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G9P[8] became the predominant rotavirus A (RVA) genotype in China in 2012. To evaluate its genetic composition at the whole-genome level, 115 G9P[8] RVA strains isolated from children under 5 years old were sequenced and characterized. All 13 strains in 2016 and 2017 and an additional 54 strains in 2018 were genotyped as G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E1-H1. The other 48 strains in 2018 were all genotyped as G9-P[8]-I1-R1-C1-M1-A1-N1-T1-E2-H1, with the NSP4 gene characterized as a DS-1-like genotype. The time of the most recent common ancestor (tMRCA) and evolution rates of the VP7, VP4, and NSP4 (E1 and E2) genes of these strains were estimated by Bayesian evolutionary dynamics analysis. We estimated the evolution rates (nt substitutions per site per year) as 1.38 × 10–3 [the 95% highest posterior density (HPD) was 1.09–1.72 × 10–3] for VP7, 0.87 × 10–3 (95% HPD: 0.75–1.00 × 10–3) for VP4, 0.56 × 10–3 (95% HPD: 0.41–0.73 × 10–3) for NSP4-E1, and 1.35 × 10–3 (95% HPD: 0.92–1.86 × 10–3) for NSP4-E2. The tMRCA was estimated to be 1935.4 (95% HPD: 1892.4–1961.3) for VP7, 1894.3 (95% HPD: 1850.5–1937.8) for VP4, 1929.4 (95% HPD: 1892.4–1961.3) for NSP4-E1, and 1969.2 (95% HPD: 1942.2–1985.3) for NSP4-E2. The baseline genetic information in this study is expected to improve our understanding of the genomic and evolutionary characteristics of the rotavirus genome. Furthermore, it will provide a basis for the development of next-generation rotavirus vaccines for humans.

Through isothermal hot compression experiments at various strain rates and temperatures, the thermal deformation behavior of Zn-2.0Cu-0.15Ti alloy is investigated. The Arrhenius-type model is utilized to forecast flow stress behavior. Results show that the Arrhenius-type model accurately reflects the flow behavior in the entire processing region. The dynamic material model (DMM) reveals that the optimal processing region for the hot processing of Zn-2.0Cu-0.15Ti alloy has a maximum efficiency of about 35%, in the temperatures range (493–543 K) and a strain rate range (0.01–0.1 s−1). Microstructure analysis demonstrates that the primary dynamic softening mechanism of Zn-2.0Cu-0.15Ti alloy after hot compression is significantly influenced by temperature and strain rate. At low temperature (423 K) and low strain rate (0.1 s−1), the interaction of dislocations is the primary mechanism for the softening Zn-2.0Cu-0.15Ti alloys. At a strain rate of 1 s−1, the primary mechanism changes to continuous dynamic recrystallization (CDRX). Discontinuous dynamic recrystallization (DDRX) occurs when Zn-2.0Cu-0.15Ti alloy is deformed under the conditions of 523 K/0.1 s−1, while twinning dynamic recrystallization (TDRX) and CDRX are observed when the strain rate is 10 s−1.

This study consisted of two rounds of cross-sectional observations designed to evaluate the persistence of immune protection induced high antigen content hepatitis B (HB) vaccine at 60 μg/1.0 ml formulations administered at a three-dose schedule (Days 0, 28, and 56) in non-responders to routine HB vaccination. In the original phase 3 study, we enrolled 1091 healthy participants (16–60 years old) seronegative for antibody against HB surface antigen (anti-HBs) after primary vaccination. Participants were randomized (2:2:1) to receive three booster doses of HB vaccine containing 60 μg, 30 μg, or 10 μg of antigen per dose 28 days apart. In the group receiving the 60 μg HB vaccine, 428 participants’ serum samples were available at pre-vaccination and 28 days after each vaccine dose and were included in immunogenicity analysis. With two written informed consents, we collected blood samples from 276 (67.2%) participants in 2014 and 239 (58.2%) in 2019, who had completed the full course of revaccination and reached the seropositive (anti-HBs≥10 mIU/ml) standard in the 60 μg vaccine group of the original phase 3 study. The HBV seropositive rate was found to decrease from 96.0% in 28 days after receiving the third dose of 60 μg HB vaccine, to 48.2% in 2014, and to 40.6% in 2019, with anti-HBs GMC of seropositive individuals was 584.0 mIU/ml, 142.4 mIU/ml, and 169.1 mIU/ml, respectively. Analysis of 181 vaccinees who had serologic test results available both in 2014 and in 2019, and results revealed a dynamic trend in anti-HBs titer similar to that for the whole immune persistence cohort. Of paramount importance, the serologic test results found that 24.9% (45/181) participants had higher anti-HBs concentrations in 2019 than in 2014, this could be interpreted as natural boosters, secondary to HBV exposure without infection because protected. In conclusion, protective antibody persists about 11 years after immunization of Chinese non-responders with 3 doses of 60 μg HB vaccine. Booster doses of vaccine do not seem necessary to ensure long-term protection.

Background: The test-negative design has been used widely in evaluation of various vaccines’ effectiveness, such as influenza, rotavirus, and so on. Recently, there have been some studies about EV-71 vaccine effectiveness by using test-negative design(TND). However, the validity of the TND application in EV-71 vaccines has not been evaluated. Methods: This study is set upon prior methods to evaluate the validity of TND for influenza vaccine by using a randomized controlled clinical trial database. Vaccine effectiveness estimated by TND (VE-TND) in modified intention-to-treat population (mITT) and per-protocol-set population(PPS) was derived from a large randomized placebo-controlled clinical trial (RCT) of inactivated monovalent EV-71 vaccine in China. Derived VE-TND estimates were compared to the original vaccine efficacy results in RCT (VE-RCT). Results: We totally enrolled 7325 participants who seeked medical care for suspected EV-71 infected diseases during the surveillance. There are no significant differences between cases(test-positive) and controls(test-negative) on sex, age, height, and weight. TND vaccine effectiveness estimates were similar to original RCT vaccine efficacy estimates, both in modified intention-to-treat population and per-protocol populations. Conclusions: This study supports that TND, as an appropriate observational study design is valid to measure EV-71 vaccine effectiveness.

To evaluate rotavirus (RV) disease burden and circulating strains of RV among Chinese children younger than 5-years old who had diarrhea from 2011 to 2018. PubMed, Web of Science, Embase, CNKI and WANFANG databases were systematically searched to identify studies that reported RV prevalence in mainland China. After data extraction, a fixed-effects model or a random-effects model was applied to estimate RV positivity and proportions of G and P types. Statistical analysis was conducted using R software. We initially reviewed 1323 studies, and identified 69 studies that were eligible. The overall proportion of RV gastroenteritis (RVGE) among children under 5-years old who presented with diarrhea and sought medical care was 34.0% (95% CI: 31.3, 36.8), and RV positivity was higher among inpatients (39.7%) than outpatients (23.9%). Western areas of China had the highest proportion of RVGE (42.7%), and RV positivity was highest for children who were 6 months-old to 2 years-old. The most prevalent G types were G3 (26.1%), G9 (17.5%), and G1 (12.8%), the most prevalent P type was P[8] (56.8%) and the most prevalent G-P combination was G9P[8] (20.9%). RV continues to be a main cause of acute gastroenteritis in Chinese children who are younger than 5 years old. Following the introduction of an RV vaccine in 2011, monitoring of the disease burden of RV diarrhea and circulating strains in China remain important for assessments of vaccine efficacy.

