Malaria control with genetically manipulated insect vectors

At a recent workshop, experts discussed the benefits, risks, and research priorities associated with using genetically manipulated insects in the control of vector-borne diseases.     

A cholesterol biosynthesis inhibitor blocks Staphylococcus aureus virulence

Staphylococcus aureus produces hospital- and community-acquired infections, with methicillin-resistant S. aureus posing a serious public health threat. The golden carotenoid pigment of S. aureus, staphyloxanthin, promotes resistance to reactive oxygen species and host neutrophil-based killing, and early enzymatic steps in staphyloxanthin production resemble those for cholesterol biosynthesis. We determined the crystal structures of S. aureus dehydrosqualene synthase (CrtM) at 1.58 angstrom resolution, finding structural similarity to human squalene synthase (SQS). We screened nine SQS inhibitors and determined the structures of three, bound to CrtM. One, previously tested for cholesterol-lowering activity in humans, blocked staphyloxanthin biosynthesis in vitro (median inhibitory concentration approximately 100 nM), resulting in colorless bacteria with increased susceptibility to killing by human blood and to innate immune clearance in a mouse infection model. This finding represents proof of principle for a virulence factor-based therapy against S. aureus.     

Expanded repeat in canine epilepsy

Epilepsy afflicts 1% of humans and 5% of dogs. We report a canine epilepsy mutation and evidence for the existence of repeat-expansion disease outside humans. A canid-specific unstable dodecamer repeat in the Epm2b (Nhlrc1) gene recurrently expands, causing a fatal epilepsy and contributing to the high incidence of canine epilepsy. Tracing the repeat origins revealed two successive events, starting 50 million years ago, unique to canid evolution. A genetic test, presented here, will allow carrier and presymptomatic diagnosis and disease eradication. Clinicopathologic characterization establishes affected animals as a model for Lafora disease, the most severe teenage-onset human epilepsy.     

Stress and fold localization in thin elastic membranes

Thin elastic membranes supported on a much softer elastic solid or a fluid deviate from their flat geometries upon compression. We demonstrate that periodic wrinkling is only one possible solution for such strained membranes. Folds, which involve highly localized curvature, appear whenever the membrane is compressed beyond a third of its initial wrinkle wavelength. Eventually the surface transforms into a symmetry-broken state with flat regions of membrane coexisting with locally folded points, reminiscent of a crumpled, unsupported membrane. We provide general scaling laws for the wrinkled and folded states and proved the transition with numerical and experimental supported membranes. Our work provides insight into the interfacial stability of such diverse systems as biological membranes such as lung surfactant and nanoparticle thin films.