Haematopoietic development and immunological function in the absence of cathepsin D

Background: Cathepsin D is a well-characterized aspartic protease expressed ubiquitously in lysosomes. Cathepsin D deficiency is associated with a spectrum of pathologies leading ultimately to death. Cathepsin D is expressed at high levels in many cells of the immune system, but its role in immune function is not well understood. This study examines the reconstitution and function of the immune system in the absence of cathepsin D, using bone marrow radiation chimaeras in which all haematopoietic cells are derived from cathepsin D deficient mice.Results: Cathepsin D deficient bone marrow cells fully reconstitute the major cellular components of both the adaptive and innate immune systems. Spleen cells from cathepsin D deficient chimaeric mice contained an increased number of autofluorescent granules characteristic of lipofuscin positive lysosomal storage diseases. Biochemical and ultrastructural changes in cathepsin D deficient spleen are consistent with increased autolysosomal activity. Chimaeric mice were immunised with either soluble (dinitrophenylated bovine gamma globulin) or particulate (sheep red blood cells) antigens. Both antigens induced equivalent immune responses in wild type or cathepsin D deficient chimaeras.Conclusion: All the parameters of haematopoietic reconstitution and adaptive immunity which were measured in this study were found to be normal in the absence of cathepsin D, even though cathepsin D deficiency leads to dysregulation of lysosomal function

Rapid global ocean-atmosphere response to Southern Ocean freshening during the last glacial

This is the final version of the article. Available from Springer Nature via the DOI in this record.Contrasting Greenland and Antarctic temperatures during the last glacial period (115,000 to 11,650 years ago) are thought to have been driven by imbalances in the rates of formation of North Atlantic and Antarctic Deep Water (the 'bipolar seesaw'). Here we exploit a bidecadally resolved (14)C data set obtained from New Zealand kauri (Agathis australis) to undertake high-precision alignment of key climate data sets spanning iceberg-rafted debris event Heinrich 3 and Greenland Interstadial (GI) 5.1 in the North Atlantic (~30,400 to 28,400 years ago). We observe no divergence between the kauri and Atlantic marine sediment (14)C data sets, implying limited changes in deep water formation. However, a Southern Ocean (Atlantic-sector) iceberg rafted debris event appears to have occurred synchronously with GI-5.1 warming and decreased precipitation over the western equatorial Pacific and Atlantic. An ensemble of transient meltwater simulations shows that Antarctic-sourced salinity anomalies can generate climate changes that are propagated globally via an atmospheric Rossby wave train.A challenge for testing mechanisms of past climate change is the precise correlation of palaeoclimate records. Here, through climate modelling and the alignment of terrestrial, ice and marine (14)C and (10)Be records, the authors show that Southern Ocean freshwater hosing can trigger global change.This work was funded by the Australian Research Council (FL100100195, DP170104665 and SR140300001) and the Natural Environment Research Council (NE/H009922/1 and NE/H007865/1)

Comparison of handheld rebound tonometry with Goldmann applanation tonometry in children with glaucoma:a cohort study

OBJECTIVE: To test agreement of two methods to measure intraocular pressure (IOP): rebound tonometry (RBT) and gold standard Goldmann applanation tonometry (GAT) in children with glaucoma. DESIGN: Observational prospective cohort study. SETTING: Tertiary paediatric glaucoma clinic at a single centre. PARTICIPANTS: 102 individuals attending a paediatric glaucoma clinic, mean (SD) age 11.85 (3.17), of whom 53 were male. PRIMARY AND SECONDARY OUTCOME MEASURES: Intraocular pressure, central corneal thickness, child preference for measurement method. RESULTS: Limits of agreement for intraobserver and interobserver were, respectively, (−2.71, 2.98) mm Hg and (−5.75, 5.97) mm Hg. RBT frequently gave higher readings than GAT and the magnitude of disagreement depend on the level of IOP being assessed. Differences of 10 mm Hg were not uncommon. RBT was the preferred method for 70% of children. CONCLUSIONS: There is poor agreement between RBT and GAT in children with glaucoma. RBT frequently and significantly overestimates IOP. However, ‘normal’ RBT readings are likely to be accurate and may spare children an examination under anaesthesia (EUA). High RBT readings should prompt the practitioner to use another standard method of IOP measurement if possible, or consider the RBT measurement in the context of clinical findings before referring the child to a specialist clinic or considering EUA