The immune system mobilizes to kill invading pathogens and tumor cells in response to peptides derived from those sources. The collection of pieces in this themed issue highlights the mechanistic roles of peptides in both the innate and adaptive immune systems and how these could be manipulated by chemical biologists to treat disease. The cover image depicts the frequency of words, in the form of a word cloud, in the abstracts of the Commentary, Perspective and Review articles in this issue. Cover art by Erin Dewalt.

The identification of three Arabidopsis thaliana hydroxyproline O-arabinosyltransferases—transmembrane proteins localized to the Golgi—allows characterization of enzyme substrates and investigation of the biological consequences of this post-translational modification in cell wall assembly and biosynthesis. This photograph shows a transmission electron micrograph of Arabidopsis thaliana, with the cell walls colored yellow and the Golgi apparatus shown in red. Cover art by Erin Dewalt, based on imagery from Yoshikatsu Matsubayashi. Article, p726

The neurosteroid pregnenolone (P5) is known to be required for zebrafish embryonic cell movement and microtubule stability. By binding the microtubule plus-end tracking protein CLIP-170 (depicted as a bulldozer) and opening it from its folded state to promote binding to microtubules, p150Glued and LIS1, P5 enhances polymerization of tubulin (bricks) into microtubules to facilitate cell migration and the development of the organism (buildings). Cover art by Erin Dewalt, based on artwork from Wei-Yao Ku. Article, p636.

An optical pulse-chase system shows differences in the half-lives of mutant huntingtin protein, depending on the neuronal type, helping to explain how certain subsets of neurons are more susceptible to Huntington's disease. The changes in protein clearance can be attributed to cell type-specific differences in proteostasis mechanisms, represented here as a tiger, determining the longevity of a neuron (tree). Cover art by Erin Dewalt, based on original artwork by Maria Zhalnina, inspired by Dalì's Dream Caused by the Flight of a Bee Around a Pomegranate a Second Before Awakening, The Three Sphinxes of Bikini and The Persistence of Memory. Article, p586

The rational redesign of a P450 active site to change the heme redox potential yields an engineered 'P411' that can be used for high efficiency cyclopropanations in cells. The image depicts the bacterium containing the engineered enzyme as a synthetic chemistry reactor. Cover art by Erin Dewalt, based on imagery from Lei Chen and Yan Liang (L2XY2.com). Article, p485; News & Views, p470

RAF family members ARAF, BRAF, CRAF, KSR1 and KSR2 are depicted as players of American football in an open, inactive conformation (first panel) to be dimerized (tackled) by their family members upon catching the ball (an ATP-competitive RAF kinase inhibitor). The inhibitor (football) stabilizes a closed conformation of the RAF kinase domain in the second panel, leading to dimerization (third panel) and allosteric activation of the binding partner (purple player, fourth panel). Cover art by Erin Dewalt, based on original artwork from Michael Hind. Article, p428

PreQ1, a biosynthetic precursor of the tRNA nucleotide queuosine, regulates expression of queuosine biosynthetic genes in the Firmicutes phylum via two distinct classes of preQ1 riboswitch. The cover features the three-dimensional structure of preQ1 bound to a class II preQ1 riboswitch from Lactobacillus rhamnosus, determined by X-ray crystallographic analysis by Liberman et al. Cover art by Erin Dewalt, based on imagery provided by Joseph Wedekind on a background micrograph of a Streptococcus sp. bacterial cluster by Janice Haney Carr. Brief Communication, p353

At the top of the quorum sensing (QS) hierarchy of Pseudomonas aeruginosa is the las system, consisting of a synthase, LasI, that generates 3OC12HSL for interaction with its cognate receptor on neighboring cells. A new QS molecule, IQS, is generated by ambBCDE, sits atop the las signaling hierarchy and is critical for cell-cell communication. Tests of P. aeruginosa infection of the nematode C. elegans (pictured) showed the importance of IQS in pathogenicity. Cover art by Erin Dewalt, based on an image from Lian-hui Zhang. Article, p339; News & Views, p292

In this issue, we explore how chemical biology can add necessary rigor to the processes of target identification, selection or validation, whether the target is a protein, another type of biomolecule or even a phenotype. The cover image depicts a series of darts, labeled with chemical probes, hitting their targets, and it represents the importance of understanding both the molecular target for a particular chemical entity and the number of molecules (both on- and off-target) engaged by that entity in the biological context of the experimental model. Cover art by Erin Dewalt, based on an image from Thinkstockphotos.com

'Reader' proteins serve as important epigenetic sensors of post-translational modifications of chromatin. James et al. identified UNC1215 as a selective inhibitor of the methyllysine reader L3MBTL3 and applied this chemical probe to identify BCLAF1 as a methyllysinedependent interaction partner for L3MBTL3. The cover image shows UNC1215 binding to L3MBTL3 as revealed by X-ray crystallographic analysis. Cover art by Erin Dewalt, based on an image provided by Dmitri Kireev. Article, p184.

Zebrafish provide a powerful platform to interrogate metabolic processes on a whole-organism scale. This painting shows zebrafish expressing organ-specific fluorescent proteins that report on the metabolic changes associated with prolonged fasting. Cover art by Erin Dewalt, based on imagery from Joseph Schine. Article, p97; News & Views, p68

The structure of acanthaporin, a neurotoxic and antimicrobial pore-forming protein from the pathogen Acanthamoeba culbertsoni reveals a currently unknown protein fold and a pH-dependent histidine switch that controls interconversion between the inactive dimer and the active monomer. Cover art by Erin Boyle, based on an image from Matthias Leippe. Article, p37