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Neutrophils exert either pro- or anti-tumor activities. However, few studies have focused on neutrophils at the tumor initiation stage. In this study, we unexpectedly found a subcutaneous nodule in the groin areas of mice inoculated with tumor cells. The nodule was developed 24 h after the inoculation, filled with tumor cells and massively recruited neutrophils, being designated as neutrophil-infiltrated nodules (NINs). 22% of the neutrophils in NINs are surface TLR9 (sTLR9) expressing neutrophils (sTLR9+neutrophils). With tumor progression, sTLR9+neutrophils were sustainably increased in NINs/tumor tissues, reaching to 90.8% on day 13 after inoculation, with increased expression of IL-10 and decreased or no expression of TNFα.In vivoadministration of CpG 5805 significantly reduced sTLR9 expression of the sTLR9+neutrophils. The reduction of sTLR9 on neutrophils in NINs contributed to the induction of an anti-tumor microenvironment conductive to the inhibition of tumor growth. Overall, the study provides insights for understanding the role of sTLR9+neutrophils in the tumor development, especially in the early stages.

Ni-rich layered oxide LiNi0.8Co0.15Al0.05O2 is a promising cathode material for high-power lithium-ion batteries due to its high energy density and low cost. However, obtaining LiNi0.8Co0.15Al0.05O2 with a large and uniform particle size and without undesired Al-related phases using some conventional synthesis methods is quite difficult. These problems seriously affect the electrochemical performance of LiNi0.8Co0.15Al0.05O2, thus impeding its wide application. Here, we propose a simple strategy to synthesize LiNi0.8Co0.15Al0.05O2 using CoAl-layered double hydroxide (CoAl-LDH) nanosheet-coated Ni(OH)2 as the precursor. Compared with LiNi0.8Co0.15Al0.05O2 synthesized from nickel-cobalt-aluminum hydroxide and Al(OH)3-coated nickel-cobalt hydroxide precursors, LiNi0.8Co0.15Al0.05O2 produced using the proposed approach showed good sphericity, a large and uniform particle size, a pure phase, and excellent electrochemical performance. The superior properties are attributed to the dual effects of the buffer layer and synergistic diffusion. Specifically, the CoAl-LDH coating layer reacts with LiOH during the lithiation-calcination process to form a Li1-x(Co0.75Al0.25)1+xO2 mesophase as the buffer layer, which increases the formation temperature of the layered structure and reduces Li+/Ni2+ cation mixing, making a well-ordered crystal structure. Moreover, spectroscopic analysis results and density functional theory calculations indicated a synergistic diffusion effect between Co and Al, and the presence of Co on the surface promotes the diffusion of Al during the lithiation-calcination process, thus avoiding the formation of undesired Al-related phases and allowing for a uniform element distribution.

The surface Toll-like receptor 9 (sTLR9) has been identified on the surface of the B cells and was presumed to be a negative regulator of B cell responses. CpG ODN, a TLR9 agonist, has been successfully used as an adjuvant of hepatitis B vaccine to enhance antibody responses. However, it is unknown whether the sTLR9 is involved in regulating the activation and maturation of B cells in the antibody responses induced by CpG ODN-adjuvanted vaccines. In this study, we immunized mice with hepatitis B vaccine adjuvanted by CpG ODN (CpG 5805) and found that CpG 5805 enhanced the antibody response to vaccine and meanwhile down-regulated the sTLR9 levels on B cells. With antibody feeding assay and flow cytometry analysis, we further found that CpG 5805 induced a movement of the sTLR9 in B cells, internalized first and then mobilized to endosomes. Accompanied with the movement, CD80, CD86, CD40, and MHC II molecules were significantly up-regulated on the B cells. Interestingly, the B cells with internalized sTLR9 enlarged morphologically, and the sTLR9 levels were obviously lower and CD40 levels were obviously higher on the enlarged B cells. Together, the data presented here uncover that CpG ODN can induce the mobilization and relocation of sTLR9 in B cells, thereby triggering the B cell vigor by relieving the negative regulatory effect of sTLR9 on B cells, which may be one of the mechanisms for CpG ODN acting as a vaccine adjuvant to enhance the antibody response.Key points• CpG ODN-enhanced antibody response positively associates with B cell sTLR9 reduction.• CpG ODN reduces the sTLR9 levels by relocating it from B cell surface to endosomes.• sTLR9 reduction arouses B cell vigor via promoting B cell maturation and activation. Graphical Abstract.

