Search

Abstract. Bacille Calmette–Guérin (BCG) vaccine is designed to provide protection against tuberculosis (TB). However, numerous epidemiological, clinical, and immunological studies have shown that BCG vaccination affects neonatal and infant mortality, which may be related to the reduction of TB-unrelated infections and diseases by BCG vaccine. We aimed to discuss the off-target effects of BCG vaccine on un-TB infections and diseases, as well as the potential mechanism and influencing factors. Literature was retrieved mainly from PubMed using medical subject headings "BCG, variations, and non-specific, heterologous or off-target". Studies have showed that BCG vaccination can prevent various heterologous infections, including respiratory tract infections, leprosy, and malaria, treat viral infections including human papillomavirus and herpes simplex virus infection as immunotherapy, and improve the immune responses as vaccine adjuvant. Besides, BCG vaccine can reduce the recurrence rate of non-muscle-invasive bladder cancer, and may provide protection against autoimmune diseases. These off-target effects of BCG vaccine are thought to be achieved by modulating heterologous lymphocyte responses or inducing trained immunity, which were found to be sex-differentiated and affected by the BCG vaccine strains, sequence or time of vaccination.

Background To assess the immunogenicity and safety of two-dose regimen of inactivated COVID-19 vaccines in patients with pulmonary tuberculosis (PTB) and explored the potential benefits of additional dose.Research design and methods In total, 182 PTB patients were randomly (1:1) assigned to the standard-dose group to receive three standard doses of inactivated COVID-19 vaccines, or the double-dose boosting group to receive two standard doses plus a double dose, with a 28-day interval. Forty healthy controls were assigned to receive two doses of inactivated COVID-19 vaccines 28 days apart. The primary endpoint was neutralizing antibodies 28 days after the second vaccination.Results Two doses of inactivated COVID-19 vaccines induced comparable neutralizing antibodies in PTB patients and the healthy controls, with GMTs against ancestral SARS-CoV-2 of 36.8 vs 31.4 (p = 0.4618) and seroconversion rates of 83.9% vs 87.5% (p = 0.6965). In the PTB patients, a third dose at day 56 led to a modest increase in neutralizing antibodies compared to the second dose, with a GMT fold increase of 1.3–1.8. Most adverse reactions were mild pain at the injection site.Conclusions Inactivated COVID-19 vaccine was safe and immunogenic in PTB patients, and two-dose immunization could induce moderate level of humoral responses similar to the healthy adults.Clinical trials registration www.clinicaltrials.gov identifier: NCT05148949.

Long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) have emerged as critical regulators in essentially all biological processes across eukaryotes. They exert their functions through chromatin remodeling, transcriptional regulation, interacting with RNA-binding proteins (RBPs), serving as microRNA sponges, etc. Although non-coding RNAs are typically more species-specific than coding RNAs, a number of well-characterized lncRNA (such as XIST and NEAT1) and circRNA (such as CDR1as and ciRS-7) are evolutionarily conserved. The studies on conserved lncRNA and circRNAs across multiple species could facilitate a comprehensive understanding of their roles and mechanisms, thereby overcoming the limitations of single-species studies. In this review, we provide an overview of conserved lncRNAs and circRNAs, and summarize their conserved roles and mechanisms.

Abstract Purpose This prospective study aimed to compare the postoperative evaluation of the quadrant method measuring four points and Bernard method in femoral tunnel position evaluation on 3-Dimensional (3D) reconstructed computed tomography (CT) following the arthroscopic single-bundle anterior cruciate ligament (ACL) reconstruction. Methods Thirty-eight patients with ACL tears that were reconstructed using single-bundle ACL reconstruction between May 2021 and March 2023 were included in this study. Postoperative 3D CT images were obtained after the operation. The femoral tunnel position was measured by use of the quadrant method measuring four points and Bernard method. Results Average mean position of the femoral tunnel insertion center on the 3D CT image was at 26.16 ± 6.27% in the x-coordinate and at 24.36 ± 5.52% in the y-coordinate according to the Bernard method. Meanwhile, the position of the femoral insertion of the ACL measured by the quadrant method measuring four points was 24.2% ± 6.86% in the x-coordinate and 21.16% ± 5.14% in the y-coordinate. Conclusions Both the quadrant method measuring four points and Bernard method were effective in femoral tunnel position evaluation on 3D reconstructed CT. Application of the quadrant method measuring four points on 3D CT showed the advantage that measurement can be taken regardless of the shape of the bone tunnel.

This work aimed to investigate the corrosion behavior of Si-18at%Y alloys in air oxidation and water-oxygen corrosion environments. The objective was to understand how different times, temperatures, and the presence or absence of water vapor affected the distribution and transformation of the alloy’s phases. The results revealed that extended duration facilitates growth of yttrium silicate, while higher temperature promotes stable phase transformation. The distribution and type of yttrium silicate are influenced by the presence of SiO2. At lower temperatures, water vapor facilitated the formation of SiO2, whereas at higher temperatures, it depleted SiO2 and inhibited the generation of yttrium silicate.

BackgroundHeterologous booster vaccines are more effective than homologous booster vaccines in combating the coronavirus disease 2019 (COVID-19) outbreak. However, our understanding of homologous and heterologous booster vaccines for COVID-19 remains limited.MethodsWe recruited 34 healthy participants from two cohorts who were primed with two-dose inactivated COVID-19 vaccine before, vaccinated with COVID-19 inactivated vaccine and adenovirus-vectored vaccine (intramuscular and aerosol inhalation of Ad5-nCoV) as a third booster dose. We assessed the immune responses of participants before and 14 days after vaccination, including levels of neutralizing antibodies, IgG, and cytokines, and quantified the transcriptional profile of peripheral blood mononuclear cells (PBMCs).ResultsThe Ad5-nCoV group showed a significantly higher neutralizing antibody geometric mean titer (GMT) compared to the ICV group after 14 days of heterologous boosting. The intramuscular Ad5-nCoV group had a GMT of 191.8 (95% CI 129.0, 285.1) compared to 38.1 (95% CI 23.1, 62.8) in the ICV1 group (p

Abstract Introduction Persistent nasal carriage has been associated with Staphylococcus aureus infection. Previous S. aureus studies in Asia have primarily focused on clinical patients, providing limited information on persistent nasal carriage among the general adult population. Methods This study examined 143 healthy adults in a community in Jiangsu, China. Nasal swab samples were collected 10 times. The colonization status was identified using SPA typing. We also determined antimicrobial susceptibility, genotype, and genomic characteristics of S. aureus. Results The prevalence of S. aureus nasal carriage among the community individuals was on average 16.78%. The carriage rates of methicillin-resistant S. aureus and multidrug-resistant S. aureus were 6.29% and 7.69%, respectively. We identified 8.39% persistent carriers, 39.16% intermittent carriers, and 52.45% noncarriers. Furthermore, family members displayed concordance in terms of genotype and genomic characteristics. Conclusion Persistent nasal sampling captured intermittent carriers that were missed during short-term sampling, thus highlighting the necessity for regular community testing. SPA typing can serve as a rapid method for determining S. aureus colonization. The potential for intrafamilial transmission of S. aureus is evident, with persistent carriers being the most probable source of infection.

Abstract Background Aging is a very complex physiological phenomenon, and sEVs are involved in the regulation of this mechanism. Serum samples from healthy individuals under 30 and over 60 years of age were collected to analyze differences in sEVs proteomics. Results Based on PBA analysis, we found that sEVs from the serum of elderly individuals highly express TACSTD2 and identified a subpopulation marked by TACSTD2. Using ELISA, we verified the upregulation of TACSTD2 in serum from elderly human and aged mouse. In addition, we discovered that TACSTD2 was significantly increased in samples from tumor patients and had better diagnostic value than CEA. Specifically, 9 of the 13 tumor groups exhibited elevated TACSTD2, particularly for cervical cancer, colon cancer, esophageal carcinoma, liver cancer and thyroid carcinoma. Moreover, we found that serum sEVs from the elderly (especially those with high TACSTD2 levels) promoted tumor cell (SW480, HuCCT1 and HeLa) proliferation and migration. Conclusion TACSTD2 was upregulated in the serum of elderly individuals and patients with tumors, and could serve as a dual biomarker for aging and tumors.

