Zebrafish atlastin controls motility and spinal motor axon architecture via inhibition of the BMP pathway. Fassier Coralie,Hutt James A,Scholpp Steffen,Lumsden Andrew,Giros Bruno,Nothias Fatiha,Schneider-Maunoury Sylvie,Houart Corinne,Hazan Jamilé Nature neuroscience To better understand hereditary spastic paraplegia (HSP), we characterized the function of atlastin, a protein that is frequently involved in juvenile forms of HSP, by analyzing loss- and gain-of-function phenotypes in the developing zebrafish. We found that knockdown of the gene for atlastin (atl1) caused a severe decrease in larval mobility that was preceded by abnormal architecture of spinal motor axons and was associated with a substantial upregulation of the bone morphogenetic protein (BMP) signaling pathway. Overexpression analyses confirmed that atlastin inhibits BMP signaling. In primary cultures of zebrafish spinal neurons, Atlastin partially colocalized with type I BMP receptors in late endosomes distributed along neurites, which suggests that atlastin may regulate BMP receptor trafficking. Finally, genetic or pharmacological inhibition of BMP signaling was sufficient to rescue the loss of mobility and spinal motor axon defects of atl1 morphants, emphasizing the importance of fine-tuning the balance of BMP signaling for vertebrate motor axon architecture and stability. 10.1038/nn.2662

Effects of single or conjoint administration of lactic acid bacteria as potential probiotics on growth, immune response and disease resistance of snakehead fish (Channa argus). Kong Yidi,Gao Chunshan,Du Xiaoyan,Zhao Jing,Li Min,Shan Xiaofeng,Wang Guiqin Fish & shellfish immunology Lactic acid bacteria (LAB) has been documented to promoting growth, enhancing immunity and disease resistance. In this study, we aimed to evaluate the single or conjoint effects of Lactococcus lactis L19 (Genbank: MT102745.1) and Enterococcus faecalis W24 (Genbank: MT102746.1) isolated from the intestine of Channa argus (C. argus) on growth performance, immune response and disease resistance of C. argus. A total of 720 apparently healthy C. argus (9.50 ± 0.03 g) were randomly divided into four equal groups. Fish were fed with a basal diet (CK) supplemented with L. lactis (L19), E. faecalis (W24), and L. lactis L19 + E. faecalis W24 (L + W) at 1.0 × 10 cfu/g basal diet for 56 days. After feeding, the final body weight (FBW), weight gain (WG), feed efficiency ratio (FER), specific growth rate (SGR) and protein efficiency ratio (PER) had significantly increased (p < 0.05), especially with L19. The results indicated that single or conjoint administration of LAB as potential probiotics can induce high levels of IgM, ACP, AKP, LZM, C3 and C4 activity in serum, which may effectively induce humoral immunity, and L19 induce even higher levels. Meanwhile, when compared to CK group, the results of qPCR showed that LAB administration significantly up-regulated (p < 0.05) the expression of IL-1β, IL-6, IL-10, TNF-α, IFN-γ, HSP70, HSP90, TGF-β in the spleen, head kidney, gill, liver and intestine of C. argus. After challenge with Aeromonas veronii, the survival rates in all LAB-fed groups were significantly higher (p < 0.05) than that of the CK group, and the L19 group showed the highest (63.3%) disease resistance. Our data indicated that L. lactis L19 and E. faecalis W24, as a feed additive at 1.0 × 10 cfu/g feed, could promote growth performance, enhance immune response and disease resistance of C. argus, with greatest effects in fish fed L. lactis L19 for 56 days. Hence, these LAB additives could be used as promising probiotics for C. argus. L19 was more effective than W24 or the mixture of the two for promoting growth performance, enhancing immune response and disease resistance of C. argus. 10.1016/j.fsi.2020.05.003

HSP90 inhibition overcomes EGFR amplification-induced resistance to third-generation EGFR-TKIs. Watanabe Sho,Goto Yasushi,Yasuda Hiroyuki,Kohno Takashi,Motoi Noriko,Ohe Yuichiro,Nishikawa Hiroyoshi,Kobayashi Susumu S,Kuwano Kazuyoshi,Togashi Yosuke Thoracic cancer BACKGROUND:Patients with non-small cell lung cancer (NSCLC) harboring activating EGFR mutations are sensitive to epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) but inevitably develop resistance to the inhibitors mostly through acquisition of the secondary T790M mutation. Although third-generation EGFR-TKIs overcome this resistance by selectively inhibiting EGFR with EGFR-TKI-sensitizing and T790M mutations, acquired resistance to third-generation EGFR-TKIs invariably develops. METHODS:Next-generation sequencing (NGS) and fluorescence in situ hybridization (FISH) analysis were performed in an EGFR T790M-mutated NSCLC patient who had progressed after a third-generation EGFR-TKI, TAS-121. EGFR-mutated cell lines were subjected to a cell proliferation assay and western blotting analysis with EGFR-TKIs and a heat shock protein 90 (HSP90) inhibitor. RESULTS:NGS and FISH analysis revealed EGFR amplification in the resistant cancer cells. While EGFR L858R/T90M-mutated cell line was sensitive to osimertinib or TAS-121 in vitro, EGFR-overexpressing cell lines displayed resistance to these EGFR-TKIs. Western blot analysis showed that EGFR phosphorylation and overexpression of EGFR in cell lines was not suppressed by third-generation EGFR-TKIs. In contrast, an HSP90 inhibitor reduced total and phosphorylated EGFR and inhibited the proliferation of resistant cell lines. CONCLUSIONS:EGFR amplification confers resistance to third-generation EGFR-TKIs which can be overcome by HSP90 inhibition. The results provide a preclinical rationale for the use of HSP90 inhibitors to overcome EGFR amplification-mediated resistance. 10.1111/1759-7714.13839

Transcriptome profiling of immune response to Yersinia ruckeri in spleen of rainbow trout (Oncorhynchus mykiss). Wang Di,Sun Simeng,Li Shaowu,Lu Tongyan,Shi Dongfang BMC genomics BACKGROUND:Yersinia ruckeri is a pathogen that can cause enteric redmouth disease in salmonid species, damaging global production of economically important fish including rainbow trout (Oncorhynchus mykiss). Herein, we conducted the transcriptomic profiling of spleen samples from rainbow trout at 24 h post-Y. ruckeri infection via RNA-seq in an effort to more fully understand their immunological responses. RESULTS:We identified 2498 differentially expressed genes (DEGs), of which 2083 and 415 were up- and down-regulated, respectively. We then conducted a more in-depth assessment of 78 DEGs associated with the immune system including CCR9, CXCL11, IL-1β, CARD9, IFN, TNF, CASP8, NF-κB, NOD1, TLR8α2, HSP90, and MAPK11, revealing these genes to be associated with 20 different immunological KEGG pathways including the Cytokine-cytokine receptor interaction, Toll-like receptor signaling, RIG-I-like receptor signaling, NOD-like receptor signaling, and MAPK signaling pathways. Additionally, the differential expression of 8 of these DEGs was validated by a qRT-PCR approach and their immunological importance was then discussed. CONCLUSIONS:Our findings provide preliminary insight on molecular mechanism underlying the immune responses of rainbow trout following Y. ruckeri infection and the base for future studies of host-pathogen interactions in rainbow trout. 10.1186/s12864-021-07611-4