Allelic exclusion of the immunoglobulin heavy chain locus is independent of its nuclear localization in mature B cells

In developing B cells, the immunoglobulin heavy chain (IgH) locus is thought to move from repressive to permissive chromatin compartments to facilitate its scheduled rearrangement. In mature B cells, maintenance of allelic exclusion has been proposed to involve recruitment of the non-productive IgH allele to pericentromeric heterochromatin. Here, we used an allele-specific chromosome conformation capture combined with sequencing (4C-seq) approach to unambigously follow the individual IgH alleles in mature B lymphocytes. Despite their physical and functional difference, productive and non-productive IgH alleles in B cells and unrearranged IgH alleles in T cells share many chromosomal contacts and largely reside in active chromatin. In brain, however, the locus resides in a different repressive environment. We conclude that IgH adopts a lymphoid-specific nuclear location that is, however, unrelated to maintenance of allelic exclusion. We additionally find that in mature B cells—but not in T cells—the distal V_H regions of both IgH alleles position themselves away from active chromatin. This, we speculate, may help to restrict enhancer activity to the productively rearranged V_H promoter element.     

Coxsackie adenovirus receptor (CAR) regulates integrin function through activation of p44/42 MAPK

The coxsackie B virus and adenovirus receptor (CAR) is an attachment receptor for Adenovirus serotype 5 (Ad5) and in many cell types forms homodimers with neighbouring cells as part of a cell adhesion complex. CAR co-operates with cell surface integrin receptors to enable efficient viral entry, but little is known about the mechanism of crosstalk between these two receptor types. Here we show that overexpression of CAR in human epithelial cells leads to increased basal activation of p44/42 MAPK and this is required for efficient Ad5 infection. We demonstrate that CAR forms homodimers in cis and that this dimerisation is enhanced in the presence of Ad5 in a phospho-p44/42-dependent manner. CAR-induced p44/42 activation also leads to increased activation of β1 and β3 integrins. Analysis of CAR mutants demonstrates that the cyto domain of CAR is required for CAR-induced p44/42 activation, integrin activation and localisation to cell junctions. This data for the first time demonstrates that signalling downstream of CAR can have a dual effect on integrins and CAR itself in order to promote efficient viral binding to cell membranes.     

The impact of informal care-giving networks on adult children's care-giver burden

Previous research on the care-giver burden experienced by adult children has typically focused on the adult child and parent dyad. This study uses information on multiple informal care-givers and examines how characteristics of the informal care-giving network affect the adult child's care-giver burden. In 2007, 602 Dutch care-givers who were assisting their older parents reported on parental and personal characteristics, care activities, experienced burden and characteristics of other informal care-givers. A path model was applied to assess the relative impact of the informal care-giving network characteristics on the care-giver burden. An adult child experienced lower care-giver burden when the informal care-giving network size was larger, when more types of tasks were shared across the network, when care was shared for a longer period, and when the adult child had no disagreements with the other members of the network. Considering that the need for care of older parents is growing, being in an informal care-giving network will be of increasing benefit for adult children involved in long-term care. More care-givers will turn into managers of care, as they increasingly have to organise the sharing of care among informal helpers and cope with disagreements among the members of the network.