The AS03-adjuvanted H5N1 influenza vaccine induces significantly higher immune responses compared to the non-adjuvanted H5N1 vaccine. However, the immunological mechanisms underlying this enhancement remain unclear. We aimed to identify the key genes and pathways involved in the immune response to the AS03-adjuvanted H5N1 vaccine compared to the non-adjuvanted H5N1 vaccine. The expression profiles of GSE102012 and GSE112293 were downloaded from the Gene Expression Omnibus database to identify differentially expressed genes between AS03-adjuvanted and non-adjuvanted H5N1 vaccine groups. Subsequently, the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses were performed using the Database for Annotation, Visualization, and Integrated Discovery online tool. The protein–protein interaction (PPI) networks were constructed by the Search Tool for the Retrieval of Interacting Genes database. Through cluster analysis of the PPI network, three hub genes, namely NR4A1, SDC1, and ID3, were identified as pivotal players in the intricate network of interactions. The ID3 was up-regulated, and the other two hub genes were down-regulated. The results of the GO analysis highlighted enrichment in seven biological processes, three cellular components, and two molecular functions among the differentially expressed genes. The KEGG pathway analysis revealed the involvement of the Cushing syndrome pathway. The AS03-adjuvanted H5N1 vaccine may enhance immune responses through suppressing the NR4A1 gene and the SDC1 gene, upregulating the ID3 gene, and reducing cortisol production compared to the non-adjuvanted H5N1 vaccine.

ABSTRACTEffectiveness of heterologous booster regimes with ad5 vectored COVID-19 vaccine in a large, diverse population during the national-scale outbreak of SARS-CoV-2 omicron predominance in China has not been reported, yet. We conducted a large-scale cohort-control study in six provinces in China, and did a retrospective survey on the COVID-19 attack risk during this outbreak. Participant aged ≥18 years in five previous trials who were primed with 1 to 3 doses of ICV received heterologous booster with either intramuscular or orally inhaled ad5 vectored COVID-19 vaccine were included in the heterologous-trial cohort. We performed propensity score-matching at a ratio of 1:4 to match participants in the heterologous-trial cohort individually with the community individuals who received three-dose of ICV as a control (ICV-community cohort). From February 4 to April 10, 2023, 41504 (74.5%) of 55710 individuals completed the survey. The median time since the most recent vaccination to the onset of the symptoms of COVID-19 was 303.0 days (IQR 293.0-322.0). The attack rate of COVID-19 in the heterologous-trial cohort was 55.8%, while that in the ICV-community cohort was 64.6%, resulting in a relative effectiveness of 13.7% (95% CI 11.9 to 15.3). In addition, a higher relative effectiveness against COVID-19 associated outpatient visits, and admission to hospital was demonstrated, which was 25.1% (95% CI 18.9 to 30.9), and 48.9% (95% CI 27.0 to 64.2), respectively. The heterologous booster with ad5 vectored COVID-19 vaccine still offered some additional protection in preventing COVID-19 breakthrough infection versus homologous three-dose regimen with ICV, 10 months after vaccination.

IntroductionVarious COVID-19 vaccine trials have shown that vaccines can successfully prevent symptomatic cases of COVID-19 and death. Head-to-head comparisons help to better understand the immune response characteristics of different COVID-19 vaccines in humans.MethodsWe randomly selected 20 participants from each of five ongoing Phase II trials of COVID-19 vaccines. Here, SARS-CoV 2-specific immune responses to DNA vaccine (INO-4800), mRNA vaccine (BNT162b2), Adenovirus-vectored vaccine (CONVIDECIA), Protein subunit vaccine (Recombinant COVID- 19 Vaccine (Sf9 Cells)), Inactivated Vaccine (KCONVAC) were examined longitudinally in healthy adults between Jan 15, 2021 and July 5, 2021 for 6 months. RBD-IgG titres were detected by ELISA, neutralising antibody titer were detected by pseudoviral neutralization and immune cell response were detected by flow cytometry.ResultsAt the first visit (V1), 100% of individuals who received the BNT162b2, CONVIDECIA, or KCONVAC vaccines experienced seroconversion of neutralizing and binding antibodies in the serum. Except for the Recombinant COVID-19 Vaccine (Sf9 Cells) vaccine having the highest neutralizing antibody GMT at the second visit (although there was no statistically significant difference in geometric mean titers between V1 and V2), the rest of the vaccines had the highest levels of binding antibodies and neutralizing antibodies at V1. The neutralizing antibodies GMT of all vaccines showed a significant decrease at V3 compared to V1. The neutralizing antibody GMT against the omicron variant of all vaccines at V1 showed a significant decrease compared to the wild strain. We observed statistically significant differences in Tcm cells and RBD-specific memory B cells among various vaccines.DiscussionBNT162b2 (mRNA vaccine) exhibits the highest antibody levels among the five vaccines evaluated, regardless of whether the target is the wild-type virus or its variants. However, its cellular immune response may be weaker compared to CONVIDECIA (adenovirus type 5 vector vaccine).

BackgroundWe aimed to evaluate the efficacy, safety, and immunogenicity of a SARS-CoV-2 mRNA vaccine (Omicron BA.5) LVRNA012 given as the booster in immunized but SARS-CoV-2 infection-free adults in China.MethodsThis is a single-center, randomized, double-blind, placebo-controlled phase 3 clinical trial enrolling healthy adult participants (≥18 years) who had completed two or three doses of inactivated COVID-19 vaccines at least 6 months before, in Bengbu, Anhui province, China. Eligible participants were randomly assigned (1:1) to receive a booster intramuscular vaccination with an LVRNA012 vaccine (100ug) or placebo. The primary endpoint was the protective efficacy of a booster dose of the LVRNA012 vaccine or placebo against symptomatic COVID-19 of any severity 14 days after vaccination. Laboratory-confirmed COVID-19 infections were identified from 14 days to 180 days after intervention, with active surveillance for symptomatic illness 8 times per month between 7 to 90 days and at least once per month between 90 to 180 days after intervention.Results2615 participants were recruited and randomly assigned in a 1:1 ratio to either the vaccine group (1308) or the placebo group (1307). A total of 141 individuals (46 in the LVRNA012 group and 95 in the placebo group) developed symptomatic COVID-19 infection 14 days after the booster immunization, showing a vaccine efficacy of 51.9% (95% CI, 31.3% to 66.4%). Most infections were detected 90 days after intervention during a period when XBB was prevalent in the community. Adverse reactions were reported by 64% of participants after the LVRNA012 vaccination, but most of them were mild or moderate. The booster vaccination with the LVRNA012 mRNA vaccine could significantly enhance neutralizing antibody titers against the Omicron variant XBB.1.5 (GMT 132.3 [99.8, 175.4]) than did those in the placebo group (GMT 12.5 [8.4, 18.7]) at day 14 for the previously immunized individuals.ConclusionThe LVRNA012 mRNA vaccine is immunogenic, and shows robust efficacy in preventing COVID-19 during the omicron-predominate period.Clinical trial registrationClinicalTrials.gov, identifier NCT05745545.