Abstract We examined the safety and efficacy of human umbilical cord mesenchymal stem cell (hUC-MSC) infusion for immune non-responder (INR) patients with chronic HIV-1 infection, who represent an unmet medical need even in the era of efficient antiretroviral therapy (ART). Seventy-two INR patients with HIV were enrolled in this phase II randomized, double-blinded, multicenter, placebo-controlled, dose-determination trial (NCT01213186) from May 2013 to March 2016. They were assigned to receive high-dose (1.5 × 106/kg body weight) or low-dose (0.5 × 106/kg body weight) hUC-MSC, or placebo. Their clinical and immunological parameters were monitored during the 96-week follow-up study. We found that hUC-MSC treatment was safe and well-tolerated. Compared with baseline, there was a statistical increase in CD4+ T counts in the high-dose (P

Ischemia/reperfusion injury is a common pathophysiological process in the clinic. It causes various injuries, multiple organ dysfunction, and even death. There are several possible mechanisms about ischemia/reperfusion injury, but the influence on intestinal myenteric neurons and the underlying mechanism are still unclear. C57BL6/J mice were used to establish the ischemia/reperfusion model in vivo. Peritoneal macrophages were used for ATP depletion and hypoxia/reoxygenation experiment in vitro. L-cysteine, as the substrate of hydrogen sulfide, is involved in many physiological and pathological processes, including inflammation, metabolism, neuroprotection, and vasodilation. In the current study, we confirmed that intestinal ischemia/reperfusion led to the injury of myenteric neurons. From experiments in vitro and in vivo, we demonstrated that L-cysteine protected myenteric neurons from the injury. AOAA reversed the protective effect of L-cysteine. Also, L-cysteine played a protective role mainly by acting on intestinal macrophages via decreasing the expression of NLRP3, cleaved caspase-1, and mature IL-1β. L-cysteine increased cystathionine beta synthase and H2S produced by intestinal macrophages to protect myenteric mature neurons and enteric neural precursor cells from apoptosis. Moreover, the addition of IL-1β-neutralizing antibody alleviated the injury of myenteric neurons and enteric neural precursor cells caused by intestinal ischemia/reperfusion. Our study provided a new target for the protection of myenteric neurons in clinical intestinal ischemia/reperfusion injury.

Abstract The global spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) requires an urgent need to find effective therapeutics for the treatment of coronavirus disease 2019 (COVID-19). In this study, we developed an integrative drug repositioning framework, which fully takes advantage of machine learning and statistical analysis approaches to systematically integrate and mine large-scale knowledge graph, literature and transcriptome data to discover the potential drug candidates against SARS-CoV-2. Our in silico screening followed by wet-lab validation indicated that a poly-ADP-ribose polymerase 1 (PARP1) inhibitor, CVL218, currently in Phase I clinical trial, may be repurposed to treat COVID-19. Our in vitro assays revealed that CVL218 can exhibit effective inhibitory activity against SARS-CoV-2 replication without obvious cytopathic effect. In addition, we showed that CVL218 can interact with the nucleocapsid (N) protein of SARS-CoV-2 and is able to suppress the LPS-induced production of several inflammatory cytokines that are highly relevant to the prevention of immunopathology induced by SARS-CoV-2 infection.

Rotavirus, which causes acute gastroenteritis and severe diarrhea, has posed a great threat to children worldwide over the last 30 y. Since no specific drugs and therapies against rotavirus are available, vaccination is considered the most effective method of decreasing the morbidity and mortality related to rotavirus-associated gastroenteritis. To date, six rotavirus vaccines have been developed and licensed by local governments. Notably, Rotarix™ and RotaTeq™ have been recommended as universal agents against rotavirus infection by the World Health Organization; however, lower efficacies were found in less-developed and developing regions with medium and high child mortality than well-developed ones with low child mortality. For now, two promising novel vaccines, Rotavac™ and RotaSiil™ were pre-qualified by the World Health Organization in 2018. Other rotavirus vaccines in the pipeline including neonatal strain (RV3-BB) and several non-replicating rotavirus vaccines with a parenteral delivery strategy are currently undergoing investigation, with the potential to improve the performance of, and eliminate the safety concerns associated with, previous live oral rotavirus vaccines. This paper reviews the important developments in rotavirus vaccines in the last 20 y and discusses problems and challenges that require investigation in the future.

An axial compressor has high efficiency under design conditions, but its stable working range is narrow. Adjusting the rotational speed can effectively expand the stable working range. In this paper, a five-stage axial compressor for a specific compressed air energy storage (CAES) system is taken as the research object, and different rotational speed (DRS) characteristics are studied with NUMECA software. Firstly, the influence of DRS on overall aerodynamic performance is explored, and the working flow range of the compressor is increased from 11.5% to 54.0%. Secondly, the effect of DRS on inlet parameters of the first stage rotor is analyzed, and the reasonable distribution of inlet parameters is obtained. Thirdly, the changing law of the internal flow is investigated at DRS. The corner separation is gradually enhanced when the rotational speed increases, and the leakage flow velocity at the rotor tip gradually improves. Finally, the loss distribution of tip clearance is researched. The result shows that the loss distribution increases significantly in both circumferential and spanwise directions when the speed increases. This work aims to provide a reference for the stable and efficient operation of axial compressors in CAES systems under the wide working range.

The oblique flow compressor is one of the important components in the compressed air energy storage (CAES) system. The structural shape of the radial inlet chamber (RIC) directly affects the compressor performance, and a reasonable RIC design should achieve the smallest total pressure loss and outlet distortion as much as possible to meet the structural design. To study the influence of splitter blades, 4 RICs equipped with different numbers of splitter blades are designed, and the performance of 4 RICs and the overall performance of the compressor is calculated. The results show that with the increase in the number of splitter blades, the stall margin increases from 6.3% to 13.94%. At the design point, the isentropic efficiency is highest for the RIC with 17 splitter blades, and the pressure ratio is highest for the RIC with 11 splitter blades. Compared with the direct axial intake mode, the uniformity of the relative leakage distribution and the attack angle distribution of the impeller leading edge under 4 radial intake modes are poor. However, with an increase in the number of splitter blades, the uniformity of the relative tip leakage and the attack angle distribution gradually increase. The flow loss of RIC will increase simultaneously, though the uniformity of the outlet aerodynamic parameters distribution improves, and the influence on the downstream component performance gradually weakens. There is an optimal number of splitter blades in RIC, which balances the total pressure loss and distortion coefficient.

Abstract In response to the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) pandemic, over 200 vaccine candidates against coronavirus disease 2019 (COVID-2019) are under development and currently moving forward at an unparalleled speed. The availability of surrogate endpoints would help to avoid large-scale filed efficacy trials and facilitate the approval of vaccine candidates, which is crucial to control COVID-19 pandemic. Several phase 3 efficacy trials of COVID-19 vaccine candidates are under way, which provide opportunities for the determination of COVID-19 correlates of protection. In this paper, we review current knowledge for existence of COVID-19 correlates of protection, methods for assessment of immune correlates of protection and issues related to COVID-19 correlates of protection.

