Alogliptin is a potent, selective inhibitor of the serine protease dipeptidyl peptidase IV (DPP-4). Herein, we describe the structure-based design and optimization of alogliptin and related quinazolinone-based DPP-4 inhibitors. Following an oral dose, these noncovalent inhibitors provide sustained reduction of plasma DPP-4 activity and a lowering of blood glucose in animal models of diabetes. Alogliptin is currently undergoing phase III trials in patients with type 2 diabetes.

018. Figure 4 depicts a recently obtained cocrystal structure (PDB code 2ONC).

Usefulness of complex demodulation (CDM) in assessing the frequency components of cardiovascular variability was assessed and, subsequently, this technique was utilized to determine the time-dependent responses of the low-frequency (LF) and high-frequency (HF) amplitudes of heart rate and blood pressure variabilities during postural tilt. CDM provides the time-dependent changes in amplitude of a particular frequency component on a continuous basis. Analysis of simulated data showed that CDM has sufficient frequency resolution to separately measure LF and HF amplitudes with a time resolution < 15 s and that CDM is robust to alterations in the frequency of the components. Analysis of actual data during postural tilt test in 23 young healthy subjects demonstrated that the HF amplitude of heart rate, an index of cardiac parasympathetic tone, rapidly decayed with head-up tilt (P < 0.01) and increased quickly showing an overshoot with tilt back to the supine position (P < 0.01). The LF amplitude of blood pressure, an index of vasomotor sympathetic activity, showed marked rhythmic fluctuation at an interval of 48-100 s during head-up tilt (P < 0.01), synchronizing with similar fluctuation in the LF amplitude of heart rate (P < 0.01). These results suggest that CDM can be used to provide a continuous assessment of cardiovascular variability components and that the dynamic responses of autonomic circulatory control to upright posture result in a phasic modulation of LF amplitude.

Aim Mangroves are intertidal plants with sea-dispersed propagules, hence their population structure can offer valuable insights into the biogeographical processes driving population subdivision in coastal species. In this study, we used molecular markers and ocean circulation simulations to examine the effects of ocean currents and land masses on the genetic structure of the major mangrove species Rhizophora mucronata. Location Southeast Asia.Methods We assessed the genetic structure of 13 R. mucronata populations from continental Southeast Asia and Sumatra using 10 microsatellite loci. We first examined the relative effects of geographical distance and land mass (the Malay Peninsula) in shaping the genetic structure of R. mucronata in Southeast Asia. We then characterized the genetic structure of R. mucronata and compared it to the simulated ocean circulation patterns within our study region. ResultsDespite the low genetic diversity, significant genetic structuring was detected across R. mucronata populations. Contrary to observations on other mangrove species, genetic differentiation in R. mucronata was not found across the coasts of the Malay Peninsula, nor was it correlated with geographical distance. Instead, the most distinct genetic discontinuity was found at the boundary between the Andaman Sea and the Malacca Strait, and this can be explained by the prevailing ocean currents in this region.Main conclusions Our study presents novel evidence that the genetic structure of R. mucronata is maintained by ocean current-facilitated propagule dispersal.

We recently identified a gene (TPO1, YLL028w) that encodes a polyamine transport protein on the vacuolar membrane in yeast [Tomitori, Kashiwagi, Sakata, Kakinuma and Igarashi (1999) J. Biol. Chem. 274, 3265-3267]. Because the existence of one or more other genes for a polyamine transport protein on the vacuolar membrane was expected, we searched sequence databases for homologues of the protein encoded by TPO1. Membrane proteins encoded by the open reading frames YGR138c (TPO2), YPR156c (TPO3) and YOR273c (TPO4) were postulated to be polyamine transporters and, indeed, were subsequently shown to be polyamine transport proteins on the vacuolar membrane. Cells overexpressing these genes were resistant to polyamine toxicity and showed an increase in polyamine uptake activity and polyamine content in vacuoles. Furthermore, cells in which these genes were disrupted showed an increased sensitivity to polyamine toxicity and a decrease in polyamine uptake activity and polyamine content in vacuoles. Resistance to polyamine toxicity in cells overexpressing the genes was overcome by bafilomycin A(1), an inhibitor of the vacuolar H(+)-ATPase. Among the four polyamine transporters, those encoded by TPO2 and TPO3 were specific for spermine, whereas those encoded by TPO1 and TPO4 recognized spermidine and spermine. These results suggest that polyamine content in the cytoplasm of yeast is elaborately regulated by several polyamine transport systems in vacuoles. Furthermore, it was shown that Glu-207, Glu-324 (or Glu-323) and Glu-574 of TPO1 protein were important for the transport activity.