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ObjectiveA comprehensive immune landscape for HBV infection is pivotal to achieve HBV cure.DesignWe performed single-cell RNA sequencing of 2 43 000 cells from 46 paired liver and blood samples of 23 individuals, including six immune tolerant, 5 immune active (IA), 3 acute recovery (AR), 3 chronic resolved and 6 HBV-free healthy controls (HCs). Flow cytometry and histological assays were applied in a second HBV cohort for validation.ResultsBoth IA and AR were characterised by high levels of intrahepatic exhausted CD8+ T (Tex) cells. In IA, Tex cells were mainly derived from liver-resident GZMK+ effector memory T cells and self-expansion. By contrast, peripheral CX3CR1+ effector T cells and GZMK+ effector memory T cells were the main source of Tex cells in AR. In IA but not AR, significant cell–cell interactions were observed between Tex cells and regulatory CD4+ T cells, as well as between Tex and FCGR3A+ macrophages. Such interactions were potentially mediated through human leukocyte antigen class I molecules together with their receptors CANX and LILRBs, respectively, contributing to the dysfunction of antiviral immune responses. By contrast, CX3CR1+GNLY+ central memory CD8+ T cells were concurrently expanded in both liver and blood of AR, providing a potential surrogate marker for viral resolution. In clinic, intrahepatic Tex cells were positively correlated with serum alanine aminotransferase levels and histological grading scores.ConclusionOur study dissects the coordinated immune responses for different HBV infection phases and provides a rich resource for fully understanding immunopathogenesis and developing effective therapeutic strategies.

Background Restoration of HBV-specific T cell immunity is a promising approach for the functional cure of chronic Hepatitis B (CHB), necessitating the development of valid assays to boost and monitor HBV-specific T cell responses in patients with CHB. Methods We analyzed hepatitis B virus (HBV) core- and envelope (env)-specific T cell responses using in vitro expanded peripheral blood mononuclear cells (PBMCs) from patients with CHB exhibiting different immunological phases, including immune tolerance (IT), immune activation (IA), inactive carrier (IC), and HBeAg-negative hepatitis (ENEG). Additionally, we evaluated the effects of metabolic interventions, including mitochondria-targeted antioxidants (MTA), polyphenolic compounds, and ACAT inhibitors (iACAT), on HBV-specific T-cell functionality. Results We found that HBV core- and env-specific T cell responses were finely coordinated and more profound in IC and ENEG than in the IT and IA stages. HBV env-specific T cells were more dysfunctional but prone to respond to metabolic interventions using MTA, iACAT, and polyphenolic compounds than HBV core-specific T-cells. The responsiveness of HBV env-specific T cells to metabolic interventions can be predicted by the eosinophil (EO) count and the coefficient of variation of red blood cell distribution width (RDW-CV). Conclusion These findings may provide valuable information for metabolically invigorating HBV-specific T-cells to treat CHB. Graphical abstract

We introduced the fuzzy axioms of choice, fuzzy Zorn’s lemma and fuzzy well-ordering principle, which are the fuzzy versions of the axioms of choice, Zorn’s lemma and well-ordering principle, and discussed the relations among them. As an application of fuzzy Zorn’s lemma, we got the following results: (1) Every proper fuzzy ideal of a ring was contained in a maximal fuzzy ideal. (2) Every nonzero ring contained a fuzzy maximal ideal. (3) Introduced the notion of fuzzy nilpotent elements in a ring R, and proved that the intersection of all fuzzy prime ideals in a commutative ring R is the union of all fuzzy nilpotent elements in R. (4) Proposed the fuzzy version of Tychonoff Theorem and by use of fuzzy Zorn’s lemma, we proved the fuzzy Tychonoff Theorem.

Inspired by the open problems “How to define the notions of fantastic filters and states in EQ-algebras” in [LIU, L. Z.—ZHANG, X. Y.: Implicative and positive implicative prefilters of EQ-algebras, J. Intell. Fuzzy Syst. 26 (2014), 2087–2097], we introduce the notions of fantastic filters and investigate the existence of Bosbach states and Riečan states on EQ-algebras by use of fantastic filters. Firstly, we prove that a residuated EQ-algebra has a Bosbach state if and only if it has a fantastic filter. We also establish that a good EQ-algebra has a state-morphism if and only if it has a prime fantastic filter. Furthermore, we introduce the notion of QI-EQ-algebras and obtain the necessary and sufficient condition for a residuated QI-EQ-algebra having Riečan states. Finally, we introduce the notion of semi-divisible EQ-algebras and give an example of a semi-divisible residuated EQ-algebra, which is not a semi-divisible residuated lattice. We also prove that every semi-divisible residuated EQ-algebra admits Riečan states. These works generalize a series of existing results about existence of states in several algebras, such as residuated lattices, NM-algebras, MTL-algebras, BL-algebras and so on.

