Single-cell landscape of immune cells during the progression from HBV infection to HBV cirrhosis and HBV-associated hepatocellular carcinoma.

Introduction: Immune cells play crucial roles in the development of chronic hepatitis B virus (HBV) infection, leading to cirrhosis and hepatocellular carcinoma (HCC). However, their functions at different disease stages are not fully understood. Methods: In this study, we used single-cell RNA sequencing (scRNA-seq) to characterize the human liver immune microenvironment at different disease stages. We analyzed scRNA-seq data from 118,455 immune cells obtained from livers of six healthy individuals, four patients with HBV infection, five patients with HBV cirrhosis, and three patients with HBV-associated HCC. Results: Our results showed an accumulation of scar-associated macrophages during disease progression, and we identified two relevant immune subsets, Macrophage-CD9/IL18 and macrophage-CD9/IFI6. Macrophage-CD9/IL18 expanded from HBV infection to cirrhosis, while macrophage-CD9/IFI6 expanded from cirrhosis to HCC. We verified the existence of Macrophage-CD9/IFI6 using multiplex immunofluorescence staining. We also found an increase in cytotoxic NK Cell-GNLY during progression from cirrhosis to HCC. Additionally, the proportion of CD4 T cell-TNFAIP3, CD8 T cell-TNF (effector CD8 T cells), and CD8 T cell-CD53 increased, while the proportion of Treg cells decreased from HBV infection to cirrhosis. The proportion of Treg and CD8 T cell-LAG3 (Exhausted CD8 T cell) enhanced, while the proportion of CD8 T cell-TNF (effector CD8 T cells) decreased from cirrhosis to HCC. Furthermore, GSEA enrichment analyses revealed that MAPK, ERBB, and P53 signaling pathways in myeloid cells were gradually inhibited from HBV infection to cirrhosis and HCC. Discussion: Our study provides important insights into changes in the hepatic immune environment during the progression of HBV-related liver disease, which may help improve the management of HBV-infected liver diseases.

Spatio-temporal variation of soil microplastics as emerging pollutant after long-term application of plastic mulching and organic compost in apple orchards.

Microplastics (MPs) pollution in agroecosystems have aroused great alarm and widespread concern. However, the spatial distribution and temporal variation characteristics of MPs in apple orchards with long-term plastic mulching and organic compost input are still poorly understood. This study investigated MPs accumulation characteristics and vertical distribution after applying plastic mulch and organic compost in apple orchards for 3 (AO-3), 9 (AO-9), 17 (AO-17), and 26 (AO-26) years on the Loess Plateau. The clear tillage (no plastic mulching and organic composts) area was used as a control (CK). At a soil depth of 0-40 cm, AO-3, AO-9, AO-17, and AO-26 treatments increased the abundances of MPs, and the black fibers and fragments of rayon and polypropylene were dominant. In the 0-20 cm soil layer, the abundances of MPs increased with the treatment time; the abundance was 4333 pieces kg-1 after 26 years of treatment, gradually decreasing with soil depth. In different treatments and soil layers, the percentages of MPs <1000 µm were dominant (>50%). The AO-17 and AO-26 treatments significantly increased the MPs with the size of 0-500 µm at 0-40 cm and the abundances of pellets in 0-60 cm soil. In conclusion, the long-term (≥17 years) application of plastic mulching and organic composts increased the abundances of small particles at 0-40 cm, and plastic mulching contributed the most to MPs, while organic composts increased the complexity and diversity of MPs.

The MdBBX22-miR858-MdMYB9/11/12 module regulates proanthocyanidin biosynthesis in apple peel.

Proanthocyanidins (PAs) have antioxidant properties and are beneficial to human health. The fruit of apple (Malus × domestica Borkh.), especially the peel, is rich in various flavonoids, such as PAs, and thus is an important source of dietary antioxidants. Previous research on the regulation of PAs in apple has mainly focussed on the transcription level, whereas studies conducted at the post-transcriptional level are relatively rare. In this study, we investigated the function of mdm-miR858, a miRNA with multiple functions in plant development, in the peel of apple fruit. We showed that mdm-miR858 negatively regulated PA accumulation by targeting MdMYB9/11/12 in the peel. During fruit development, mdm-miR858 expression was negatively correlated with MdMYB9/11/12 expression and PA accumulation. A 5'-RACE experiment, GUS staining assays and transient luminescent assays indicated that mdm-miR858 cleaved and inhibited the expression of MdMYB9/11/12. Overexpression of mdm-miR858 in apple calli, tobacco and Arabidopsis reduced the accumulation of PAs induced by overexpression of MdMYB9/11/12. Furthermore, we found that MdBBX22 bound to the mdm-miR858 promoter and induced its expression. Overexpression of MdBBX22 induced the expression of mdm-miR858 to inhibit the accumulation of PAs in apple calli overexpressing MdMYB9/11/12. Under light stress, MdBBX22 induced mdm-miR858 expression to inhibit PA accumulation and thereby indirectly enhanced anthocyanin synthesis in the peel. The present results revealed that the MdBBX22-miR858-MdMYB9/11/12 module regulates PA accumulation in apple. The findings provide a reference for further studies of the regulatory mechanism of PA accumulation and the relationship between PAs and anthocyanins.