The excessively expressed interferon-α (IFN-α) might contribute to the uncontrolled inflammatory responses, causing pathological damage during influenza virus infection. However, the correlation of the pathological damage with the expression profile of IFN-α subtypes in the focus of infection with influenza viruses is poorly understood. To investigate this, we detected the IFN-α subtype dominance in human respiratory epithelial cells and mouse lungs, both of which were infected with influenza viruses. It was found that IFN-α1, IFN-α6, IFN-α14, and IFN-α16 were dominantly expressed in respiratory epithelial cells from the patients infected with IAV, whereas IFN-α5, IFN-α8, and IFN-α21 were dominantly expressed in respiratory epithelial cells from the patients infected with less pathogenic IBV and that IFN-α1, IFN-α9, and IFN-α15 were dominantly expressed in lungs of the mice infected with H1N1 IAV, and IFN-α2, IFN-α12, and IFN-α13 were dominantly expressed in lungs of the mice infected with less pathogenic H9N2 IAV. Compared with H9N2 IAV, H1N1 IAV induced higher mortality rates and more obvious body weight loss in the mice. In addition, IAV or H1N1 IAV induced a significantly higher level of CXCL10 mRNA in the human respiratory epithelial cells or the mouse lungs, respectively. In mice, the high level of Cxcl10 mRNA was accompanied by the abundant infiltrated neutrophils and more severe pathological changes in the lungs. Together, the data presented here indicate that the pathogenicity of influenza viruses is correlated with the IFN-α subtypes induced by influenza viruses. KEY POINTS: • Different influenza viruses induce differential inflammation responses. • Various influenza viruses induce diverse expression profiles of IFN-α subtypes. • The locally produced IFN-α subtypes correlated to the differential inflammation. Graphical abstract.

Natural killer group 2 member D (NKG2D) ligands (NKG2DLs) on tumor cells engage NKG2D and mediate killing by NKG2D+ immune cells. However, tumor cells with high levels of NKG2DLs are still malignant and proliferate rapidly. We investigated the reason for NKG2DL‐expressing cell progression. Tumor cells in mice were assessed for their NKG2DL expression, ability to attract immune cells, tumorigenicity, mTOR, and signal transducer and activator of transcription 3 (STAT3) signaling activation. Antibody blockade was used to determine the effect of NKG2DL‐NKG2D interaction on signaling activation in vitro. Retinoic acid early inducible gene 1 (Rae1) was related to the expression of other NKG2DLs, the promotion of tumorigenicity, Mmp2 expression, mTOR and STAT3 phosphorylation in GL261 cells, and the recruitment of NKG2D+ cells in mice. Rae1 also induced NKG2DL expression, mTOR, and STAT3 phosphorylation in GL261 cells and LLC cells, but not in B16 and Pan02 cells, which did not express NKG2DLs, when cocultured with PBMCs; the induced phosphorylation was eliminated by Rae1‐NKG2D blockade. Inhibition of mTOR and/or STAT3 decreased PBMC‐induced migration and proliferation of GL261 cells in vitro. Rae1, a NKG2DL on tumor cells, plays a driving role in the expression of other NKG2DLs and in tumor development in mice by activating mTOR and STAT3 pathways, relying on its interaction with NKG2D on immune cells., Rae1, one of the NKG2DLs in mice, possibly drives expression of other NKG2DLs and tumor development in vivo through the activation of mTOR and STAT3 pathways in tumor cells depending on binding of NKG2D on immune cells. Our study provides new insight in the tumor‐promoting effect of NKG2DLs on tumor cells and should be noted with regard to immunotherapy of tumors.

Existing testability models are difficult to describe the multi-state characteristics of the system, so it is necessary to study the testability modeling method applicable to multi-state systems. A testability model with structure and function as the object is established in this paper. In order to describe the relationship between system state and test, the calculation method of the detectable state set of the test set is introduced. In order to quantitatively describe the testability of the system state, the concept of state detection rate is proposed for the first time. A test point optimization method that comprehensively considers the system fault detection rate, fault isolation rate, and state detection rate under the constraints of test cost is proposed. A numerical example shows that the best test set obtained by this method cannot only complete the system fault detection and isolation, but also obtain more system state.

Tumor immunotherapies have shown promising antitumor effects, especially immune checkpoint inhibitors (ICIs). However, only 12.46% of the patients benefit from the ICIs, the rest of them shows limited effects on ICIs or even accelerates the tumor progression due to the lack of the immune cell infiltration and activation in the tumor microenvironment (TME). In this study, we administrated a combination of Toll-like receptor 9 (TLR9) agonist CpG ODN and Transforming growth factor-β2 (TGF-β2) antisense oligodeoxynucleotide TIO3 to mice intraperitoneally once every other day for a total of four injections, and the first injection was 24 h after LLC cell inoculation. We found that the combination induced the formation of TME toward the enrichment and activation of CD8