Compared with traditional machine learning, intrusion detection based on deep learning has the advantage of feature extraction. Auto-encoders, owing to having good feature extraction and dimensionality reduction ability, are known for the superior performance. However, the network structure selection is time-consuming and laborious. The essential features cannot be automatically extracted according to different distribution characteristics of the data set. Moreover, the existing data pre-processing method fails to adapt the model better. Based on the stack sparse auto-encoders (SSAE), we propose a new intrusion detection model named DBSO-SSAE. The algorithm is based on difference brain storm optimization (DBSO) which automatically adapts to selection network framework. Meanwhile, a new normalization strategy is introduced to further improve the accuracy of the model. The simulation results show that DBSO-SSAE greatly reduces the complexity of manual tuning and increases the adaptability of the network model.

Adoptive immunotherapy using chimeric antigen receptors-modified T cells (CAR-T) is a promising approach for cancer treatment. However, CARs currently applied in the clinics cannot be effectively regulated and the safety of CAR-T cell therapies remains a major concern. To improve the safety of CAR-T cells, we designed a synthetic splitting CAR (ssCAR) that can regulate T cell functions exogenously. Epidermal growth factor receptor variant III (EGFRvIII) was used as a molecular target for ssCAR. Our results indicate that both EGFRvIII and small molecule are needed for the activation of the ssCAR-T cells. AP21967 dose-dependently increased the expression of T cell activation, production of cytokines and extent of cell lysis. In conclusion, the gene switch designed in this study allows for temporal and spatial control over engineered T cells in a dose-and time-dependent manner by AP21967. Our work demonstrates the feasibility and improved safety profile of this novel treatment approach.

The principle of balancing a high speed cantilever rotor at full speed has been put forward by low-speed and high-speed balancing. The portable field dynamic balancing instrument based on the microcontroller is discussed from the hardware, the software and the signal process in detail. With the developed instrument, the whole-machine balancing experiment was conducted on a saucer-separating centrifuge RJ-460. The vibration of the saucer-separating centrifuge decreased from 3.8mm/s to 0.3mm/s at 1200r/min and decreased from 9.8mm/s to 0.6mm/s at 7200r/min. The experimental results indicated that the principle of balance is correct and the designed instrument is reliable and promising.

Human augmenter of liver regeneration (hALR) is a sulfhydryl oxidase that is highly expressed in spermatogonia and early spermatocytes. To investigate the physiological effects of hALR in spermatogenesis, we generated a hALR transgenic mouse model driven by the human TSPY (testis-specific protein, Y-encoded) promoter that allows the transgene to be specifically activated in the testes. hALR content was found to be increased in both germ cells. The histological and TUNEL analysis of transgenic testes revealed a number of spermatogenetic defects including primary spermatocyte overpopulation followed by depletion through apoptosis, degenerating and detached nucleated germ cells, haploid cell loss and intraepithelial vacuoles of varying sizes. In line with these features, adult transgenic male mice also displayed a reduction in fertility. Our data suggest that regulated spatial and temporal expression of hALR is required for normal testicular development and spermatogenesis, and overexpression of hALR results in influencing the sperm morphology and quantity and the eventual reduction in male fertility. Present findings in the mouse may be of interest to human male fertility.

PKHDL1 (the gene for Polycystic Kidney and Hepatic Disease Like-1) had been recently identified, but characteristics of the gene product, Fibrocystin-L (FPC-L), still remain unknown. We therefore produced a rabbit polyclonal antibody hFL-Np to explore the cellular characteristics of this novel protein.Based on the hydrophobic/hydrophilic analyses, chose a cDNA fragment which encodes 633L-768K amino acids of the FPC-L and amplified it by RT-PCR. The PCR product was then cloned into a prokaryotic expression vector pGEX-GST. With IPTG induction, the antigen hFL-N was produced and further purified. A rabbit was immunized with the antigen and its antiserum was collected. Applied Western blot with the polyclonal antiserum hFL-Np and validated the antibody specific for FPC-L protein. In addition, also used immunofluorescence staining with hFL-Np to detect the subcellular distribution in cultured HEK293 cells.The prokaryotic expression vector pGEX-hFL-N was successfully constructed and a hFL-N antigen was produced in E.coli Rossetta cells. Using the antigen, a polyclonal antibody hFL-Np was produced and the specificity for FPC-L was also proved by biochemistry and cellular assays. Using the antibody, the cellular staining reveals that FPC-L was a cytosolic protein.We produced an anti-FPC-L polyclonal antibody hFL-Np. By biochemistry and cellular characterization, proved that the polyclonal antibody hFL-Np is specific for FPC-L and demonstrated FPC-L is a cytosolic protein. The finding provides a platform for further dissecting FPC-L functions in mammalian development.