Ferroptosis: Redox Imbalance and Hematological Tumorigenesis.

Ferroptosis is a novel characterized form of cell death featured with iron-dependent lipid peroxidation, which is distinct from any known programmed cell death in the biological processes and morphological characteristics. Recent evidence points out that ferroptosis is correlated with numerous metabolic pathways, including iron homeostasis, lipid metabolism, and redox homeostasis, associating with the occurrence and treatment of hematological malignancies, such as multiple myeloma, leukemia, and lymphoma. Nowadays, utilizing ferroptosis as the target to prevent and treat hematological malignancies has become an active and challenging topic of research, and the regulatory network and physiological function of ferroptosis also need to be further elucidated. This review will summarize the recent progress in the molecular regulation of ferroptosis and the physiological roles and therapeutic potential of ferroptosis as the target in hematological malignancies.

Sexual dysfunction in patients with myasthenia gravis.

BACKGROUND: Myasthenia gravis (MG) is an autoimmune disease that causes fatigueable muscle weakness. Sexual dysfunction (SD) is a common condition, but the association between SD and MG remains poorly understood. METHODS: An observational study was conducted to explore SD incidence and risk factors in MG patients. The study enrolled 158 MG patients and 161 age- and sex-matched healthy individuals. SD was investigated using the Female Sexual Function Inventory (FSFI), the abridged International Index of Erectile Function-5 (IIEF-5), and the Chinese Index of Premature Ejaculation-5 (CIPE-5). The mental health was evaluated using Hamilton Depression Scale (HAMD) and Hamilton Anxiety Scale (HAMA). RESULTS: A total of 52 male patients and 106 female patients were finally included. The average age of these patients was 41.82 ± 10.44 years. The incidence of female SD was significantly higher in MG patients (48.11%) than in healthy people (22.64%) (P < 0.001). The incidence of SD in male MG patients was also higher. Age and depression were significantly correlated with decreased libido, wakefulness, lubrication, orgasm, and satisfaction scores, indicating that these are risk factors for SD. Age (OR:1.13, CI%:1.06-1.21, P < 0.001) and HAMD scores (OR:1.53, CI%:1.0-2.13, P = 0.011) are independent risk factors for SD of MG patients. CONCLUSION: SD is a common problem in MG, and its severity does not change with the severity of the disease. Age and depression are risk factors for sexual dysfunction.

The immune regulatory effects of tetrahedral framework nucleic acid on human T cells via the mitogen-activated protein kinase pathway.

OBJECTIVES: Autoimmune diseases are a heterogeneous group of diseases which lose the immunological tolerance to self-antigens. It is well recognized that irregularly provoked T cells participate in the pathological immune responses. As a novel nanomaterial with promising applications, tetrahedral framework nucleic acid (TFNA) nanostructure was found to have immune regulatory effects on T cells in this study. MATERIALS AND METHODS: To verify the successful fabrication of TFNA, the morphology of TFNA was observed by atomic force microscopy (AFM) and dynamic light scattering. The regulatory effect of TFNA was evaluated by flow cytometry after cocultured with CD3+ T cells isolated from healthy donors. Moreover, the associated signaling pathways were investigated. Finally, we verified our results on the T cells from patients with neuromyelitis optica spectrum disorder (NMOSD), which is a typical autoimmune disease induced by T cells. RESULTS: We revealed the alternative regulatory functions of TFNA in human primary T cells with steady status via the JNK signaling pathway. Moreover, by inhibiting both JNK and ERK phosphorylation, TFNA exhibited significant suppressive effects on IFNγ secretion from provoking T cells without affecting TNF secretion. Similar immune regulatory effects of TFNA were also observed in autoreactive T cells from patients with NMOSD. CONCLUSIONS: Overall, our results revealed a potential application of TFNA in regulating the adaptive immune system, as well as shed a light on the treatment of T cell-mediated autoimmune diseases.

Mortality of neuromyelitis optica spectrum disorders in a Chinese population.

OBJECTIVE: Neuromyelitis optica spectrum disorder (NMOSD) is a rapidly disabling disease. Epidemiologic studies have suggested varying NMOSD mortality across ethnic groups. However, NMOSD mortality data in China are scarce. This study's objectives were to explore mortality and causes of death among Chinese NMOSD patients and to identify independent predictors of death. METHODS: We performed a retrospective study with a 10-year follow-up of Chinese NMOSD patients. A Cox proportional hazards model was used to identify independent predictors of death. RESULTS: Five hundred and sixty-nine patients were included; 24 patients died during follow-up, for overall mortality of 4.2%. In these patients, the median disease duration at the time of death was 3.4 years. The most common cause of death was secondary infection (62.5%), especially respiratory infection (45.8%). The second most common cause of death was extensive cervical myelitis with respiratory failure (16.7%). Other causes included suicide (8.3%), cancer (4.2%), cerebral embolism (4.2%), and unknown causes (4.2%). The multivariate Cox analyses indicated that a short first interattack interval (HR = 0.93, 95% CI 0.89-0.98, p = 0.003), lack of regular immunotherapy (HR = 10.34, 95% CI 4.05-26.37, p < 0.001), and older age at onset were independent predictors of death. Every increasing decade of onset age increased the risk of death 2.59 times (95% CI 1.74-3.86, p < 0.001). INTERPRETATION: Infections were more common in patients not treated with any immunotherapy, indicating that early and consequent immunotherapy might prevent death by infections, which is of great importance for further treatment of NMOSD patients to avoid undertreatment due to fear of treatment-associated infections.