Nanoimprint technology has the advantages of low cost, high precision, high fidelity and high yield. The metal nanoparticle fluid is non-Newtonian fluid, which is used as the imprint transfer medium to realize high fidelity of pattern because of its shear thinning effect. In order to functionalize the metal nanoparticles microstructure, the subsequent sintering step is required to form a metal interconnect wire. Metal interconnect wire with fewer grain boundaries and fewer holes have excellent mechanical and electronic properties. In this paper, the pseudoplastic metal nanoparticle fluid was formed by Ag nanoparticle and precursor solution, and then the thermal diffusion process was completed by microwave sintering after interconnects were embossed. The influence of microwave and thermal atmosphere on the microstructure and performance of Ag Interconnect wires was analyzed and discussed, and the Ag Interconnect wires performance was determined under the influence of time and temperature parameters. In our experiments, the interconnects after microwave sintering can achieve 39% of the conductivity of bulk silver. The microwave sintering module might be integrated as the heat treatment module of the metal micro/nano pattern directly imprint lithography.

To develop a method for in vitro assembly of recombinant proteins expressed in E. coli into chimeric virus-like particles (cVLPs).A fusion protein (Bepi-Cap-A) between capsid protein (Cap) of PCV2b and B cell epitope (Bepi) of IBDV was expressed in E. Coli, and purified. For assembling them into cVLPs (Bepi-Cap-VLP), the Bepi-Cap-A was suspended in buffer C [0.03% ("%" stands for "v/v" unless otherwise indicated) polyethylene glycol, 0.4 M Tris, 10 mM β-mercaptoethanol, 5% glycerol, 0.02% (w/v) gellan gum, 0.1 M glycine, 0.03% Tween 80, 500 mM NaCl], and incubated. After centrifugation, the pellet was resuspended in buffer D [50 mM NaThe data provide a method which is feasible for in vitro assembly of recombinant proteins into chimeric virus-like particles.

BackgroundFinding conservative T cell epitopes in the proteome of numerous variants of SARS-COV-2 is required to develop T cell activating SARS-COV-2 capable of inducing T cell responses against SARS-COV-2 variants.MethodsA computational workflow was performed to find HLA restricted CD8+ and CD4+ T cell epitopes among conserved amino acid sequences across the proteome of 474727 SARS-CoV-2 strains.ResultsA batch of covserved regions in the amino acid sequences were found in the proteome of the SARS-COV-2 strains. 2852 and 847 peptides were predicted to have high binding affinity to distint HLA class I and class II molecules. Among them, 1456 and 484 peptides are antigenic. 392 and 111 of the antigenic peptides were found in the conseved amino acid sequences. Among the antigenic-conserved peptides, 6 CD8+ T cell epitopes and 7 CD4+ T cell epitopes were identifed. The T cell epitopes could be presented to T cells by high-affinity HLA molecules which are encoded by the HLA alleles with high population coverage.ConclusionsThe T cell epitopes are conservative, antigenic and HLA presentable, and could be constructed into SARS-COV-2 vaccines for inducing protective T cell immunity against SARS-COV-2 and their variants.

Plasmonic lasers, which use the strong confinement of surface plasmon polaritons, are key parts to realize ultracompact coherent light sources at deep subwavelength scales. We propose a plasmonic laser composed of a silicon substrate, ZnO nanowire, dielectric layer, metal layer, and electrode. In this structure, the superimposed coupling of the surface plasmon mode at the metal interface with the high refractive index gain nanowire mode makes the electric field in the spacer layer significantly enhanced. The ZnO nanowire is used as gain material to provide gain compensation. The optical and electrical properties are simulated with the geometric parameters and dielectric layer material. The results show that the structure has strong confinement of the optical field and can realize a deep subwavelength constraint at a lower threshold level. It provides theoretical support for realizing ultracompact coherent light sources.

Manganese (Mn2+) has been reported to activate macrophages and NK cells, and to induce the production of type-I interferons (IFNs) by activating the cGAS-STING pathway. Few studies have been conducted on its adjuvanticity to microbial vaccines, and on the involvement of the interferon regulatory factor (IRF) 5 signaling pathway in the adjuvanticity. In this study, we demonstrated that Mn2+ could facilitate various microbial vaccines to induce enhanced antibody responses, and facilitate the influenza virus vaccine to induce protective immunity against the influenza virus challenge. When formulated in vaccines, Mn2+ could activate murine CD4+ T cells, CD8+ T cells, B cells and DCs, and induce the expression and phosphorylation of TANK-binding kinase 1 (TBK1) and IRF5 in the splenocytes of the immunized mice, resulting in the increased expression of type-I IFNs, TNF-α, B cell-activating factor of the TNF family (BAFF) and B lymphocyte-induced maturation protein-1 (Blimp-1). The induced TBK1 could recruit and bind the IRF5. Furthermore, the Mn2+ induced expression of IRF5 and Blimp-1 was prohibited by a IRF5 interfering oligonucleotide. The data suggest the Mn2+ could be used as a novel type of adjuvants for microbial vaccines, and the activation of IRF5 signaling pathway might involve in the adjuvanticity.

