Capped diaminopropionamide-glycine dipeptides are inhibitors of CC chemokine receptor 2 (CCR2)

A new series of CCR2 antagonists has been discovered that incorporates intramolecular hydrogen bonding as a strategy for rigidifying the scaffold. The structure-activity relationship was established through initial systematic modification of substitution pattern and chain length, followed by independent optimization of three different substituents (benzylamine, carboxamide, and benzamide). Several of the acyclic compounds display 10-30 nM binding affinity for CCR2. Moreover, these antagonists are able to block both MCP-1-induced Ca(2+) flux and monocyte chemotaxis, and are selective for binding to CCR2 over CCR1 and CCR3.     

Social cognition in humans

We review a diversity of studies of human social interaction and highlight the importance of social signals. We also discuss recent findings from social cognitive neuroscience that explore the brain basis of the capacity for processing social signals. These signals enable us to learn about the world from others, to learn about other people, and to create a shared social world. Social signals can be processed automatically by the receiver and may be unconsciously emitted by the sender. These signals are non-verbal and are responsible for social learning in the first year of life. Social signals can also be processed consciously and this allows automatic processing to be modulated and overruled. Evidence for this higher-level social processing is abundant from about 18 months of age in humans, while evidence is sparse for non-human animals. We suggest that deliberate social signalling requires reflective awareness of ourselves and awareness of the effect of the signals on others. Similarly, the appropriate reception of such signals depends on the ability to take another person's point of view. This ability is critical to reputation management, as this depends on monitoring how our own actions are perceived by others. We speculate that the development of these high level social signalling systems goes hand in hand with the development of consciousness.     

CC chemokine receptor-3 (CCR3) antagonists: improving the selectivity of DPC168 by reducing central ring lipophilicity

DPC168, a benzylpiperidine-substituted aryl urea CCR3 antagonist evaluated in clinical trials, was a relatively potent inhibitor of the 2D6 isoform of cytochrome P-450 (CYP2D6). Replacement of the cyclohexyl central ring with saturated heterocycles provided potent CCR3 antagonists with improved selectivity against CYP2D6. The favorable preclinical profile of DPC168 was maintained in an acetylpiperidine derivative, BMS-570520.     

Avian Clock gene polymorphism: evidence for a latitudinal cline in allele frequencies

In comparison with most animal behaviours, circadian rhythms have a well-characterized molecular genetic basis. Detailed studies of circadian clock genes in 'model' organisms provide a foundation for interpreting the functional and evolutionary significance of polymorphic circadian clock genes found within free-living animal populations. Here, we describe allelic variation in a region of the avian Clock orthologue which encodes a functionally significant polyglutamine repeat (ClkpolyQcds), within free-living populations of two passerine birds, the migratory bluethroat (Luscinia svecica) and the predominantly nonmigratory blue tit (Cyanistes caeruleus). Multiple ClkpolyQcds alleles were found within populations of both species (bluethroat: 12 populations, 7 alleles; blue tit: 14 populations, 9 alleles). Some populations of both species were differentiated at the ClkpolyQcds locus as measured by F(ST) and R(ST) values. Among the blue tit, but not bluethroat populations, we found evidence of latitudinal clines in (i) mean ClkpolyQcds repeat length, and (ii) the proportions of three ClkpolyQcds genotype groupings. Parallel analyses of microsatellite allele frequencies, which are considered to reflect selectively neutral processes, indicate that interpopulation allele frequency variation at the ClkpolyQcds and microsatellite loci does not reflect the same underlying demographic processes. The possibility that the observed interpopulation ClkpolyQcds allele frequency variation is, at least in part, maintained by selection for microevolutionary adaptation to photoperiodic parameters correlated with latitude warrants further study.     

Cell-bionics: tools for real-time sensor processing

The accurate monitoring of the physiological status of cells, tissues and whole organisms demands a new generation of devices capable of providing accurate data in real time with minimal perturbation of the system being measured. To deliver on the promise of cell-bionics advances over the past decade in miniaturization, analogue signal processing, low-power electronics, materials science and protein engineering need to be brought together. In this paper we summarize recent advances in our research that is moving us in this direction. Two areas in particular are highlighted: the exploitation of the physical properties inherent in semiconductor devices to perform very low power on chip signal processing and the use of gene technology to tailor proteins for sensor applications. In the context of engineered tissues, cell-bionics could offer the ability to monitor the precise physiological state of the construct, both during 'manufacture' and post-implantation. Monitoring during manufacture, particularly by embedded devices, would offer quality assurance of the materials components and the fabrication process. Post-implantation monitoring would reveal changes in the underlying physiology as a result of the tissue construct adapting to its new environment.     

Sensing capability of the localized surface plasmon resonance of gold nanorods

We demonstrate the feasibility of using the longitudinal component of gold nanorod's surface plasmon resonance in biomolecular sensing. The sensitive dependence of the absorption maximum on the dielectric constant of the particle interfacial region makes gold nanorods a promise for constructing a biomolecular sensing scheme. The sensor containing gold nanorods, with a mean aspect ratio of 5.2, exhibits a sensitivity of ca. 366 nm/RIU (refractive index unit), which increases accordingly with the increase of the particle mean aspect ratios. Such a biosensor was further modified to demonstrate its effectiveness in quantitative detection for selective binding events, such as biotin/streptavidin pairs, through a process in which biotin molecules were chemically attached to the gold nanorods' surface prior to detection measurements. Results showed that the spectral lambda(max) shifts linearly to the concentrations of the streptavidin. The results from both experiment and model calculations strongly indicate the efficacy of the longitudinal surface plasmon absorption band in biosensing.     

Imaging apoptosis for detecting plaque instability: rendering death a brighter facade

The relatively poor correlation between the risk of atherosclerotic plaque rupture and the degree of luminal obstruction before this event implies a strong imperative for in vivo detection of the processes underlying progressive plaque destabilization. In addition to the morphologic characteristics, apoptosis and inflammation comprise two important indicators of plaque instability. Apoptotic macrophage death results in enlargement of the plaque necrotic core and positive vascular remodelling, whereas apoptosis of the smooth muscle cells leads to attenuation of the fibrous cap. Imaging of apoptotic cells with annexin A5 provides an opportunity for the non-invasive assessment of cell death, and hence plaque vulnerability. The clinical detection of apoptosis could therefore promote the development of novel intervention strategies.     

Synthesis of 7-thiaarachidonic acid as a mechanistic probe of prostaglandin H synthase-2

The mechanism by which prostaglandin synthase converts arachidonic acid to prostaglandin G(2), creating five new chiral centers in the process, is still incompletely understood. The first radical intermediate has been characterized by EPR spectroscopy but subsequent proposed intermediates have not succumbed to detection. We report the synthesis of 7-thiaarachidonic acid designed to stabilize one of the proposed radical intermediates, which may allow its detection.     

Oxazolidinones as novel human CCR8 antagonists

High-throughput screening of the corporate compound collection led to the discovery of a novel series of N-substituted-5-aryl-oxazolidinones as potent human CCR8 antagonists. The synthesis, structure-activity relationships, and optimization of the series that led to the identification of SB-649701 (1a), are described.     

Identification of the benzodiazepines as a new class of antileishmanial agent

The continual increase in drug resistance; the lack of new chemotherapeutic agents; the toxicity of existing agents and the increasing morbidity with HIV co-infection mean the search for new antileishmanial agents has never been more urgent. We have identified the benzodiazepines as a structural class for antileishmanial hit optimisation, and demonstrated that their in vitro activity is comparable with the clinically used drug, sodium stibogluconate, and that the compounds are not toxic to macrophages.