Abstract
Background
The high cost and insufficient supply of human papillomavirus (HPV) vaccines have slowed the pace of controlling cervical cancer. A phase III clinical trial was conducted to ...evaluate the efficacy, safety, and immunogenicity of a novel Escherichia coli-produced bivalent HPV-16/18 vaccine.
Methods
A multicenter, randomized, double-blind trial started on November 22, 2012 in China. In total, 7372 eligible women aged 18–45 years were age-stratified and randomly assigned to receive three doses of the test or control (hepatitis E) vaccine at months 0, 1, and 6. Co-primary endpoints included high-grade genital lesions and persistent infection (over 6 months) associated with HPV-16/18. The primary analysis was performed on a per-protocol susceptible population of individuals who were negative for relevant HPV type-specific neutralizing antibodies (at day 0) and DNA (at day 0 through month 7) and who received three doses of the vaccine. This report presents data from a prespecified interim analysis used for regulatory submission.
Results
In the per-protocol cohort, the efficacies against high-grade genital lesions and persistent infection were 100.0% (95% confidence interval = 55.6% to 100.0%, 0 of 3306 in the vaccine group vs 10 of 3296 in the control group) and 97.8% (95% confidence interval = 87.1% to 99.9%, 1 of 3240 vs 45 of 3246), respectively. The side effects were mild. No vaccine-related serious adverse events were noted. Robust antibody responses for both types were induced and persisted for at least 42 months.
Conclusions
The E coli-produced HPV-16/18 vaccine is well tolerated and highly efficacious against HPV-16/18–associated high-grade genital lesions and persistent infection in women.
Interferon regulatory factor (IRF) 3 and IRF7 are master regulators of type I interferon (IFN‐I)‐dependent antiviral innate immunity. Upon viral infection, a positive feedback loop is formed, wherein ...IRF7 promotes further induction of IFN‐I in the later stage. Thus, it is critical to maintain a suitably low level of IRF7 to avoid the hyperproduction of IFN‐I. In this study, we find that early expression of IFN‐I‐dependent STAT1 promotes the expression of XAF1 and that XAF1 is associated specifically with IRF7 and inhibits the activity of XIAP. XAF1‐knockout and XIAP‐transgenic mice display resistance to viral infection, and this resistance is accompanied by increases in IFN‐I production and IRF7 stability. Mechanistically, we find that the XAF1‐XIAP axis controls the activity of KLHL22, an adaptor of the BTB‐CUL3‐RBX1 E3 ligase complex through a ubiquitin‐dependent pathway. CUL3‐KLHL22 directly targets IRF7 and catalyzes its K48‐linked ubiquitination and proteasomal degradation. These findings reveal unexpected functions of the XAF1‐XIAP axis and KLHL22 in the regulation of IRF7 stability and highlight an important target for antiviral innate immunity.
Synopsis
A XAF1‐XIAP‐KLHL22 axis functions as a major regulator to control IRF7 protein abundance and helps maintaining proper IFN‐I production.
XAF1‐KO and XIAP transgenic mice display resistance to viral infection.
XAF1‐KO and XIAP transgenic mice show increased IFN‐I production and IRF7 stability.
KLHL22 directly targets IRF7, catalyzes its K48‐linked ubiquitination and promotes its proteasomal degradation.
The XAF1‐XIAP axis controlls the activity of KLHL22 through ubiquitin‐dependent pathways.
A XAF1‐XIAP‐KLHL22 axis functions as a major regulator to control IRF7 protein abundance and helps maintaining proper IFN‐I production.
The lithium metal anode has attracted soaring attention as an ideal battery anode. Unfortunately, nonuniform Li nucleation results in uncontrollable growth of dendritic Li, which incurs serious ...safety issues and poor electrochemical performance, hindering its practical applications. Herein, this study shows that uniform Li nucleation/growth can be induced by an ultralight 3D current collector consisting of in situ nitrogen‐doped graphitic carbon foams (NGCFs) to realize suppressing dendritic Li growth at the nucleating stage. The N‐containing functional groups guide homogenous growth of Li nucleus nanoparticles and the initial Li nucleus seed layer regulates the following well‐distributed Li growth. Benefiting from such favorable Li growth behavior, superior electrochemical performance can be achieved as evidenced by the high Coulombic efficiency (≈99.6% for 300 cycles), large capacity (10 mA h cm−2, 3140 mA h g−1NGCF‐Li), and ultralong lifespan (>1200 h) together with low overpotential (<25 mV at 3 mA cm−2); even under a high current density up to 10 mA cm−2, it still displays low overpotential of 62 mV.
Uniform Li nucleation/growth can be induced by an ultralight 3D current collector consisting of in situ nitrogen‐doped graphitic carbon foams for high‐performance lithium‐metal anodes. The N‐containing functional groups guide initial homogeneous formation of Li nanoparticles and the initial nucleus seed layer regulates the even Li growth that follows. Significantly improved electrochemical performance can be achieved.
