A Bi-GRU-attention neural network to identify motor units from high-density surface electromyographic signals in real time.

To utilize surface electromyographics (sEMG) for control purposes, it is necessary to perform real-time estimation of the neural drive to the muscles, which involves real-time decomposition of the EMG signals. In this paper, we propose a Bidirectional Gate Recurrent Unit (Bi-GRU) network with attention to perform online decomposition of high-density sEMG signals. The model can give different levels of attention to different parts of the sEMG signal according to their importance using the attention mechanism. The output of gradient convolutional kernel compensation (gCKC) algorithm was used as the training label, and simulated and experimental sEMG data were divided into windows with 120 sample points for model training, the sampling rate of sEMG signal is 2048 Hz. We test different attention mechanisms and find out the ones that could bring the highest F1-score of the model. The simulated sEMG signal is synthesized from Fuglevand method (J. Neurophysiol., 1993). For the decomposition of 10 Motor Units (MUs), the network trained on simulated data achieved an average F1-score of 0.974 (range from 0.96 to 0.98), and the network trained on experimental data achieved an average F1-score of 0.876 (range from 0.82 to 0.97). The average decomposition time for each window was 28 ms (range from 25.6 ms to 30.5 ms), which falls within the lower bound of the human electromechanical delay. The experimental results show the feasibility of using Bi-GRU-Attention network for the real-time decomposition of Motor Units. Compared to the gCKC algorithm, which is considered the gold standard in the medical field, this model sacrifices a small amount of accuracy but significantly improves computational speed by eliminating the need for calculating the cross-correlation matrix and performing iterative computations.

Ectopic breast tissue of the vulva.

Ectopic mammary gland tissue in the vulva is an exceptionally rare disease. We present a case of a 62-year-old woman with a left vulvar mass of 30 years duration that progressively increased in size. The patient reported having pressure and discomfort, especially during movement. Surgical excision was performed, and a histopathological examination revealed a well-differentiated ectopic breast. We also review other cases of vulvar ectopic breast to further comprehend the characteristics of this rare disease.  Clinicians and pathologists should always consider it as a differential diagnosis when presented with a vulvar mass.

Immuno-persistence of the different primary polio vaccine schedules and immunogenicity of the booster dose by sabin inactivated or bivalent oral poliovirus vaccine in children aged 4 years: an open-label, randomised, controlled phase 4 trial in China.

Background: Sabin inactivated and bivalent oral poliovirus vaccine (sIPV, bOPV) were commonly used in China since 2016. We conducted an open-label, randomised, controlled phase 4 trial to assess immune persistence following sequential immunisation with sIPV or bOPV, and immunogenicity and safety of a booster dose of poliovirus vaccine in children aged 4 years. Methods: Participants from a previous clinical trial with three different sequential schedules with sIPV (I) or bOPV (B) at ages 2, 3, and 4 months (Groups I-B-B, I-I-B, I-I-I) in 2017 were followed-up. The children were further divided into five subgroups after sIPV was given for Group I-B-B, and sIPV or bOPV randomly given for Group I-I-B and Group I-I-I (128 children in Groups I-B-B-I, 60 in Group I-I-B-B, 64 in Group I-I-B-I, 68 in Group I-I-I-B, 67 in Group I-I-I-I). Immune persistence and immunogenicity were assessed by measuring poliovirus type-specific antibodies, and safety were analysed in all children who received the booster dose. Findings: Between Dec 5, 2020 and Jun 30, 2021, we respectively enrolled 381 participants in the immune persistence analysis, and 352 participants in per protocol (PP) analysis of the immunogenicity of the booster immunisation. Seropositivity rates of antibodies against poliovirus types 1 and 3 were all >90% four years after primary immunisation, while for poliovirus type 2 were 46.83%, 75.41%, and 90.23% (χ2 = 60.948, P < 0.001) for Groups I-B-B, I-I-B, and I-I-I, respectively. After the booster dose, seropositivity rates were 100% for all three serotypes in Group I-B-B-I, I-I-B-I and I-I-I-I; In Group I-I-B-B and I-I-I-B, the seropositivity rates for types 1 and 3 were all 100%, for type 2 were 92.59% and 98.46%. The geometric mean titres (GMTs) against poliovirus 1 and 3 were all high in five groups (>1860.73), and the GMTs against type 2 were significantly lower in groups booster with bOPV: Group I-I-B-B (50.60) and Group I-I-I-B (247.84). There was no significant difference in seropositivity rates or GMTs for all three serotypes (P > 0.05) between Group I-I-B-I and I-I-I-I. No serious adverse events occurred during the study. Interpretation: Our findings suggest that at least two sIPV doses are needed in the current routine poliovirus immunisation schedule, and schedules containing 3 or 4 doses of sIPV provide better protection against poliovirus type 2 than the current sIPV-sIPV-bOPV-bOPV schedule in China. Funding: Medical and Health Science and Technology of Zhejiang Province (2021KY118). This trial was registered with ClinicalTrials.gov (NCT04576910).

