Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4)

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson’s disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041.     

Aeroallergens, Allergic Disease, and Climate Change: Impacts and Adaptation

Recent research has shown that there are many effects of climate change on aeroallergens and thus allergic diseases in humans. Increased atmospheric carbon dioxide concentration acts as a fertilizer for plant growth. The fertilizing effects of carbon dioxide, as well as increased temperatures from climate change, increase pollen production and the allergen content of pollen grains. In addition, higher temperatures are changing the timing and duration of the pollen season. As regional climates change, plants can move into new areas and changes in atmospheric circulation can blow pollen- and spore-containing dust to new areas, thus introducing people to allergens to which they have not been exposed previously. Climate change also influences the concentrations of airborne pollutants, which alone, and in conjunction with aeroallergens, can exacerbate asthma or other respiratory illnesses. The few epidemiological analyses of meteorological factors, aeroallergens, and allergic diseases demonstrate the pathways through which climate can exert its influence on aeroallergens and allergic diseases. In addition to the need for more research, there is the imperative to take preventive and adaptive actions to address the onset and exacerbation of allergic diseases associated with climate variability and change.     

Is use of translocation for the conservation of subpopulations of oribi Ourebia ourebi (Zimmermann) effective? A case study

In South Africa, the oribi, Ourebia ourebi is an endangered small antelope that requires conservation management and intervention to prevent their extinction. Use of translocation for the conservation of subpopulations facing local extinction in the wild has been proposed. In this study, fifteen oribi from threatened populations were captured and released (November 2004) on a private game reserve in KwaZulu-Natal, South Africa. Radio telemetry was used to monitor the dispersal and survival of translocated oribi. Only one death occurred during that period. All other released oribi survived, and most remained in close proximity of the release site for more than a year postrelease. Reproduction also occurred. This suggests that, translocation could be a viable option for conserving wild populations of oribi, assuming that other factors, such as availability of suitable grassland habitat and that poaching has been curtailed, are met.     

Extreme tolerance to ammonia fumes in African naked mole-rats: animals that naturally lack neuropeptides from trigeminal chemosensory nerve fibers

Naked mole-rats (Heterocephalus glaber) naturally lack neuropeptides associated with the signaling of chemical irritants from C type trigeminal nerve fibers. The goal of the present study was to assess behavioral responses of these animals to stimulation of the trigeminal chemosensory system, and to determine if stimulation would increase post-synaptic activity in the trigeminal nucleus, as seen in laboratory mice and rats. The results show that naked mole-rats are behaviorally insensitive to capsaicin solution applied to the nostrils and to ammonia fumes in a behavioral avoidance test. Centrally, the number of c Fos labeled cells in the spinal trigeminal nucleus increased from exposure to ammonia although the magnitude of the increase was less than for rats. The increase observed in naked mole-rats likely reflects activity from glutamate release, which appears insufficient to drive pain and aversion behaviors. The results support the idea that neuropeptides in the C fibers of the trigeminal system may be required to signal the aversive quality of specific chemical irritants. The natural lack of neuropeptides in naked mole-rats may be an adaptation to living in a challenging subterranean environment with extremely high levels of ammonia and carbon dioxide, stimuli known to excite trigeminal chemosensory C fibers.     

Measures of postprandial lipoproteins are not associated with coronary artery disease in patients with type 2 diabetes mellitus

Individuals with type 2 diabetes mellitus (DM) characteristically have elevated fasting and postprandial (PP) plasma triglycerides (TG). Previous case-control studies indicated that PPTG levels predict the presence of coronary artery disease (CAD) in people without DM; however, the data for patients with DM are conflicting. Therefore, we conducted a case-control study in DM individuals, 84 with (+) and 80 without (−) CAD. Our hypothesis was that DM individuals with or without CAD would have similar PPTG levels, but CAD+ individuals would have more small d<1.006 g/L lipoprotein particles. Several markers of PP lipid metabolism were measured over 10 h after a fat load. PP lipoprotein size and particle number were also determined. There was no significant difference in any measure of PP lipid metabolism between CAD+ and CAD−, except for apoB48, which was actually higher in CAD−. We followed 69 CAD− participants for a mean 8.7 years; 33 remained free of any cardiovascular event. There were no PP differences at baseline between these 33 who remained CAD− and either the 36 original CAD− who subsequently developed CAD or the original CAD+ group.PP measurements of TG-rich lipoproteins do not predict the presence of CAD in individuals with DM.     

Rickettsia Sca2 is a bacterial formin-like mediator of actin-based motility

Diverse intracellular pathogens subvert the host actin-polymerization machinery to drive movement within and between cells during infection. Rickettsia in the spotted fever group (SFG) are Gram-negative, obligate intracellular bacterial pathogens that undergo actin-based motility and assemble distinctive 'comet tails' that consist of long, unbranched actin filaments. Despite this distinct organization, it was proposed that actin in Rickettsia comet tails is nucleated by the host Arp2/3 complex and the bacterial protein RickA, which assemble branched actin networks. However, a second bacterial gene, sca2, was recently implicated in actin-tail formation by R. rickettsii. Here, we demonstrate that Sca2 is a bacterial actin-assembly factor that functionally mimics eukaryotic formin proteins. Sca2 nucleates unbranched actin filaments, processively associates with growing barbed ends, requires profilin for efficient elongation, and inhibits the activity of capping protein, all properties shared with formins. Sca2 localizes to the Rickettsia surface and is sufficient to promote the assembly of actin filaments in cytoplasmic extract. These results suggest that Sca2 mimics formins to determine the unique organization of actin filaments in Rickettsia tails and drive bacterial motility, independently of host nucleators.