The FLT3-ITD mutation occurs in about 30% of acute myeloid leukemia (AML) and is associated with poor prognosis. However, FLT3 inhibitors are only partially effective and prone to acquired resistance. Here, we identified Yes-associated protein 1 (YAP1) as a tumor suppressor in FLT3-ITD+ AML. YAP1 inactivation conferred FLT3-ITD+ AML cell resistance to chemo- and targeted therapy. Mass spectrometric assay revealed that DNA damage repair gene poly (ADP-ribose) polymerase 1 (PARP1) might be the downstream of YAP1, and the pro-proliferative effect by YAP1 knockdown was partly reversed via PARP1 inhibitor. Importantly, histone deacetylase 10 (HDAC10) contributed to decreased YAP1 acetylation levels through histone H3 lysine 27 (H3K27) acetylation, leading to the reduced nuclear accumulation of YAP1. Selective HDAC10 inhibitor chidamide or HDAC10 knockdown activated YAP1, enhanced DNA damage, and significantly attenuated FLT3-ITD+ AML cell resistance. In addition, combination chidamide with FLT3 inhibitors or chemotherapy agents synergistically inhibited growth and increased apoptosis of FLT3-ITD+ AML cell lines and acquired resistant cells from the relapse FLT3-ITD+ AML patients. These findings demonstrate that the HDAC10-YAP1-PARP1 axis maintains FLT3-ITD+ AML cells and targeting this axis might improve clinical outcomes in FLT3-ITD+ AML patients.

BackgroundHeterologous boost vaccination has been proposed as an option to elicit stronger and broader, or longer-lasting immunity. We assessed the safety and immunogenicity of heterologous immunization with a recombinant adenovirus type-5-vectored Coronavirus Disease 2019 (COVID-19) vaccine (Convidecia, hereafter referred to as CV) and a protein-subunit-based COVID-19 vaccine (ZF2001, hereafter referred to as ZF).Methods and findingsWe conducted a randomized, observer-blinded, placebo-controlled trial, in which healthy adults aged 18 years or older, who have received 1 dose of Convidecia, with no history of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, were recruited in Jiangsu, China. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or placebo control (trivalent inactivated influenza vaccine (TIV)) administered at 28 days after priming, and received the third injection with ZF2001 at 5 months, referred to as CV/ZF/ZF (D0-D28-M5) and CV/ZF (D0-M5) regimen, respectively. Sixty participants were randomly assigned (2:1) to receive either 1 dose of ZF2001 or TIV administered at 56 days after priming, and received the third injection with ZF2001 at 6 months, referred to as CV/ZF/ZF (D0-D56-M6) and CV/ZF (D0-M6) regimen, respectively. Participants and investigators were masked to the vaccine received but not to the boosting interval. Primary endpoints were the geometric mean titer (GMT) of neutralizing antibodies against wild-type SARS-CoV-2 and 7-day solicited adverse reactions. The primary analysis was done in the intention-to-treat population. Between April 7, 2021 and May 6, 2021, 120 eligible participants were randomly assigned to receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 28 days and 5 months post priming, and receive ZF2001/ZF2001 (n = 40) or TIV/ZF2001 (n = 20) 56 days and 6 months post priming. Of them, 7 participants did not receive the third injection with ZF2001. A total of 26 participants (21.7%) reported solicited adverse reactions within 7 days post boost vaccinations, and all the reported adverse reactions were mild, with 13 (32.5%) in CV/ZF/ZF (D0-D28-M5) regimen, 7 (35.0%) in CV/ZF (D0- M5) regimen, 4 (10.0%) in CV/ZF/ZF (D0-D56-M6) regimen, and 2 (10.0%) in CV/ZF (D0-M6) regimen, respectively. At 14 days post first boost, GMTs of neutralizing antibodies in recipients receiving ZF2001 at 28 days and 56 days post priming were 18.7 (95% CI 13.7 to 25.5) and 25.9 (17.0 to 39.3), respectively, with geometric mean ratios of 2.0 (1.2 to 3.5) and 3.4 (1.8 to 6.4) compared to TIV. GMTs at 14 days after second boost of neutralizing antibodies increased to 107.2 (73.7 to 155.8) in CV/ZF/ZF (D0-D28-M5) regimen and 141.2 (83.4 to 238.8) in CV/ZF/ZF (D0-D56-M6) regimen. Two-dose schedules of CV/ZF (D0-M5) and CV/ZF (D0-M6) induced antibody levels comparable with that elicited by 3-dose schedules, with GMTs of 90.5 (45.6, 179.8) and 94.1 (44.0, 200.9), respectively. Study limitations include the absence of vaccine effectiveness in a real-world setting and current lack of immune persistence data.ConclusionsHeterologous boosting with ZF2001 following primary vaccination with Convidecia is more immunogenic than a single dose of Convidecia and is not associated with safety concerns. These results support flexibility in cooperating viral vectored and recombinant protein vaccines.Trial registrationStudy on Heterologous Prime-boost of Recombinant COVID-19 Vaccine (Ad5 Vector) and RBD-based Protein Subunit Vaccine; ClinicalTrial.gov NCT04833101.

The molecular mechanism underlying the protective role of propofol against myocardial ischemia/reperfusion (I/R) injury remains poorly understood. Previous studies have shown that ferroptosis is an imperative pathological process in myocardial I/R injury. We hypothesized that propofol prevents myocardial I/R injury by inhibiting ferroptosis via the AKT/p53 signaling pathway. The ferroptosis-inducing agent erastin (E) and AKT inhibitor MK2206 (MK) were used to investigate the role of propofol in myocardial I/R injury. H9C2 cells treated without any reagents, erastin for 24 h, propofol for 1 h before adding erastin were assigned as the control (C), E, and E + P group, respectively. Cell viability, reactive oxygen species (ROS), and the expression of antioxidant enzymes, including ferritin heavy chain 1 (FTH1), cysteine/glutamate transporter (XCT), and glutathione peroxidase 4 (GPX4) in H9C2 cells. Rat hearts from the I/R + P or I/R groups were treated with or without propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min. Rat hearts from the I/R + P + MK or I/R + MK groups were treated with or without propofol for 20 min, with a 10-min treatment of MK2206 before stopping perfusion. Myocardial histopathology, mitochondrial structure, iron levels, and antioxidant enzymes expression were assessed. Our results demonstrated that erastin increased H9C2 cell mortality and reduced the expression of antioxidant enzymes. I/R, which reduced the expression of antioxidant enzymes and increased iron or p53 (p < 0.05), boosted myocardium pathological and mitochondrion damage. Propofol inhibited these changes; however, the effects of propofol on I/R injury were antagonized by MK (p < 0.05). In addition, AKT siRNA inhibited the propofol-induced expression of antioxidant enzymes (p < 0.05). Our findings confirm that propofol protects myocardium from I/R injury by inhibiting ferroptosis via the AKT/p53 signal pathway.