Ni-rich layered oxide LiNi

The excessive activation of interferon regulatory factor 7 (IRF7) promotes the development of acute lung injury (ALI) caused by influenza A virus (IAV). However, the deficiency of IRF7 increases the susceptibility to deadly IAV infection in both humans and mice. To test whether the attenuation rather than the abolishment of IRF7 activity in local infectious sites could alleviate IAV-induced ALI, we established IAV-infected mouse model and trachea/lung-tissue culture systems, and designed two IRF7-interfering oligodeoxynucleotides, IRF7-rODN M1 and IRF7-rODN A1, based on the mouse and human consensus sequences of IRF7-binding sites of Ifna/IFNA genes, respectively. In the model mice, we found a close relationship between the IAV-induced ALI and the level/activity of IRF7 in local infectious sites, and also found that the reduced IRF7 level or activity in the lungs of mice treated with IRF7-rODN M1 led to decreased mRNA levels of Ifna genes, reduced neutrophil infiltration in the lungs and prolonged survival of mice. Furthermore, we found that the effects of IRF7-rODN M1 on alleviating IAV-induced ALI could be correlated to the reduced translocation of IRF7, caused by the IRF7-rODN M1, from cytosol to nucleus in IAV-infected cells. These data suggest that the proper attenuation of IRF7 activity in local infectious sites could be a novel approach for treating IAV-induced ALI.

Sepsis is a major cause of patient mortality and morbidity from bacterial infections. Although neutrophils are known to be important in the development of sepsis, how distinctive neutrophil subtypes regulate inflammatory processes involved in septicemia remains unclear. Preconditioning protects organisms against subsequent higher-dose exposures to the same, or even different, stimuli. Several studies have reported various effects of preconditioning on immune cells. However, the detailed mechanisms underlying neutrophil-mediated protection through preconditioning in sepsis remain unknown. Methods: Flow cytometry was conducted to sort the mice peritoneal lavage cells and the blood samples from patients with sepsis. Western blotting and ELISA were carried out to elucidate the expression of TLR9 signal transduction pathway proteins. Histological analysis was used to assess the effect of InP on intestine and liver structure in tlr9-/- and cav-1-/- mice. Fluorescence microscopy, Co-IP, and FRET were carried out to determine the association of TLR9 with Cav-1. Results: We show that membrane toll-like receptor-9 positive (mTLR9+) neutrophils exert a protective effect against fatal bacterial infections through the process of inflammatory preconditioning (InP). InP, which occurs in the setting of a low-dose bacterial challenge, active ingredient is Monophosphoryl lipid A (MPLA), triggers the membrane translocation of TLR9 from the neutrophil cytosol, where it binds to Cav-1. Our findings showed that InP enables TLR9 to facilitate MyD88-mediated TRAF3 and IRF3 signal transduction. Depletion of either TLR9 or Cav-1 largely eliminates the neutrophil-mediated InP effect in sepsis models in vitro and in vivo. Further, examination of clinical samples from patients with sepsis showed that clinical outcomes and likelihood of recovery are closely correlated with mTLR9 and Cav-1 expression in circulating neutrophils. Conclusion: These results demonstrate that the TLR9-Cav-1 axis is a critical signaling pathway involved in the regulation of neutrophil-dependent MPLA mediated InP, and the presence of mTLR9+ neutrophils could be an attractive indicator of clinical outcomes in bacterial sepsis that could be further explored as a potential therapeutic target.

Neutrophils, classified as professional phagocytes, are crucial in killing bacteria and preventing inflammation. When studying the roles of neutrophils in the development of the septic peritonitis induced by E. coli, we noticed some of the larger cells existed among peritoneal lavage fluid cells (PLCs). Besides the large size, their nuclei are segmented and flat, and squeezed to the marginal zone of the inner membrane. The cells, therefore, were designated as E. coli induced larger neutrophils (e-Neus). Further studies showed that, the e-Neus were ly6G positive, indicating the e-Neus were a type of neutrophils. The enlarged cell size and marginal nucleus of the e-Neus were caused by engulfing abundant of E. coli, marking the active participation of the e-Neus in clearance of E. coli. Functionally, the e-Neus generated reactive oxygen species (ROS) and IL-10. Furthermore, the occurrence and accumulation of the e-Neus were closely correlated with the severity of septic peritonitis and mortality of the mice. Overall, the e-Neus presented here may enrich the understandings on neutrophil transitions in response to various insults, and could be used to evaluate the severity of septic peritonitis induced by E. coli.