Background & Aims: Previous studies demonstrated oxytocin treatment effectiveness in reducing mortality and reversing liver fibrosis in mice. However, the underlying mechanism remains obscure, given the absence of oxytocin receptor expression in hepatic stellate cells, the primary liver fibrosis effector cells. Methods: A comprehensive map of cell populations in fibrotic liver was generated using single-cell sequencing. The map enabled our study of the target cells of oxytocin action in the liver in more dimensions. Furthermore, we elucidated the mechanism of the oxytocin signaling system in hepatic macrophages using oxytocin receptor-specific knockout mice and liver fibrosis animal models. Results: The carbon tetrachloride-induced hepatic fibrosis and bile duct ligation hepatic fibrosis mouse models demonstrated that oxytocin reversed hepatic fibrosis in mice. The mapped liver cell populations demonstrated that oxytocin promoted the phenotypic switch from Ly6high to Ly6Clow in myeloid-derived macrophages. The phenotypic control of oxytocin signaling system activation on this phenotypic switch was validated using myeloid-specific oxytocin receptor knockout mice. Subsequent studies demonstrated that the calcium inward flow induced by oxytocin receptor activation activated the key orphan nuclear receptor NR4A1, which controls macrophage phenotypic switching. Specifically, calcium ions activated CREB, a key target regulator of NR4A1 expression. Conclusions: The findings established hepatic macrophages as a hub responsible for the oxytocin-mediated alleviation of liver fibrosis. This study revealed a novel pathway where oxytocin regulates macrophage phenotype. Impact and implications: Previous studies revealed for the first time the expression of oxytocin receptors in the liver. The present study shows that oxytocin reverses hepatic fibrosis and that hepatic macrophages are the central hub of oxytocin-mediated alleviation of hepatic fibrosis by promoting a phenotypic switch in hepatic macrophages, transitioning from Ly6high to Ly6Clow expression. The present study reveals a novel pathway by which oxytocin regulates macrophage phenotype. In addition, the potential applications of oxytocin and its analogues, as traditional drugs for clinical application, in the treatment of liver fibrosis deserve to be further explored.

Despite the recent advancements achieved by federated learning (FL), its real-world deployment is significantly impeded by the heterogeneous learning environment, specifically manifesting as devices with various computing capabilities, non-I.I.D. (Independent Identically and Distributed) data distribution and dynamic wireless transmission conditions. Such learning heterogeneity greatly harms the learning performance, e.g., convergence and learning accuracy. Therefore, we introduce the AMA-FES (adaptive-mixing aggregation, feature-extractor sharing) framework with an asynchronous aggregation scheme to address these challenges. To mitigate the impact of the non-I.I.D. data, we propose the AMA scheme to maintain the training stability by compromising between the previous global model and the synchronised local model updates, avoiding abrupt changes to a completely new model. To reduce computation load, we introduce the FES scheme, enabling the computing-limited devices to update only the classifier. To address the asynchronous model updates caused by the transmission delay, we perform asynchronous aggregation with staleness-based weighting. We implement the AMA-FES framework in a practical scenario where mobile UAVs act as FL training clients to conduct image classification tasks. The experimental results validate the effectiveness of the AMA-FES scheme in restoring training stability and learning accuracy without causing extra computation or communication expenditures in heterogeneous wireless networks.

Abstract Intestinal epithelial renewal, which depends on the proliferation and differentiation of intestinal stem cells (ISCs), is essential for epithelial homoeostasis. Understanding the mechanism controlling ISC activity is important. We found that death receptor 5 (DR5) gene deletion (DR5-/-) mice had impaired epithelial absorption and barrier function, resulting in delayed weight gain, which might be related to the general reduction of differentiated epithelial cells. In DR5-/- mice, the expression of ISC marker genes, the number of Olfm4+ ISCs, and the number of Ki67+ and BrdU+ cells in crypt were reduced. Furthermore, DR5 deletion inhibited the expression of lineage differentiation genes driving ISC differentiation into enterocytes, goblet cells, enteroendocrine cells, and Paneth cells. Therefore, DR5 gene loss may inhibit the intestinal epithelial renewal by dampening ISC activity. The ability of crypts from DR5-/- mice to form organoids decreased, and selective DR5 activation by Bioymifi promoted organoid growth and the expression of ISC and intestinal epithelial cell marker genes. Silencing of endogenous DR5 ligand TRAIL in organoids down-regulated the expression of ISC and intestinal epithelial cell marker genes. So, DR5 expressed in intestinal crypts was involved in the regulation of ISC activity. DR5 deletion in vivo or activation in organoids inhibited or enhanced the activity of Wnt, Notch, and BMP signalling through regulating the production of Paneth cell-derived ISC niche factors. DR5 gene deletion caused apoptosis and DNA damage in transit amplifying cells by inhibiting ERK1/2 activity in intestinal crypts. Inhibition of ERK1/2 with PD0325901 dampened the ISC activity and epithelial regeneration. In organoids, when Bioymifi’s effect in activating ERK1/2 activity was completely blocked by PD0325901, its role in stimulating ISC activity and promoting epithelial regeneration was also eliminated. In summary, DR5 in intestinal crypts is essential for ISC activity during epithelial renewal under homoeostasis.

Abstract Introduction ReCOV is a recombinant protein vaccine that aims to induce cross-neutralization against SARS-CoV-2 variants. The phase I and phase II studies were conducted in New Zealand and the Philippines, respectively, for ReCOV primary series. Methods Both studies were randomized, double-blind, placebo-controlled designed among COVID-19 vaccine-naïve healthy adults who received two doses of study vaccination with a 21-day interval. In phase I, 100 younger (15–55 years) and older (56–80 years) subjects were 4:1 randomized to receive ReCOV (20 µg or 40 µg) or placebo. In the phase II study, 347 subjects (≥ 18 years) were 2:1 randomized to receive 40 µg ReCOV or placebo. Subjects that received ReCOV were followed up for 6 months after the second dosing. The safety outcomes included solicited and unsolicited AEs, SAEs, and AESIs. The immunogenicity outcomes were live-virus neutralizing antibody (NAb) against prototype, while pseudovirus NAbs against several SARS-CoV-2 variants were included in phase II as well. Results No related SAE, AESI, or AE leading to early discontinuation were reported. The AE incidences were higher in ReCOV groups than placebo group in phase I while they were similar between study groups in phase II. The majority of solicited AEs were mild or moderate with median duration of 1.0–4.0 days. The common (≥ 10%) solicited AEs in phase I were injection site reactions, headache, pyrexia, fatigue, and myalgia, and common reported (≥ 5%) ones in phase II included injection site pain, headache, and pyrexia. Robust neutralizing activities against the prototype were observed in ReCOV groups, peaking at 14 days post the second dosing: in phase I, the GMTs for 20 μg and 40 μg ReCOV groups were 1643.2 IU/mL (95% CI 1188.5, 2271.9) and 1289.2 IU/mL (95% CI 868.3, 1914.1) in younger adults, and 1122.3 IU/mL (95% CI 722.6, 1743.1) and 680.3 IU/mL (95% CI 440.2, 1051.4) in older adults, respectively, while in the ReCOV group of phase II, the GMTs for subjects with seronegative and seropositive status at baseline were 3741.0 IU/mL (95% CI 3113.4, 4495.0) and 6138.3 IU/mL (95% CI 5255.1, 7169.9), respectively. In phase II, substantial levels of pseudovirus NAbs against SARS-CoV-2 variants were demonstrated; the peak GMTs for prototype, Omicron BA.2, and BA.4/5 were 8857, 4441, and 2644, and 15,667.3, 7334.3, and 4478.8 among seronegative and seropositive subjects, respectively. The neutralization persisted till 6 months post the second dosing, with only 2.5- to 5.2-fold declines for Omicron variants. Conclusions Two doses of 20 µg and 40 µg ReCOV are safe and immunogenic against SARS-CoV-2 prototype. The cross-neutralizing activities against Omicron variants support ReCOV advance to late-stage clinical trials. Trial Registration Phase I study, clinicaltrials.gov NCT04818801; phase II study, clinicaltrials.gov NCT05084989.

