This is the second volume of a two-volume co-authored study that explores the history of the concept of barbarism from the eighteenth century to the present and highlights its foundational role in... Show moreThis is the second volume of a two-volume co-authored study that explores the history of the concept of barbarism from the eighteenth century to the present and highlights its foundational role in modern European and Western identity. It constitutes an original comparative and interdisciplinary exploration of the concept’s modern European and Western history and combines overviews with detailed analyses of representative works of literature, art, fi lm, philosophy, and political and cultural theory. Volume 2 broaches figurations of barbarism and mobilizations of the barbarian across diverse contexts, media, and fields from the early twentieth century to our present: from avant-garde manifestoes to contemporary multilingual literature and adaptations of the Medea myth, from anticolonial to eco-socialist texts, from political philosophy and ethno-anthropology to contemporary pop culture, from Russian poetry to Western political rhetoric, from Europe to Latin America, from cinema to art biennials, and from (neo-)Marxists to the Alt-Right. Show less
Background and Aims: In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor-Like Type 1 (ACVRL1) gene encoding... Show moreBackground and Aims: In hereditary hemorrhagic telangiectasia (HHT), severe liver vascular malformations are associated with mutations in the Activin A Receptor-Like Type 1 (ACVRL1) gene encoding ALK1, the receptor for bone morphogenetic protein (BMP) 9/BMP10, which regulates blood vessel development. Here, we established an HHT mouse model with exclusive liver involvement and adequate life expectancy to investigate ALK1 signaling in liver vessel formation and metabolic function. Approach and Results: Liver sinusoidal endothelial cell (LSEC)-selective Cre deleter line, Stab2-iCreF3, was crossed with Acvrl1-floxed mice to generate LSEC-specific Acvrl1-deficient mice (Alk1(HEC-KO)). Alk1(HEC-KO) mice revealed hepatic vascular malformations and increased posthepatic flow, causing right ventricular volume overload. Transcriptomic analyses demonstrated induction of proangiogenic/tip cell gene sets and arterialization of hepatic vessels at the expense of LSEC and central venous identities. Loss of LSEC angiokines Wnt2, Wnt9b, and R-spondin-3 (Rspo3) led to disruption of metabolic liver zonation in Alk1(HEC-KO) mice and in liver specimens of patients with HHT. Furthermore, prion-like protein doppel (Prnd) and placental growth factor (Pgf) were upregulated in Alk1(HEC-KO) hepatic endothelial cells, representing candidates driving the organ-specific pathogenesis of HHT. In LSEC in vitro, stimulation or inhibition of ALK1 signaling counter-regulated Inhibitors of DNA binding (ID)1-3, known Alk1 transcriptional targets. Stimulation of ALK1 signaling and inhibition of ID1-3 function confirmed regulation of Wnt2 and Rspo3 by the BMP9/ALK1/ID axis. Conclusions: Hepatic endothelial ALK1 signaling protects from development of vascular malformations preserving organ-specific endothelial differentiation and angiocrine signaling. The long-term surviving Alk1(HEC-KO) HHT model offers opportunities to develop targeted therapies for this severe disease. Show less
