Modulation of the immunogenicity of the Trypanosoma congolense cysteine protease, congopain, through complexation with α2-macroglobulin

The protozoan parasite Trypanosoma congolense is the main causative agent of livestock trypanosomosis. Congopain, the major lysosomal cysteine proteinase of T. congolense, contributes to disease pathogenesis, and antibody-mediated inhibition of this enzyme may contribute to mechanisms of trypanotolerance. The potential of different adjuvants to facilitate the production of antibodies that would inhibit congopain activity was evaluated in the present study. Rabbits were immunised with the recombinant catalytic domain of congopain (C2), either without adjuvant, with Freund’s adjuvant or complexed with bovine or rabbit α2-macroglobulin (α2M). The antibodies were assessed for inhibition of congopain activity. Rabbits immunised with C2 alone produced barely detectable anti-C2 antibody levels and these antibodies had no effect on recombinant C2 or native congopain activity. Rabbits immunised with C2 and Freund’s adjuvant produced the highest levels of anti-C2 antibodies. These antibodies either inhibited C2 and native congopain activity to a small degree, or enhanced their activity, depending on time of production after initial immunisation. Rabbits receiving C2-α2M complexes produced moderate levels of anti-C2 antibodies and these antibodies consistently showed the best inhibition of C2 and native congopain activity of all the antibodies, with maximum inhibition of 65%. Results of this study suggest that antibodies inhibiting congopain activity could be raised in livestock with a congopain catalytic domain-α2M complex. This approach improves the effectiveness of the antigen as an anti-disease vaccine candidate for African trypanosomosis

The INT6 Cancer Gene and MEK Signaling Pathways Converge during Zebrafish Development

BACKGROUND: Int-6 (integration site 6) was identified as an oncogene in a screen of tumorigenic mouse mammary tumor virus (MMTV) insertions. INT6 expression is altered in human cancers, but the precise role of disrupted INT6 in tumorigenesis remains unclear, and an animal model to study Int-6 physiological function has been lacking. PRINCIPAL FINDINGS: Here, we create an in vivo model of Int6 function in zebrafish, and through genetic and chemical-genetic approaches implicate Int6 as a tissue-specific modulator of MEK-ERK signaling. We find that Int6 is required for normal expression of MEK1 protein in human cells, and for Erk signaling in zebrafish embryos. Loss of either Int6 or Mek signaling causes defects in craniofacial development, and Int6 and Erk-signaling have overlapping domains of tissue expression. SIGNIFICANCE: Our results provide new insight into the physiological role of vertebrate Int6, and have implications for the treatment of human tumors displaying altered INT6 expression

"A mercer ye wot az we be" : The authorship of the Kenilworth Letter reconsidered

The authorship of the Kenilworth Letter, an account of the festivities staged at Kenilworth Castle during Queen Elizabeth I's 1575 progress, has long been a matter of debate, with some scholars suggesting that the work was a pseudonymous hoax foisted upon an unwitting Robert Langham. New findings, together with a re-examination of the existing evidence, suggest the following: first, that the Letter began life as a bona fide missive from Langham to his fellow mercer Humphrey Martin, which, though envisioned for circulation in manuscript, was almost certainly not - in the first instance at least - intended for publication; and second, that William Patten, to whom the Letter sometimes has been attributed in the past, may have been instrumental in the initial efforts to print the work, albeit without Langham's knowledge or permission. Also considered is the wider context of Elizabethan mercery, with particular reference to the close (but often overlooked) political, economic, and cultural ties between the court and the City of London. In addition, this article explores the extent to which the Letter offers a reliable guide to the people, places, and events it describes