Heterogeneity in thymic emigrants: implications for thymectomy and immunosenescence.

The development of mature, antigen-inexperienced (naive) T cells begins in the thymus and continues after export into the periphery. Post-thymic maturation of naive T cells, in humans, coincides with the progressive loss of markers such as protein tyrosine kinase 7 (PTK7) and platelet endothelial cell adhesion molecule-1 (CD31). As a consequence, subpopulations of naive T cells can be recognised raising questions about the processes that give rise to the loss of these markers and their exact relationship to recent thymic emigrants (RTE). Here, we combine a mathematical survival analysis approach and data from healthy and thymectomised humans to understand the apparent persistence of populations of 'veteran' PTK7 (+) T cells in thymectomised individuals. We show that a model of heterogeneity in rates of maturation, possibly linked to natural variation in TCR signalling thresholds or affinity for self-antigens, can explain the data. This model of maturation predicts that the average post-thymic age of PTK7 (+) T cells will increase linearly with the age of the host suggesting that, despite the immature phenotype, PTK7 (+) cells do not necessarily represent a population of RTE. Further, the model predicts an accelerated increase in the average post-thymic age of residual PTK7 (+) T cells following thymectomy and may also explain in part the prematurely aged phenotype of the naive T cell pool in individuals thymectomised early in life

Age is not just a number: Naive T cells increase their ability to persist in the circulation over time

The processes regulating peripheral naive T-cell numbers and clonal diversity remain poorly understood. Conceptually, homeostatic mechanisms must fall into the broad categories of neutral (simple random birth-death models), competition (regulation of cell numbers through quorum-sensing, perhaps via limiting shared resources), adaptation (involving cell-intrinsic changes in homeostatic fitness, defined as net growth rate over time), or selection (involving the loss or outgrowth of cell populations deriving from intercellular variation in fitness). There may also be stably maintained heterogeneity within the naive T-cell pool. To distinguish between these mechanisms, we confront very general models of these processes with an array of experimental data, both new and published. While reduced competition for homeostatic stimuli may impact cell survival or proliferation in neonates or under moderate to severe lymphopenia, we show that the only mechanism capable of explaining multiple, independent experimental studies of naive CD4+ and CD8+ T-cell homeostasis in mice from young adulthood into old age is one of adaptation, in which cells act independently and accrue a survival or proliferative advantage continuously with their post-thymic age. However, aged naive T cells may also be functionally impaired, and so the accumulation of older cells via 'conditioning through experience' may contribute to reduced immune responsiveness in the elderly

Algorithm for AEEG data selection leading to wireless and long term epilepsy monitoring

Published versio

An analogue bandpass filter realisation of the Continuous Wavelet Transform

The Continuous Wavelet Transform (CWT) is a highly useful signal processing technique for which low power implementations are desirable, for example to allow the transform to be used in battery powered, portable devices. This paper describes a Low Power CWT (LPCWT) implementation that is based around the mathematical approximation of a mother wavelet and uses application specific information to guide the approximation process. Simulations comparing the LPCWT and CWT are carried out with the two giving equivalent signal processing performance. The LPCWT is suitable for realisation in any desired circuit topology.Published versio

Optimizing the scale of markets for water quality trading

Applying market approaches to environmental regulations requires establishing a spatial scale for trading. Spatially large markets usually increase opportunities for abatement cost savings but increase the potential for pollution damages (hot spots), vice versa for spatially small markets. We develop a coupled hydrologic-economic modeling approach for application to point source emissions trading by a large number of sources and apply this approach to the wastewater treatment plants (WWTPs) within the watershed of the second largest estuary in the U.S. We consider two different administrative structures that govern the trade of emission permits: one-for-one trading (the number of permits required for each unit of emission is the same for every WWTP) and trading ratios (the number of permits required for each unit of emissions varies across WWTP). Results show that water quality regulators should allow trading to occur at the river basin scale as an appropriate first-step policy, as is being done in a limited number of cases via compliance associations. Larger spatial scales may be needed under conditions of increased abatement costs. The optimal scale of the market is generally the same regardless of whether one-for-one trading or trading ratios are employed

Spatial heterogeneity and peptide availability determine CTL killing efficiency in vivo

