Long live the worm. Wild-type Caenorhabditis elegans worms grown on solid agar with a low concentration of a small-molecule inhibitor illustrate the outcome of the visual screening process used to find the piperidine analog dafadine-A. Dafadine-A causes a constitutive dauer phenotype, distal-tip migration defects and an extension in worm lifespan by acting on DAF-9, a cytochrome p450 in the insulin signaling pathway. Cover art by Erin Dewalt, based on an image from Trevor Kwok and Peter Roy. Brief Communication, p891

An in silico high-throughput screen of the dopamine D3 receptor based on a homology model prior to publication of the crystal structure and a subsequent virtual screen based on the crystal structure of the receptor after it became available both identified new ligands with verified activities. The image is a rendition of the homology model of the G protein–coupled receptor, plus seven new ligands from the homology model screen. Cover art by Erin Dewalt, based on an image from Ryan Coleman. Article, p769

Enteric bacteria must travel through the highly acidic mammalian stomach to reach their primary infection site, the intestine. The insertion of a flexible and genetically encodable photocrosslinking amino acid in HdeA, a chaperone that protects against acid stress in Escherichia coli, now allows the identification of HdeA’s client proteins, including two other chaperones that form a cooperative network with HdeA to speed protein refolding. This image of a distressed gold surface highlights the harsh conditions the bacteria must endure. Cover art by Erin Dewalt, based on a photograph from ©iStockPhoto.com/Raquielle. Article, p671

Non-natural amino acids with different electrostatic surface potentials (as depicted on the cover as a color gradient) into the Shaker voltage-sensing potassium channel were introduced by nonsense suppression mutagenesis by Pless et al. to find that salt bridges are not necessary during channel gating, but rather, two of the acidic residues may occupy a hydrophilic water-filled vestibule that creates an energetically favorable environment for movement of positive charges during channel gating. Cover art by Erin Dewalt, based on images from Christopher Ahern.

Cells transmit information about their health and environment by translating a diversity of chemical and physical inputs into downstream signals—outputs—that control cellular function. This image of an electronic network illustrates the complexity that can underlie cellular signaling: the glowing silver nodes represent points of input, where cellular sensors detect important changes. These changes are typically conveyed through molecular switches, often complex circuits themselves, represented by the closed connections between nodes in the image. Cover art by Erin Dewalt, based on an original photo from ©iStockphoto.com/Eduardo Antonio Fuentes.

The integration of biochemical pathway analysis and genome-scale modeling extends metabolic engineering to the production of non-natural commodity chemicals. In this fermentation broth, engineered Escherichia coli use sugar feedstocks to synthesize 1,4–butanediol. Cover art by Erin Dewalt, based on a photograph from Genomatica. Article, p445; News & Views, p408

'Big science' initiatives and investigator-driven 'small science' research in chemical biology will both contribute to a more integrated view of biological systems. Cover art representing a scientific puzzle by Erin Dewalt, based on an original image of the asexual stages of the human malaria parasite Plasmodium falciparum in red blood cells provided by Xin-zhuan Su.

Mutation of the tumor suppressor p53 results in dominant-negative activities that cannot be fully explained by current models. Xu et al. report a mechanism explaining how mutation of p53 can structurally destabilize the DNA-binding domain and increase the exposure of an aggregation nucleation sequence. This can trigger an aggregation cascade involving not only wild-type p53 but its homologs p63 and p73. The image depicts the destabilization that exposes the aggregating sequence and the formation of inactive protein aggregates. The photo of Van Gogh’s The Starry Night was obtained from Google Art Project and adapted by Jie Xu. Cover art by Erin Dewalt. Article, p285; News & Views, p248

The mechanisms by which different species control biomineralization remain mysterious. Sato et al. now demonstrate that, surprisingly, small glycolytic metabolites stabilize amorphous calcium carbonate in crayfish and possibly other crustaceans in a regulated manner. In this cover image, a crayfish stands on top of a scanning electron microscope image of a gastrolith, or 'stomach stone'. The fibrous materials visible are chitin, and the small particles are amorphous calcium carbonate. Cover art by Erin Dewalt, based on an original microscopy image provided by Toshihiro Kogure and an original photograph from ©iStockphoto.com/Olga Demchishina. Brief Communication, p197; News & Views, p192

Triptolide is a bioactive natural product isolated from the thunder god vine, a plant used in traditional Chinese medicine. Titov et al. report the identification of the molecular target for triptolide as XPB, a component of the transcription factor TFIIH required for transcription and nucleotide excision repair. The cover image shows an inflorescence of the thunder god vine (Tripterygium wilfordii Hook F). The photo of a specimen from the University of Strasbourg Botanical Garden (Strasbourg, France) was taken by Frédéric Tournay. Cover art by Erin Dewalt. Article, p182

Neutrophil granulocytes can fight microbes either by phagocytosis or by formation of neutrophil extracellular traps (NETs), an extracellular structure that captures and kills bacteria, fungi and parasites. Using a chemical genetics approach, Hakkim et al. identified the Raf-MEK-ERK signaling system downstream of PKC in formation of NETs. The cover image shows a group of neutrophils that have developed NETs (yellow) after contact with Shigella flexneri bacteria (blue). Cover art by Erin Dewalt, based on an image from Volker Brinkmann. Article, p75

In inflamed arthritis tissue, activated B cells and macrophages contribute to joint inflammation, cartilage destruction and bone loss. Specific Btk inhibition, explored by a new chemical probe, CGI1746, has the potential to interrupt the BCR and FcgR signaling pathways in these cells and ameliorate arthritis. The montage by Karin Reif with images from Ziprasidon, a painting by the artist Klari Reis (www.klariart.com), depicts activated B cells and macrophages in synovial tissue. Cover art by Erin Dewalt.Article, p41