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While dysregulation of RNA splicing has been recognized as an emerging target for cancer therapy, the functional significance of RNA splicing and individual splicing factors in brain tumors is poorly understood. Here, we identify SON as a master regulator that activates PTBP1-mediated oncogenic splicing while suppressing RBFOX2-mediated non-oncogenic neuronal splicing in glioblastoma multiforme (GBM). SON is overexpressed in GBM patients and SON knockdown causes failure in intron removal from the PTBP1 transcript, resulting in PTBP1 downregulation and inhibition of its downstream oncogenic splicing. Furthermore, SON forms a complex with hnRNP A2B1 and antagonizes RBFOX2, which leads to skipping of RBFOX2-targeted cassette exons, including the PTBP2 neuronal exon. SON knockdown inhibits proliferation and clonogenicity of GBM cells in vitro and significantly suppresses tumor growth in orthotopic xenografts in vivo. Collectively, our study reveals that SON-mediated RNA splicing is a GBM vulnerability, implicating SON as a potential therapeutic target in brain tumors. Splicing factor PTBP1 is reported to promote oncogenic functions in glioblastoma (GBM). Here the authors show splicing factor SON upregulates PTBP1 expression while supresses its paralog PTBP2 through alternative splicing and the inhibition of SON reduces GBM stemness and growth. [ABSTRACT FROM AUTHOR]

Astrocytes are an early and important target of Zika virus (ZIKV) infection in the developing brain, but the impacts of infection on astrocyte function remain controversial. Given that nonhuman primate (NHP) models of ZIKV infection replicate aspects of neurologic disease seen in human infections, we cultured primary astrocytes from the brain tissue of infant rhesus macaques and then infected the cells with Asian or African lineage ZIKV to identify transcriptional patterns associated with infection in these cells. The African lineage virus appeared to have greater infectivity and promote stronger antiviral signaling, but infection by either strain ultimately produced typical virus response patterns. Both viruses induced hypoxic stress, but the Asian lineage strain additionally had an effect on metabolic and lipid biosynthesis pathways. Together, these findings describe an NHP astrocyte model that may be used to assess transcriptional signatures following ZIKV infection. [ABSTRACT FROM AUTHOR]

A major racial disparity in prostate cancer (PCa) is that African American (AA) patients have a higher mortality rate than European American (EA) patients. We filtered the SEER 2009–2011 records and divided them into four groups regarding patient races and cancer grades. On such a partition, we performed a series of statistical analyses to further clarify the aforementioned disparity. Molecular evidence for a primary result of the epidemiological analysis was obtained from gene expression data. The results include: (1) Based on the registry-specific measures, a significant linear regression of total mortality rate (as well as PCa specific mortality rate) on the percentage of (Gleason pattern-based) high-grade cancers (PHG) is demonstrated in EAs (p < 0.01) but not in AAs; (2) PHG and its racial disparity are differentiated across ages and the groups defined by patient outcomes; (3) For patients with cancers in the same grade category, i.e. the high or low grade, the survival stratification between races is not significant in most geographical areas; and (4) The genes differentially expressed between AAs' and EAs' tumors of the same grade category are relatively rare. The perception that prostate tumors are more lethal in AAs than in EAs is reasonable regarding AAs' higher PHG, while high grade alone could not imply aggressiveness. However, this perception is questionable when the comparison is focused on cases within the same grade category. Supporting observations for this conclusion hold a remarkable implication for erasing racial disparity in PCa. That is, "Equal grade, equal outcomes" is not only a verifiable hypothesis but also an achievable public health goal. [ABSTRACT FROM AUTHOR]

Waterborne pathogenic mycobacteria can form biofilms, and certain species can cause hard-to-treat human lung infections. Astronaut health could therefore be compromised if the spacecraft environment or water becomes contaminated with pathogenic mycobacteria. This work uses Mycobacterium marinum to determine the physiological changes in a pathogenic mycobacteria grown under low-shear modeled microgravity (LSMMG). M. marinum were grown in high aspect ratio vessels (HARVs) using a rotary cell culture system subjected to LSMMG or the control orientation (normal gravity, NG) and the cultures used to determine bacterial growth, bacterium size, transcriptome changes, and resistance to stress. Two exposure times to LSMMG and NG were examined: bacteria were grown for ~40 h (short), or 4 days followed by re-dilution and growth for ~35 h (long). M. marinum exposed to LSMMG transitioned from exponential phase earlier than the NG culture. They were more sensitive to hydrogen peroxide but showed no change in resistance to gamma radiation or pH 3.5. RNA-Seq detected significantly altered transcript levels for 562 and 328 genes under LSMMG after short and long exposure times, respectively. Results suggest that LSMMG induced a reduction in translation, a downregulation of metabolism, an increase in lipid degradation, and increased chaperone and mycobactin expression. Sigma factor H ( sigH ) was the only sigma factor transcript induced by LSMMG after both short and long exposure times. In summary, transcriptome studies suggest that LSMMG may simulate a nutrient-deprived environment similar to that found within macrophage during infection. SigH is also implicated in the M. marinum LSMMG transcriptome response., Competing Interests: The authors declare no conflict of interest.