciting 92.4% seroconversion under Day 0,14 schedule and 97.4% under Day 0,28 schedule. 28 days after two-dose vaccination, the Nab levels of individual schedules range from 23.8 to 65.4 among different dosage and vaccination schedules.CONCLUSIONSFavorable safety and immunogenicity of CoronaVac was demonstrated on both schedules and both dosages, which support the conduction of phase 3 trial with optimum schedule/dosage per different scenarios.

<span id="ChDivSummary" name="ChDivSummary" class="abstract-text">目的探讨褪黑素（melatonin,MLT）对胰岛素抵抗（insulin resistance,IR）肝HepG2细胞葡萄糖内生的影响及其机制。方法 HepG2 IR细胞模型采用高糖(25 mmol·L^-1)联合高胰岛素(1μmol·L^-1)培养诱导建立。MLT (10 nmol·L^-1)处理模型细胞6 h后检测糖消耗及糖原含量,GSK-3β、Akt和FoxO1蛋白磷酸化水平检测采用Western blot,免疫荧光法检测FoxO1蛋白核外排情况。结果 IR HepG2细胞经MLT处理后,葡萄糖的摄取和糖原合成增加,p-GSK-3β和p-Akt蛋白水平分别增高约66%和48%,FoxO1磷酸化水平明显提高且细胞质含量增加。结论 MLT可能通过Akt/GSK-3β及Akt/FoxO1信号通路促进胰岛素抵抗HepG2细胞的糖原合成和抑制糖异生,从而改善糖代谢。</span>

The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in an unprecedented public health crisis. Because of the novelty of the virus, there are currently no SARS-CoV-2-specific treatments or vaccines available. Therefore, rapid development of effective vaccines against SARS-CoV-2 are urgently needed. Here, we developed a pilot-scale production of PiCoVacc, a purified inactivated SARS-CoV-2 virus vaccine candidate, which induced SARS-CoV-2-specific neutralizing antibodies in mice, rats, and nonhuman primates. These antibodies neutralized 10 representative SARS-CoV-2 strains, suggesting a possible broader neutralizing ability against other strains. Three immunizations using two different doses, 3 or 6 micrograms per dose, provided partial or complete protection in macaques against SARS-CoV-2 challenge, respectively, without observable antibody-dependent enhancement of infection. These data support the clinical development and testing of PiCoVacc for use in humans.