Impact of endometriosis on female sexual function: an updated systematic review and meta-analysis.

Introduction: Endometriosis can lead to a state of chronic inflammation marked by the presence of scarring and adhesions within the pelvis and/or other parts of the body. Recent estimates suggest that globally this condition affects approximately 10% of women in the reproductive age group. Aims: In this study we sought updated evidence on the association between endometriosis and sexual function in female patients. Methods: We used standard assessment tools to conduct a systematic search of the PubMed, EMBASE, and Scopus databases for observational studies that documented the association of endometriosis with female sexual function. A random-effects model was used for the analysis, and effect sizes were reported as the weighted mean difference (WMD) or OR with 95% CIs. Results: A total of 13 studies were selected for inclusion in our investigation. All of the included studies were cross-sectional in design. The data on sexual function in most of the studies were collected by using the Female Sexual Function Index (FSFI) tool, for which higher scores suggest better sexual function. The risk of sexual dysfunction (based on specific cutoffs for the FSFI score) was higher in women with than in women without endometriosis (OR 1.71; 95% CI, 1.21-2.43). In addition, when we used continuous scores to examine the risk of sexual dysfunction, diagnosis of endometriosis was associated with significantly lower overall FSFI scores (WMD, -3.40; 95% CI, -5.13 to -1.66) and lower scores on all of its 6 domains, ie, desire (WMD, -0.27; 95% CI, -0.53 to -0.02), arousal (WMD, -0.43; 95% CI, -0.79 to -0.07), lubrication (WMD, -0.49; 95% CI, -0.66 to -0.31), orgasm (WMD, -0.65; 95% CI, -1.07 to -0.23), satisfaction (WMD, -0.52; 95% CI, -0.77 to -0.26), and pain (WMD, -1.06; 95% CI, -1.57 to -0.55). Conclusion: The findings of this study suggest that female patients with endometriosis have suboptimal sexual function compared with healthy female subjects. Patients with endometriosis should be offered sexual counseling and supportive care by a multidisciplinary team of gynecologists, psychologists, and sexual therapists.

Comparative Study on MNVT of OPV Type I and III Reference Products in Different Periods.

Widespread vaccination using the oral live attenuated polio vaccine (OPV) and Sabin strain inactivated vaccine (sIPV) have greatly reduced the incidence of polio worldwide. In the period post-polio, the virulence of reversion of the Sabin strain makes the use of OPV gradually becoming one of the major safety hazards. The verification and release of OPV has become the top priority. The monkey neurovirulence test (MNVT) is the gold standard for detecting whether OPV meets the criteria, which are recommended by the WHO and Chinese Pharmacopoeia. Therefore, we statistically analyzed the MNVT results of type I and III OPV at different stages: 1996-2002 and 2016-2022. The results show that the upper and lower limits and C value of the qualification standard of type I reference products in 2016-2022 have decreased compared with the corresponding scores in the 1996-2002 period. The upper and lower limit and C value of the qualified standard of type III reference products were basically the same as the corresponding scores in the 1996-2002. We also found significant differences in the pathogenicity of the type I and III in the cervical spine and brain, with the decreasing trend in the diffusion index of the type I and type III in the cervical spine and brain. Finally, two evaluation criteria were used to judge the OPV test vaccines from 2016 to 2022. The vaccines all met the test requirements under the evaluation criteria of the above two stages. Based on the characteristics of OPV, data monitoring was one of the most intuitive methods to judge changes in virulence.