Aims: Vincristine (VCR), an antineoplastic drug, induces peripheral neuropathy characterized by nerve damage, limiting its use and reducing the quality of life of patients. VCR causes myenteric neuron damage, inhibits gastrointestinal motility, and results in constipation or paralytic ileus in patients. Oxytocin (OT) is an endogenous neuropeptide produced by the enteric nerve system, which regulates gastrointestinal motility and exerts neuroprotective effects. This study aimed to investigate whether OT can improve VCR-induced gastrointestinal dysmotility and evaluate the underlying mechanism.Methods: Mice were injected either with saline or VCR (0.1 mg/kg/d, i. p.) for 14 days, and OT (0.1 mg/kg/d, i.p.) was applied 1 h before each VCR injection. Gastrointestinal transit and the contractile activity of the isolated colonic segments were assessed. The concentration of OT in plasma was measured using ELISA. Immunofluorescence staining was performed to analyze myenteric neurons and reactive oxygen species (ROS) levels. Furthermore, the indicators of oxidative stress were detected. The protein expressions of Nrf2, ERK1/2, P-ERK1/2, p38, and P-p38 in the colon were tested using Western blot.Results: VCR reduced gastrointestinal transit and the responses of isolated colonic segments to electrical field stimulation and decreased the amount of neurons. Furthermore, VCR reduced neuronal nitric oxide synthase and choline acetyltransferase immunopositive neurons in the colonic myenteric nerve plexus. VCR increased the concentration of OT in plasma. Exogenous OT pretreatment ameliorated the inhibition of gastrointestinal motility and the injury of myenteric neurons caused by VCR. OT pretreatment also prevented the decrease of superoxide dismutase activity, glutathione content, total antioxidative capacity, and Nrf2 expression, the increase of ROS levels, and the phosphorylation of ERK1/2 and p38 MAPK following VCR treatment.Conclusion: Our results suggest that OT pretreatment can protect enteric neurons from VCR-induced injury by inhibiting oxidative stress and MAPK pathways (ERK1/2, p38). This may be the underlying mechanism by which it alleviates gastrointestinal dysmotility.

Background: Currently, the recombinant subunit vaccine and live attenuated vaccine in the prevention of herpes zoster are approved for marketing in China. This study aims to evaluate the cost-effectiveness of the recombinant subunit vaccine and the live attenuated vaccine in the Chinese population. Methods: A decision tree–Markov analysis model was utilized to estimate expected costs and quality-adjusted life years (QALYs), comparing the lifetime cost-effectiveness of vaccination with the recombinant subunit vaccine (London, United Kingdom, Shingrix, GSK) to that of the live attenuated vaccine (Changchun, China, Ganwei, Changchun Bcht) in the Chinese population, with the primary outcome measure being the incremental cost-effectiveness ratio (ICER). Results: In the base-case analysis, the ICERs for the recombinant subunit vaccine ranged by age from USD 3428 to USD 5743 per QALY, while the ICERs for the live attenuated vaccine ranged from USD 4017 to USD 18,254 per QALY, compared with no vaccination. Among all age groups, the category of 60 to 69 years was the optimal age for vaccination. The results were most sensitive to changes in herpes zoster incidence, vaccine efficacy, and discount rate. Even with a two-dose compliance rate of 20% for the recombinant subunit vaccine, vaccination remained cost-effective. ZVL would need to reduce costs by at least 12.2% compared to RZV to have a cost-effectiveness advantage. Conclusions: The recombinant subunit vaccine and the live attenuated vaccine were both cost-effective in the Chinese population, but, relatively, the recombinant subunit vaccine had a greater advantage in disease prevention and cost-effectiveness in all age groups above 50 years.

Background: Though children infected by SARS-CoV-2 generally experience milder symptoms compared to adults, severe cases can occur. Additionally, children can transmit the virus to others. Therefore, the availability of safe and effective COVID-19 vaccines for children and adolescents is crucial. Method: A single-center, randomized, double-blind clinical trial was conducted in Funing County, Yancheng City, Jiangsu Province, China. Healthy children and adolescents were divided into two subgroups (6–12 years old or 13–17 years old) and randomly assigned to one of three groups to receive one dose of Ad5-nCoV (3 × 1010 vp/dose). Another group, aged 18–59, received one dose of Ad5-nCoV (5 × 1010 vp/dose) as the control group. At 28, 90, 180, and 360 days post-vaccination, we measured the geometric mean titer (GMT)/concentration (GMC) of neutralizing and binding antibodies against the prototype SARS-CoV-2 strain, as well as serum antibody levels against the BA.4/5 variant. We also evaluated the incidence of adverse events within 28 days post-vaccination. Results: A total of 2413 individuals were screened from 3 June 2021 to 25 July 2021, of whom 2021 eligible participants were enrolled, including 1009 aged 6~17 years in the children and adolescent group and 1012 aged 18–59 years in the adults group. The GMT of anti-wild SARS-CoV-2 neutralizing antibodies was 18.6 (95% CI, 16.6–20.9) in children and adolescents and 13.2 (95% CI, 11.6–15.0) in adults on day 28. The incidence of solicited adverse reactions between the adult group (49.4% [124/251]) and the children and adolescent group (46.3% [156/337]) was not statistically significant. The neutralizing antibody levels decreased by a factor of 3.29 from day 28 to day 360 post-vaccination. Conclusions: A single dose of Ad5-nCoV at 3 × 1010 virus particles/dose is safe in children and adolescents, and it elicited significant immune response, which was not only non-inferior but also superior to that in adults aged 18–59 years.

Abstract The end‐to‐end separation algorithm with superior performance in the field of speech separation has not been effectively used in music separation. Moreover, since music signals are often dual channel data with a high sampling rate, how to model long‐sequence data and make rational use of the relevant information between channels is also an urgent problem to be solved. In order to solve the above problems, the performance of the end‐to‐end music separation algorithm is enhanced by improving the network structure. Our main contributions include the following: (1) A more reasonable densely connected U‐Net is designed to capture the long‐term characteristics of music, such as main melody, tone and so on. (2) On this basis, the multi‐head attention and dual‐path transformer are introduced in the separation module. Channel attention units are applied recursively on the feature map of each layer of the network, enabling the network to perform long‐sequence separation. Experimental results show that after the introduction of the channel attention, the performance of the proposed algorithm has a stable improvement compared with the baseline system. On the MUSDB18 dataset, the average score of the separated audio exceeds that of the current best‐performing music separation algorithm based on the time‐frequency domain (T‐F domain).

Colon cancer is increasing worldwide and is commonly regarded as hormone independent, yet recent reports have implicated sex hormones in its development. Nevertheless, the role of hormones from the hypothalamus–hypophysis axis in colitis-associated colorectal cancer (CAC) remains uncertain. In this study, we observed a significant reduction in the expression of the oxytocin receptor (OXTR) in colon samples from both patient with colitis and patient with CAC. To investigate further, we generated mice with an intestinal-epithelium-cell-specific knockout of OXTR. These mice exhibited markedly increased susceptibility to dextran-sulfate-sodium-induced colitis and dextran sulfate sodium/azoxymethane-induced CAC compared to wild-type mice. Our findings indicate that OXTR depletion impaired the inner mucus of the colon epithelium. Mechanistically, oxytocin was found to regulate Mucin 2 maturation through β1-3-N-acetylglucosaminyltransferase 7 (B3GNT7)-mediated fucosylation. Interestingly, we observed a positive correlation between B3GNT7 expression and OXTR expression in human colitis and CAC colon samples. Moreover, the simultaneous activations of OXTR and fucosylation by l-fucose significantly alleviated tumor burden. Hence, our study unveils oxytocin’s promising potential as an affordable and effective therapeutic intervention for individuals affected by colitis and CAC.

