Several compounds, including the HIV protease inhibitor ritonavir and a synthetic peptide, disrupt the interaction between CD95 (blue ribbon) and PLCγ1 (orange ribbon) by mimicking the structure of the CD95/Fas calcium-inducing domain, which mediates binding to PLCγ1 at the membrane (grey sticks). These inhibitors limit calcium signaling and Th17 migration driven by the soluble CD95 ligand, s-CD95L, as well as inflammation in lupus mice. In HIV patients treated with HIV protease inhibitors, PBMCs show impairment of the non-apoptotic pro-migratory CD95 pathway.

See Legembre et al.

The cover depicts the structure of tRNAMet bearing an N 4-acetylcytidine (ac4C) modification at the first position of the anticodon. The acetyltransferase TmcAL introduces the ac4C modification, and loss of TmcAL results in misdecoding of the AUA codon.

See Taniguchi et al.

The cover depicts the distribution of the cell polarity regulators, the PKC-3 complex (cyan) and the PAR-1–PAR-2 complex (magenta), in a Caenorhabditis elegans zygote and in Saccharomyces cerevisiae cells, which is regulated by a combination of cortical exclusion and stabilization by a circuit consisting of aPKC and the PRBH protein PAR-2.

See Motegi et al.

A computational design approach was used to obtain a glycine-binding protein that could be developed into a genetically encoded FRET-based optical sensor, GlyFS. GlyFS was used to monitor hippocampal glycine levels in brain tissue, with the sensitivity to determine differences in spines and shafts, as well dynamics induced by high- and low-frequency stimulation. Shown here are astroglial branches in grey and a single dendritic fragment in red.

See Henneberger et al.

In Rauwolfia serpentina (pictured) and other alkaloid-producing plants, sarpagan bridge enzyme can catalyze either cyclization or aromatization, depending on the substrate, to produce diverse classes of monoterpene indole alkaloid products.

See O’Connor et al.

The cover depicts the distribution of copper in brain tissue slices of larval zebrafish, imaged using the fluorescent probe Copper Fluor-4 and stylized to appear as an oil painting. Rows depict various developmental stages of either wild-type or copper-deficient zebrafish, while columns depict anterior-to-posterior slices (left to right).

See Chang, C et al.

The cover depicts a Wnt protein (white dots) interacting with a Frizzled (Fzd)-expressing intestinal crypt containing intestinal stem cells (yellow beads), paneth cells (orange beads), transit amplifying cells (blue beads) and enterocytes (gray beads) enclosing a luminal structure. Disruption of Wnt–Fzd signaling with a Fzd7-binding peptide impairs stem cell function.

See Hannoush, R et al.

The jasmonoyl-isoleucine (JA-Ile) receptor COI1 is conserved between Arabidopsis and Marchantia, with the COI1 ligand in Marchantia identified as two isomers of the JA-Ile precursor dinor-OPDA. The cover depicts a fluorescence image of a Marchantia polymorpha (Mp) gemma showing localization of the MpJAZ co-receptor (green) in the nucleus. Chloroplast autofluorescence is shown in red.

See Solano et al.

The cover depicts a red seaweed Laurencia spp. Bacteria living on red seaweeds degrade algal cell walls made of carbohydrate polymers such as agar. Agars contain methylated sugars, which suppress degradation by bacterial enzymes. Discovery of a new class of sugar demethylating enzymes from the P450 cytochrome monooxygenase family defines a mechanism to enhance bacterial agar degradation.

Cover design by Erin Dewalt based on an image provided by Wilfried Thomas.

Diversity in the function of nucleic acids, proteins and other biological macromolecules is due in large part to the chemical modifications that they undergo during their biosynthesis and as they take part in their biological functions. The collection of pieces in this themed issue highlights the structural and functional importance of several post-translational modifications of proteins, as well as chemical modifications of nucleic acids, lipids, and carbohydrates. The cover image depicts a subset of the myriad chemical modifications explored in this issue as pattern pieces that are used to tailor biological macromolecules. Cover art by Erin Dewalt.

The cover depicts infection of an Arabidopsis plant by the fungus Botrytis cinerea. Jasmonylisoleucine is a phytohormone that regulates plant defense against fungal pathogens and whose synthesis was thought to be dependent on OPDA reductase 3 (OPR3) activity. An OPR3-indendent pathway was identified that produces 4,5-didehydrojasmonate as a precursor for jasmonyl-isoleucine. Cover design by Erin Dewalt, based on an image taken by Andrea Chini. Article, p171; News & Views, p109

Potent small-molecule inhibitors of the endosomal Toll-like receptor TLR8 bind a unique site on the inactive dimer interface to stabilize the resting state. The representation of TLR8 dimeric complexes is based on X-ray crystallographic structures, with the computationally simulated protein surface in color. The compounds suppress TLR8-mediated proinflammatory signaling in cell lines, in human primary cells, and in tissue from rheumatoid arthritis and osteoarthritis patients, highlighting TLR8 inhibition as a potential therapeutic approach for these diseases. Cover art by Erin Dewalt, based on artwork created by Cuncun Zhao. Article, p58