Juvenile Paget’s disease with compound heterozygous mutations in TNFRSF11B presenting with recurrent clavicular fractures and a mild skeletal phenotype

Juvenile Paget’s disease (JPD) is a rare recessively-inherited bone dysplasia. The great majority of cases described to date have had homozygous mutations in TNFRSF11B, the gene encoding osteoprotegerin. We describe a boy who presented with recurrent clavicular fractures following minor trauma (8 fractures from age 2 to 11). He was of normal height and despite mild lateral bowing of the thighs and anterior bowing of the shins he remained physically active. Abnormal modelling was noted in ribs and humeri on clavicular radiographs, and a skeletal survey at the age of 7 showed generalised diaphyseal expansion of the long bones with thickening of the periosteal and endosteal surfaces of the cortices. On biochemical evaluation, serum alkaline phosphatase was noted to be persistently elevated. The diagnosis of JPD was confirmed by the finding of compound heterozygous mutations in TNFRSF11B: a maternally-inherited A > G missense mutation at position 1 of the first amino acid codon (previously reported) and a paternally-inherited splice acceptor site mutation in intron 3 at a highly conserved position (not previously reported). Bioinformatics analysis suggested both mutations were disease-causing. Compound heterozygote mutations in TNFRSF11B causing JPD have been previously reported only once – in a boy who also had a relatively mild skeletal phenotype. The milder features may lead to delay in diagnosis and diagnostic confusion with other entities, but the extraskeletal features of JPD may nonetheless develop

Immunogenicity of a Yersinia pestis Vaccine Antigen Monomerized by Circular Permutation

Caf1, a chaperone-usher protein from Yersinia pestis, is a major protective antigen in the development of subunit vaccines against plague. However, recombinant Caf1 forms polymers of indeterminate size. We report the conversion of Caf1 from a polymer to a monomer by circular permutation of the gene. Biophysical evaluation confirmed that the engineered Caf1 was a folded monomer. We compared the immunogenicity of the engineered monomer with polymeric Caf1 in antigen presentation assays to CD4 T-cell hybridomas in vitro, as well as in the induction of antibody responses and protection against subcutaneous challenge with Y. pestis in vivo. In C57BL/6 mice, for which the major H-2(b)-restricted immunodominant CD4 T-cell epitopes were intact in the engineered monomer, immunogenicity and protective efficacy were preserved, although antibody titers were decreased 10-fold. Disruption of an H-2(d)-restricted immunodominant CD4 T-cell epitope during circular permutation resulted in a compromised T-cell response, a low postvaccination antibody titer, and a lack of protection of BALB/c mice. The use of circular permutation in vaccine design has not been reported previously

Historicizing Entrepreneurial Networks

In recent years, there has been increased interest in the role of context in different entrepreneurial processes. This article builds on this line of research by deploying a microhistorical‐informed approach to contextualize and make sense of the ways in which the correspondence network of the nineteenth‐century British entrepreneur, Isaac Holden, changed over time. In the process, it contributes to our understanding of entrepreneurial networks by illustrating: (a) how networking activities take place through specific communication platforms with their own socio‐technical qualities; (b) how entrepreneurs have the capacity to actively shape and co‐create the context within which their networking activity takes place; and (c) how entrepreneurial networking activity can take place in conjunction with—or as a result of—networking activity in other social movements