Abstract Circular RNAs (circRNAs) have emerged as crucial regulators in physiology and human diseases. However, evolutionarily conserved circRNAs with potent functions in cancers are rarely reported. In this study, a mammalian conserved circRNA circLARP1B is identified to play critical roles in hepatocellular carcinoma (HCC). Patients with high circLARP1B levels have advanced prognostic stage and poor overall survival. CircLARP1B facilitates cellular metastatic properties and lipid accumulation through promoting fatty acid synthesis in HCC. CircLARP1B deficient mice exhibit reduced metastasis and less lipid accumulation in an induced HCC model. Multiple lines of evidence demonstrate that circLARP1B binds to heterogeneous nuclear ribonucleoprotein D (HNRNPD) in the cytoplasm, and thus affects the binding of HNRNPD to sensitive transcripts including liver kinase B1 (LKB1) mRNA. This regulation causes decreased LKB1 mRNA stability and lower LKB1 protein levels. Antisense oligodeoxynucleotide complementary to theHNRNPD binding sites in circLARP1B increases the HNRNPD binding to LKB1 mRNA. Through the HNRNPD–LKB1–AMPK pathway, circLARP1B promotes HCC metastasis and lipid accumulation. Results from AAV8‐mediated hepatocyte‐directed knockdown of circLARP1B or Lkb1 in mouse models also demonstrate critical roles of hepatocytic circLARP1B regulatory pathway in HCC metastasis and lipid accumulation, and indicate that circLARP1B may be potential target of HCC treatment.

Little is known about the transition mechanisms that govern early lymphoid lineage progenitors from common lymphoid progenitors (CLP). Pellino2 (PELI2) is a newly discovered E3 ubiquitin ligase, which plays important roles in inflammation and the immune system. However, the physiological and molecular roles of PELI2 in the differentiation of immune cells are largely unknown. Here, by using a conditional knockout mouse model, we demonstrated that PELI2 is required for early B-cell development and stressed hematopoiesis. PELI2 interacted with and stabilized PU.1 via K63-polyubiquitination to regulate IL-7R expression. The defects of B-cell development induced by PELI2 deletion were restored by overexpression of PU.1. Similarly, PELI2 promoted TCF3 protein stability via K63-polyubiquitination to regulate IL-7R expression, which is required for the proliferation of B-cell precursor acute lymphoblastic leukemia (BCP-ALL) cells. These results underscore the significance of PELI2 in both normal B lymphopoiesis and malignant B-cell acute lymphoblastic leukemia via the regulation of IL-7R expression, providing a potential therapeutic approach for BCP-ALL.

ABSTRACTAntibody persistence and safety up to 12 months of heterologous orally administered adenovirus type-5 vector-based COVID-19 vaccine (Ad5-nCoV) in individuals who were primed with two-dose inactivated SARS-CoV-2 vaccine (CoronaVac) previously, has not been reported yet. This randomized, open-label, single-centre trial included Chinese adults who have received two-dose CoronaVac randomized to low-dose or high-dose aerosolised Ad5-nCoV group, or CoronaVac group. In this report, we mainly evaluated the geometric mean titres (GMTs) of neutralizing antibodies (NAbs) against live wild-type SARS-CoV-2 virus and omicron BA.4/5 pseudovirus at 12 months after the booster dose and the incidence of serious adverse events (SAEs) till month 12. Of 419 participants, all were included in the safety analysis and 120 (28.64%) were included in the immunogenicity analysis. Serum NAb GMT against live wild-type SARS-CoV-2 was 204.36 (95% CI 152.91, 273.14) in the low-dose group and 171.38 (95% CI 121.27, 242.19) in the high-dose group at month 12, significantly higher than the GMT in the CoronaVac group (8.00 [95% CI 4.22, 15.17], p

This randomized, double-blind, placebo-controlled phase 1/2 trial aimed at evaluating the safety and immunogenicity of Ad5-nCoV via aerosolized or intramuscular or intramuscular–aerosolized routes in SARS-CoV-2-negative adults aged over 18 years. In the phase 1 trial, participants were sequentially enrolled into one of five regimen cohorts: Low-Dose (two doses of aerosolized Ad5-nCoV with 0.5 × 1010 viral particles [vps] per dose), Middle-Dose (two doses of aerosolized Ad5-nCoV with 1.0 × 1010 vps per dose), High-Dose (two doses of aerosolized Ad5-nCoV with 2.0 × 1010 vps per dose), Mixed (intramuscular Ad5-nCoV with 5.0 × 1010 vps [first dose] and aerosolized Ad5-nCoV with 2.0 × 1010 vps [second dose]), and Single-Dose (one dose of aerosolized Ad5-nCoV with 1.0 × 1010 vps). Eligible participants in the phase 2 trial were stratified by 18–59 years old or ≥60 years old and then were sequentially enrolled into one of six regimen cohorts: Low-Dose, Middle-Dose, High-Dose, Mixed, Single-Dose, and Intramuscular (one dose of intramuscular Ad5-nCoV with 1.0 × 1010 vps). The intervals between the two doses were 56 days. Participants were randomly allocated in 3:1 (phase 1) and 5:1 (phase 2) ratios to receive either Ad5-nCoV or the placebo in each cohort. This study is registered on ClinicalTrials.gov, NCT04840992. Most adverse reactions that occurred during the solicited period were mild and moderate. One serious adverse event (myelodysplastic syndrome) was considered potentially related to the aerosolized Ad5-nCoV. The GMTs of neutralizing antibodies in the Mixed group were the highest with 57.03 (95% CI: 23.95, 135.80) and 97.37 (95% CI: 74.30, 127.59) in phase 1 and 2 trials, respectively, 28 days after the second dose (p < 0.0001), which showed significantly higher immune responses compared to other regimens with aerosolized or intramuscular Ad5-nCoV alone.

The NOD-, LRR-, and pyrin domain–containing protein 3 (NLRP3) inflammasome is a crucial component of the innate immune system that initiates inflammatory responses. Posttranslational modifications (PTMs) of NLRP3, including ubiquitination and phosphorylation, control inflammasome activation and determine the intensity of inflammation. However, the role of other PTMs in controlling NLRP3 inflammasome activation remains unclear. This study found that TLR priming induced NLRP3 ISGylation (a type of PTM in which ISG15 covalently binds to the target protein) to stabilize the NLRP3 protein. Viral infection, represented by SARS-COV-2 infection, and type I IFNs induced expression of ISG15 and the predominant E3 ISGylation ligases HECT domain- and RCC1-like domain–containing proteins (HERCs; HERC5 in humans and HERC6 in mice). HERCs promoted NLRP3 ISGylation and inhibited K48-linked ubiquitination and proteasomal degradation, resulting in the enhancement of NLRP3 inflammasome activation. Concordantly, Herc6 deficiency ameliorated NLRP3-dependent inflammation as well as hyperinflammation caused by viral infection. The results illustrate the mechanism by which type I IFNs responses control inflammasome activation and viral infection–induced aberrant NLRP3 activation. This work identifies ISGylation as a PTM of NLRP3, revealing a priming target that modulates NLRP3-dependent immunopathology.

Alternative splicing (AS) is a common and pivotal process for eukaryotic gene expression regulation, which enables a precursor RNA to produce multiple transcript variants with diverse cellular functions. Aberrant AS represents a hallmark of cancer, engaged in all stages of tumorigenesis from initiation to metastasis. Accumulating pieces of evidence have revealed the involvement of non-coding RNAs (ncRNAs) in regulating AS in human cancers. In this review, we overview the underlying mechanisms of non-coding RNAs, including microRNAs (miRNAs), long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) modulated AS at diverse levels in human cancers, and summarize their regulatory functions in tumorigenesis.

