Substitution of pseudokinase domain residue Val-617 by large non-polar amino acids causes activation of JAK2

Explaining the uniqueness of the acquired somatic JAK2 V617F mutation, which is present in more than 95% of polycythemia vera patients, has been a challenge. The V617F mutation in the pseudokinase domain of JAK2 renders the unmutated kinase domain constitutively active. We have performed random mutagenesis at position 617 of JAK2 and tested each of the 20 possible amino acids for ability to induce constitutive signaling in Ba/F3 cells expressing the erythropoietin receptor. Four JAK2 mutants, V617W, V617M, V617I, and V617L, were able to induce cytokine independence and constitutive downstream signaling. Only V617W induced a level of constitutive activation comparable with V617F. Also, only V617W stabilized tyrosine-phosphorylated suppressor of cytokine signaling 3 ( SOCS3), a mechanism by which JAK2 V617F overcomes inhibition by SOCS3. The V617W mutant induced a myeloproliferative disease in mice, mainly characterized by erythrocytosis and megakaryocytic proliferation. Although JAK2 V617W would predictably be pathogenic in humans, the substitution of the Val codon, GTC, by TTG, the codon for Trp, would require three base pair changes, and thus it is unlikely to occur. We discuss how the predicted conformations of the activated JAK2 mutants can lead to better screening assays for novel small molecule inhibitors.

Marie Sallé, a Wise Professional Woman of Influence

This study maps the extent of Sallé's influence while identifying her self agency in moulding her image and developing her career.

Marie Sallé and the development of the ballet en action

Sallé's ballets en action are evaluated in terms of Enlightenment dramaturgical principles, and her role in shaping this aesthetic is mooted.

Marie Sallé, Handel, Rameau and the development of narrative dance music:Bericht vom Internationalen Symposium an der Hochschule fur Musik und Theater Leipzig

Paradigmatic analysis reveals that these two composers developed distinct responses to creating narrative in dance music

Marie Sallé as muse, Handel's music for mime

Considers Handel's musical response to a dancer-choreographer in line with then-current styles of dance

'Dancing at the English Opera':'Marie Salle's letter to the Duchess of Richmond

A letter from dancer Marie Salle to her patroness dated 1731 reveals her ambitions to dance at the English opera.

'Marie Salle'

This dictionary entry, which highlights the choreographer's significance to the historical study of music, is placed in a very high profile and reputable online resource.

Depicting Characters and danced Narratives: Handel, 'The Italian troupe', and Marie Sallé

Handel’s London career afforded opportunities for responding to dancers working in distinct styles of movement—most notably the Italian troupe resident at the King’s Theatre in 1726-27, and Marie Sallé at Covent Garden in 1734-35. By studying the dances from Admeto (1727) and Ariodante (1735), this paper will explore Handel's response to the serious and grotesque styles, as well as to the character and narrative modes.