Background: Compared with trivalent influenza vaccines, quadrivalent influenza vaccines are expected to provide wider protection against influenza B virus infections. We developed a novel quadrivalent subunit influenza vaccine which was distinct from the influenza vaccines available on the market in production process. In this research, we evaluated the safety and immunogenicity of the quadrivalent subunit influenza vaccine in animal models. Methods: In toxicity assessment, 40 SD rats were randomly assigned to be intramuscularly injected with 1.0 ml of the tested vaccine (33 μg/ml) or 0.9% sodium chloride solution. In irritation assessment, eight rabbits were randomly assigned to receive 0.5 ml of tested vaccine or phosphate buffer solution intramuscularly. Thirty-two guinea pigs were randomly assigned to be intramuscularly injected with high-dose tested vaccine (0.5 ml), low-dose tested vaccine (0.05 ml), ovalbumin, or 0.9% sodium chloride solution, respectively, for sensitization assessment. In immunogenicity assessment, 50 BALB/c mice were equally randomized to receive one dose of tested vaccine, two doses of tested vaccine with an interval of 14 days, 0.5 ml of trivalent subunit influenza vaccine, 0.5 ml of monovalent subunit influenza vaccine, or 0.5 ml of phosphate buffer solution. Orbital blood was collected before and 28 and 42 days after administration of the injections for detecting influenza antibody titers. Results: No abnormal toxicity and irritation in rats and rabbits showed in the gross autopsy and histopathological examinations. The results of sensitization in guinea pigs indicated that no obvious allergic symptoms observed in the high-dose and low-dose vaccine groups within 30 min after twice provocations, and the result of sensitization evaluation was negative. Vaccine induced significant immune responses in mice with 100% seroconversion rates at 28 and 42 days after the first dose. The geometric mean titers (GMTs) of hemagglutination inhibition (HI) antibodies at day 28 in one-dose quadri–vaccine and two-dose quadri–vaccine groups were comparable to those in the tri–vaccine or mono-vaccine groups for shared influenza strains. However, the GMTs of HI antibodies against H1N1 (P = 0.025) and BV (P = 0.049) at day 42 in one-dose quadri–vaccine group were significantly lower than those in the tri–vaccine or mono-vaccine groups. The GMTs of HI antibodies against H1N1, H3N1, BY, and BV at day 28 and day 42 were comparable between one-dose quadri–vaccine and two-dose quadri–vaccine groups. Conclusions: The quadrivalent subunit influenza vaccine was safe and immunogenic in animal models. One dose of the vaccine could elicit a satisfactory antibody response in mice.

Purpose: To explore the molecular genetic mechanisms underlying different responsiveness to Enterovirus 71 (EV71) vaccine. Methods: We recruited 10,245 healthy children into a phase 3 clinical trial to evaluate the efficacy of EV71 vaccine in 2012. Fifty subjects from the trial were divided into the potent immune response group (20 subjects) and the ineffective immune response group (30 subjects). Whole-exome sequencing was performed for these 50 samples and we conducted bioinformatics analyses based on online public database. Results: A total of 222,180 germline variants were detected across 50 subjects. Single nucleotide variant (SNV)-based screening of the subjects with potent or ineffective immune response allowed the identification of a potentially detrimental heterozygous missense variant (c.3784C>T) in EEA1. We also retained TRIM59 and ABCA7 genes that contain different loss of function (LoF) variants shared in two cases and involved in the immune response process. Then, we conducted high-resolution typing of 9 classical HLA genes, HLA-DRB1*03:01, HLA-DQA1*05:01 and HLA-DQB1*02:01 alleles were frequently (recurrence ≥5) observed only in ineffective immune responders. Conclusions: Our study is a meaningful attempt on the comparison of genomic profiles between potent and ineffective immune responders induced by EV71 vaccine, and several candidate potentially detrimental genes were identified.

Abstract Background Chemoresistance is emerging as a major barrier to successful treatment in acute myeloid leukemia (AML), and evasion of apoptosis is among the fundamental underlying mechanisms. Therefore, unraveling molecular networks that drive this process constitutes an urgent unmet need. Herein, we aim to characterize the role and molecular mechanism of the tumor necrosis factor ɑ-induced protein 8 (TNFAIP8), a novel anti-apoptotic molecule, in AML chemoresistance. Methods The expression levels of TNFAIP8 were assessed in AML patients and cell lines by RT-qPCR and western blots. The transcriptional regulation of TNFAIP8 was analyzed with luciferase reporter assay and ChIP followed by RT-qPCR. Functional experiments were conducted to evaluate the effects of TNFAIP8 on apoptosis, drug sensitivity and proliferation of AML cells. Potential effects of TNFAIP8 on the activation of extracellular signal-regulated kinase (ERK) pathway were detected by western blots. CoIP and P21-activated kinase (PAK) pull-down assay were performed to ascertain the upstream target. The overall effects of TNFAIP8 on AML were examined in murine models. Results Upregulated TNFAIP8 expression was first confirmed in human AML patients and cell lines. E74 like ETS transcription factor 1 (ELF1) was then identified to contribute to its aberrant expression. Through manipulating TNFAIP8 expression, we described its role in protecting AML cells from apoptosis induced by chemotherapeutic agents and in promoting drug resistance. Notably, the leukemia-promoting action of TNFAIP8 was mediated by sustaining activity of the ERK signaling pathway, through an interaction with Rac family small GTPase 1 (Rac1). In addition, in vivo experiments confirmed that TNFAIP8 suppression lowered leukemia infiltration and improved survival. Conclusion Our data provide a molecular basis for the role of TNFAIP8 in chemoresistance and progression of AML and highlight the unique function of TNFAIP8 as an attractive therapeutic target.

Enterovirus 71 (EV71) is the dominant pathogen in severe and fatal hand–foot–mouth disease (HFMD) cases. Since 2015, three inactivated EV71 vaccines have been approved in China. The vaccination coverage of the EV71 vaccine has been relatively low, especially in rural areas. A cross-sectional survey from July 19 to August 22, 2018, was conducted in three rural counties of northern Jiangsu Province among parents of children aged 6–60 months. We adopted a pretested validated questionnaire to assess knowledge, awareness, and attitude of HFMD and EV71 vaccines among respondents and used univariate and multivariate binary logistic analyses to explore potential factors associated with the acceptance of EV71 vaccines. Of the 1,112 parents who participated, 87.8% were willing to vaccinate their children with EV71 vaccines. Parents over 40 y old were less likely to have their children vaccinated [adjusted odds ratio (aOR) = 2.12, 95% confidence interval (CI): 1.13–3.97]. Parents who lived in Ganyu (aOR = 0.50, 95% CI: 0.31–0.79) or Xinyi county (aOR = 0.33, 95% CI: 0.20–0.53), had a university or higher degree (aOR = 0.26, 95% CI: 0.11–0.64), had good knowledge of EV71 vaccines (aOR = 0.81, 95% CI: 0.67–0.98), perceived their children’s disease susceptibility, and worried about the severity of HFMD had a higher willingness to vaccinate their children. Most parents were willing to vaccinate their children against EV71-related HFMD. Parental age, location, education level, knowledge of EV71 vaccines, concern about susceptibility, and severity of HFMD were all factors that influenced willingness to vaccinate.

Vaccination has been one of the major revolutions in the history of human health. Vaccination programs have targeted entire populations such as infants or elderly subjects as a matter of being efficient with time and resources. These general populations are heterogeneous in terms of factors such as ethnicity, health status, and socio-economics. Thus, there have been variations in the safety and effectiveness profiles of certain vaccinations according to current population-wide strategies. As the concept of precision medicine has been raised in recent years, many researchers have suggested that vaccines could be administered more precisely in terms of particular target populations, vaccine formulations, regimens, and dosage levels. This review addresses the concept and framework of precision immunization, summarizes recent and representative clinical trials of among specific populations, mentions important factors to be addressed in customizing vaccinations, and provides suggestions on the establishment of precision immunization with the goal of maximizing the effectiveness of vaccines in general.