In response to the call for safer high‐energy‐density storage systems, high‐voltage solid‐state Li metal batteries have attracted extensive attention. Therefore, solid electrolytes are required to be ...stable against both Li anode and high‐voltage cathodes; nevertheless, the requirements still cannot be completely satisfied. Herein, a heterogeneous multilayered solid electrolyte (HMSE) is proposed to broaden electrochemical window of solid electrolytes to 0–5 V, through different electrode/electrolyte interfaces to overcome the interfacial instability problems. Oxidation‐resistance poly(acrylonitrile) (PAN) is in contact with the cathode, while reduction tolerant polyethylene glycol diacrylate contacts with Li metal anode. A Janus and flexible PAN@Li1.4Al0.4Ge1.6(PO4)3 (80 wt%) composite electrolyte is designed as intermediate layer to inhibit dendrite penetration and ensure compact interface. Paired with LiNi0.6Co0.2Mn0.2O2 and LiNi0.8Co0.1Mn0.1O2 cathodes, which are rarely used in solid‐state batteries, the solid‐state Li metal batteries with HMSE exhibit excellent electrochemical performance including high capacity and long cycle life. Besides, the Li||Li symmetric batteries maintain a stable polarization less than 40 mV for more than 1000 h under 2 mA cm−2 and effective inhibition of dendrite formation. This study offers a promising approach to extend the applications of solid electrolytes for high‐voltage solid‐state Li metal batteries.
A heterogeneous multilayered structure that expands the electrochemical window of solid electrolytes is designed. The oxidation‐resistant poly(acrylonitrile) (PAN) and reduction‐tolerant polyethylene glycol diacrylate integrated with the Janus and flexible PAN@Li1.4Al0.4Ge1.6(PO4)3 (80 wt%) composite electrolyte broaden the electrochemical window to 0–5 V, resulting in excellent performance for high‐voltage solid‐state Li‐metal batteries. Additionally, the thickness of electrolyte is below 25 μm.
During the outbreak of coronavirus disease 2019 (COVID-19), consistent and considerable differences in disease severity and mortality rate of patients treated in Hubei province compared to those in ...other parts of China have been observed. We sought to compare the clinical characteristics and outcomes of patients being treated inside and outside Hubei province, and explore the factors underlying these differences.
Collaborating with the National Health Commission, we established a retrospective cohort to study hospitalised COVID-19 cases in China. Clinical characteristics, the rate of severe events and deaths, and the time to critical illness (invasive ventilation or intensive care unit admission or death) were compared between patients within and outside Hubei. The impact of Wuhan-related exposure (a presumed key factor that drove the severe situation in Hubei, as Wuhan is the epicentre as well the administrative centre of Hubei province) and the duration between symptom onset and admission on prognosis were also determined.
At the data cut-off (31 January 2020), 1590 cases from 575 hospitals in 31 provincial administrative regions were collected (core cohort). The overall rate of severe cases and mortality was 16.0% and 3.2%, respectively. Patients in Hubei (predominantly with Wuhan-related exposure, 597 (92.3%) out of 647) were older (mean age 49.7
44.9 years), had more cases with comorbidity (32.9%
19.7%), higher symptomatic burden, abnormal radiologic manifestations and, especially, a longer waiting time between symptom onset and admission (5.7
4.5 days) compared with patients outside Hubei. Patients in Hubei (severe event rate 23.0%
11.1%, death rate 7.3%
0.3%, HR (95% CI) for critical illness 1.59 (1.05-2.41)) have a poorer prognosis compared with patients outside Hubei after adjusting for age and comorbidity. However, among patients outside Hubei, the duration from symptom onset to hospitalisation (mean 4.4
4.7 days) and prognosis (HR (95%) 0.84 (0.40-1.80)) were similar between patients with or without Wuhan-related exposure. In the overall population, the waiting time, but neither treated in Hubei nor Wuhan-related exposure, remained an independent prognostic factor (HR (95%) 1.05 (1.01-1.08)).
There were more severe cases and poorer outcomes for COVID-19 patients treated in Hubei, which might be attributed to the prolonged duration of symptom onset to hospitalisation in the epicentre. Future studies to determine the reason for delaying hospitalisation are warranted.
