Neuromuscular disease

Sarcolemma-localized nNOS is required to maintain activity after mild exercise. Kobayashi, Y. M. et al. Nature 456, 511–515 (2008).

Many neuromuscular conditions are characterized by an exaggerated exercise-induced fatigue response. Using mouse models, Kobayashi and colleagues show that the exaggerated fatigue response to mild exercise is due to a lack of contraction-induced signalling from sarcolemma-localized neuronal nitric oxide synthase (nNOS), which decreases cyclic GMP-mediated vasomodulation in the vessels that supply active muscle after mild exercise. These results suggest that patients with an exaggerated fatigue response might benefit from treatment strategies — such as PDE5 inhibition — that improve nNOS signalling.

HIV

Human domain antibodies to conserved sterically restricted regions on gp120 as exceptionally potent cross-reactive HIV-1 neutralizers. Chen, W. et al. Proc. Natl Acad. Sci. USA 105, 17121–17126 (2008)

HIV-1 has acquired the ability to escape neutralization by antibodies generated by the immune system. This paper describes the identification and characterization of a human antibody heavy-chain variable domain that targets highly conserved but sterically restricted CD4-induced structures on the HIV-1 envelope glycoprotein. Such antibodies are potent and broadly cross-reactive HIV-1 inhibitors that could have potential for prevention and therapy of HIV-1 and could help identify conserved structures that are essential for viral replication.

Malaria

Selection of a trioxaquine as an antimalarial drug candidate. Coslédan, M. et al. Proc. Natl Acad. Sci. USA 105, 17579–17584 (2008)

Coslédan and colleagues describe the preparation, pharmacological properties and in vivo activity of an antimalarial drug candidate. From a selection of 120 trioxaquines and trioxolaquinines that had in vitro activity, 72 compounds were tested orally in malaria-infected mice, of which 25 underwent toxicological testing. Finally, one compound with good oral bioavailability was shown to be highly active on multidrug-resistant Plasmodium falciparum strains obtained from fresh patient isolates, and completely cured mice infected with chloroquine-sensitive and chloroquine-resistant strains of Plasmodium.

Physiology

H2S as a physiologic vasorelaxant: hypertension in mice with deletion of cystathionine γ-lyase. Yang, G. et al. Science 322, 587–590 (2008)

Several gaseous signalling molecules have important roles in mammalian physiology. This paper shows that H2S is physiologically generated by cystathionine γ-lyase (CSE). Mice lacking this enzyme had reduced H2S levels in serum, heart, aorta and other tissues, and displayed pronounced hypertension and diminished endothelium-dependent vasorelaxation. CSE was activated by calcium–calmodulin, which is a mechanism for H2S formation in response to vascular activation. So, H2S is a vasodilator and regulator of blood pressure, which raises the possibility that enhancement of H2S formation could be an alternative approach for the treatment of hypertension.