The rapid widespread Omicron subvariant BA.5 of SARS-CoV-2 has become a potential imminent pandemic threat, but available vaccines lack high efficacy against this subvariant. Thus, it is urgent to find highly protective vaccination strategies within available SARS-CoV-2 vaccines. Here, by using a SARS-CoV-2 pseudovirus neutralization assay, we demonstrated that the aerosol inhalation of adenoviral vector COVID-19 vaccine after two dose of inactivated vaccine (I-I-Ad5) led to higher levels of neutralizing antibodies against D614G strain (2041.00[95% CI, 1243.00–3351.00] vs 249.00[149.10–415.70]), Omicron BA.2 (467.10[231.00–944.40] vs 72.21[39.31–132.70]), BA.2.12.1(348.5[180.3–673.4] vs 53.17[31.29–90.37]), BA.2.13 (410.40[190.70–883.3] vs 48.48[27.87–84.32]), and BA.5 (442.40 vs 56.08[35.14–89.51]) than three inactivated vaccine doses (I-I-I). Additionally, the level of neutralizing antibodies against BA.5 induced by I-I-Ad5 was 2.41-fold higher than those boosted by a third dose of RBD subunit vaccine (I-I-S) (p = 0.1308). The conventional virus neutralizing assay confirmed that I-I-Ad5 induced higher titre of neutralizing antibodies than I-I-I (116.80[84.51–161.5] vs 4.40[4.00–4.83]). In addition, I-I-Ad5 induced higher, but later, anti-RBD IgG and IgA in plasma than I-I-I. Our study verified that mucosal immunization with aerosol inhalation of adenoviral vector COVID-19 vaccine may be an effective strategy to control the probable wave of BA.5 pandemic in addition to two inactivated vaccines.

This study identifies the evolutionarily conserved Exportin 4 as an essential regulator in the nuclear export of circRNAs. Defective circRNA export results in R-loop formation and DNA damage in cells, as well as testis and neurological defects in mice.

We aimed to evaluate the effectiveness or efficacy of heterologous or homologous COVID-19 vaccine regimens against COVID-19-related outcomes after primary immunization with two doses of CoronaVac or Sinopharm COVID-19 vaccines. PubMed, EMBASE, Web of Science, and Cochrane Library databases were searched up to 31 October 2022. The primary measure was vaccine effectiveness against COVID-19 infection with homologous or heterologous booster. The results showed heterologous and homologous booster significantly improved effectiveness against COVID-19 infection compared to primary immunization. The effectiveness against COVID-19 infection was 89.19% (95%CI 78.49, 99.89) for heterologous mRNA vaccine booster, 87.00% (95%CI 82.14, 91.85) for non-replicating vector vaccine booster, 69.99% (95%CI 52.16, 87.82) for homologous booster, and 51.48% (95%CI 41.75, 61.21) for two doses of inactivated vaccine. Homologous and heterologous regimens were also effective against SARS-CoV-2 variants, and more evidence is still needed to confirm our findings.

Previous reports have shown that heterologous boosting with the AD5-vectored COVID-19 vaccine Convidecia based on a primary series of two doses of inactivated vaccine induces increasing immune responses. However, the immune persistence until 6 months after the heterologous prime-boost immunization was limited. Participants were from two single-center, randomized, controlled, observer-blinded trials, which involved individuals of 18–59 years of age and over 60 years of age. Eligible participants who previously primed with one dose or two doses of CoronaVac were stratified and randomly assigned to inoculate a booster dose of Convidecia or CoronaVac. Neutralizing antibodies against a live SARS-CoV-2 prototype virus and Delta and Omicron (B.1.1.529) variants, pseudovirus neutralizing antibodies against Omicron BA.4/5 variants, and anti-SARS-CoV-2 RBD antibodies at month 6 were detected, and the fold decreases and rate difference were calculated by comparing the levels of antibodies at month 6 with the peak levels at month 1. The neutralizing antibody titers against prototype SARS-CoV-2, RBD-specific IgG antibodies, and the Delta variant in the heterologous regimen of the CoronaVac plus Convidecia groups were significantly higher than those of the homologous prime-boost groups. In three-dose regimen groups, the geometric mean titers (GMTs) of neutralizing antibodies against prototype SARS-CoV-2 were 30.6 (95% CI: 25.1; 37.2) in the heterologous boosting group versus 6.9 (95% CI: 5.6; 8.6) in the homologous boosting group (p < 0.001) at month 6 in participants aged 18–59 years, and in the two-dose regimen, the neutralizing antibody GMTs were 8.5 (95% CI: 6.2; 11.7) and 2.7 (2.3 to 3.1) (heterologous regimen group versus CoronaVac regimen group, p < 0.001). Participants aged over 60 years had similar levels of neutralizing antibodies against the prototype, with GMTs of 49.1 (38.0 to 63.6) in the group receiving two doses of CoronaVac plus one dose of Convidecia versus 9.4 (7.7 to 11.4) in the group receiving three doses of CoronaVac (p < 0.001) and 11.6 (8.4 to 16.0) in the group receiving one dose of CoronaVac and one dose of Convidecia versus 3.3 (2.7 to 4.0) in the group receiving two doses of CoronaVac (p < 0.001). Compared with day 14, over sixfold decreases in neutralizing antibody GMTs were observed in the heterologous groups of the three- or two-dose regimen groups of younger and elderly participants, while in the homologous regimen groups, the GMTs of neutralizing antibodies decreased about fivefold in the two age groups. The heterologous prime-boost regimen with two doses of CoronaVac and one dose of Convidecia was persistently more immunogenic than the regimen of the homologous prime-boost with three doses of CoronaVac.

Abstract. A large-scale vaccination of coronavirus disease-19 (COVID-19) in adults has been conducted for nearly a year, and there is a growing recognition that immunization for children is also essential. It has been months since emergency use of pediatric COVID-19 vaccine was approved, we reviewed the prevalence and transmission of COVID-19 in children. The prevalence of COVID-19 in children is reduced due to vaccination even in a Delta prevalent period, so an increase in the vaccination rate is needed in children. Although the precise role of children in the transmission requires more research to uncover, they likely played a significant role, according to the available literature. We also described four candidate COVID-19 vaccines for children on their safety and immunogenicity and the impact of severe acute respiratory syndrome coronavirus 2 variants on childhood vaccination. Safety issues on pediatric vaccines post-approval, like adverse events following immunization and adverse events of special interest require studies on long-term and effective regulatory mechanisms.

Abstract Background Multiple lines of evidence have demonstrated that circular RNAs (circRNAs) play oncogenic or tumor-suppressive roles in various human cancers. Nevertheless, the biological functions of circRNAs in small cell lung cancer (SCLC) are still elusive. Methods CircVAPA (annotated as hsa_circ_0006990) was identified by mining the circRNA profiling dataset of six paired SCLC tissues and the RNA-seq data of serum samples from 36 SCLC patients and 118 healthy controls. The circVAPA expression level was evaluated using quantitative real-time PCR in SCLC cells and tissues. Cell viability, colony formation, cell cycle and apoptosis analysis assays and in vivo tumorigenesis were used to reveal the biological roles of circVAPA. The underlying mechanism of circVAPA was investigated by Western blot, RNA pulldown, RNA immunoprecipitation, dual-luciferase reporter assay and rescue experiments. Results We revealed that circVAPA, derived from exons 2-4 of the vesicle-associated membrane protein-associated protein A (VAPA) gene, exhibited higher expression levels in SCLC cell lines, clinical tissues, and serum from SCLC patients than the controls, and facilitated SCLC progression in vitro and in vivo. Mechanistically, circVAPA activated the phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway by modulating the miR-377-3p and miR-494-3p/insulin-like growth factor 1 receptor (IGF1R) axis to accelerate SCLC progression. Furthermore, circVAPA depletion markedly enhanced the inhibitory effects of BMS-536924, an IGF1R kinase inhibitor in cellular and xenograft mouse models. Conclusions CircVAPA promotes SCLC progression via the miR-377-3p and miR-494-3p/IGF1R/AKT axis. We hope to develop clinical protocols of combinations of circVAPA inhibition and BMS-536924 addition for treating SCLC with circVAPA upregulation.

