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.

Differences in Abdominal and Liver Fat Accumulation Between Obesity-Matched Adults With and Without Type 2 Diabetes

Despite attempts to identify the mechanisms by which obesity leads to the development of Type 2 Diabetes (T2D), it remains unclear why some but not all adults with obesity develop T2D. Given the established associations between visceral adipose tissue (VAT) and liver fat with insulin resistance, we hypothesized that compared to age and obesity matched adults who were non-diabetic (NT2D), adults with T2D would have greater amounts of VAT and liver fat. The International Study of Prediction of Intra-Abdominal Adiposity and Its Relationship with Cardiometabolic Risk/Intra-Abdominal Adiposity (INSPIRE ME IAA) aims to study the associations between VAT and liver fat and risk of developing T2D and cardiovascular disease. Four thousand, five hundred and four participants were initially recruited; from this, 2383 White and Asian adults were selected for this ancillary analysis. The NT2D and T2D groups were matched for age, body mass index (BMI) and waist circumference (WC). The T2D and NT2D groups were also compared to participants with either impaired fasting glucose (IFG) or impaired glucose tolerance (IGT; IFG/IGT)). Abdominal adipose tissue was measured by computed tomography; liver fat was estimated using computed tomography-derived mean attenuation. Secondary analysis determined whether differences existed between NT2D and T2D groups in VAT and liver fat accumulation within selected BMI categories for Whites and Asians. We report across sex and race, T2D and IFG/IGT groups had elevated VAT and liver fat compared to the NT2D group (p<0.05). VAT was not different between IFG/IGT and T2D groups (p>0.05), however liver fat was greater in the T2D group compared to the IFG/IGT group in both Whites and Asians (p<0.05). Within each BMI category, the T2D group had elevated VAT and liver fat compared to the age and anthropometrically matched NT2D group in both Whites and Asians (p<0.05). With few exceptions, abdominal subcutaneous adipose tissue was not different in the T2D or IFG/IGT groups compared to the NT2D group independent of sex and race. Compared to age and obesity-matched adults who are NT2D, we observe that White and Asian adults with T2D, and those with IFG/IGT, present with greater levels of both VAT and liver fat.

Accumulation of entanglement in a continuous variable memory

We study entanglement accumulation in a memory built out of two continuous variable systems interacting with a qubit that mediates their indirect coupling. We show that, in contrast with the case of bidimensional Hilbert spaces, entanglement superior to one ebit can be accumulated in the memory, even though no entangled resource is used. The protocol is immediately implementable and we assess the role of the main imperfections.

Effect of reduced pH on inorganic polyphosphate accumulation by Burkholderia cepacia complex isolates.

Aims: Burkholderia cepacia complex (Bcc) isolates causing pulmonary infection in cystic fibrosis (CF) patients grow within an acidic environment in the lung. As exposure to acid pH has been shown to increase intracellular inorganic polyphosphate (polyP) formation in some bacteria, we investigated the inter-relationship between acidic pH and polyP accumulation in Bcc isolates.