Construing the child reader: a cognitive stylistic analysis of the opening to Neil Gaiman’s The Graveyard Book

Neil Gaiman’s The Graveyard Book (2009) charts the story of Nobody Owens, a boy who is adopted by supernatural entities in the local graveyard after his family is murdered. This article draws on the notion of the “construed reader,” and combines two cognitive stylistic frameworks to analyse the opening section of the novel. In doing so, the article explores the representation and significance of the family home in relation to what follows in the narrative. The analysis largely draws on Text World Theory (Werth, 1999; Gavins, 2007), but also integrates some aspects of Cognitive Grammar (Langacker, 2008), which allows for a more nuanced discussion of textual features. The article pays particular attention to the way Gaiman frames his narrative and positions his reader to view the fictional events from a distinctive vantage point and subsequently demonstrates that a stylistic analysis of children’s literature can lay bare how such writing is designed with a young readership in mind

X Chromosome Dose and Sex Bias in Autoimmune Diseases:Increased Prevalence of 47,XXX in Systemic Lupus Erythematosus and Sjögren's Syndrome

OBJECTIVE: More than 80% of autoimmune disease is female dominant, but the mechanism for this female bias is poorly understood. We suspected an X chromosome dose effect and hypothesized that trisomy X (47,XXX , 1 in ~1,000 live female births) would be increased in female predominant diseases (e.g. systemic lupus erythematosus [SLE], primary Sjögren’s syndrome [SS], primary biliary cirrhosis [PBC] and rheumatoid arthritis [RA]) compared to diseases without female predominance (sarcoidosis) and controls. METHODS: We identified 47,XXX subjects using aggregate data from single nucleotide polymorphism (SNP) arrays and confirmed, when possible, by fluorescent in situ hybridization (FISH) or quantitative polymerase chain reaction (q-PCR). RESULTS: We found 47,XXX in seven of 2,826 SLE and three of 1,033 SS female patients, but only in two of the 7,074 female controls (p=0.003, OR=8.78, 95% CI: 1.67-86.79 and p=0.02, OR=10.29, 95% CI: 1.18-123.47; respectively). One 47,XXX subject was present for ~404 SLE women and ~344 SS women. 47,XXX was present in excess among SLE and SS subjects. CONCLUSION: The estimated prevalence of SLE and SS in women with 47,XXX was respectively ~2.5 and ~2.9 times higher than in 46,XX women and ~25 and ~41 times higher than in 46,XY men. No statistically significant increase of 47,XXX was observed in other female-biased diseases (PBC or RA), supporting the idea of multiple pathways to sex bias in autoimmunity

Targeting acute myeloid leukemia by dual inhibition of PI3K signaling and Cdk9-mediated Mcl-1 transcription

Resistance to cell death is a hallmark of cancer and renders transformed cells resistant to multiple apoptotic triggers. The Bcl-2 family member, Mcl-1, is a key driver of cell survival in diverse cancers, including acute myeloid leukemia (AML). A screen for compounds that downregulate Mcl-1 identified the kinase inhibitor, PIK-75, which demonstrates marked proapoptotic activity against a panel of cytogenetically diverse primary human AML patient samples. We show that PIK-75 transiently blocks Cdk7/9, leading to transcriptional suppression of MCL-1, rapid loss of Mcl-1 protein, and alleviation of its inhibition of proapoptotic Bak. PIK-75 also targets the p110α isoform of PI3K, which leads to a loss of association between Bcl-xL and Bak. The simultaneous loss of Mcl-1 and Bcl-xL association with Bak leads to rapid apoptosis of AML cells. Concordantly, low Bak expression in AML confers resistance to PIK-75–mediated killing. On the other hand, the induction of apoptosis by PIK-75 did not require the expression of the BH3 proteins Bim, Bid, Bad, Noxa, or Puma. PIK-75 significantly reduced leukemia burden and increased the survival of mice engrafted with human AML without inducing overt toxicity. Future efforts to cotarget PI3K and Cdk9 with drugs such as PIK-75 in AML are warranted