Abstract. Background:. The new emerging avian influenza A H7N9 virus, causing severe human infection with a mortality rate of around 41%. This study aims to provide a novel treatment option for the prevention and control of H7N9. Methods:. H7 hemagglutinin (HA)-specific B cells were isolated from peripheral blood plasma cells of the patients previously infected by H7N9 in Jiangsu Province, China. The human monoclonal antibodies (mAbs) were generated by amplification and cloning of these HA-specific B cells. First, all human mAbs were screened for binding activity by enzyme-linked immunosorbent assay. Then, those mAbs, exhibiting potent affinity to recognize H7 HAs were further evaluated by hemagglutination-inhibiting (HAI) and microneutralization in vitro assays. Finally, the lead mAb candidate was selected and tested against the lethal challenge of the H7N9 virus using murine models. Results:. The mAb 6-137 was able to recognize a panel of H7 HAs with high affinity but not HA of other subtypes, including H1N1 and H3N2. The mAb 6-137 can efficiently inhibit the HA activity in the inactivated H7N9 virus and neutralize 100 tissue culture infectious dose 50 (TCID50) of H7N9 virus (influenza A/Nanjing/1/2013) in vitro, with neutralizing activity as low as 78 ng/mL. In addition, the mAb 6-137 protected the mice against the lethal challenge of H7N9 prophylactically and therapeutically. Conclusion:. The mAb 6-137 could be an effective antibody as a prophylactic or therapeutic biological treatment for the H7N9 exposure or infection.

Abstract In this work, pitch-based carbon fibers were utilized to reinforce silicon carbide (SiC) composites via reaction melting infiltration (RMI) method by controlling the reaction temperature and resin carbon content. Thermal conductivities and bending strengths of composites obtained under different preparation conditions were characterized by various analytical methods. Results showed the formation of SiC whiskers (SiCw) during RMI process according to vapor—solid (VS) mechanism. SiCw played an important role in toughening the Cpf/SiC composites due to crack bridging, crack deflection, and SiCw pull-out. Increase in reaction temperature during RMI process led to an initial increase in thermal conductivity along in-plane and thickness directions of composites, followed by a decline. At reaction temperature of 1600 °C, thermal conductivities along the in-plane and thickness directions were estimated to be 203.00 and 39.59 W/(m·K), respectively. Under these conditions, bending strength was recorded as 186.15±3.95 MPa. Increase in resin carbon content before RMI process led to the generation of more SiC matrix. Thermal conductivities along in-plane and thickness directions remained stable with desirable values of 175.79 and 38.86 W/(m·K), respectively. By comparison, optimal bending strength improved to 244.62±3.07 MPa. In sum, these findings look promising for future application of pitch-based carbon fibers for reinforcement of SiC ceramic composites.

Mammalian cells employ various adaptive responses to cope with multiple stresses to maintain homeostasis. Functional roles of non-coding RNAs (ncRNAs) in response to cellular stresses have been proposed, and systematical investigations about the crosstalk among distinct types of RNAs are required. Here, we challenged HeLa cells with thapsigargin (TG) and glucose deprivation (GD) treatments to induce endoplasmic reticulum (ER) and metabolic stresses, respectively. Ribosomal RNA (rRNA)-depleted RNA sequencing (RNA-seq) was then performed. Characterization of the RNA-seq data revealed a series of differentially expressed long non-coding RNAs (lncRNAs) and circular RNAs (circRNAs) with parallel changes responsive to both stimuli. We further constructed the lncRNA/circRNA-mRNA co-expressing network, competing endogenous RNA (ceRNA) network in the lncRNA/circRNA-miRNA-mRNA axis, and lncRNA/circRNA-RNA binding protein (RBP) interactome map. These networks indicated the potential cis and/or trans regulatory roles of lncRNAs and circRNAs. Moreover, Gene Ontology analysis demonstrated that these identified ncRNAs were associated with several essential biological processes known to be related to cellular stress responses. In conclusion, we systematically established functional regulatory networks of lncRNA/circRNA-mRNA, lncRNA/circRNA-miRNA-mRNA and lncRNA/circRNA-RBP to perceive the potential interactions and biological processes during cellular stresses. These results provided insights in ncRNA regulatory networks of stress responses and the basis for further identification of pivotal factors involved in cellular stress responses.

Tumor metastasis is a hallmark of colorectal cancer (CRC), in which exosome plays a crucial role with its function in intercellular communication. Plasma exosomes were collected from healthy control (HC) donors, localized primary CRC and liver-metastatic CRC patients. We performed proximity barcoding assay (PBA) for single-exosome analysis, which enabled us to identify the alteration in exosome subpopulations associated with CRC progression. By in vitro and in vivo experiments, the biological impact of these subpopulations on cancer proliferation, migration, invasion, and metastasis was investigated. The potential application of exosomes as diagnostic biomarkers was evaluated in 2 independent validation cohorts by PBA. Twelve distinct exosome subpopulations were determined. We found 2 distinctly abundant subpopulations: one ITGB3-positive and the other ITGAM-positive. The ITGB3-positive cluster is rich in liver-metastatic CRC, compared to both HC group and primary CRC group. On the contrary, ITGAM-positive exosomes show a large-scale increase in plasma of HC group, compared to both primary CRC and metastatic CRC groups. Notably, both discovery cohort and validation cohort verified ITGB3+ exosomes as potential diagnostic biomarker. ITGB3+ exosomes promote proliferation, migration, and invasion capability of CRC. In contrast, ITGAM+ exosomes suppress CRC development. Moreover, we also provide evidence that one of the sources of ITGAM+ exosomes is macrophage. ITGB3+ exosomes and ITGAM+ exosomes are proven 2 potential diagnostic, prognostic, and therapeutic biomarkers for management of CRC.

Gamma-aminobutyric acid (GABA) is an important inhibitory neurotransmitter. Recently, it is considered to be a bioactive molecule with various health benefits. Ulcerative colitis (UC) is a chronic inflammatory disorder. An intestinal barrier defect is considered as one of the key events in the pathogenesis of UC. However, the issue of whether GABA is involved with intestinal inflammation remains debatable. In the present study, we investigated the effects of GABA on intestinal barrier function in healthy mice and susceptibility to UC in a dextran sulphate sodium (DSS) mouse model. Our results indicate that GABA treatment fails to induce significant colitis in healthy mice, however, GABA treatment enhances susceptibility to DSS-induced colitis in mice. Further, our results revealed GABA induces an intestinal barrier defect by inhibiting colonic epithelium proliferation and promoting its apoptosis. Accordingly, use of GABA treatment as applied for human health requires careful consideration.

Summary: Background: BNT162b2, an mRNA vaccine against COVID-19, is being utilised worldwide, but immunogenicity and safety data in Chinese individuals are limited. Methods: This phase 2, randomised, double-blind, placebo-controlled trial included healthy or medically stable individuals aged 18–85 years enrolled at two clinical sites in China. Participants were stratified by age (≤55 or >55 years) and randomly assigned (3:1) by an independent randomisation professional to receive two doses of intramuscular BNT162b2 30 μg or placebo, administered 21 days apart. Study participants, study personnel, investigators, statisticians, and the sponsor's study management team were blinded to treatment assignment. Primary immunogenicity endpoints were the geometric mean titers (GMTs) of neutralising antibodies to live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and seroconversion rates (SCR) 1 month after the second dose. Safety assessments included reactogenicity within 14 days of vaccination, adverse events (AEs), and clinical laboratory parameters. Randomised participants who received at least one dose were included in the efficacy and safety analyses on a complete case basis (incomplete/missing data not imputed). Results up to 6 months after the second dose are reported. Findings: Overall, 959 participants (all of Han ethnicity) who were recruited between December 5th, 2020 and January 9th, 2021 received at least one injection (BNT162b2, n=720; placebo, n=239). At 1 month after the second dose, the 50% neutralising antibody GMT was 294.4 (95% CI; 281.1–308.4) in the BNT162b2 group and 5.0 (95% CI; 5.0–5.0) in the placebo group. SCRs were 99.7% (95% CI; 99.0%–100.0%) and 0% (95% CI; 0.0%–1.5%), respectively (p

