The mesencephalic astrocyte-derived neurotrophic factor (MANF) has been recently identified as a neurotrophic factor, but its role in hepatic fibrosis is unknown. Here, we found that MANF was upregulated in the fibrotic liver tissues of the patients with chronic liver diseases and of mice treated with CCl₄. MANF deficiency in either hepatocytes or hepatic mono-macrophages, particularly in hepatic mono-macrophages, clearly exacerbated hepatic fibrosis. Myeloid-specific MANF knockout increased the population of hepatic Ly6C^high macrophages and promoted HSCs activation. Furthermore, MANF-sufficient macrophages (from WT mice) transfusion ameliorated CCl₄-induced hepatic fibrosis in myeloid cells-specific MANF knockout (MKO) mice. Mechanistically, MANF interacted with S100A8 to competitively block S100A8/A9 heterodimer formation and inhibited S100A8/A9-mediated TLR4-NF-κB signal activation. Pharmacologically, systemic administration of recombinant human MANF significantly alleviated CCl₄-induced hepatic fibrosis in both WT and hepatocytes-specific MANF knockout (HKO) mice. This study reveals a mechanism by which MANF targets S100A8/A9-TLR4 as a "brake" on the upstream of NF-κB pathway, which exerts an impact on macrophage differentiation and shed light on hepatic fibrosis treatment.

MAGED4B belongs to the melanoma-associated antigen family; originally found in melanoma, it is expressed in various types of cancer, and is especially enriched in glioblastoma. However, the functional role and molecular mechanisms of MAGED4B in glioma are still unclear. In this study, we found that the MAGED4B level was higher in glioma tissue than that in non-cancer tissue, and the level was positively correlated with glioma grade, tumor diameter, Ki-67 level, and patient age. The patients with higher levels had a worse prognosis than those with lower MAGED4B levels. In glioma cells, MAGED4B overexpression promoted proliferation, invasion, and migration, as well as decreasing apoptosis and the chemosensitivity to cisplatin and temozolomide. On the contrary, MAGED4B knockdown in glioma cells inhibited proliferation, invasion, and migration, as well as increasing apoptosis and the chemosensitivity to cisplatin and temozolomide. MAGED4B knockdown also inhibited the growth of gliomas implanted into the rat brain. The interaction between MAGED4B and tripartite motif-containing 27 (TRIM27) in glioma cells was detected by co-immunoprecipitation assay, which showed that MAGED4B was co-localized with TRIM27. In addition, MAGED4B overexpression down-regulated the TRIM27 protein level, and this was blocked by carbobenzoxyl-L-leucyl-L-leucyl-L-leucine (MG132), an inhibitor of the proteasome. On the contrary, MAGED4B knockdown up-regulated the TRIM27 level. Furthermore, MAGED4B overexpression increased TRIM27 ubiquitination in the presence of MG132. Accordingly, MAGED4B down-regulated the protein levels of genes downstream of ubiquitin-specific protease 7 (USP7) involved in the tumor necrosis factor-alpha (TNF-α)-induced apoptotic pathway. These findings indicate that MAGED4B promotes glioma growth via a TRIM27/USP7/receptor-interacting serine/threonine-protein kinase 1 (RIP1)-dependent TNF-α-induced apoptotic pathway, which suggests that MAGED4B is a potential target for glioma diagnosis and treatment.
Humans ; Tumor Necrosis Factor-alpha ; DNA-Binding Proteins/metabolism* ; Ubiquitin-Specific Peptidase 7 ; Cisplatin ; Temozolomide ; Transcription Factors ; Glioma ; Cell Proliferation ; Melanoma ; Cell Line, Tumor ; Apoptosis ; Nuclear Proteins/genetics*

Colorectal cancer (CRC), a malignant tumor worldwide consists of microsatellite instability (MSI) and stable (MSS) phenotypes. Although SHP2 is a hopeful target for cancer therapy, its relationship with innate immunosuppression remains elusive. To address that, single-cell RNA sequencing was performed to explore the role of SHP2 in all cell types of tumor microenvironment (TME) from murine MC38 xenografts. Intratumoral cells were found to be functionally heterogeneous and responded significantly to SHP099, a SHP2 allosteric inhibitor. The malignant evolution of tumor cells was remarkably arrested by SHP099. Mechanistically, STING-TBK1-IRF3-mediated type I interferon signaling was highly activated by SHP099 in infiltrated myeloid cells. Notably, CRC patients with MSS phenotype exhibited greater macrophage infiltration and more potent SHP2 phosphorylation in CD68⁺ macrophages than MSI-high phenotypes, suggesting the potential role of macrophagic SHP2 in TME. Collectively, our data reveals a mechanism of innate immunosuppression mediated by SHP2, suggesting that SHP2 is a promising target for colon cancer immunotherapy.

