Synthesis, Kinetic Evaluation and Utilization of a Biotinylated Dipeptide Proline Diphenyl Phosphonate for the Disclosure of Dipeptidyl Peptidase IV-like Serine Proteases

In this study, we report on the synthesis, kinetic characterisation, and application of a novel biotinylated and active site-directed inactivator of dipeptidyl peptidase IV (DPP-IV). Thus, the dipeptide-derived proline diphenyl phosphonate NH(2)-Glu(biotinyl-PEG)-Pro(P)(OPh)(2) has been prepared by a combination of classical solution- and solid-phase methodologies and has been shown to be an irreversible inhibitor of porcine DPP-IV, exhibiting an over all second-order rate constant (k(i)/K(i)) for inhibition of 1.57 x 10(3) M(-1) min(-1). This value compares favourably with previously reported rates of inactivation of DPP-IV by dipeptides containing a P(1) proline diphenyl phosphonate grouping [B. Boduszek, J. Oleksyszyn, C.M. Kam, J. Selzler, R.E. Smith, J.C. Powers, Dipeptide phophonates as inhibitors of dipeptidyl peptidase IV, J. Med. Chem. 37 (1994) 3969-3976; B.F. Gilmore, J.F. Lynas, C.J. Scott, C. McGoohan, L. Martin, B. Walker, Dipeptide proline diphenyl phosphonates are potent, irreversible inhibitors of seprase (FAPalpha), Biochem, Biophys. Res. Commun. 346 (2006) 436-446.], thus demonstrating that the incorporation of the side-chain modified (N-biotinyl-3-(2-(2-(3-aminopropyloxy)-ethoxy)-ethoxy)-propyl) glutamic acid residue at the P(2) position is compatible with inhibitor efficacy. The utilisation of this probe for the detection of both purified dipeptidyl peptidase IV and the disclosure of a dipeptidyl peptidase IV-like activity from a clinical isolate of Porphyromonas gingivalis, using established electrophoretic and Western blotting techniques previously developed by our group, is also demonstrated.

The Growth, Learning and Development Study: Summary of Research, Findings and Recommendations.

The Growth, Learning and Development (GLAD) study aimed to examine how a broad range of factors influence child weight during the first year of life. Assessments were undertaken within a multidisciplinary team framework. The sample was drawn from the community and data collection was undertaken in the four Greater Belfast Trusts. Twohundred and thirty-four families took part, each receiving a total of five home visits during which physical growth, oral-motor skills and development were assessed. Psychosocial evaluation examined parent-child interaction, feeding and other parental and child characteristics using quantitative and observational techniques. This paper outlines the main findings and recommendations from the GLAD study.

Maternal mental health and non-organic failure to thrive.

This study reports on the first phase of a large-scale, longitudinal, multidisciplinary community study examining the growth, learning and development of young children with a particular focus on failure to thrive without organic cause. However, the group identified in this study may be better described as weight faltering. This paper examines the psychological data collected using the Parenting Stress Index, Rosenberg Self-Esteem and the General Health Questionnaire in relation to child growth. There were no significant differences between the mothers of the weight faltering and control children in terms of parenting stress, maternal depression, maternal perceptions of their parenting competence or maternal self-esteem. Maternal sensitivity to comments about child size, regardless of direction, had a negative impact on mood.

2-D R-matrix propagation: A large scale electron scattering simulation dominated by the multiplication of dynamically changing matrices

We examine the computational aspects of propagating a global R-matrix, R, across sub-regions in a 2-D plane. This problem originates in the large scale simulation of electron collisions with atoms and ions at intermediate energies. The propagation is dominated by matrix multiplications which are complicated because of the dynamic nature of R, which changes the designations of its rows and columns and grows in size as the propagation proceeds. The use of PBLAS to solve this problem on distributed memory HPC machines is the main focus of the paper.