CaliciNet China, a network of provincial, county, and city laboratories coordinated by the Chinese Centers for Disease Control and Prevention, was launched in October 2016 to monitor the epidemiology and genotype distribution of norovirus outbreaks in China. During October 2016–September 2018, a total of 556 norovirus outbreaks were reported, and positive fecal samples from 470 (84.5%) outbreaks were genotyped. Most of these outbreaks were associated with person-to-person transmission (95.1%), occurred in childcare centers or schools (78.2%), and were reported during November–March of each year (63.5%). During the 2-year study period, 81.2% of all norovirus outbreaks were typed as GII.2[P16]. In China, most norovirus outbreaks are reported by childcare centers or schools; GII.2[P16] is the predominant genotype. Ongoing surveillance by CaliciNet China will provide information about the evolving norovirus genotype distribution and outbreak characteristics important for the development of effective interventions, including vaccines.

Rabies is a highly fatal zoonotic disease caused by the rabies virus invading the central nervous system. When suspected of exposure to the rabies virus, post-exposure prophylaxis should be administered as soon as possible. Monoclonal antibodies (mAbs) neutralizing the rabies virus could be better in human rabies post-exposure prophylaxis than equine or human rabies immune globulin in terms of supply, cost, and efficacy. This article reviews anti-rabies mAbs produced by multiple techniques, and the results of clinical trials for anti-rabies mAbs cocktails recognizing non-overlapping epitopes are also discussed.

Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways, and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells from 3 left-sided and 3 right-sided CRC patients were profiled by single-cell RNA-Seq (scRNA-Seq). Right-sided CRC harbors a significant proportion of exhausted CD8+ T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of preexhausted/exhausted T cells were favorable prognostic markers. Notably, we identified a potentially novel RBP4+NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.

Background: This exploratory study aimed to assess the immunogenicity and safety of 1 and 2 doses of meningococcal serogroups A and C tetanus toxoid-conjugate vaccine (MenAC-TT) in toddles. Methods: Healthy participants aged 12–23 months were randomized into two groups to receive 1 or 2 doses of the tested vaccine. The interval was 28 days between two doses. Blood samples were collected at day 0 before the immunization and day 28 post-each dose. Safety observation was conducted during 28 days after each vaccination. Serious adverse event (SAE) was conducted throughout 6 month observation period. Results: Overall 301 toddles were vaccinated. Twenty-eight days post full-course vaccination, ≥97.20% toddles had titers ≥1:8 and ≥81.48% had titers ≥1:128 for MenA and MenC in the two schedules groups. There were no significant differences between the two schedule groups for each titer thresholds and serogroups. Up to month 12 post the first dose, titers ≥1:8 and 1:128 were declined to 71.32–80.83% and 26.67–57.85% for each meningococcal serogroups. Most adverse reactions (ARs) were mild or moderate, and the incidence of grade 3 ARs was below 3.33%. The incidence of redness was significantly higher in the two doses group than that in the one dose group, in terms of grade 1 and grade 2 were higher. No SAEs were considered causally related to vaccination. Conclusion: The MenAC-TT showed similarly safety and immunogenicity profile in toddles with two schedules. It will be more important to provide the data for formulating appropriate immunization strategies in different age groups in China.

Abstract Phenotypic polarization of macrophages is regulated by a milieu of cues in the local tissue microenvironment. Currently, little is known about how the intrinsic regulators modulate proinflammatory (M1) versus prohealing (M2) macrophages activation. Here, it is observed that insulin‐like growth factor 2 messenger RNA (mRNA)‐binding protein 2 (IGF2BP2)‐deleted macrophages exhibit enhanced M1 phenotype and promote dextran sulfate sodium induced colitis development. However, the IGF2BP2−/− macrophages are refractory to interleukin‐4 (IL‐4) induced activation and alleviate cockroach extract induced pulmonary allergic inflammation. Molecular studies indicate that IGF2BP2 switches M1 macrophages to M2 activation by targeting tuberous sclerosis 1 via an N6‐methyladenosine (m6A)‐dependent manner. Additionally, it is also shown a signal transducer and activators of transcription 6 (STAT6)‐high mobility group AT‐hook 2‐IGF2BP2‐peroxisome proliferator activated receptor‐γ axis involves in M2 macrophages differentiation. These findings highlight a key role of IGF2BP2 in regulation of macrophages activation and imply a potential therapeutic target of macrophages in the inflammatory diseases.

Reasonable optimization of development well type is the prerequisite to realize the economic and effective development of coalbed methane (CBM). However, the existing CBM development well type optimization methods are disadvantageous in many aspects. CBM is a kind of typical unconventional natural gas resource, and its study focuses on single-well evaluation. In this paper, the assessment method and the evaluation index (EI) for CBM development well type optimization based on the long-run marginal cost (LRMC) were constructed on the basis of CBM characteristics from the perspective of economic feasibility. Then, the corresponding decision making criteria were established. Finally, this newly developed method was applied to the well-type optimization of different development blocks in two important CBM development basins in China. And the following research and application results were obtained. First, under the current technical and economic conditions, both directional well and horizontal well are economically feasible to the development of Block A in the Qinshui Basin and Block B in eastern margin of the Ordos Basin, and the economically optimal well type is a horizontal well in Block A and a directional well in Block B. Second, compared with single-well steady daily gas production and single-well investment, the evaluation results on the schemes of different well types present critical value, above which the economic benefit of different schemes are equivalent. Third, EI of different well types is affected by many factors, e.g. geological characteristic of gas reservoirs, single-well production profile, CBM selling price, investment and cost. Therefore, it is necessary to carry out dynamic analysis and update in time based on the change of various influential factors so as to ensure the rationality of decision-making. In conclusion, this newly developed method is intrinsically consistent with traditional evaluation methods, and it is more advantageous with strong operability, intuitive evaluation results and quick and accurate optimization of CBM development well types. Keywords: Coalbed methane (CBM), Long-run marginal cost (LRMC), Development well, Well-type optimization, Directional wells, Horizontal wells, Surface development, Decision making criteria, Critical point

Clinical trials that study immunogenicity of combination vaccines often have less power than desirable. To make up for the reduction in statistical power at the study level, researchers have to increase the study sample size. To study immunogenicity variables, we used the geometric mean concentration of immune response after vaccination as immunologic endpoint and compared 3 sample size calculation methods: the “Inflation factors” method, the “Incrementing” method, and the “Bonferroni correction” method when there are multiple continuous co-primary endpoints. The parameters were set according to the actual situation of the use of combination vaccines and the simulation results were used as reference. The present study demonstrates that all 3 methods are applicable when the effect size of each endpoint is similar and the endpoints are at most weakly correlated, but when there is a true difference in effect sizes among endpoints, the “Incrementing” method has the best performance.

Abstract Background Long intergenic RNAs (lincRNAs) play critical roles in eukaryotic cells, but systematic analyses of the lincRNAs of an animal for phenotypes are lacking. We generate CRISPR knockout strains for Caenorhabditis elegans lincRNAs and evaluate their phenotypes. Results C. elegans lincRNAs demonstrate global features such as shorter length and fewer exons than mRNAs. For the systematic evaluation of C. elegans lincRNAs, we produce CRISPR knockout strains for 155 of the total 170 C. elegans lincRNAs. Mutants of 23 lincRNAs show phenotypes in 6 analyzed traits. We investigate these lincRNAs by phenotype for their gene expression patterns and potential functional mechanisms. Some C. elegans lincRNAs play cis roles to modulate the expression of their neighboring genes, and several lincRNAs play trans roles as ceRNAs against microRNAs. We also examine the regulation of lincRNA expression by transcription factors, and we dissect the pathway by which two transcription factors, UNC-30 and UNC-55, together control the expression of linc-73. Furthermore, linc-73 possesses a cis function to modulate the expression of its neighboring kinesin gene unc-104 and thus plays roles in C. elegans locomotion. Conclusions By using CRISPR/cas9 technology, we generate knockout strains of 155 C. elegans lincRNAs as valuable resources for studies in noncoding RNAs, and we provide biological insights for 23 lincRNAs with the phenotypes identified in this study.