Abstract Background The aim of the current study was to investigate the effect of macrophage polarization on the expression of oxytocin (OT) and the oxytocin receptor (OTR) in enteric neurons. Methods In this study, we used a classic colitis model and D-mannose model to observe the correlation between macrophage polarization and OT signalling system. In order to further demonstrate the effect of macrophages, we examined the expression of OT signalling system after depletion of macrophages. Results The data showed that, in vitro, following polarization of macrophages to the M1 type by LPS, the macrophage supernatant contained proinflammatory cytokines (IL-1β, IL-6 and TNF-α) that inhibited the expression of OT and OTR in cultured enteric neurons; following macrophage polarization to the M2 type by IL4, the macrophage supernatant contained anti-inflammatory cytokines (TGF-β) that promoted the expression of OT and OTR in cultured enteric neurons. Furthermore, M1 macrophages decreased the expression of the OT signalling system mainly through STAT3/NF-κB pathways in cultured enteric neurons; M2 macrophages increased the expression of the OT signalling system mainly through activation of Smad2/3 and inhibition of the expression of Peg3 in cultured enteric neurons. In a colitis model, we demonstrated that macrophages were polarized to the M1 type during the inflammatory phase, with significant decreased in the expression of OT and OTR. When macrophages were polarized to the M2 type during the recovery phase, OT and OTR expression increased significantly. In addition, we found that D-mannose increased the expression of OT and OTR through polarization of macrophages to the M2 type. Conclusions This is the first study to demonstrate that macrophage polarization differentially regulates the expression of OT and OTR in enteric neurons.

The presence of maternal poliovirus antibodies may interfere with the immune response to inactivated polio vaccine (IPV), and its influence on the safety of vaccination is not yet understood. A total of 1146 eligible infants were randomly assigned (1:1) to the IPV and Sabin IPV (SIPV) groups to compare and analyze the efficacy of the two vaccines in preventing poliovirus infection. We pooled the SIPV and IPV groups and reclassified them into the maternal poliovirus antibody-positive group (MAPG; ≥1: 8) and the maternal poliovirus antibody-negative group (MANG;

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) variants have been reported to be resistant to several neutralizing antibodies (NAbs) targeting Receptor Binding Domain (RBD) and N Terminal Domain (NTD) of spike (S) protein and thus inducing immune escape. However, fewer studies were carried out to investigate the neutralizing ability of S2-specific antibodies. In this research, 10 monoclonal antibodies (mAbs) targeting SARS-CoV-2 S2 subunit were generated from Coronavirus Disease 2019 (COVID-19) convalescent patients by phage display technology and molecular cloning technology. The binding activity of these S2-mAbs toward SARS-CoV-2 S, SARS-CoV-2 S2, SARS-CoV-2 RBD, SARS-CoV-2 NTD, severe acute respiratory syndrome coronavirus (SARS-CoV) S, SARS-CoV S2 and Middle East Respiratory Syndrome Coronavirus (MERS-CoV) S proteins were evaluated by enzyme-linked immunosorbent assay (ELISA). Their neutralizing potency toward SARS-CoV-2 wild-type (WT), B.1.1.7, B.1.351, P.1, B.1.617.2, B.1.1.1 and B.1.621 variants were determined by pseudo-virus-based neutralization assay. Results showed that S2E7-mAb had cross-activity to S or S2 proteins of SARS-CoV-2, SARS-CoV and MERS-CoV, while with limited neutralizing activity to pseudo-viruses of SARS-CoV-2 WT and variants. It is undeniable that the binding and neutralizing activities of the S2-targeting mAbs are significantly weaker than the previously reported antibodies targeting RBD and NTD, but our study may provide some evidences for understanding immune protection and identifying targets for vaccine design based on the conserved S2 subunit.

Since TND could be an appropriate method to assess vaccine effectiveness, we want to know whether it may be used for the estimation of vaccine immunological surrogate endpoints, like case-control study. We conducted two study designs (test-negative design (TND) VS matched case-control design (MCC)) to evaluate immunological surrogate endpoint against EV71-associated diseases. We calculated sensitivity (proportion of participants with EV71-associated disease who have a titer less than the cutoff at day 56), specificity (proportion of matched controls who have a titer equal or greater than the cutoff at day 56), and corresponding Youden index ([sensitivity + specificity] − 1). Then, we compared them between TND and MCC. In test-negative design, we totally enrolled 7029 subjects, 49 tested positive as cases and 6980 tested negative as controls in per-protocol population. In matched case-control design, we totally enrolled 305 subjects, 51 as cases, and 254 as controls in whole cohort. In sensitivity and specificity comparison, TND and MCC’s results were similar to each other, except for a titer of 1:4. Nonetheless, in Youden index comparison, MCC’s results were slightly higher than the TND’s, except for a titer of 1:4. EV71 vaccine immunological surrogate endpoints derived from TND was similar to MCC’s. Our results supported that TND could become an alternative research design with the progress of surveillance.

CoronaVac, also known as the Sinovac inactivated SARS-CoV-2 vaccine, has been widely implemented in combating the COVID-19 pandemic. We summarized the results of clinical trials and real-world studies of CoronaVac in this review. The overall efficacy for the prevention of symptomatic COVID-19 (before the emergence of variants of concern) using two doses of 3 μg CoronaVac was 67.7% (95% CI, 35.9% to 83.7%). Effectiveness in preventing hospitalizations, ICU admissions, and deaths was more prominent than that in preventing COVID-19. A third dose inherited the effectiveness against non-variants of concern and increased effectiveness against severe COVID-19 outcomes caused by omicron variants compared to two doses. Most adverse reactions were mild. Few vaccine-related serious adverse reactions have been reported. Moreover, three-dose regimen significantly increased the seroconversion levels of neutralizing antibodies against omicron as compared to two-dose regimen. This review of CoronaVac may provide a scientific basis for optimizing global immunization strategies.

Global solar radiation (GSR) reaching the Earth’s surface can directly alter the energy balance of the climate system. The potential influence of inhomogeneity issues on Chinese GSR records on dimming and brightening in China has been argued for years. In this study, we explored the temporal evolution and spatial distribution of the long-term trend of GSR in eastern China (EC) during 1961–2018 using a homogenized GSR dataset, which removed the artificial signals. Results demonstrate that EC experienced a significant dimming period from 1961 to 1999, a brightening period from 2010 until 2018 and a leveling-off period between them (2000–2010), which resulted from opposite trends of GSR in the northern (dimming) and southern (brightening) regions of EC. The reduction of cloud coverage after the dimming period (2000) induced an early coming brightening in the southern region of China between 2000 and 2010, while the increase in aerosols and the rapidly extending cloud fraction resulted in the continuing dimming in northern China.

Demands for increasing production and living functions often threaten ecological functions. Reliable quantification of land use multifunctionality (LUMF) contributes to identify and coordinate these conflicts. However, the comprehensive LUMF indicator system and fine spatial resolutions restricted each other. Previous assessments were limited to coarse grids or administrative units, thus failing to provide detailed spatial information and causing scale biases, particularly in landscapes with strong heterogeneity. Combining big data mining and fusion techniques, this study built a comprehensive and quantitative evaluation scheme of production-living-ecology (PLE) land functions with spatial detail. The scheme was applied in the karst region of southwestern China as a case study. Data on socioeconomic status, remote sensing, and location points were fused using a variable-boundary spatialized approach to quantify human activity extent and degree of convenience. Specific environmental characteristics, such as topography and karst rocky desertification, were integrated into the spatialized PLE functions. The results showed that the global distribution of the production and living functions presented some similarity, yet the high production and living functions were not completely aligned. Also, the spatial patterns of the living and production functions usually showed opposite formations to the ecology function. Unlike the global relationship, the enlarged PLE relationships in the study regions validated the importance and necessity of fine spatial information. Local relationships between the production-living and production-ecology functions were significantly different in areas with various economic development levels, particularly in built-up areas. Regions with strong synergistic relationships of PLE functions were rare and were usually found in sightseeing areas of ecology and agriculture. These results demonstrated the effectiveness of our proposed method of spatializing PLE functions with spatial detail. The findings provide detailed spatial information on local anthropogenic and physical differences and support for balancing PLE functions and policy-making about land use optimization in practice.