Effects of drought stress on photosynthesis and photosynthetic electron transport chain in young apple tree leaves.

In our study, the effects of water stress on photosynthesis and photosynthetic electron transport chain (PETC) were studied in several ways, including monitoring the change of gas exchange parameters, modulated chlorophyll fluorescence, rapid fluorescence induction kinetics, reactive oxygen species (ROS), antioxidant enzyme activities and D1 protein levels in apple leaves. Our results show that when leaf water potential (ψ w) is above -1.5 MPa, the stomatal limitation should be the main reason for a drop of photosynthesis. In this period, photosynthetic rate (P N), stomatal conductance (G s), transpiration rate (E) and intercellular CO2 concentration (C i) all showed a strong positive correlation with ψ w Modulated chlorophyll fluorescence parameters related to photosynthetic biochemistry activity including maximum photochemical efficiency (Fv/Fm), actual photochemical efficiency of PSII (ΦPSII), photochemical quenching coefficient (q P) and coefficient of photochemical fluorescence quenching assuming interconnected PSII antennae (q L) also showed a strong positive correlation as ψ w gradually decreased. On the other hand, in this period, Stern-Volmer type non-photochemical quenching coefficient (NPQ) and quantum yield of light-induced non-photochemical fluorescence quenching [Y (NPQ)] kept going up, which shows an attempt to dissipate excess energy to avoid damage to plants. When ψ w was below -1.5 MPa, P N continued to decrease linearly, while C i increased and a 'V' model presents the correlation between C i and ψ w by polynomial regression. This implies that, in this period, the drop in photosynthesis activity might be caused by non-stomatal limitation. Fv/Fm, ΦPSII, q P and q L in apple leaves treated with water stress were much lower than in control, while NPQ and Y (NPQ) started to go down. This demonstrates that excess energy might exceed the tolerance ability of apple leaves. Consistent with changes of these parameters, excess energy led to an increase in the production of ROS including H2O2 and O2 •- Although the activities of antioxidant enzymes like catalase (CAT), superoxide dismutase (SOD) and peroxidase (POD) increased dramatically and ascorbate peroxidase (APX) decreased in apple leaves with drought stress, it was still not sufficient to scavenge ROS. Consequently, the accumulation of ROS triggered a reduction of net D1 protein content, a core protein in the PSII reaction center. As D1 is responsible for the photosynthetic electron transport from plastoquinone A (QA) to plastoquinone B (QB), the capacity of PETC between QA and QB was considerably downregulated. The decline of photosynthesis and activity of PETC may result in the shortage of adenosine triphosphate (ATP) and limitation the regeneration of RuBP (J max), a key enzyme in CO2 assimilation. These are all non-stomatal factors and together contributed to decreased CO2 assimilation under severe water stress.

Intraoperative Anterior Migration of the Prestige-LP Cervical Disc Owing to an Inappropriate Implantation Sequence During Continuous 2-Level Artificial Cervical Disc Replacement: A Case Report with 8-Year Follow-Up.

BACKGROUND: Owing to its unique advantages, 2-level artificial cervical disc replacement (ACDR) is gaining attention. Among artificial discs designed for use in ACDR, the Food and Drug Administration-approved Prestige-LP Cervical Disc is widely used. There are no standard implantation sequences for 2-level ACDR using the Prestige-LP disc, and complications resulting from inappropriate implantation sequences remain unknown. CASE DESCRIPTION: A 45-year-old woman underwent continuous 2-level ACDR using the Prestige-LP disc and experienced anterior migration of a previously inserted artificial disc after secondary disc implantation at an upper segment owing to an inappropriate implantation sequence during surgery. Intraoperative radiographs showed stable index levels and artificial discs. We tapped the migrated disc back into its correct position and recommended a postoperative functional exercise plan to the patient. We followed the patient for 8 years to verify the safety of our solution. We developed an implantation strategy for 2-level ACDR to avoid this complication in the future. CONCLUSIONS: During 2-level ACDR, a top-down sequence should be used to implant prostheses. When anterior disc migration occurs, intraoperative radiographs should be obtained to ensure stability of the index levels. If there is no instability, the migrated tab can be tapped back into its correct position. In addition, limiting motion rather than allowing intermittent movement of the neck for at least 3 months is important to promote union between bone and prosthesis.