Influence of endotoxin on the stereoselective pharmacokinetics of oxprenolol,propranolol, and verapamil in the rat

The influence of endotoxin-induced inflammation on the enantioselective pharmacokinetics of propranolol, oxprenolol, and verapamil, which bind to α₁-acid glycoprotein, was studied in the rat. The racemic mixtures were given orally. In the control animals, for propranolol and oxprenolol, the plasma concentrations of the (R)-enantiomer were higher than those of the (S)-enantiomer, while for verapamil the reverse was true. Protein binding and intrinsic clearance are the main factors responsible for this enantioselectivity. After endotoxin treatment, for the three drugs tested the plasma concentrations and the plasma binding of both enantiomers were significantly increased. This effect was more pronounced for (R)-propranolol, (R)-oxprenolol, and (S)-verapamil than for their respective antipodes. The enantioselective effect of endotoxin on the plasma concentrations of the drugs studied seems mainly due to the enantioselective increase in binding to α₁-acid glycoprotein. © 1994 Wiley-Liss, Inc.     

A scientific approach to agent selection

Abstract  The prioritisation of potential agents on the basis of likely efficacy is an important step in biological control because it can increase the probability of a successful biocontrol program, and reduce risks and costs. In this introductory paper we define success in biological control, review how agent selection has been approached historically, and outline the approach to agent selection that underpins the structure of this special issue on agent selection. Developing criteria by which to judge the success of a biocontrol agent (or program) provides the basis for agent selection decisions. Criteria will depend on the weed, on the ecological and management context in which that weed occurs, and on the negative impacts that biocontrol is seeking to redress. Predicting which potential agents are most likely to be successful poses enormous scientific challenges. 'Rules of thumb', 'scoring systems' and various conceptual and quantitative modelling approaches have been proposed to aid agent selection. However, most attempts have met with limited success due to the diversity and complexity of the systems in question. This special issue presents a series of papers that deconstruct the question of agent choice with the aim of progressively improving the success rate of biological control. Specifically they ask: (i) what potential agents are available and what should we know about them? (ii) what type, timing and degree of damage is required to achieve success? and (iii) which potential agent will reach the necessary density, at the right time, to exert the required damage in the target environment?     

Effects of shear stress on endothelial cells: possible relevance for ultrasound applications

This review forms part of a series of papers resulting from a workshop on safety of ultrasound applications. The physical effects of ultrasound include generation of steady streaming in large fluid volumes, and micro-streaming around contrast bubbles. Such streaming induces shear stress acting on the vascular endothelium. This review provides a discussion on the levels of endothelial shear stress associated with diagnostic ultrasound applications, and on the biological effects of shear stress acting on the endothelial cells. Depending on vessel size and ultrasound characteristics, shear stresses associated with streaming and micro-streaming may exceed the physiological levels associated with the flow of blood by many orders of magnitude. The resulting biological effects could range anywhere from activation of normal shear stress sensors such as ion channels, damage of the endothelial surface layer, reversible perforation of the membrane, to cell detachment and lysis. The possible presence of such biological effects does not necessarily mean that the effects are harmful for the individual. However, considering the ever-increasing use of ultrasound, a further investigation into these shear stress-related effects, using both experiments and modelling, is desired. Apart from safety concerns, such effects may provide a base for strategies aimed at targeted delivery of drugs.     

Limit behaviour of spatially growing cell cultures

Growing cell cultures often exhibit branch patterns. The cultures are usually modelled as free boundary problems. Here, we review some of these models and investigate the appearance of branch patterns using methods from asymptotic analysis. Two extreme cases--large kinetics and small kinetics--are considered. For large kinetics the models reduce to the well-studied Stefan problem, which is known to exhibit a diffusive-instability and hence shows branch patterns. Considering small kinetics, small perturbations are smoothed out resulting in regular shapes of the cultures. The branching phenomenon in general can be understood as somewhere between these two extremes. Not relying on special assumptions, the presented analysis is very general.     

A P system and a constructive membrane-inspired DNA algorithm for solving the Maximum Clique Problem

We present a P system with replicated rewriting to solve the Maximum Clique Problem for a graph. Strings representing cliques are built gradually. This involves the use of inhibitors that control the space of all generated solutions to the problem. Calculating the maximum clique for a graph is a highly relevant issue not only on purely computational grounds, but also because of its relationship to fundamental problems in genomics. We propose to implement the designed P system by means of a DNA algorithm. This algorithm is then compared with two standard papers that addressed the same problem and its DNA implementation in the past. This comparison is carried out on the basis of a series of computational and physical parameters. Our solution features a significantly lower cost in terms of time, the number and size of strands, as well as the simplicity of the biological implementation.     

Synthesis and structure-activity relationships of 16-modified analogs of 2-methoxyestradiol

A series of 16-modified 2-methoxyestradiol analogs were synthesized and evaluated for antiproliferative activity toward HUVEC and MDA-MB-231 cells, and for susceptibility to conjugation. In addition, the estrogenicity of these analogs was accessed by measuring cell proliferation of the estrogen-dependent cell line MCF7 in response to compound treatment. It was observed that antiproliferative activity dropped as the size of the 16 substituent increased. Selected analogs tested in glucuronidation assays had similar rates of clearance to 2-methoxyestradiol, but had enhanced clearance in sulfonate conjugation assays.     

