Transcriptome Analysis Identifies Key Metabolic Changes in the Brain of Takifugu rubripes in Response to Chronic Hypoxia.

The brain is considered to be an extremely sensitive tissue to hypoxia, and the brain of fish plays an important role in regulating growth and adapting to environmental changes. As an important aquatic organism in northern China, the economic yield of Takifugu rubripes is deeply influenced by the oxygen content of seawater. In this regard, we performed RNA-seq analysis of T. rubripes brains under hypoxia and normoxia to reveal the expression patterns of genes involved in the hypoxic response and their enrichment of metabolic pathways. Studies have shown that carbohydrate, lipid and amino acid metabolism are significant pathways for the enrichment of differentially expressed genes (DEGs) and that DEGs are significantly upregulated in those pathways. In addition, some biological processes such as the immune system and signal transduction, where enrichment is not significant but important, are also discussed. Interestingly, the DEGs associated with those pathways were significantly downregulated or inhibited. The present study reveals the mechanism of hypoxia tolerance in T. rubripes at the transcriptional level and provides a useful resource for studying the energy metabolism mechanism of hypoxia response in this species.

Characterization of the Therapeutic Effects of Novel Chimeric Antigen Receptor T Cells Targeting CD38 on Multiple Myeloma.

Multiple myeloma (MM) is a tumor type characterized by the unregulated proliferation of clonal plasma cells in the bone marrow. Immunotherapy based on chimeric antigen receptor T cell (CAR-T) therapy has achieved exciting success in the treatment of hematological malignant tumors. CD38 is highly and evenly expressed in MM and is an attractive target for MM treatment. Here, we successfully constructed two novel second-generation CAR-T cells targeting CD38 by retroviral vector transduction. CD38 CAR-T cells could be activated effectively after stimulation with CD38-positive tumor cells and secrete cytokines such as IFN-γ and TNF-α to promote tumor cell apoptosis in in vitro experiments. Real-time fluorescence monitoring experiments, luciferase detection experiments and flow cytometry experiments revealed the efficient and specific killing abilities of CD38 CAR-T cells against CD38-positive tumor cells. The proliferation ability of CD38 CAR-T cells in vitro was higher than that of untransduced T cells. Further antitumor experiments in vivo showed that CD38 CAR-T cells could be quickly activated to secrete IFN-γ and eliminate tumors. Thus, novel CD38-targeted second-generation CAR-T cells have efficient and specific antitumor activity and may become a novel therapy for the clinical treatment of MM.

Comparative transcriptomic analysis of the brain in Takifugu rubripes shows its tolerance to acute hypoxia.

Hypoxia in water that caused by reduced levels of oxygen occurred frequently, due to the complex aquatic environment. Hypoxia tolerance for fish depends on a complete set of coping mechanisms such as oxygen perception and gene-protein interaction regulation. The present study examined the short-term effects of hypoxia on the brain in Takifugu rubripes. We sequenced the transcriptomes of the brain in T. rubripes to study their response mechanism to acute hypoxia. A total of 167 genes were differentially expressed in the brain of T. rubripes after exposed to acute hypoxia. Gene ontology and KEGG enrichment analysis indicated that hypoxia could cause metabolic and neurological changes, showing the clues of their adaptation to acute hypoxia. As the most complex and important organ, the brain of T. rubripes might be able to create a self-protection mechanism to resist or reduce damage caused by acute hypoxia stress.

Co-Expression of miR155 or LSD1 shRNA Increases the Anti-Tumor Functions of CD19 CAR-T Cells.

Chimeric antigen receptor (CAR) T cells targeting CD19 antigen have produced remarkable clinical outcomes for cancer patients. However, identifying measures to enhance effector function remains one of the most challenging issues in CD19-targeted immunotherapy. Here, we report a novel approach in which a microRNA (miRNA) or short-hairpin RNA (shRNA) cassette was integrated into CAR-expressing retroviral vectors. Using this system, we generated anti-CD19 CAR-T cells co-expressing miR155 or LSD1 shRNA and found that anti-CD19 CAR-T cells with miR155 upregulation or LSD1 downregulation exhibited increased anti-tumor functions in vitro and in vivo. Transcriptional profiling analysis by RNA sequencing revealed the targets of miR155 and LSD1 in anti-CD19 CAR-T cells. Our experiments indicated that introduction of miRNA or shRNA expression into anti-CD19 CAR T-cells might be an effective strategy to improve the anti-tumor effects of CAR-T cell therapy.

A novel cocrystal composed of CL-20 and an energetic ionic salt.

A novel nitroamine/energetic ionic salt cocrystal explosive containing CL-20 and 1-AMTN in a 1 : 1 molar ratio is presented. The structure of this cocrystal is determined by single-crystal X-ray diffraction (SC-XRD). The predicted detonation performance is slightly higher than that of RDX, a state-of-the-art explosive. In small-scale impact drop tests, the cocrystal exhibits a surprisingly low sensitivity relative to CL-20. These features make this cocrystal a very promising explosive to replace RDX.