Testis- specific Y-encoded- like protein 1 and cholesterol metabolism: Regulation of CYP1B1 expression through Wnt signaling.

The cytochromes P450 (CYPs) represent a large gene superfamily that plays an important role in the metabolism of both exogenous and endogenous compounds. We have reported that the testis-specific Y-encoded-like proteins (TSPYLs) are novel CYP gene transcriptional regulators. However, little is known of mechanism(s) by which TSPYLs regulate CYP expression or the functional consequences of that regulation. The TSPYL gene family includes six members, TSPYL1 to TSPYL6. However, TSPYL3 is a pseudogene, TSPYL5 is only known to regulates the expression of CYP19A1, and TSPYL6 is expressed exclusively in the testis. Therefore, TSPYL 1, 2 and 4 were included in the present study. To better understand how TSPYL1, 2, and 4 might influence CYP expression, we performed a series of pull-downs and mass spectrometric analyses. Panther pathway analysis of the 2272 pulled down proteins for all 3 TSPYL isoforms showed that the top five pathways were the Wnt signaling pathway, the Integrin signaling pathway, the Gonadotropin releasing hormone receptor pathway, the Angiogenesis pathway and Inflammation mediated by chemokines and cytokines. Specifically, we observed that 177 Wnt signaling pathway proteins were pulled down with the TSPYLs. Subsequent luciferase assays showed that TSPYL1 knockdown had a greater effect on the activation of Wnt signaling than did TSPYL2 or TSPYL4 knockdown. Therefore, in subsequent experiments, we focused our attention on TSPYL1. HepaRG cell qRT-PCR showed that TSPYL1 regulated the expression of CYPs involved in cholesterol-metabolism such as CYP1B1 and CYP7A1. Furthermore, TSPYL1 and ß-catenin regulated CYP1B1 expression in opposite directions and TSPYL1 appeared to regulate CYP1B1 expression by blocking ß-catenin binding to the TCF7L2 transcription factor on the CYP1B1 promoter. In ß-catenin and TSPYL1 double knockdown cells, CYP1B1 expression and the generation of CYP1B1 downstream metabolites such as 20-HETE could be restored. Finally, we observed that TSPYL1 expression was associated with plasma cholesterol levels and BMI during previous clinical studies of obesity. In conclusion, this series of experiments has revealed a novel mechanism for regulation of the expression of cholesterol-metabolizing CYPs, particularly CYP1B1, by TSPYL1 via Wnt/ß-catenin signaling, raising the possibility that TSPYL1 might represent a molecular target for influencing cholesterol homeostasis.

Single cell transcriptomics reveals distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with opioid use disorder.

The opioid epidemic represents a national crisis. Oxycodone is one of the most prescribed opioid medications in the United States, whereas buprenorphine is currently the most prescribed medication for opioid use disorder (OUD) pharmacotherapy. Given the extensive use of prescription opioids and the global opioid epidemic, it is essential to understand how opioids modulate brain cell type function at the single-cell level. We performed single nucleus RNA-seq (snRNA-seq) using iPSC-derived forebrain organoids from three male OUD subjects in response to oxycodone, buprenorphine, or vehicle for seven days. We utilized the snRNA-seq data to identify differentially expressed genes following drug treatment using the Seurat integrative analysis pipeline. We utilized iPSC-derived forebrain organoids and single-cell sequencing technology as an unbiased tool to study cell-type-specific and drug-specific transcriptional responses. After quality control filtering, we analyzed 25787 cells and identified sixteen clusters using unsupervised clustering analysis. Our results reveal distinct transcriptional responses to oxycodone and buprenorphine by iPSC-derived brain organoids from patients with OUD. Specifically, buprenorphine displayed a significant influence on transcription regulation in glial cells. However, oxycodone induced type I interferon signaling in many cell types, including neural cells in brain organoids. Finally, we demonstrate that oxycodone, but not buprenorphine activated STAT1 and induced the type I interferon signaling in patients with OUD. These data suggest that elevation of STAT1 expression associated with OUD might play a role in transcriptional regulation in response to oxycodone. In summary, our results provide novel mechanistic insight into drug action at single-cell resolution.

