Objective
Protein tyrosine phosphatase nonreceptor type 22 (PTPN22) is associated with an increased risk of systemic lupus erythematosus (SLE). PTPN22 encodes Lyp, and a disease‐associated coding variant bears an R620W substitution (LypW). LypW carriage is associated with impaired production of type I interferon (IFN) by myeloid cells following Toll‐like receptor (TLR) engagement. The aim of this study was to investigate the effects of LypW carriage on TLR signaling in patients with SLE.
Methods
Plasma IFNα concentrations and whole‐blood IFN gene scores were compared in SLE patients who were LypW carriers and those who were noncarriers. TLR‐7 agonist R848–stimulated IFNα and tumor necrosis factor levels, IFN‐dependent gene expression, and STAT‐1 activation were determined in peripheral blood mononuclear cells (PBMCs) and/or plasmacytoid dendritic cells (PDCs) obtained from these patients. The effect of LypW expression on the systemic type I IFN response to R848 stimulation in vivo was assessed in transgenic mice.
Results
Plasma IFNα levels and whole‐blood IFN gene signatures were comparable in SLE patients who were LypW carriers and those who were noncarriers. However, PBMCs from LypW carriers produced less IFNα and showed reduced IFN‐dependent gene up‐regulation and STAT‐1 activation after R848 stimulation. The frequency of PDCs producing IFNα2 and the per‐cell IFNα2 levels were significantly reduced in LypW carriers. LypW‐transgenic mice displayed reduced TLR‐7–induced circulating type I IFN responses.
Conclusion
PDCs from SLE patients carrying the disease‐associated PTPN22 variant LypW showed a reduced capacity for TLR‐7 agonist–induced type I IFN production, even though LypW carriers displayed systemic type I IFN activation comparable with that observed in noncarriers. LypW carriage identifies SLE patients who may harbor defects in TLR‐ and PDC‐dependent host defense or antiinflammatory functions.
As the timing of spring productivity blooms in near-shore areas advances due to warming trends in global climate, the selection pressures on out-migrating salmon smolts are shifting. Species and stocks that leave natal streams earlier may be favoured over later-migrating fish. The low post-release survival of hatchery fish during recent years may be in part due to static release times that do not take the timing of plankton blooms into account. This study examined the effects of release time on the migratory behaviour and survival of wild and hatchery-reared coho salmon (Oncorhynchus kisutch) using acoustic and coded-wire telemetry. Plankton monitoring and near-shore seining were also conducted to determine which habitat and food sources were favoured. Acoustic tags (n = 140) and coded-wire tags (n = 266,692) were implanted into coho salmon smolts at the Seymour and Quinsam Rivers, in British Columbia, Canada. Differences between wild and hatchery fish, and early and late releases were examined during the entire lifecycle. Physiological sampling was also carried out on 30 fish from each release group. The smolt-to-adult survival of coho salmon released during periods of high marine productivity was 1.5- to 3-fold greater than those released both before and after, and the fish's degree of smoltification affected their downstream migration time and duration of stay in the estuary. Therefore, hatchery managers should consider having smolts fully developed and ready for release during the peak of the near-shore plankton blooms. Monitoring chlorophyll a levels and water temperature early in the spring could provide a forecast of the timing of these blooms, giving hatcheries time to adjust their release schedule.
This paper considers the tax position of a landowner who plans to sell his land to a developer. It assumes that he wants to participate in the development gain, ideally by leaving part of the consideration unascertained until a future date. This can be achieved through a number of different structures, and commercial factors will normally dictate which one. However, the tax implications of sharing in the development gain can be substantial and should be borne in mind. The first part of this paper looks at the tax consequences of a sale by one landowner. The second part considers the further issue, which arises when several landowners pool their land before sale in order to share the profits in proportion to their original interests.
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