The aim of this study was to evaluate the diagnostic value of artificial intelligence algorithm combined with ultrasound endoscopy in early esophageal cancer and precancerous lesions by comparing the examination of conventional endoscopy and artificial intelligence algorithm combined with ultrasound endoscopy, and by comparing the real-time diagnosis of endoscopy and the ultrasonic image characteristics of artificial intelligence algorithm combined with endoscopic detection and pathological results. 120 cases were selected. According to the inclusion and exclusion criteria, 80 patients who met the criteria were selected and randomly divided into two groups: endoscopic examination combined with ultrasound imaging based on intelligent algorithm processing (cascade region-convolutional neural network (Cascade RCNN) model algorithm group) and simple use of endoscopy group (control group). This study shows that the ultrasonic image of artificial intelligence algorithm is effective, and the detection performance is better than that of endoscopic detection. The results are close to the gold standard of doctor recognition, and the detection time is greatly shortened, and the recognition time is shortened by 71 frames per second. Compared with the traditional convolutional neural network (CNN) algorithm, the accuracy and recall of image analysis and segmentation using feature pyramid network are increased. The detection rates of CNN model, Cascade RCNN model, and endoscopic detection alone in early esophageal cancer and precancerous lesions are 56.3% (45/80), 88.8% (71/80), and 44.1% (35/80), respectively. The detection rate of Cascade RCNN model and CNN model was higher than that of endoscopy alone, and the difference was statistically significant ( P < 0.05 ). The sensitivity, specificity, positive predictive value, and negative predictive value of Cascade RCNN model were higher than those of CNN model, which was close to the gold standard for physician identification. This provided a reference basis for endoscopic ultrasound identification of early upper gastrointestinal cancer or other gastrointestinal cancers.

LiMn2O4 is one of the most promising cathode materials due to its high abundance and low cost. However, the practical application of LiMn2O4 is greatly limited owing to its low volumetric energy density. Therefore, increasing its energy density is an urgent problem to be resolved. Herein, using the simple and mass production preferred solid-state reaction, surficial Nb-doped LiMn2O4 composed of the truncated octahedral or spherical-like primary particles are successfully synthesized. Auger electron spectroscopy (AES) and X-ray diffraction (XRD) characterizations confirm that most of Nb5+ enrich in the surficial layer of the particles to form a LiMn2-xNbxO4 phase. This kind of doping can increase the specific discharge capacity of LiMn2O4 materials. Contrast with the pristine LiMn2O4, the discharge capacity of LiMn1.99Nb0.01O4-based 18650R-type battery increases from 1497 to 1705 mAh with the volumetric energy density increasing by ~ 13.9%, benefiting from the joint increments of the specific discharge capacity from 119.5 to 123.7 mAh g−1 and the compacted density from 2.81 to 3.10 g cm−3. Furthermore, the capacity retention after 500 cycles at 1 C (1500 mA) is also improved by 17.1%.

Individuals fail to elicit protective antibody after hepatitis B vaccination remain at risk for hepatitis B virus infection. Analysis of the transcriptome of peripheral blood mononuclear cells (PBMCs) is essential to elucidate the characteristics of gene expression in non-responders. In this study, we enrolled seven responders who had received three injections and seven non-responders who had six injections of hepatitis B vaccine before. All the participants were then vaccinated with a three-dose boost regimen. Microarray analysis and Luminex assay were applied to examine mRNA expression and Th1/Th2/Th9/Th17/Th22/Treg cytokine and chemokine profiles in non-responders and responders. Differentially expressed genes in PBMCs of non-responders at 5 time points, i.e. pre-vaccination, 3(rd), 7(th), 28(th) day post the first dose vaccination and 7(th) day post the second dose vaccination indicated a dense network trend. Compared with responders, nine coding genes (BPI, DEFA1B, DEFA4, CEACAM8, MMP8, FOLR3, LTF, TCN1 and TKTL1) were significantly up-regulated in non-responders at all 5 time points, which could probably be the characteristic genes in hepatitis B vaccine non-responsiveness. Gene ontology analysis revealed that most of the DEGs were related with immune responses. Validation results of these 9 genes using quantitative real-time polymerase chain reaction were mostly consistent with the results of microarray. Cytokine analysis demonstrated that IL-27 and CXCL12 concentrations in responders were significantly higher than non-responders on the 3(rd) day after the first dose and 7(th) day after the second dose of vaccination, respectively. No significant difference was observed in other cytokine and chemokine signatures between the two groups. In conclusion, our results revealed characteristic transcriptome and cytokine changes in hepatitis B vaccine non-responders after boost immunization.