Alum/CpG Adjuvanted Inactivated COVID-19 Vaccine with Protective Efficacy against SARS-CoV-2 and Variants.

Since the beginning of the COVID-19 pandemic, numerous variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) have emerged, including five variants of concern (VOC) strains listed by the WHO: Alpha, Beta, Gamma, Delta and Omicron. Extensive studies have shown that most of these VOC strains, especially the currently dominant variant Omicron, can escape the host immune response induced by existing COVID-19 vaccines to different extents, which poses considerable risk to the health of human beings around the world. In the present study, we developed a vaccine based on inactivated SARS-CoV-2 and an adjuvant consisting of aluminum hydroxide (alum) and CpG. The immunogenicity and safety of the vaccine were investigated in rats. The candidate vaccine elicited high titers of SARS-CoV-2-spike-specific IgG antibody and neutralizing antibody in immunized rats, which not only neutralize the original SARS-CoV-2, but also showed great cross-neutralization activity against the Beta, Delta and Omicron variants.

TRAF4 hyperactivates HER2 signaling and contributes to Trastuzumab resistance in HER2-positive breast cancer.

The HER2 receptor modulates downstream signaling by forming homodimers and heterodimers with other members of the HER family. For patients with HER2-positive breast cancer, Trastuzumab, an anti-HER2 monoclonal antibody as first-line therapy has shown significant survival benefits. However, the development of acquired resistance to Trastuzumab continues to be a significant obstacle. TNF receptor-associated factor 4 (TRAF4) upregulation was discovered to be associated with a worse clinical outcome. Here we identified TRAF4 overexpression as one of the putative mechanisms for HER2-positive breast cancer cells to maintain HER2 signaling during Trastuzumab treatment, while TRAF4 knockdown reduced HER2 stability and improved Trastuzumab sensitivity. Mechanistically, TRAF4 regulates HER2 level through its impact on SMAD specific E3 ubiquitin protein ligase protein 2 (SMURF2). The development of a membrane-associated protein complex containing HER2, TRAF4, and SMURF2 has been observed. SMURF2 bound to the HER2 cytoplasmic domain, and directly ubiquitinated it leading to HER2 degradation, whereas TRAF4 stabilized HER2 by degrading SMURF2 and inhibiting the binding of SMURF2 to HER2. Moreover, downregulation of TRAF4 has decreased the AKT/mTOR signaling. In conclusion, we discovered a new HER2 signaling regulation that involves the TRAF4-SMURF2 complex, a possible mechanism that might contribute to anti-HER2 resistance, making TRAF4 a viable target for treating HER2 + breast cancer.

Vaccination with Omicron Inactivated Vaccine in Pre-vaccinated Mice Protects against SARS-CoV-2 Prototype and Omicron Variants.

In response to the fast-waning immune response and the great threat of the Omicron variant of concern (VOC) to the public, we report the pilot-scale production of an inactivated Omicron vaccine candidate that induces high levels of neutralizing antibody titers to protect against the Omicron virus. Here, we demonstrate that the inactivated Omicron vaccine is safe and effective in recalling immune responses to the HB02, Omicron, and Delta viruses after one or two doses of BBIBP-CorV. In addition, the efficient productivity and good genetic stability of the manufactured inactivated vaccine is proved. These results support the further evaluation of the Omicron vaccine in a clinical trial.

The Clinical and Genetic Features in Chinese Children With Steroid-Resistant or Early-Onset Nephrotic Syndrome: A Multicenter Cohort Study.

Steroid-resistant nephrotic syndrome (SRNS) is one of the major causes of end-stage kidney disease (ESKD) in children and young adults. For approximately 30% of children with SRNS results from a genetic cause. In this study, genotype-phenotype correlations in a cohort of 283 pediatric patients with SRNS or early-onset NS (nephrotic syndrome presenting within the first year of life) from 23 major pediatric nephrology centers in China were analyzed. All patients were performed with next-generation sequencing and Sanger sequencing. The overall mutation detection rate was 37.5% (106 of 283 patients). WT1 was the most frequently detected mutation, followed by NPHS1, NPHS2, and ADCK4, and these four major causative genes (WT1, NPHS1, NPHS2, and ADCK4) account for 73.6% of patients with monogenic SRNS. Thirteen of 106 individuals (12.3%) carried mutations in ADCK4 that function within the coenzyme Q10 biosynthesis pathway. In the higher frequently ADCK4-related SRNS, two mutations, c.737G>A (p.S246N) and c.748G>C (p.D250H), were the most prevalent. Our study provides not only definitive diagnosis but also facilitate available targeted treatment for SRNS, and prediction of prognosis and renal outcome. Our indications for genetic testing are patients with FSGS, initial SRNS, cases of positive family history or those with extra-renal manifestations.