More than 300 COVID-19 vaccine candidates have been developed or are currently in development. COVID-19 vaccines on the World Health Organization’s Emergency Use Listing and other COVID-19 vaccine products conditionally approved by national regulatory authorities are already in large-scale use, thus preventing severe illness or death and inducing herd immunity at the population level in the SARS-CoV-2 pandemic. In this review, we systemically assess the efficacy and effectiveness of COVID-19 vaccines in clinical trials or real-world studies, in various populations, including healthy adults, children, older people, pregnant people, people with cancer, and people receiving long-term hemodialysis or solid organ transplantation. In addition, we review available evidence regarding the effectiveness of COVID-19 vaccine immunization strategies in people with a history of SARS-CoV-2 infection, and the enhanced effectiveness conferred by various booster immunizations. We also discuss knowledge gaps in the persistence and spectrum of vaccine protection of currently available COVID-19 vaccines.

Accumulating evidence suggests that many immune responses are influenced by local nutrient concentrations in addition to the programming of intermediary metabolism within immune cells. Humoral immunity and germinal centers (GC) are settings in which these factors are under active investigation. Hypoxia is an example of how a particular nutrient is distributed in lymphoid follicles during an antibody response, and how oxygen sensors may impact the qualities of antibody output after immunization. Using exclusively a bio-informatic analysis of mRNA levels in GC and other B cells, recent work challenged the concept that there is any hypoxia or that it has any influence. To explore this proposition, we performed new analyses of published genomics data, explored potential sources of disparity, and elucidated aspects of the apparently conflicting conclusions. Specifically, replicability and variance among data sets derived from different naïve as well as GC B cells were considered. The results highlight broader issues that merit consideration, especially at a time of heightened focus on scientific reports in the realm of immunity and antibody responses. Based on these analyses, a standard is proposed under which the relationship of new data sets should be compared to prior “fingerprints” of cell types and reported transparently to referees and readers. In light of independent evidence of diversity within and among GC elicited by protein immunization, avoidance of overly broad conclusions about germinal centers in general when experimental systems are subject to substantial constraints imposed by technical features also is warranted.

Both hydrogen peroxide (H2O2, H) and ischemia/reperfusion (I/R) can damage cardiomyocytes, which was inhibited by propofol (P). The present research was designed to examine whether propofol can reduce myocardial I/R injury by activating protein kinase C (PKC)/nuclear factor erythroid-2-related factor 2 (NRF2) pathway in H9C2 cells and rat Langendorff models. H9C2 cells were disposed of no reagents (C), H2O2 for 24 h (H), propofol for 1 h before H2O2 (H+P), and chelerythrine (CHE, PKC inhibitor) for 1 h before propofol and H2O2 (H+P+CHE). N = 3. The PKC gene of H9C2 was knocked down by siRNA and overexpressed by phorbol 12-myristate 13-acetate (PMA, PKC agonist). The cell viability and the expressions of PKC, NRF2, or heme oxygenase-1(HO-1) were evaluated. Propofol significantly reduced H9C2 cell mortality induced by H2O2, and significantly increased NRF2 nuclear location and HO-1 expression, which were restrained by siRNA knockout of PKC and promoted by PMA. Rat hearts were treated with KrebsHenseleit solution for 120 min (C), with (I/R+P) or without (I/R) propofol for 20 min before stopping perfusion for 30 min and reperfusion for 60 min, and CHE for 10 min before treated with propofol. N = 6. The levels of lactate dehydrogenase (LDH), superoxide dismutase (SOD), and creatine kinase-MB (CK-MB) in perfusion fluid and antioxidant enzymes in the myocardium were assessed. I/R, which increased LDH and CK-MB expression and reduced SOD expression, boosted the pathological damage and infarcts of the myocardium after reperfusion. However, propofol restrained all these effects, an activity that was antagonized by CHE. The results suggest that propofol pretreatment protects against I/R injury by activating of PKC/NRF2 pathway.

Summary: Liver aging impairs the ability of hepatocyte regeneration. Recent studies have found that oxytocin (OT) plays an important role in promoting tissue repair and maintaining differentiation and regeneration of stem cells. Here, we reported that OT receptors, which are specifically located in hepatocytes, decrease with aging in human and mice. Interestingly, the level of serum OT also decline with age. Notably, OT promotes hepatocyte regeneration only in aged mice but not in young mice in vitro and in vivo. Further studies reveal that OT promotes autophagy in either AML12 mouse hepatocytes or aged mice after partial hepatectomy or with CCl4-induced acute liver injury. In conclusion, OT promotes liver regeneration, especially in aged mice, which may be achieved by promoting autophagy. All these results support the possibility of OT and its analog being a potent anti-aging drug and promote liver rejuvenation.

Antimony (Sb)-resistant bacteria have potential applications in the remediation of Sb-contaminated sites. However, the effect of Sb(III) exposure on whole-cell metabolic change has not been studied. Herein, we combined untargeted metabolomics with a previous proteomics dataset and confirmatory gene transcription analysis to identify metabolic responses to Sb(III) exposure in Agrobacterium tumefaciens GW4. Dynamic changes in metabolism between control and Sb(III)-exposed groups were clearly shown. KEGG pathway analysis suggested that with Sb(III) exposure: (1) the branching pathway of gluconeogenesis is down-regulated, resulting in the up-regulation of pentose phosphate pathway to provide precursors of anabolism and NADPH; (2) glycerophospholipid and arachidonic acid metabolisms are down-regulated, resulting in more acetyl-CoA entry into the TCA cycle and increased capacity to produce energy and macromolecular synthesis; (3) nucleotide and fatty acid synthesis pathways are all increased perhaps to protect cells from DNA and lipid peroxidation; (4) nicotinate metabolism increases which likely leads to increased production of co-enzymes (e.g., NAD+ and NADP+) for the maintenance of cellular redox and Sb(III) oxidation. Expectedly, the total NADP+/NADPH content, total glutathione, and reduced glutathione contents were all increased after Sb(III) exposure in strain GW4, which contribute to maintaining the reduced state of the cytoplasm. Our results provide novel information regarding global bacterial responses to Sb(III) exposure from a single gene level to the entire metabolome and provide specific hypotheses regarding the metabolic change to be addressed in future research.

