The evolution of the natural killer complex; a comparison between mammals using new high-quality genome assemblies and targeted annotation.

Natural killer (NK) cells are a diverse population of lymphocytes with a range of biological roles including essential immune functions. NK cell diversity is in part created by the differential expression of cell surface receptors which modulate activation and function, including multiple subfamilies of C-type lectin receptors encoded within the NK complex (NKC). Little is known about the gene content of the NKC beyond rodent and primate lineages, other than it appears to be extremely variable between mammalian groups. We compared the NKC structure between mammalian species using new high-quality draft genome assemblies for cattle and goat; re-annotated sheep, pig, and horse genome assemblies; and the published human, rat, and mouse lemur NKC. The major NKC genes are largely in the equivalent positions in all eight species, with significant independent expansions and deletions between species, allowing us to propose a model for NKC evolution during mammalian radiation. The ruminant species, cattle and goats, have independently evolved a second KLRC locus flanked by KLRA and KLRJ, and a novel KLRH-like gene has acquired an activating tail. This novel gene has duplicated several times within cattle, while other activating receptor genes have been selectively disrupted. Targeted genome enrichment in cattle identified varying levels of allelic polymorphism between the NKC genes concentrated in the predicted extracellular ligand-binding domains. This novel recombination and allelic polymorphism is consistent with NKC evolution under balancing selection, suggesting that this diversity influences individual immune responses and may impact on differential outcomes of pathogen infection and vaccination

Grid approximation of a singularly perturbed boundary value problem modelling heat transfer in the case of flow over a flat plate with suction of the boundary layer

AbstractIn the present paper we consider a boundary value problem on the semiaxis (0,∞) for a singularly perturbed parabolic equation with the two perturbation parameters ε1 and ε2 multiplying, respectively, the second and first derivatives with respect to the space variable. Depending on the relation between the parameters, the differential equation can be either of reaction–diffusion type or of convection–diffusion type. Correspondingly, the boundary layer can be either parabolic or regular. For this problem we consider the case when the boundary layer can be controlled by continuous suction of the fluid out of the boundary layer (model problems of this type appear in the mathematical modelling of heat transfer processes for flow past a flat plate). Errors in the approximations generated by standard numerical methods can be unsatisfactorily large for small values of the parameter ε1. We construct a monotone finite difference scheme on piecewise uniform meshes which generates numerical solutions converging ε-uniformly with order O(N−1lnN+N0−1), where N0 is the number of nodes in the time mesh and N is the number of meshpoints on a unit interval of the semiaxis in x. Although the solution of problem has a singularity only for ε1→0, the character of the boundary layer depends essentially on the vector-valued parameter ε=(ε1,ε2). This prevents us from constructing an ε-uniformly convergent scheme having a transition parameter which is independent of the parameter ε2

Implementing a participatory model of micro health insurance among rural poor with evidence from Nepal

This paper reports on two voluntary, contributory, contextualised, community-based health insurance (CBHI) schemes, launched in Dhading and Banke (Nepal) in 2011. The implementation followed a four-stage process: initiating (baseline survey), involving (awareness generation and engaging community in benefit-package-design), launch (enrolment and training of selected community members) and post-launch (viable claims ratio, settled within satisfactory time, sustainable affiliation). Both schemes were successful on four key parameters: effective planning; affiliation (grew from 0 to ∼10,000) and renewals (>65 per cent); claims ratio (∼50 per cent); and promptness of claim settlement (∼23 days). This model succeeded in implementing CBHI with zero premium subsidies or subsidised health-care costs. The successful operation relied in large part on the fact that members trust that they can enforce this contract. Considerable insurance education and capacity development is necessary before the launch of the CBHI, and for sustainable operations as well as for scaling

Pharmacokinetic Disposition and Clinical Outcomes in Infants and Children Receiving Intravenous Busulfan for Allogeneic Hematopoietic Stem Cell Transplantation

AbstractWe conducted a retrospective pharmacokinetic analysis of i.v. busulfan in children undergoing hematopoietic stem cell transplantation (HSCT) and describe its relation to transplantation outcomes. Forty-five children (median age, 3 yr) underwent HSCT at The Hospital for Sick Children from April 2003 through January 2006 and received i.v. busulfan every 6 h as part of their conditioning regimen. Initial busulfan doses were based on actual patient weight: <9 kg, 0.95 mg/kg per dose; 9-16 kg, 1.2 mg/kg per dose; 16-23 kg, 1.1 mg/kg per dose; 24-34 kg, 0.95 mg/kg per dose; >34 kg, 0.8 mg/kg per dose. Plasma busulfan concentrations were obtained after the first dose. The fourth and subsequent busulfan doses were adjusted to achieve an area under the concentration versus time curve (AUC) of 900-1500 μM·min. Development of hepatic venous occlusive disease (HVOD; modified Baltimore criteria) and engraftment (absolute neutrophil count ≥0.5 × 109/L) were evaluated. Busulfan pharmacokinetic parameters were calculated using 1-compartment methods. Mean busulfan pharmacokinetic parameters were maximum concentration (Cmax; 4.7 ± 0.75 μM), volume of distribution at steady state (0.68 ± 0.17 L/kg), elimination rate constant (0.0051 ± 0.0010 min−1), total body clearance (3.5 ± 1.23 mL/[min·kg]), and AUC (1271 ± 280 μM·min). Mean volume of distribution at steady state was larger in children <1 yr of age (0.77 ± 0.24 vs 0.64 ± 0.11 L/kg; P = .040) and children <4 yr of age (0.73 ± 0.18 vs 0.60 ± 0.11 L/kg; P = .001) than in older children. Compared with older children, mean weight-adjusted total body clearance was higher in children <4 yr of age (3.8 ± 1.40 versus 3.0 ± 0.76 mL/[min·kg]). HVOD was diagnosed in 8 children (18%), including 4 children <1 yr of age. Children who developed HVOD achieved a lower Cmax than did those without HVOD (4.2 ± 0.68 versus 4.8 ± 0.73 μM; P = .035). Other than Cmax, no association was observed between busulfan disposition and development of HVOD in children for whom i.v. busulfan doses were adjusted to achieve a target AUC. The influence of factors other than busulfan disposition on transplantation outcomes, such as genetic polymorphisms, should be evaluated