Immunogenicity Evaluating of the Multivalent COVID-19 Inactivated Vaccine against the SARS-CoV-2 Variants.

It has been reported that the novel coronavirus (COVID-19) has caused more than 286 million cases and 5.4 million deaths to date. Several strategies have been implemented globally, such as social distancing and the development of the vaccines. Several severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants have appeared, such as Alpha, Beta, Gamma, Delta, and Omicron. With the rapid spread of the novel coronavirus and the rapidly changing mutants, the development of a broad-spectrum multivalent vaccine is considered to be the most effective way to defend against the constantly mutating virus. Here, we evaluated the immunogenicity of the multivalent COVID-19 inactivated vaccine. Mice were immunized by multivalent COVID-19 inactivated vaccine, and the neutralizing antibodies in serum were analyzed. The results show that HB02 + Delta + Omicron trivalent vaccine could provide broad spectrum protection against HB02, Beta, Delta, and Omicron virus. Additionally, the different multivalent COVID-19 inactivated vaccines could enhance cellular immunity. Together, our findings suggest that the multivalent COVID-19 inactivated vaccine can provide broad spectrum protection against HB02 and other virus variants in humoral and cellular immunity, providing new ideas for the development of a broad-spectrum COVID-19 vaccine.

The pheromone affects reproductive physiology and behavior by regulating hormone in juvenile mice.

Pheromones could promote hormone secretions and regulate sexual behavior. It was unclear whether multiparous pheromone could induce variations in puberty. The aim was to ascertain whether pheromone in urine of multiparous females induced central precocious puberty (CPP) in juvenile C57BL/6J females. The precocious puberty was examined by vaginal smear, lordosis reaction, HE stain, and ELISA analysis. Results suggested that the first vaginal opening and the first estrus were significantly earlier. The time interval of the first vaginal opening and estrus was significantly shortened. It was interesting that the first estrus was significantly correlated with the first vaginal opening and the time interval of the first estrus. In the first estrus, female lordosis reaction, the number of mature follicles, and the weight of the ovary and uterus significantly increased. The level of luteinizing hormones also significantly increased. Thus, multiparous pheromone can regulate sex hormone to induce CPP in juvenile C57BL/6J females.

Early assessment of the safety and immunogenicity of a third dose (booster) of COVID-19 immunization in Chinese adults.

Inducing durable and effective immunity against severe acute respiratory syndrome Coronavirus 2 (SARS-CoV-2) via vaccination is essential to combat the current pandemic of coronavirus disease 2019 (COVID-19). It has been noticed that the strength of anti-COVID-19 vaccination-induced immunity fades over time, which calls for an additional vaccination regime, as known as booster immunization, to restore immunity among previously vaccinated populations. Here we report a pilot open-label trial of a third dose of BBIBP-CorV, an inactivated SARS-CoV-2 vaccine (Vero cell), on 136 participants aged between 18 to 63 years. Safety and immunogenicity in terms of neutralizing antibody titers and cytokine/chemokine responses were analyzed as the main endpoint until day 28. While systemic reactogenicity was either absent or mild, SARS-CoV-2-specific neutralizing antibody titers rapidly arose in all participants within 4 weeks, surpassing the peak antibody titers elicited by the initial two-dose immunization regime. Broad increases of cellular immunity-associated cytokines and chemokines were also detected in the majority of participants after the third vaccination. Furthermore, in an exploratory study, a newly developed recombinant protein vaccine, NVSI-06-08 (CHO Cells), was found to be safe and even more effective than BBIBP-CorV in eliciting humoral immune responses in BBIBP-CorV-primed individuals. Together, these results indicate that a third immunization schedule with either homologous or heterologous vaccine showed favorable safety profiles and restored potent SARS-CoV-2-specific immunity, providing support for further trials of booster vaccination in larger populations.

