Calmodulin triggers activity-dependent rRNA biogenesis via interaction with DDX21.

Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and memory formation. However, the signaling cascades that couple neuronal activity to the translational events remains elusive. In this study, we identified the role of calmodulin (CaM), a conserved Ca2+-binding protein, in rRNA biogenesis in neurons. We found the CaM-regulated rRNA synthesis is Ca2+-dependent and necessary for nascent protein synthesis and axon growth in hippocampal neurons. Mechanistically, CaM interacts with nucleolar DDX21 in a Ca2+-dependent manner to regulate nascent rRNA transcription within nucleoli. We further found CaM alters the conformation of DDX21 to liberate the DDX21-sequestered RPA194, the catalytic subunit of RNA polymerase I, to facilitate transcription of rDNA. Using high-throughput screening, we identified the small molecules Batefenterol and Indacaterol that attenuate the CaM-DDX21 interaction and suppress nascent rRNA synthesis and axon growth in hippocampal neurons. These results unveiled the previously unrecognized role of CaM as a messenger to link the activity-induced Ca2+ influx to the nucleolar events essential for protein synthesis. We thus identified the ability of CaM to transmit information to the nucleoli of neurons in response to stimulation.Significance statement Protein synthesis in response to neuronal activity, known as activity-dependent translation, is critical for synaptic plasticity and long-term memory formation. In this study, we identify the novel role of calmodulin (CaM), a highly conserved Ca2+-binding protein, which is well-known by regulating myriad vital biological processes, in activity-dependent translation by regulating rRNA synthesis in neurons. We find that CaM can shuttle into the nucleolus upon depolarization and modulate the activity-induced de novo rRNA biogenesis, which is associated with ribosome assembly and protein synthesis in neurons. Mechanistically, CaM interacts with DDX21, an RNA helicase directly associated with Pol I subunit, to regulate the transcription of rDNA. Our study demonstrates CaM as a messenger linking neuronal activity to ribosome-dependent protein biosynthesis.

Dietary γ-mangostin triggers immunogenic cell death and activates cGAS signaling in acute myeloid leukemia.

Immunogenic cell death (ICD), one of cell-death types through release of damage-associated molecular patterns from dying tumor cells, activates tumor-specific immune response and elicits anti-tumor immunity by traditional radiotherapy and chemotherapy. However, whether natural products could induce ICD in leukemia is not elucidated. Here, we report dietary γ-mangostin eradicates murine primary leukemic cells and prolongs the survival of leukemic mice. As well, it restrains primary leukemic cells and CD34+ leukemic progenitor cells from leukemia patients. Strikingly, γ-mangostin attenuates leukemic cells by inducing ICD as characterized by expression of HSP90B1, ANXA1 and IL1B. Additionally, γ-mangostin accelerates cytoplasmic chromatin fragments generation, promoting DNA damage response, and enhances cGAS activation, leading to up-regulation of chemokines. Meanwhile, it induces HDAC4 degradation and acetylated histone H3 accumulation, which promotes chemokines transcription. Ultimately, CD8+ T cell is activated and recruited by γ-mangostin-induced chemokines in the microenvironment. Our study identifies γ-mangostin triggers ICD and activates cGAS signaling through DNA damage response and epigenetic modification. Therefore, dietary γ-mangostin would act as a potential agent to provoke anti-tumor immunity in the prevention and treatment of leukemia.

Flubendazole, FDA-approved anthelmintic, targets breast cancer stem-like cells.

Cancer stem-like cell (CS-like cell) is considered to be responsible for recurrence and drug resistance events in breast cancer, which makes it a potential target for novel cancer therapeutic strategy. The FDA approved flubendazole, has been widely used in the treatment of intestinal parasites. Here, we demonstrated a novel effect of flubendazole on breast CS-like cells. Flubendazole inhibited breast cancer cells proliferation in dose- and time-dependent manner and delayed tumor growth in xenograft models by intraperitoneal injection. Importantly, flubendazole reduced CD44high/CD24low subpopulation and suppressed the formation of mammosphere and the expression of self-renewal related genes including c-myc, oct4, sox2, nanog and cyclinD1. Moreover, we found that flubendazole induced cell differentiation and inhibited cell migration. Consistently, flubendazole reduced mesenchymal markers (ß-catenin, N-cadherin and Vimentin) expression and induced epithelial and differentiation marker (Keratin 18) expression in breast cancer cells. Mechanism study revealed that flubendazole arrested cell cycle at G2/M phase and induced monopolar spindle formation through inhibiting tubulin polymerization. Furthermore, flubendazole enhanced cytotoxic activity of conventional therapeutic drugs fluorouracil and doxorubicin against breast cancer cells. In conclusion, our findings uncovered a remarkable effect of flubendazole on suppressing breast CS-like cells, indicating a novel utilization of flubendazole in breast cancer therapy.

[Experimental study on characteristics of biodiesel exhausted particle].

A particle emission experiment of a direct-injection turbocharged diesel engine with biodiesel and diesel was carried out. A pump of 80 L/min and fiber glass filters with diameter of 90 mm was used to sample engine particles in exhaust pipe. The size distribution, soluble organic fraction (SOF) and 16 polycyclic aromatic hydrocarbons (PAHs) of particles were analyzed by a laser diffraction particle size analyzer and GC-MS. The results indicate that the volume weighted size distribution of biodiesel particle is single-peak and its median diameter d(0.5) and mean diameter d32 are decreased with the increasing speed. At the high speed the d32 and d(0.5) of biodiesel are larger than those of diesel, and quite the contrary at the low speed. SOF mass concentration and mass percentage of biodiesel are 12.3 - 31.5 mg/m3 and 38.2% - 58.0% respectively, which are much higher than those of diesel. The total PAHs emission concentration of biodiesel is 2.9 - 4.7 microg/m3 lower than that of diesel as much as 29.1% - 92.4%.

[Experimental study on particle size distributions of an engine fueled with blends of biodiesel].

The purpose of this study is to obtain the particle size distributions of an engine fueled biodiesel and its blends. A turbocharged DI diesel engine was tested on a dynamometer. A pump of 80 L/min and fiber glass filters with diameter of 90 mm were used to sample engine particles in exhaust pipe. Sampling duration was 10 minutes. Particle size distributions were measured by a laser diffraction particle size analyzer. Results indicated that higher engine speed resulted in smaller particle sizes and narrower distributions. The modes on distribution curves and mode variation were larger with dry samples than with wet samples (dry: around 10 - 12 microm vs. wet: around 4 - 10 microm). At low speed, Sauter mean diameter d32 of dry samples was the biggest with B100, the smallest with diesel fuel, and among them with B20, while at high speed, d32 the biggest with B20, the smallest with B100, and in middle with diesel. Median diameter d(0.5) also reflected the results. Except for 2 000 r/min, d32 of wet with B20 is the biggest, the smallest with diesel, and in middle with B100. The large mode variation resulted in increase of d32.