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Trypanosoma brucei is the causative agent of African sleeping sickness in humans and one of the causes of nagana in cattle. This protozoan parasite evades the host immune system by antigenic variation, a periodic switching of its variant surface glycoprotein (VSG) coat. VSG switching is spontaneous and occurs at a rate of about [10.sup.-2[-10.sup.-3] per population doubling in recent isolates from nature, but at a markedly reduced rate ([10.sup.-5][-10.sup.-6]) in laboratory-adapted strains (1-3). VSG switching is thought to occur predominantly through gene conversion, a form of homologous recombination initiated by a DNA lesion that is used by other pathogens (for example, Candida albicans, Borrelia sp. and Neisseria gonorrhoeae) to generate surface protein diversity, and by B lymphocytes of the vertebrate immune system to generate antibody diversity. Very little is known about the molecular mechanism of VSG switching in T. brucei. Here we demonstrate that the introduction of a DNA double-stranded break (DSB) adjacent to the ~70-base-pair (bp) repeats upstream of the transcribed VSG gene increases switching in vitro ~250-fold, producing switched clones with a frequency and features similar to those generated early in an infection. We were also able to detect spontaneous DSBs within the 70-bp repeats upstream of the actively transcribed VSG gene, indicating that a DSB is a natural intermediate of VSG gene conversion and that VSG switching is the result of the resolution of this DSB by break-induced replication., The T. brucei genome contains >1,000 VSG genes and pseudogenes, yet the single transcribed VSG gene is invariably found in 1 of ~15 large (40-60 kb) telomeric expression sites (4-6). [...]

One possible approach for calculation of probabilistic rate of risks in Quality management system (QMS), which is prescribed by requirements of International Standard ISO 9001:2015, is proposed in this article. Aspects of the theory of dependability and Markov techniques are used, which are applied for evaluation of probability of failures in complicated technical systems. Representation of QMS processes as a graph with controlled discrete Markov chains is suggested, which allows to evaluate a probability of customer requirements non-fulfillment as a function of an intensity of mistakes that bring to non-conformities in QMS.

The neuritogenic effect of wild-type and mutant saposins C and A from humans and mouse expressed in Escherichia coli were studied through CD spectroscopy and a variety of genetic engineering methods. The saposins C and A are polypeptides that activate the hydrolysis of glycosphingolipids. Results indicate that wild-type saposin A has no neuritogenic effect although the reduced and alkylated forms of saposin A have. The neuritogenic effect of saposin C was reduced by as much as 60% when the conserved saposin A Tyr 30 was introduced in position 31.

Activation-induced cytidine deaminase (AID) is expressed in germinal centers of lymphoid organs during immunoglobulin diversification, in bone marrow B cells after infection with Abelson murine leukemia retrovirus (Ab-MLV), and in human B cells after infection by hepatitis C virus. To understand how viruses signal AID induction in the host we asked whether the AID response was abrogated in cells deficient in the interferon pathway or in signaling via the Toll-like receptors. Here we show that AID is not an interferon responsive gene and abrogation of Toll-like receptor signaling does not diminish the AID response. However, we found that NF-kappaB was required for expression of virally induced AID. Since NF-kappaB binds and activates the AID promoter, these results mechanistically link viral infection with AID transcription. Thus, induction of AID by viruses could be the result of several signaling pathways that culminate in NF-kappaB activation, underscoring the versatility of this host defense program.