The structure design and synthesis of precursors is a key factor to improve the electrochemical properties of Ni-rich cathode materials. However, for the core-shell precursors, the structural evolution in the lithiated process and its effect on the structure and electrochemical properties of the final products has not been clearly elucidated. Herein, three LiNi0.88Co0.12O2 materials are synthesized from three different structured precursors, namely the completely coated 0.88Ni(OH)2@0.12Co(OH)2, the semi-coated & semi-doped 0.94Ni0.936Co0.064(OH)2@0.06Co(OH)2, and the completely doped Ni0.88Co0.12(OH)2, respectively. Unexpectedly, the core-shell structures of the completely coated and semi-coated & semi-doped precursors disappears, and the radial concentration distributions of Ni and Co are almost uniform in spherical LiNi0.88Co0.12O2 particles obtained by sintering with LiOH·H2O, no matter the precursor is coating type or doping type. Even so, the LiNi0.88Co0.12O2 material synthesized from the 0.88Ni(OH)2@0.12Co(OH)2 precursor still has the best electrochemical properties with the specific discharge capacity of 215 mAh g−1 at 0.1 C (20 mA g−1) and the capacity retention of 88.6% after 100 cycles. The reason is that the cobalt hydroxide coating layer on the surface of precursor acts as a barrier to decrease the diffusing rate of lithium ions into the core material, which leaves enough time to make Ni2+ be oxidized to Ni3+ as many as possible. This work not only synthesizes a high-performance LiNi0.88Co0.12O2 material, but also clearly reveals the reaction mechanism and provides valuable references for synthesizing high-performance LiNi1-x-yCoxMnyO2 (NCM) or LiNi0.8Co0.15Al0.05O2 (NCA) materials.

Rigid oxygen-deficient TiO2−x coated mesoporous hollow Si nanospheres with a mechanically and electrically robust structure have been constructed through a facile method for high-performance Li-ion battery anodes. The mesoporous hollow structure provides enough inner void space for the expansion of Si. The oxygen-deficient TiO2−x coating has functions in three aspects: (1) avoiding direct contact between Si and the electrolyte; (2) suppressing the outward expansion of the mesoporous hollow Si nanospheres; (3) improving the conductivity of the composite. The combined effect leads to high interfacial stability and structural integrity of both the material nanoparticles and the whole electrode. By virtue of the rational design, the composite yields a high reversible specific capacity of 1750.4 mA h g−1 at 0.2 A g−1, an excellent cycling stability of 1303.1 mA h g−1 at 2 A g−1 with 84.5% capacity retention after 500 cycles, and a high rate capability of 907.6 mA h g−1 even at 4 A g−1.

An approach for Brilliant Blue (BB) detection was established based on fluorescence resonance energy transfer, where YVO4:Eu nanocrystals (NCs) are used as the energy donors and BB as the energy acceptor. BB could be electrostatically combined with the YVO4:Eu NCs and the fluorescence of the nanocrystals was quenched. Under optimal conditions, the logarithm of fluorescence intensity of the YVO4:Eu NCs was linearly proportional to the BB concentration in the ranges of 2.5 × 10−6–2.5 × 10−4 and 2.5 × 10−4–2.5 × 10−3 g L−1. The limit of detection was 1.0 × 10−6 g L−1. The method was successfully applied for BB detection in juices and candies. This method has a number of advantages, such as the facile synthesis of YVO4:Eu NCs, a simple and quick quantitative procedure and competitive analytical performance.

In this work, a facile method for the preparation of dual-emission lanthanide nanoparticles (NPs) was developed. Tb3+-doped LaF3 NPs coated with 2,6-pyridinedicarboxylic acid (DPA) and Eu3+, namely LaF3:Tb@DPA-Eu NPs, could produce characteristic emissions of Tb3+ and Eu3+ under 272 nm excitation, which originated from the absorption of DPA. The LaF3:Tb@DPA-Eu NPs with tunable emission peaks and color could be synthesized by changing the concentration of Eu3+. Additionally, the obtained NPs were comprehensively characterized by various analytical methods. Transmission electron microscopy (TEM) images showed that the average size of the NPs was ~15 nm. Moreover, X-ray diffraction (XRD) analysis revealed that the products were single-phase LaF3, while the doped Tb3+ entered the LaF3 lattice to occupy the La3+ sites. Owing to their excellent water solubility and good optical properties, the LaF3:Tb@DPA-Eu NPs were used as a fluorescence probe for the detection of marbofloxacin (MAR) based on the fluorescence quench. Notably, an effective ratiometric fluorescence method was established. The approach exhibited good sensitivity and selectivity with a linear range of 0.10 ~ 10.0 μM and detection limit of 85 nM. It was successfully employed for the determination of MAR in milk samples with recoveries of 98.1%–106%. Thus, the fluorescence method based on the LaF3:Tb@DPA-Eu NPs developed herein provides a convenient and fast platform for the detection of MAR.