The rate at which a cytotoxic T lymphocyte (CTL) can survey for infected cells is a key ingredient of models of vertebrate immune responses to intracellular pathogens. Estimates have been obtained using in vivo cytotoxicity assays in which peptide-pulsed splenocytes are killed by CTL in the spleens of immunised mice. However the spleen is a heterogeneous environment and splenocytes comprise multiple cell types. Are some cell types intrinsically more susceptible to lysis than others? Quantitatively, what impacts are made by the spatial distribution of targets and effectors, and the level of peptide-MHC on the target cell surface? To address these questions we revisited the splenocyte killing assay, using CTL specific for an epitope of influenza virus. We found that at the cell population level T cell targets were killed more rapidly than B cells. Using modeling, quantitative imaging and in vitro killing assays we conclude that this difference in vivo likely reflects different migratory patterns of targets within the spleen and a heterogeneous distribution of CTL, with no detectable difference in the intrinsic susceptibilities of the two populations to lysis. Modeling of the stages involved in the detection and killing of peptide-pulsed targets in vitro revealed that peptide dose influenced the ability of CTL to form conjugates with targets but had no detectable effect on the probability that conjugation resulted in lysis, and that T cell targets took longer to lyse than B cells. We also infer that incomplete killing in vivo of cells pulsed with low doses of peptide may be due to a combination of heterogeneity in peptide uptake and the dissociation, but not internalisation, of peptide-MHC complexes. Our analyses demonstrate how population-averaged parameters in models of immune responses can be dissected to account for both spatial and cellular heterogeneity

Counting defects with the two-point correlator

We study how topological defects manifest themselves in the equal-time two-point field correlator. We consider a scalar field with Z_2 symmetry in 1, 2 and 3 spatial dimensions, allowing for kinks, domain lines and domain walls, respectively. Using numerical lattice simulations, we find that in any number of dimensions, the correlator in momentum space is to a very good approximation the product of two factors, one describing the spatial distribution of the defects and the other describing the defect shape. When the defects are produced by the Kibble mechanism, the former has a universal form as a function of k/n, which we determine numerically. This signature makes it possible to determine the kink density from the field correlator without having to resort to the Gaussian approximation. This is essential when studying field dynamics with methods relying only on correlators (Schwinger-Dyson, 2PI).Comment: 11 pages, 7 figures

An observational prospective study of topical acidified nitrite for killing methicillin-resistant Staphylococcus aureus (MRSA) in contaminated wounds

Background Endogenous nitric oxide (NO) kills bacteria and other organisms as part of the innate immune response. When nitrite is exposed to low pH, NO is generated and has been used as an NO delivery system to treat skin infections. We demonstrated eradication of MRSA carriage from wounds using a topical formulation of citric acid (4.5%) and sodium nitrite (3%) creams co-applied for 5 days to 15 wounds in an observational prospective pilot study of 8 patients. Findings Following treatment with topical citric acid and sodium nitrite, 9 of 15 wounds (60%) and 3 of 8 patients (37%) were cleared of infection. MRSA isolates from these patients were all sensitive to acidified nitrite in vitro compared to methicillin-sensitive S. aureus and a reference strain of MRSA. Conclusions Nitric oxide and acidified nitrite offer a novel therapy for control of MRSA in wounds. Wounds that were not cleared of infection may have been re-contaminated or the bioavailability of acidified nitrite impaired by local factors in the tissue

Spina bifida-predisposing heterozygous mutations in Planar Cell Polarity genes and Zic2 reduce bone mass in young mice

Fractures are a common comorbidity in children with the neural tube defect (NTD) spina bifida. Mutations in the Wnt/planar cell polarity (PCP) pathway contribute to NTDs in humans and mice, but whether this pathway independently determines bone mass is poorly understood. Here, we first confirmed that core Wnt/PCP components are expressed in osteoblasts and osteoclasts in vitro. In vivo, we performed detailed µCT comparisons of bone structure in tibiae from young male mice heterozygous for NTD-associated mutations versus WT littermates. PCP signalling disruption caused by Vangl2 (Vangl2Lp/+) or Celsr1 (Celsr1Crsh/+) mutations significantly reduced trabecular bone mass and distal tibial cortical thickness. NTD-associated mutations in non-PCP transcription factors were also investigated. Pax3 mutation (Pax3Sp2H/+) had minimal effects on bone mass. Zic2 mutation (Zic2Ku/+) significantly altered the position of the tibia/fibula junction and diminished cortical bone in the proximal tibia. Beyond these genes, we bioinformatically documented the known extent of shared genetic networks between NTDs and bone properties. 46 genes involved in neural tube closure are annotated with bone-related ontologies. These findings document shared genetic networks between spina bifida risk and bone structure, including PCP components and Zic2. Genetic variants which predispose to spina bifida may therefore independently diminish bone mass