Stroke remains a leading cause of death and disability. The low-density lipoprotein cholesterol to high-density lipoprotein cholesterol (LDL-C/HDL-C ratio) ratio has been confirmed to be a predictor of stroke. However, few studies have assessed the prognostic impact of the LDL-C/HDL-C ratio for stroke patients. We aimed to investigate the relationship between the LDL-C/HDL-C ratio and the prognosis following stroke in Chinese patients. A total of 3,410 patients who had experienced their first ischemic stroke was recruited to this study within 72 h of stroke onset. The patients were followed for at least 12 months. A multivariate regression analysis was used to assess the association between the LDL-C/HDL-C ratio and prognosis following stroke. We considered the LDL-C/HDL-C ratio as a continuous variable and stratified patients according to the LDL-C/HDL-C ratio quartile. A higher LDL-C/HDL-C ratio was associated with lower rates of death, recurrence, and moderate disability (defined as a modified Rankin scale score >2) at 3 months. Using group 1 as the reference group, the relative risk (RRs) at 3 months for death were 0.45 (95% confidence interval [CI]: 0.27, 0.77) for group 2, 0.58 (95% CI: 0.34, 0.98) for group 3, and 0.97 (95% CI: 0.60, 1.56) for group 4; for recurrence, the RRs were 0.75 (95% CI: 0.56, 0.99) for group 2, 0.65 (95% CI: 0.48, 0.89) for group 3, and 0.55 (95% CI: 0.39, 0.78) for group 4; and for moderate disability, the RRs were 0.74 (95% CI: 0.55, 0.99) for group 2, 0.65 (95% CI: 0.47, 0.89) for group 3, and 0.55 (95% CI: 0.39, 0.77) for group 4. At 12 months, patients in group 2 were the most protected against ischemic stroke death (RR: 0.57; 95% CI: 0.34, 0.95). However, there were no associations between the LDL-C/HDL-C ratio and stroke recurrence or moderate disability. A higher LDL-C/HDL-C ratio was found to protect against death, recurrence, and moderate disability at 3 months. However, there was no significant association between the LDL-C/HDL-C ratio and stroke recurrence or moderate disability at 12 months. These results nonetheless suggest that a higher LDL-C/HDL-C ratio was associated with short-term stroke prognosis.

The Tibetan Plateau and Siberia are both crucial regions in which the vegetation dynamics are sensitive to climate change. The variabilities in the normalized difference vegetation index (NDVI) over the two regions have been explored previously, but there have been few studies on the relationship of the NDVI in the two regions. Using the GIMMS-NDVI, GHCN-CAMS and NCEP reanalysis datasets and statistical and physical diagnostic methods, we show that the summer (June, July and August) NDVI over the eastern Tibetan Plateau and Lake Baikal and its adjacent eastern region of Siberia have an in-phase co-variability, especially on an interannual timescale (with a correlation coefficient of 0.69 during the time period 1982-2014). Further analyses show that precipitation and the related cloud cover and solar radiation are responsible for the variability in the NDVI over the eastern Tibetan Plateau, whereas temperature has the more important role in modulating the variability in the NDVI over the Lake Baikal region. A dipole pattern prevails over the Tibetan Plateau-Lake Baikal region and reflects the anomalies in the intensity and location of the South Asian high and the northeast Asian blocking high. This dipole pattern simultaneously modulates precipitation over the eastern Tibetan Plateau and the temperature over the Lake Baikal region and leads to the co-variability of the NDVI between the two regions. A synergistic sea surface temperature index, which reflects sea surface temperature anomalies in the eastern tropical Pacific Ocean, the northwest Pacific Ocean, the northern Indian Ocean and the subtropical north Atlantic Ocean, appears to adjust this Tibetan Plateau-Lake Baikal dipole pattern and is therefore closely related to the co-variability of the NDVI between the eastern Tibetan Plateau and the Lake Baikal region. Our results suggest that vegetation dynamics may not be only a local phenomenon in some areas, but are also likely to remotely link with variations in vegetation over other regions.

Helicobacter-induced chronic inflammation and immune disorders are closely associated with the development of gastric mucosa-associated lymphoid tissue (MALT) lymphoma. Myeloid-derived suppressor cells (MDSCs) exhibit strong immunosuppressive properties and promote the growth of various solid tumors. However, the role of MDSCs in the development of MALT lymphoma has not been elucidated so far. We detected significant infiltration and enrichment of MDSCs in patients with MALT lymphoma, as well in Helicobacter felis-infected mouse model of gastric MALT lymphoma. In addition, the expression of arginase-1 and inducible nitric oxide synthase was significantly elevated both in gastric MALT lymphoma tissues and H. felis-infected stomach. Persistent H. felis infection closely reproduced the development of gastric MALT lymphoma and was accompanied by increased numbers of γδT17 cells. Accumulation of γδT17 cells was also validated in the human gastric MALT lymphoma tissues. Furthermore, the elevated cytokines interleukin-23 and interleukin-1β, as well as chemokines CCL20/CCR6, may be involved in the accumulation of γδT17 cells and the subsequent immunosuppression. These findings highlight the role of MDSCs and γδT17 cells in immune dysregulation during gastric MALT lymphoma development and their potential as therapeutic targets.

Background: To evaluate the one-year immunogenicity and safety of a subunit plague vaccine. Methods: In the initial study, 240 healthy adults aged 18–55 years were administrated with 2 doses of 15 or 30 µg plague vaccines at day 0 and 28, respectively. In this extended follow-up study, we evaluated the immunogenicity and safety of the plague vaccine up to one year. Results: For antibody to envelope antigen faction 1 (F1) antigen, titers were up to new peaks at month 6, then declined slowly to month 12, but remained at higher levels than those at day 56. Geometric mean titers (GMTs) of F1 were significantly higher in 30 µg group than those in 15 µg group at month 6 and 12 (P < 0.0001 and P < 0.001). However, approximate 100% seroconversion rates of F1 antibodies were found in both 15 and 30 µg groups at the both time points. For antibody to recombinant virulence (rV) antigen, titers and seroconversion rates were decreased sharply at month 6 and continue to decrease at month 12. GMTs and seroconversion rates were not significantly different between the 15 and 30 µg groups, respectively. No serious adverse events (SAEs) related to vaccine occurred. Conclusion: The new plague vaccine (F1+rV) induced a robust immune response up to 12 months and showed a good safety profile in adults aged 18–55 years.

Abstract Background Acute diarrheal illness (ADI) is an important public health problem worldwide. We estimated the morbidity, distribution, and burden of self-reported ADI in China over the last three decades. Methods We used the keywords “diarrhea and morbidity” to identify studies published in Chinese by searching CNKI, WANFANG, Chongqing VIP, and SinoMed. Studies published in English were identified using the keywords “diarrhea, morbidity, and China” to search Pubmed/Medline, Embase, and Cochrane Library Data. All articles published before Dec 31, 2014 were included in the search. Data were extracted and the pooled 2-week incidence rate of ADI was calculated using the fixed-effects or random-effects model according to statistical testing for homogeneity. The incidences of each subgroup (organized by age, location, study period) were also calculated. Publication bias was examined using Begg’s test. Data manipulation and statistical analyses were undertaken using R-2.15.1 software. Results We estimated that the pooled 2-week prevalence of ADI in China was 2.04% (95% CI: 1.48–2.79) and that the corresponding incidence rate was 0.53 (95% CI: 0.38–0.73) episodes per person-year. The ADI rate was highest among children aged

Streptococcus pneumonia (S. pneumoniae) is responsible for significant morbidity and mortality throughout the world. The 23-valent pneumococcal polysaccharide vaccines (PPV23) have been widely used for many years, but challenges are remaining in some respects, especially for its effectiveness among high-risk populations and older adults. This review aims to summarize recent clinical trials and studies of PPV23 vaccination among healthy people ≥ 2 years of age and those with high-risk conditions such as pregnant women, individuals with immunocompromising diseases and other chronic conditions, and provide health officials in China and other developing countries a comprehensive understanding of the current vaccination strategies for PPV23 and for the combined use of PPV23 and pneumococcal conjugate vaccines (PCVs) in adults.