Aiming at the testability analysis of multi-state system, a testability modeling method based on structure-function-state-test is proposed. Based on the hierarchical structure analysis of the system, taking the function modeling of the structure as the core, the performance, fault and state of the function are described, and the test correlation of the system fault and state is studied. Through the analysis of a typical case, the results show that the model can: 1. Realize the system fault test correlation analysis considering the uncertain factors; 2. Realize the state test correlation analysis of the multi state system; 3. Realize the testability analysis of the multi state system by calculating the fault detection rate, fault isolation rate and state detection rate.

A Si/C composite with Si nanoparticles (nSi) uniformly dispersed in the interlayers of reduced graphene oxide scrolls (rGS) is successfully developed for high–performance Li–ion battery anodes. The rGS can deform reversibly with the repeated expansion/contraction of nSi to maintain contact between the nSi and the conductive rGS network, which can effectively buffer large volume changes and maintain continuous large–area core–shell electrical contact. Additionally, the continuous electrical network of rGS greatly enhances the electrical conductivity, and the open structures at the ends and sides of rGS provide paths for rapid diffusion of Li ions, thus enhancing the rate performance. By virtue of the rational design, the composite shows a high reversible specific capacity of 2030 mA h g −1 at 0.2 A g −1 , high cycling stability of 1200 mA h g −1 at 4 A g −1 with 99.2% capacity retention after 200 cycles, and an excellent rate performance of 1000 mA h g −1 even at 8 A g −1 .

Sexually dimorphic antibody response to vaccines has long been noticed. In addition to sex hormones, other factors such as antigens, adjuvants and strains of mice, as shown by indirect evidence, could also impact the sexual dimorphism. To clarify this, we immunized both gender mice of distinct strains with inactivated FMDV or HBsAg with or without adjuvants, and detected the specific antibody response of the mice. We found that in absence of adjuvants, the recombinant HBsAg but not the inactivated FMDV induced enhanced IgG antibody response in the female BALB/c mice. The o/w emulsion could facilitate the HBsAg to induce the comparable level of IgG antibodies in the male BALB/c mice as that in the females. The o/w emulsion rather than ISA206, a w/o/w emulsion, could assist the inactivated FMDV to induce higher levels of IgM antibodies in the female BALB/c mice. Moreover, the sexually dimorphic antibody response varied among the ICR, BALB/c and the F1 (BALB/c × C57BL/6) mice. Thus the data suggest that antigens, adjuvants and strains all impact the sexually dimorphic antibody response to vaccines and may provide insights for developing gender-based vaccines.

// Xin Li 1, * , Junpeng Wang 2, * , Yun Yao 1 , Lei Yang 1 , Zhiqin Li 3 , Cheng Yu 4 , Peiyan Zhao 1 , Yongli Yu 3 and Liying Wang 1 1 Department of Molecular Biology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun 130021, China 2 Department of Urology, Henan Provincial People’s Hospital, Zhengzhou 450003, China 3 Department of Immunology, College of Basic Medical Sciences, Norman Bethune Health Science Center, Jilin University, Changchun 130021, China 4 Department of Epidemiology and Biostatistics, School of Public Health, Jilin University, Changchun 130021, China * These authors have contributed equally to this work Correspondence to: Liying Wang, email: wlying@jlu.edu.cn Yongli Yu, email: ylyu@jlu.edu.cn Keywords: immune checkpoint inhibitor, therapy, efficacy, safety, advanced melanoma Received: February 14, 2017 Accepted: April 19, 2017 Published: July 01, 2017 ABSTRACT Objectives: We aimed to compare and rank the effects of 9 immune checkpoint inhibitor-related therapies for treating advanced melanoma. Methods: We searched Pubmed, Cochrane databases, Web of Science, and ClinicalTrials.gov for randomized controlled trials of the immune checkpoint inhibitor-related treatments for advanced melanoma. Analysis was done on a Bayesian framework. Results: Twelve trials including 5413 patients were identified. Ipilimumab plus nivolumab, nivolumab, and pembrolizumab were significantly more efficacious for progression-free survival (PFS) than ipilimumab (hazard ratio [HR], 0.38, 0.50, and 0.58, respectively), ipilimumab plus chemotherapy (0.45, 0.60, and 0.70, respectively), or ipilimumab plus sargramostim (0.44, 0.57, and 0.67, respectively). Ipilimumab plus gp100 was significantly less efficacious for PFS than the remaining eight immune checkpoint inhibitor-related strategies. Pembrolizumab was significantly more efficacious than ipilimumab and ipilimumab plus gp100 (HR, 0.66, and 0.64, respectively) in improving overall survival (OS). Nivolumab significantly improved OS over tremelimumab (HR, 0.48). Ipilimumab plus sargramostim was ranked the second most effective strategy in terms of OS and well tolerated. Nivolumab and pembrolizumab showed the best profile of acceptability, with significantly less high-grade adverse events than ipilimumab (odds ratio [OR], 0.49 and 0.50, respectively), tremelimumab (0.21 and 0.21, respectively), ipilimumab plus chemotherapy (0.13 and 0.13, respectively), or ipilimumab plus nivolumab (0.15 and 0.15, respectively). Conclusions: Nivolumab, pembrolizumab and ipilimumab plus sargramostim might be optimum treatments for advanced melanoma because they have the most favorable balance between benefits and acceptability. Ipilimumab plus nivolumab is the most effective in prolonging PFS, but is far more toxic than nivolumab and pembrolizumab.