Lycophytes and seed plants constitute the typical vascular plants. Lycophytes have been thought to have no paleo-polyploidization although the event is known to be critical for the fast expansion of seed plants. Here, genomic analyses including the homologous gene dot plot analysis detected multiple paleo-polyploidization events, with one occurring approximately 13-15 million years ago (MYA) and another about 125-142 MYA, during the evolution of the genome of Selaginella moellendorffii, a model lycophyte. In addition, comparative analysis of reconstructed ancestral genomes of lycophytes and angiosperms suggested that lycophytes were affected by more paleo-polyploidization events than seed plants. Results from the present genomic analyses indicate that paleo-polyploidization has contributed to the successful establishment of both lineages-lycophytes and seed plants-of vascular plants.
Evolution, Molecular ; Genome, Plant ; Genomics ; Phylogeny ; Polyploidy ; Selaginellaceae/genetics*

Objective To investigate the clinical application effect of the optimized hierarchical management model based on the advanced system of nursing professional competence.Methods A total of 500 nurses from 5 secondary or tertiary hospitals in Dazu district of Chongqing were selected and randomly divided into intervention group and control group,with 250 nurses in each group.The traditional management model was adopted for the control group,and the optimized hierarchical management model based on the advanced professional competence system was adopted for the intervention group.The two groups were compared in terms of nursing ability,clinical work quality,and incidence rate of adverse events.All the data were analyzed by SPSS 23.0,Chi-square test and t test were used for statistical analysis.Results There were no significant differences in age,sex,marital status,professional title,and working years between the two groups (P＞0.05).The baseline data were consistent and comparable.Compared with the control group,the intervention group had significantly higher scores of nursing ability [(82.30 ± 3.83) vs.(72.78 ± 5.33)] and nursing quality [(97.53 ± 9.71) vs.(90.17 ± 8.18)].The intervention group had a significantly lower incidence rate of adverse events than the control group [(0.9％ vs.3.9％),P＜0.05].Conclusion The optimized hierarchical management model for nursing staff based on the advanced professional competence system can improve the professional competence and clinical nursing quality of nursing staff,reduce the incidence rate of adverse events,and provide a reference for improving the level of nursing management.

Objective: To explore and analyze the intervention effect of two different case teaching methods on critical thinking of nursing interns. Methods: from July 2016 to July 2018, a total of 62 nursing students in a three grade hospital in Chongqing were selected. They were divided into control group (29) and intervention group (33) according to their internship years. The control group received routine case teaching method, while the intervention group adopted the "Internet+" case teaching method to carry out clinical teaching. Results: Nursing students in the intervention group were significantly better than those in the control group in seeking truth, open thinking, systematization ability, analytical ability, self-confidence, thirst for knowledge and maturity (t=3.978-6.875, P<0.05). Nursing students in the critical thinking grade distribution intervention group were higher than those in the control group (t=-6.522--2.202, P<0.05). In clinical decision-making ability, problem-finding ability, goal-setting ability, decision-making ability, implementation decision-making ability and evaluation feedback were also higher than those in the control group (P<0.05). The ability was higher than that of the control group (χ²=7.922, P<0.05). Conclusion case teaching based on "Internet+" can better improve the clinical thinking method of nursing students, enhance the critical thinking level and clinical decision-making ability of nursing students, and improve the quality of clinical teaching. It is worthy of popularization and application in clinical practice.

Objective: To evaluate the clinical feasibility and advantages of ultrasound guided mammotome biopsy for micro-calcifications visible in mammography. Methods: A total of 12 patients with mammography-revealed micro-calcifications examined by ultrasound guided vacuum-assisted biopsy in our hospital from Jun. 2017 to Dec. 2018 were enrolled in this study and their medical records data were analyzed. Results: All 12 patients had accepted pre-biopsy ultrasound localization and all micro-calcifications were successfully excised. Among 12 cases, 4 were revealed as benign breast diseases and 8 were diagnosed as breast cancer. Conclusions Ultrasound guided mammotome biopsy is found to be an alternative method to stereotactic biopsy in patients with US-detectable micro-calcifications, and re-scan ultrasonography focusing on the specific microcalcification area may be helpful for improving the ultrasound detection rate of micro-calcifications.

Objective To explore the effect of reflecting diary training on the ability of critical thinking of nursing students.Methods By cluster sampling,248 nursing students were selected and randomly divided into intervention group and control group with 124 students in each group.The intervention group received reflective journal training apart from the general clinical internship,while control group received general clinical internship.The critical thinking ability between groups were evaluated and compared before training,6 months after training (T2) and 1 year after training (T3) by using the Chinese version of Critical Thinking Disposition Inventory (CTDI-CV).The performed satisfaction of intervention group evaluated in T2 and T3.Results There were no significant difference of the CTDI-CV scores between groups before training (P＞0.05).It was found that the intervention group performed better and had higher scores than the control group in CTDI-CV and dimensions including searching for truth,open-mindedness,analytical ability,systematic ability,critical thinking,self-confidence,curiosity and cognitive maturity at T2 and T3.The intervention group had a high-level of satisfaction of this training program.The satisfaction of each item at T2 was over 90.2％,and at T3 was over 88.6％.Conclusion Reflecting journal training can improve the critical thinking ability of nursing students.The training program was well-received by nurses.

Purpose To investigate the expression of RNF2 in breast disease tissues and cell lines,and to analyze the association between expression of RNF2 and clinicopathological characteristics in breast carcinoma.Methods Expression of RNF2 protein and mRNA levels was detected using immunohistochemistry of EnVision two-step and qRT-PCR in breast carcinoma and benign breast disease as well as in cell lines.Results RNF2 expression was sigmificantly higher in breast carcinoma tissue specimens compared with benign breast disease specimens (P ＜0.05).Besides,the expression of RNF2 protein was significantly associated to tumor size,lymph node status and TNM stage (P ＜ 0.05 for both),but was not related to age,histological grade,the expression of ER,PR and HER-2 (P ＞ 0.05 for both).Higher expression of RNF2 mRNA was detected in breast carcinoma cell lines compared with breast epithelial cell lines (P ＜ 0.05).Conclusion RNF2 is overexpressed in breast carcinoma and can be a potential therapeutic target for breast carcinoma.