Coxsackievirus B5 (CV-B5) is associated with various human diseases such as viral encephalitis, aseptic meningitis, paralysis, herpangina, and hand, foot and mouth disease (HFMD). However, there is currently no effective vaccine against CV-B5.The seroepidemiologic characteristics of CV-B5 remained unknown. A cohort study was carried out in 176 participants aged 6–35 months from January 2012 to January 2014. The serum samples were collected and tested for CV-B5 neutralizing antibodies (NtAbs) four times during these two years. The confirmed enterovirus cases were recorded through the surveillance system, and their throat or rectal swabs were collected for pathogen detection. According to the changes of CV-B5 NtAbs, two CV-B5 epidemics were detected among these participants during the two-year follow-up. Sixty-seven cases out of all participants had seroconversion in CV-B5 NtAbs. During the first epidemic from March 2012 to September 2012, CV-B5 seropositivity rate increased significantly (6.8%, 12/176 vs. 21.6%, 38/176, P = 0.000). The seroconversion rate and geometric mean fold-increase (GMFI) were 18.2% (32/176) and 55.7, respectively; During the second epidemic from September 2012 to January 2014, CV-B5 seropositivity rate also increased (21.6%, 38/176 vs. 38.6%, 68/176, P = 0.000), and the seroconversion rate and GMFI were 19.9% (35/176) and 46.5, respectively. Only one case had CV-B5 associated HFMD during the two-year follow-up, and CV-B5 from the throat swab isolate was GI.D3 subtype, which belonged to the major pandemic strain in mainland China. CV-B5 infection was common in infants and children in Jiangsu province, China. Therefore, it's necessary to strengthen the surveillance on CV-B5 and to understand the epidemic characteristics of CV-B5 infection.

Abstract Paenibacillus ferrarius CY1T (= KCTC 33419T = CCTCC AB2013369T) is a Gram-positive, aerobic, endospore-forming, motile and rod-shaped bacterium isolated from iron mineral soil. This bacterium reduces sulfate (SO4 2−) to S2−, which reacts with Cd(II) to generate precipitated CdS. It also reduces the toxic chromate [Cr(VI)] and selenite [Se(VI)] to the less bioavailable chromite [Cr(III)] and selenium (Se0), respectively. Thus, strain CY1T has the potential to bioremediate Cd, Cr and Se contamination, which is the main reason for the interest in sequencing its genome. Here we describe the features of strain CY1T, together with the draft genome sequence and its annotation. The 9,184,169 bp long genome exhibits a G + C content of 45.6%, 7909 protein-coding genes and 81 RNA genes. Nine putative Se(IV)-reducing genes, five putative Cr(VI) reductase and nine putative sulfate-reducing genes were identified in the genome.

A phase-1 clinical trial aimed to assess the safety and immunogenicity of the type-5 adenovirus vector based Ebola vaccine (Ad5-EBOV) was conducted in China. To provide more evidence for the safety evaluation and dose-selection, an exploratory sub-study using a wireless automatic temperature measuring platform was done based on the phase-1 clinical trial. The main aim of the sub-study was to obtain more information about the occurrence of fever and detect the potential associated factors, second was to assess the feasibility of the temperature measuring platform in vaccine clinical trials. Temperature data of 3 treatment groups all presented a rising tendency during the first 6 hours after vaccination, the incidence of elevated temperature and possible associated factors were analyzed. For the incidence of elevated temperature, no marked dose-response relationship was found in 6 hours with wireless thermometers; the information from mercury thermometers showed that the grade-1 fever proportion peaked at 6 hours and there was no difference between groups, while grade-2 fever proportion peaked at 24 hours and was significantly higher in high-dose group than those in the other 2 groups. Significant differences were found between sex groups (males vs. female, incidence rate ratios (IRR) = 2.93 and 7.62 for any-grade, grade-2 fever respectively, P

Abstract This study was conducted to investigate the effects of nitric oxide (NO) in acetic acid-induced gastric ulcer of rats and the underlying mechanisms. We found that peritoneal injection of sodium nitroprusside (SNP), a NO donor, decreased the ulcer area, inflammatory cell infiltration and MPO degree in acetic acid-induced gastric ulcer in rats. This effect was abolished by a transient receptor potential vanilloid 1 (TRPV1) antagonist or prior subdiaphragmatic vagotomy. SNP increased the jejunal mesenteric afferent discharge in a dose-depended manner, which was largely diminished by pretreatment of S-nitrosylation blocker N-ethylmaleimide, TRPV1 antagonist capsazepine, genetic deletion of TRPV1, or vagotomy. Whole-cell patch clamp recording showed that SNP depolarized the resting membrane potential of NG neurons, and enhanced capsaicin-induced inward current, which were both blocked by N-ethylmaleimide. Our results suggest that NO donor SNP alleviates acetic acid-induced gastric ulcer in rats via vagus nerve, while S-nitrosylation of TRPV1 may participate in this route. Our findings reveal a new mechanism for vagal afferent activation, and a new potential anti-inflammatory target.

Ebola virus disease (EVD) has become a great threat to humans across the world in recent years. The 2014 Ebola epidemic in West Africa caused numerous deaths and attracted worldwide attentions. Since no specific drugs and treatments against EVD was available, vaccination was considered as the most promising and effective method of controlling this epidemic. So far, 7 vaccine candidates had been developed and evaluated through clinical trials. Among them, the recombinant vesicular stomatitis virus-based vaccine (rVSV-EBOV) is the most promising candidate, which demonstrated a significant protection against EVD in phase III clinical trial. However, several concerns were still associated with the Ebola vaccine candidates, including the safety profile in some particular populations, the immunization schedule for emergency vaccination, and the persistence of the protection. We retrospectively reviewed the current development of Ebola vaccines and discussed issues and challenges remaining to be investigated in the future. Trial registration: ClinicalTrial.gov identifier: NCT00374309. Trial registration: ClinicalTrial.gov identifier: NCT02326194. Trial registration: ClinicalTrial.gov identifier: NCT02401373. Trial registration: ClinicalTrial.gov identifier: NCT02575456. Trial registration: ClinicalTrial.gov identifier: NCT02231866. Trial registration: ClinicalTrial.gov identifier: NCT02240875. Trial registration: ClinicalTrial.gov identifier: NCT02289027. Trial registration: ClinicalTrial.gov identifier: NCT02231866. Trial registration: ClinicalTrial.gov identifier: NCT02267109. Trial registration: ClinicalTrial.gov identifier: NCT02325050. Trial registration: ClinicalTrial.gov identifier: NCT02313077. Trial registration: ClinicalTrial.gov identifier: NCT02376400. Trial registration: ClinicalTrial.gov identifier: NCT02376426. Trial registration: ClinicalTrial.gov identifier: NCT02416453. Trial registration: ClinicalTrial.gov identifier: NCT02564523. Trial registration: ClinicalTrial.gov identifier: NCT02543567. Trial registration: ClinicalTrial.gov identifier: NCT02509494. Trial registration: ClinicalTrial.gov identifier: NCT02543268. Trial registration: ClinicalTrial.gov identifier: NCT02267109. Trial registration: ClinicalTrial.gov identifier: NCT02283099. Trial registration: ClinicalTrial.gov identifier: NCT02287480. Trial registration: ClinicalTrial.gov identifier: NCT02296983. Trial registration: ClinicalTrial.gov identifier: NCT02287480. Trial registration: ClinicalTrial.gov identifier: NCT02269423. Trial registration: ClinicalTrial.gov identifier: NCT02280408. Trial registration: ClinicalTrial.gov identifier: NCT02564575. Trial registration: ClinicalTrial.gov identifier: NCT00605514. Trial registration: ClinicalTrial.gov identifier: NCT00997607.