Previously, we showed that an oligodeoxynucleotide (ODN) with AAAG repeats (AAAG ODN) rescued mice from fatal acute lung injury (ALI) induced by influenza virus and inhibited production of tumor necrosis factor-α (TNF-α) in the injured lungs. However, its underlying mechanisms remain to be elucidated. Upon the bioinformatic analysis revealing that the sequence of AAAG ODN is in consensus with the interferon regulatory factor 5 (IRF5) binding site in the cis-regulatory elements of proinflammatory cytokines, we tried to explore whether AAAG ODN could attenuate burn injury-induced systemic inflammatory responses by inhibiting the IRF5 pathway. Using a mouse model with sterile systemic inflammation induced by burn injury, we found that AAAG ODN prolonged the lifespan of the mice, decreased the expression of IRF5 in the injured skin, reduced the production of TNF-α and IL-6 in the blood and injured skin, and attenuated the ALI. These effects were correlated with AAAG ODN-mediated inhibition of nuclear translocation of IRF5. The data suggest that AAAG ODN could act as a cytoplasmic decoy capable of interfering the function of IRF5 and be developed as a drug candidate for the treatment of inflammatory diseases.

Cytotoxic T-lymphocyte antigen 4 (CTLA-4) is recognized as a critical inhibitory regulator of T-cell proliferation and activation, opposing the action of CD28-mediated co-stimulation. Interfering or blocking CTLA-4 can result in continuous T-cell activation required for the full immune response to pathogenic microbes and vaccines. To test if nucleic acid-based CTLA-4 inhibitors could be developed into a novel adjuvant, we designed two oligonucleotides, CMD-1 and CMD-2, with the sequences complementary to the conserve regions identical between human and mouse CTLA-4 mRNA 3' untranslated region (3' UTR), and tested their in vitro effects on CTLA-4 production and their adjuvanticity for vaccines in mice. We found that CMD-1 inhibited the antigen-induced CTLA-4 up-regulation on the CD4+ T cells by interfering its mRNA expression, maintained higher levels of CD80 and CD86 on the CD11c+ cells and promoted the recalled proliferation of the CD4+ T cells and CD19+ B cells, and that the CMD-1 enhanced the antibody response against recombinant PCV2b capsid protein or inactivated foot-and-mouth disease virus in both ICR and BALB/c mice. These data suggest that the CMD-1 could be used as a novel vaccine adjuvant capable of inhibiting inhibitory signals rather than inducing stimulatory signals of immune cells.

The present study aimed to investigate the binding of circulating mucin 1 (MUC1) antibody with serum MUC1 antigen in stage IV breast cancer. Serum samples of 61 patients with stage IV breast cancer and 64 patients with early-stage breast cancer were collected. The anti‑MUC1 antibody (IgG) and MUC1 antigen (cancer antigen 15‑3; Ca15‑3) were detected using an indirect enzyme-linked immunosorbent assay (I‑ELISA) and ELISA, respectively. The MUC1 IgG affinity was detected using a urea degradation combining ELISA. Western blot analysis and an inhibition test were performed for verification of the binding of anti‑MUC1 IgG with MUC1 antigen, and their correlation was analyzed. The results showed that there was a negative correlation between anti‑MUC1 IgG and CA15‑3 antigen in stage IV breast cancer when positive CA15‑3 antigen and/or anti‑MUC1 IgG were selected (r=‑0.417; P=0.0044). The positive anti‑MUC1 IgG with positive Ca15‑3 antigen was more common in stage IV breast cancer, compared with early‑stage breast cancer (χ2=4.629; P=0.031), however, Ca15‑3 antigen positivity was higher in stage IV breast cancer, compared with early‑stage breast cancer (χ2=10.58; P=0.001). Anti‑MUC1 IgG was able to bind to the MUC1 antigen in stage IV breast cancer. No differences in the 8R-MUCPT inhibition ratio were found between the two groups (P=0.778), and there were no differences in the affinity of anti‑MUC1 IgG (P=0.873). In stage IV breast cancer, circulating anti‑MUC1 antibody was found to bind serum MUC1 antigen, although their compatibility was low. No significant difference was found in the affinity of the anti‑MUC1 antibody between stage IV breast cancer and early‑stage breast cancer.