RGD targeted poly(L-glutamic acid)-cystamine-(Gd-DO3A) conjugate for detecting angiogenesis biomarker alpha(v) beta3 integrin with MRT, mapping

Cyclic Arg-Gly-Asp-D-Phe-Lys [c(RGDfK)] targeted poly(L-glutamic acid) (PGA)-(Gd-DO3A) conjugate with a biodegradable cystamine spacer was prepared and evaluated for in vivo detection of an angiogenesis biomarker, alpha(v)beta3 integrin, in neoplastic tissues with T1 mapping, a quantitative magnetic resonance imaging (MRI) technique. The binding activity of the c(RGDfK) containing conjugate was investigated using in vitro vitronectin assay with human prostate carcinoma DU145 cell line and Kaposi's sarcoma SLK cell line. The peptide c(RGDfK) and PGA-cystamine-(Gd-DO3A) conjugate were used as controls. The binding affinity of polymer bound c(RGDfK) was slightly lower than free c(RGDfK) peptide. The RGD targeted conjugate had higher binding affinity to the DU145 cells than the SLK cells, which was consistent to free c(RGDfK). The imaging of alpha(v)beta3 integrin with targeted PGA-cystamine-(Gd-DO3A) was evaluated in nude mice bearing DU145 and SLK xenografts at a dose of 5 micromol-Gd/kg. The targeted conjugate demonstrated higher in vivo binding affinity to the DU145 xenografts than the SLK xenografts, resulting in a significant decrease of T1 values of water protons in the periphery of the DU145 tumors as shown in the MR T1 maps. No significant decrease of T1 values was observed in the SLK tumor with the targeted conjugate and in both tumors with the non-targeted conjugate. The targeted polymeric Gd(III) chelate conjugate with a degradable spacer has the potential to be a new paradigm for safe and effective probes in molecular imaging with quantitative MR T1 mapping.     

Biosynthesis of antibiotic prodiginines in the marine bacterium Hahella chejuensis KCTC 2396

AIMS: Hahella chejuensis KCTC 2396 produces red pigments, showing antibacterial and algicidal activities. The main red-coloured metabolite of the pigments was identified as antibiotic prodigiosin. With the expectation that the red pigments are a mixture of a series of close relatives, the aim of the present study is to detect new antibiotic prodigiosin analogues and to analyse the biosynthetic pattern for prodiginines in KCTC 2396. METHODS AND RESULTS: Except prodigiosin, the other constituents in the red pigments were confirmed as well-known dipyrrolyldipyrromethene prodigiosin, norprodigiosin, and undecylprodiginine. Additionally, four new prodigiosin analogues, each of which was distinguished from prodigiosin (C(5)), according to differences in alkyl chain length (C(3)-C(7)), were detected in small quantities by liquid chromatography mass spectrometry/mass spectrometry spectroscopy. Owing to the presence of a cytotoxic methoxy group, it is expected that all the new prodigiosin analogues are bioactive. CONCLUSIONS: Four characterized prodiginines, including prodigiosin and four new prodigiosin analogues are produced in different ratio in KCTC 2396. All of the prodiginines possess a common linear tripyrrolyl structure and a cytotoxic methoxy group. SIGNIFICANCE AND IMPACT OF THE STUDY: This study shows for the first time that KCTC 2396 is able to produce antibiotic prodigiosin, undecylprodiginine and new prodigiosin analogues in a mixture of pigments. It is also shown that KCTC 2396 possesses a novel system for the simultaneous production of multiple prodiginines in a single micro-organism.     

Bayesian modeling of dynamic motion integration

The quality of the representation of an object's motion is limited by the noise in the sensory input as well as by an intrinsic ambiguity due to the spatial limitation of the visual motion analyzers (aperture problem). Perceptual and oculomotor data demonstrate that motion processing of extended objects is initially dominated by the local 1D motion cues, related to the object's edges and orthogonal to them, whereas 2D information, related to terminators (or edge-endings), takes progressively over and leads to the final correct representation of global motion. A Bayesian framework accounting for the sensory noise and general expectancies for object velocities has proven successful in explaining several experimental findings concerning early motion processing [Weiss, Y., Adelson, E., 1998. Slow and smooth: a Bayesian theory for the combination of local motion signals in human vision. MIT Technical report, A.I. Memo 1624]. In particular, these models provide a qualitative account for the initial bias induced by the 1D motion cue. However, a complete functional model, encompassing the dynamical evolution of object motion perception, including the integration of different motion cues, is still lacking. Here we outline several experimental observations concerning human smooth pursuit of moving objects and more particularly the time course of its initiation phase, which reflects the ongoing motion integration process. In addition, we propose a recursive extension of the Bayesian model, motivated and constrained by our oculomotor data, to describe the dynamical integration of 1D and 2D motion information. We compare the model predictions for object motion tracking with human oculomotor recordings.