Cooperation of ATF4 and CTCF promotes adipogenesis through transcriptional regulation.

Adipogenesis is a multi-step process orchestrated by activation of numerous TFs, whose cooperation and regulatory network remain elusive. Activating transcription factor 4 (ATF4) is critical for adipogenesis, yet its regulatory network is unclarified. Here, we mapped genome-wide ATF4 binding landscape and its regulatory network by Chip-seq and RNA-seq and found ATF4 directly modulated transcription of genes enriching in fat cell differentiation. Motifs of TFs especially CTCF were found from ATF4 binding sites, suggesting a direct role of ATF4 in regulating adipogenesis associated with CTCF and other TFs. Deletion of CTCF attenuated adipogenesis while overexpression enhanced adipocyte differentiation, indicating CTCF is indispensable for adipogenesis. Intriguingly, combined analysis of Chip-seq data of these two TFs showed that ATF4 co-localized with CTCF in the promoters of key adipogenic genes including Cebpd and PPARg and co-regulated their transactivation. Moreover, ATF4 directly regulated CTCF expression and interacted with CTCF in differentiated 3T3-L1 cells. In vivo, downregulation of ATF4 suppressed the expression of CTCF, Cebpd, and PPARg, leading to reduced adipose tissue expansion in refeeding mice. Consistently, mRNA expression of ATF4 and CTCF was positively correlated with each other in human subcutaneous adipose tissue and inversely associated with BMI, indicating a possible involvement of these two TFs in adipose development. Taken together, our data propose for the first time that ATF4 and CTCF work cooperatively to control adipogenesis and adipose development via orchestrating transcription of adipogenic genes. Our findings reveal novel therapeutic targets in obesity treatment.

Safety and immunogenicity of an inactivated COVID-19 vaccine, BBIBP-CorV, in people younger than 18 years: a randomised, double-blind, controlled, phase 1/2 trial.

BACKGROUND: Although SARS-CoV-2 infection often causes milder symptoms in children and adolescents, young people might still play a key part in SARS-CoV-2 transmission. An efficacious vaccine for children and adolescents could therefore assist pandemic control. For further evaluation of the inactivated COVID-19 vaccine candidate BBIBP-CorV, we assessed the safety and immunogenicity of BBIBP-CorV in participants aged 3-17 years. METHODS: A randomised, double-blind, controlled, phase 1/2 trial was done at Shangqiu City Liangyuan District Center for Disease Control and Prevention in Henan, China. In phases 1 and 2, healthy participants were stratified according to age (3-5 years, 6-12 years, or 13-17 years) and dose group. Individuals with a history of SARS-CoV-2 or SARS-CoV infection were excluded. All participants were randomly assigned, using stratified block randomisation (block size eight), to receive three doses of 2 µg, 4 µg, or 8 µg of vaccine or control (1:1:1:1) 28 days apart. The primary outcome, safety, was analysed in the safety set, which consisted of participants who had received at least one vaccination after being randomly assigned, and had any safety evaluation information. The secondary outcomes were geometric meant titre (GMT) of the neutralising antibody against infectious SARS-CoV-2 and were analysed based on the full analysis set. This study is registered with www.chictr.org.cn, ChiCTR2000032459, and is ongoing. FINDINGS: Between Aug 14, 2020, and Sept 24, 2020, 445 participants were screened, and 288 eligible participants were randomly assigned to vaccine (n=216, 24 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=72, 24 for each age cohort [3-5, 6-12, and 13-17 years]) in phase 1. In phase 2, 810 participants were screened and 720 eligible participants were randomly assigned and allocated to vaccine (n=540, 60 for each dose level [2/4/8 µg] in each of three age cohorts [3-5, 6-12, and 13-17 years]) or control (n=180, 60 for each age cohort [3-5, 6-12, and 13-17 years]). The most common injection site adverse reaction was pain (ten [4%] 251 participants in all vaccination groups of the 3-5 years cohort; 23 [9·1%] of 252 participants in all vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 20 [7·9%] of 252 participants in all vaccination groups of the 13-17 years cohort). The most common systematic adverse reaction was fever (32 [12·7%] of 251 participants in all vaccination groups and six [7·1%] of 84 participants in the control group of the 3-5 years cohort; 13 [5·2%] of 252 participants in the vaccination groups and one [1·2%] of 84 in the control group of the 6-12 years cohort; 26 [10·3%] of 252 participants in all vaccination groups and eight [9·5%] of 84 in the control group of the 13-17 years cohort). Adverse reactions were mostly mild to moderate in severity. The neutralising antibody GMT against the SARS-CoV-2 virus ranged from 105·3 to 180·2 in the 3-5 years cohort, 84·1 to 168·6 in the 6-12 years cohort, and 88·0 to 155·7 in the 13-17 years cohort on day 28 after the second vaccination; and ranged from 143·5 to 224·4 in the 3-5 years cohort, 127 to 184·8 in the 6-12 years cohort, and 150·7 to 199 in the 13-17 years cohort on day 28 after the third vaccination. INTERPRETATION: The inactivated COVID-19 vaccine BBIBP-CorV is safe and well tolerated at all tested dose levels in participants aged 3-17 years. BBIBP-CorV also elicited robust humoral responses against SARS-CoV-2 infection after two doses. Our findings support the use of a 4 µg dose and two-shot regimen BBIBP-CorV in phase 3 trials in the population younger than 18 years to further ascertain its safety and protection efficacy against COVID-19. FUNDING: National Program on Key Research Project of China, National Mega projects of China for Major Infectious Diseases, National Mega Projects of China for New Drug Creation, and Beijing Science and Technology Plan. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

