Bacteria directly initiate coagulation. Using microfluids, numerical simulations and mice, Kastrup et al. (p 742) provide an explanation for the correlation between bacterial infections and blood clotting. The authors found that localized clusters of some species of bacteria result in sufficient concentrations of endogenous factors, such as the zinc metalloprotease InhA1 in the case of Bacillus anthracis, to trigger the coagulation cascade directly (see also News and Views by Borenstein on p 718). A partial diagram of the hemostasis network is superimposed over the microfluids device used to investigate clotting. Cover art by Erin Boyle, based on images provided by Christian Kastrup and Helen Song.

Chemical tools are increasingly important for probing and manipulating complex biological systems, and systems-based approaches are a powerful way to understand the often pleiotropic biological effects of small molecules. In this issue we feature a collection of articles that highlight the emerging interface of chemical biology and systems biology. The cover shows an artistic representation of the human interactome built with the network analysis package AxPathBuilder (http://www.anaxomics.com/). Spherical, multispherical and daisy-flower nodes in the network represent proteins, multiprotein complexes and pathways, respectively, and edges are physical interactions between these elements. Overlaid on this network are small molecules that exhibit polypharmacology (in white and blue) or that are synergistic in combination (in yellow). Cover art by Erin Boyle based on a network image created by Núria Jiménez Bargalló (Anaxomics Biotech SL), José Manuel Mas (Anaxomics Biotech SL) and Patrick Aloy (IRB Barcelona).

Drug-induced domino effect. Using mass spectrometry, Kwon et al. (p 602) looked at the effects of the antibiotic trimethoprim on the intermediates in folate metabolism. Trimethoprim inhibition of the intended target, dihydrofolate reductase (DHFR), resulted in the accumulation of the enzyme substrate, dihydrofolate, which had the unexpected effect of inhibiting folylpoly-γ-glutamate synthetase (FP-γ-GS), another enzyme in the folate pathway (see also News and Views by Brown on p 581). Trimethoprim, DHFR, dihydrofolate and FP-γ-GS are shown on dominoes. Cover art by Erin Boyle based on images provided by Yun Kyung Kwon and Eugene Melamud.

Alkaloid production in yeast. By inserting plant biosynthetic enzymes, Hawkins and Smolke (p 564) have engineered yeast to produce reticuline, a key intermediate in benzylisoquinoline alkaloid biosynthesis. Expression of additional plant and human enzymes resulted in the production of metabolites in the sanguinarine/berberine and morphinan branches of alkaloids (see also News and Views by Keasling on p 524). A poppy, one of the natural benzylisoquinoline producers, is shown against a background of budding yeast and alkaloid structures. Cover art by Erin Boyle based on a concept from Christina Smolke and Kristy Hawkins.

Cooperativity can exist at the level of individual molecules, protein assemblies, and in cell-cell interactions. This artist's rendition captures the idea of integrating our understanding of cooperativity across these distinct length scales, and serves as a backdrop for a collection of articles in this issue meant to explore the meaning and scope of cooperativity in biological systems. Prochloron images courtesy of Mohamed Donia. Cover art by Erin Boyle.

Proteome reactivity of carbon electrophiles. To expand the range of activity-based protein profiling, Weerapana et al. (p 405) tested the reactivities of five carbon electrophiles in proteomic samples. These electrophiles displayed a variety of reactivity and specificity profiles, which suggests that these compounds will provide versatile scaffolds for designing the next generation of activity-based probes (see also News and Views by Kodadek on p 387). The three most reactive electrophiles (in white) and selected target proteins (in color) are shown in a background of unreacted proteins (in gray). Cover art by Erin Boyle based on images provided by Gabriel Simon.

A potent small-molecule inhibitor of Cdc7. In a high-throughput screen, Montagnoli et al. (p 357) identified an ATP-competitive inhibitor of Cdc7, a kinase involved in initiating DNA replication. Using this inhibitor, the authors demonstrated that Cdc7 inhibition decreases the firing of replication origins and halts DNA synthesis. In rodents, the Cdc7 inhibitor had antitumor activity, which suggests that Cdc7 is a potential target for anticancer therapeutics (see also News and Views by Jackson on p 331). Shown is an immunofluorescence image of a xenograft tumor with the Cdc7 substrate pSer40/41 Mcm2 stained in red and nuclei in blue. Cover art by Erin Boyle based on images provided by Veronica Patton and Rachele Alzani.

Mannosidase catalysis through an unusual boat-like transition state. Tailford et al. (p 306) solved the structure of β-mannosidase bound to potent inhibitors and found that all bound in a B2,5 (boat) or closely related conformation. Biochemical analysis demonstrated that these inhibitors were acting as transition state mimics. Together these results provide the first direct evidence for a boat-like transition state in β-mannosidases (see also News and Views by Palcic on p 269). Shown is the conformational map of pyranoid ring interconversion overlaid on the ceiling of a gazebo. Cover art by Erin Boyle based on chemical structures provided by Spencer Williams, Bruno Bernet and Andrea Vasella.

A carbohydrate microarray provides insights into the antimalarial immune response. Kamena et al. (p 238) spotted synthetic GPI glycans onto glass slides to create a 'GPI chip'. Using this chip, the authors characterized the binding of anti-GPI antibodies from people in malaria-endemic and malaria-free regions and before and after malarial exposure (see also News and Views by Ferguson on p (223). Shown are images of the carbohydrate microarrays incubated with human sera, Giesma-stained red blood cells infected with Plasmodium falciparum and the chemical structures of GPI glycans displayed on the microarrays. Cover art by Erin Boyle based on images provided by Faustin Kamena and Marco Tamborrini.

Transition metal ions play essential roles in all organisms, including as cofactors in complex enzyme-catalyzed reactions, and they are regulated through elaborate biological pathways. In this issue, we feature a collection of articles that highlight some of the chemical and biological frontiers of 'metals in biology'. Cover art by Erin Boyle, based on photographs from Getty Images.

Quantitative flow cytometric measurement of protein phosphorylation has been developed into a high-throughput drug screening platform that can be used throughout the drug discovery process. Using phosphoflow cytometry, Krutzik et al. (p 132) studied the effects of compounds from a natural product library on cytokine-induced phosphorylation of multiple proteins in the Jak-Stat signaling pathway in subpopulations of primary immune cells. Shown are several Tetris-inspired (http://www.tetris.com) game pieces depicting library compounds, flow cytometric histograms and scatter plots, dose-response curves, and the structure of the Stat1 protein, together forming a heatmap representation of the screening data and revealing pathway- and cell type-specific inhibitors. Cover art by Erin Boyle based on images provided by Peter O. Krutzik and Garry P. Nolan.

A connection between bone morphogenetic protein (BMP) signaling and iron balance is revealed by a small molecule. Yu et al. (p 33) found a compound called dorsomorphin that can dorsalize zebrafish embryos by virtue of being an antagonist of BMP signaling, which has a role in various developmental processes. Dorsomorphin also blocks the expression of the peptide hormone hepcidin, linking this critical iron balance regulator with BMP signaling (see also News and Views by Anderson, p 15). Shown are several images of zebrafish embryos stained in situ to reveal changes in expression of dorsal and ventral markers before and after dorsomorphin treatment. Cover art by Erin Boyle based on images provided by Chetana Sachidanandan and Randall T. Peterson.