The heterogeneous nature of tumour microenvironment (TME) underlying diverse treatment responses remains unclear in nasopharyngeal carcinoma (NPC). Here, we profile 176,447 cells from 10 NPC ...tumour-blood pairs, using single-cell transcriptome coupled with T cell receptor sequencing. Our analyses reveal 53 cell subtypes, including tumour-infiltrating CD8
T, regulatory T (Treg), and dendritic cells (DCs), as well as malignant cells with different Epstein-Barr virus infection status. Trajectory analyses reveal exhausted CD8
T and immune-suppressive TNFRSF4
Treg cells in tumours might derive from peripheral CX3CR1
CD8
T and naïve Treg cells, respectively. Moreover, we identify immune-regulatory and tolerogenic LAMP3
DCs. Noteworthily, we observe intensive inter-cell interactions among LAMP3
DCs, Treg, exhausted CD8
T, and malignant cells, suggesting potential cross-talks to foster an immune-suppressive niche for the TME. Collectively, our study uncovers the heterogeneity and interacting molecules of the TME in NPC at single-cell resolution, which provide insights into the mechanisms underlying NPC progression and the development of precise therapies for NPC.
Cleavage of transfer (t)RNA and ribosomal (r)RNA are critical and conserved steps of translational control for cells to overcome varied environmental stresses. However, enzymes that are responsible ...for this event have not been fully identified in high eukaryotes. Here, we report a mammalian tRNA/rRNA-targeting endoribonuclease: SLFN13, a member of the Schlafen family. Structural study reveals a unique pseudo-dimeric U-pillow-shaped architecture of the SLFN13 N'-domain that may clamp base-paired RNAs. SLFN13 is able to digest tRNAs and rRNAs in vitro, and the endonucleolytic cleavage dissevers 11 nucleotides from the 3'-terminus of tRNA at the acceptor stem. The cytoplasmically localised SLFN13 inhibits protein synthesis in 293T cells. Moreover, SLFN13 restricts HIV replication in a nucleolytic activity-dependent manner. According to these observations, we term SLFN13 RNase S13. Our study provides insights into the modulation of translational machinery in high eukaryotes, and sheds light on the functional mechanisms of the Schlafen family.
The role of solution aggregates on the charge transport process of conjugated polymers in electronic devices has gained increasing attention; however, the correlation of the charge carrier mobilities ...between the solution aggregates and the solid‐state films remains elusive. Herein, three polymers, FBDOPV‐2T, FBDOPV‐2F2T, and FBDOPV‐4F2T, are designed and synthesized with distinct aggregation behavior in solution. By combining contact‐free ultrafast terahertz (THz) spectroscopy and field‐effect transistor measurements, we track the charge carrier mobility of the aggregates of these polymers from the solution to the thin‐film state. Remarkably, the mobility of these three polymers is found to follow nearly the same trend (FBDOPV‐2T>FBDOPV‐2F2T≫FBDOPV‐4F2T) in both solutions and thin‐film states. The quantitative mobility correlation indicates that the charge transport properties of solution aggregates play a critical role in determining the thin‐film charge transport properties and final device performance. Our results highlight the importance of investigating and controlling solution aggregation structures towards efficient organic electronic devices.
Different aggregation structures of three BDOPV‐based polymers in solution were obtained via subtle adjustment of the molecular structures. By employing contact‐free ultrafast terahertz (THz) spectroscopy, we directly reveal that the correlation of the charge carrier mobilities between the solution aggregates and the solid‐state films remains highly consistent.
The focal nature of atherosclerotic lesions suggests an important role of local hemodynamic environment. Recent studies have demonstrated significant roles of Yes-associated protein (YAP) and ...transcriptional coactivator with PDZ-binding motif (TAZ) in mediating mechanotransduction and vascular homeostasis. The objective of this study is to investigate the functional role of YAP/TAZ in the flow regulation of atheroprone endothelial phenotypes and the consequential development of atherosclerotic lesions. We found that exposure of cultured endothelial cells (ECs) to the atheroprone disturbed flow resulted in YAP/TAZ activation and translocation into EC nucleus to up-regulate the target genes, including cysteine-rich angiogenic inducer 61 (CYR61), connective tissue growth factor (CTGF), and ankyrin repeat domain 1 (ANKRD1). In contrast, the athero-protective laminar flow suppressed YAP/TAZ activities. En face analysis of mouse arteries demonstrated an increased nuclear localization of YAP/TAZ and elevated levels of the target genes in the endothelium in atheroprone areas compared with athero-protective areas. YAP/TAZ knockdown significantly attenuated the disturbed flow induction of EC proliferative and proinflammatory phenotypes, whereas overexpression of constitutively active YAP was sufficient to promote EC proliferation and inflammation. In addition, treatment with statin, an antiatherosclerotic drug, inhibited YAP/TAZ activities to diminish the disturbed flow-induced proliferation and inflammation. In vivo blockade of YAP/TAZ translation by morpholino oligos significantly reduced endothelial inflammation and the size of atherosclerotic lesions. Our results demonstrate a critical role of the activation of YAP/TAZ by disturbed flow in promoting atheroprone phenotypes and atherosclerotic lesion development. Therefore, inhibition of YAP/TAZ activation is a promising athero-protective therapeutic strategy.
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