PP2A protects podocytes against Adriamycin-induced injury and epithelial-to-mesenchymal transition via suppressing JIP4/p38-MAPK pathway.

Protein phosphatase 2A (PP2A) is one of the major protein serine/threonine phosphatases (PPPs) with regulatory effects on several cellular processes, but its role and function in Adriamycin (ADR)-treated podocytes injury needs to be further explored. Mice podocytes were treated with ADR and PP2A inhibitor (okadaic acid, OA). After transfection, cell apoptosis was detected by flow cytometry. Expressions of podocytes injury-, apoptosis- and epithelial-to-mesenchymal transition (EMT)- and JNK-interacting protein 4/p38-Mitogen-Activated Protein Kinase (JIP4/p38-MAPK) pathway-related factors were measured using quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot as needed. Interaction between PP2A and JIP4/MAPK pathway was confirmed using co-immunoprecipitation (Co-Ip) assay. In podocytes, ADR inhibited PP2A, Nephrin and Wilms' tumor (WT) 1 expressions yet upregulated apoptosis and Desmin expression, and suppressing PP2A expressionenhanced the effects. PP2A overexpression reversed the effects of ADR on PP2A and podocyte injury-related factors expressions and apoptosis of podocytes. JIP4 was the candidate gene interacting with both PP2A and p38-MAPK pathway, and PP2A overexpression alleviated the effects of ADR on p38-MAPK pathway-related factors expressions. Additionally, in ADR-treated podocytes, PP2A suppression enhanced the effects of ADR, yet silencing of JIP4 reversed the effects of PP2A suppression on regulating p38-MAPK pathway-, apoptosis- and EMT-related factors expressions and apoptosis, with upregulations of B-cell lymphoma-2 (Bcl-2) and E-cadherin and down-regulations of Bcl-2 associated protein X (Bax), cleaved (C)-casapse-3, N-cadherin, Vimentin and Snail. PP2A protects ADR-treated podocytes against injury and EMT by suppressing JIP4/p38-MAPK pathway, showing their interaction in podocytes.

[Progress in genetic research on tooth agenesis associated with Wnt/beta-catenin signaling pathway].

Tooth agenesis is the most common form of congenital craniofacial dysplasia seen in stomatology clinics, which may be caused by genetic and/or environmental factors. Tooth development is regulated by a series of signaling pathways, and variants in any of these strictly balanced signaling cascades can result in tooth agenesis and/or other oral defects. Notably, variants of genes of the Wnt/beta-catenin signaling pathway are important cause for both non-syndromic and syndromic tooth agenesis. This article has provided a review for the molecular genetics of tooth agenesis associated with Wnt/beta-catenin signaling pathway, which may shed lights on the etiology and molecular mechanism of this disease.