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Many pathogens encode transporters that extract heme directly from host proteins. In this study, the authors demonstrate the utility of de novo-designed proteins in understanding the mechanism behind this process and how it can be inhibited in pathogenic E. coli.

Polygenic scores for body mass index and obesity constructed using data from 5 million people with different ancestries were associated with distinct weight gain trajectories from early childhood to adulthood.

The authors show that transcranial magnetic disruption of the right temporoparietal junction decreases strategic behavior during competitive interactions. The altered behavior relates to neural activity changes both locally and in interconnected prefrontal areas. These brain networks may causally underlie the ability to predict the behavior of other agents.

In this study, the authors assess the global response to the toxic aldehyde glyoxal (GO) in Pseudomonas aeruginosa, suggesting that GO controls quorum sensing during infection through a mechanism involving a novel protein, ArqI.

Filamin C is a key actin-binding protein involved in cardiomyopathies and musculoskeletal disorders. Here, Wang et al reveal that it interacts with the heat shock protein HSPB7 under biomechanical stress, forming a stable hetero-dimer which is regulated by phosphorylation.

Brain-machine interfaces are hindered by neuroinflammation. Here, the authors found that bacterial sequences invade the brain post-microelectrode implantation. Antibiotic-treated mice showed reduced bacterial presence and altered neuroinflammatory profile, temporarily improving recording performance.

The development of IDH variant inhibitors is a breakthrough as it is the first time metabolism has been successfully targeted by small molecule drugs in cancer. Here the authors report studies on resistance to the pioneer drug ivosidenib leading to identification of inhibitors retaining activity.

BamA carries out the essential process of folding outer membrane β-barrels in Gram-negative bacteria and is a potential antibiotic target. Here, the authors discover macrocyclic peptide inhibitors that trap BamA in distinct structural conformations.

A large genome-wide association study of more than 5 million individuals reveals that 12,111 single-nucleotide polymorphisms account for nearly all the heritability of height attributable to common genetic variants.

A genome-wide association meta-analysis study of blood lipid levels in roughly 1.6 million individuals demonstrates the gain of power attained when diverse ancestries are included to improve fine-mapping and polygenic score generation, with gains in locus discovery related to sample size.

Stereotactic needle biopsies are currently performed for diagnosis only in glioblastoma; this study highlights the depth of information available through multi-omics analysis.

Medium- and branched-chain diols and amino alcohols are important industrial feedstocks, but they are biosynthetically challenging to produce. Here the authors introduce a modular polyketide synthase platform for the efficient production of these compounds.

An allosteric inhibitor of the proteolytic activity of the CBM signalosome complex scaffolding protein MALT1 acts as a pharmacological chaperone to stabilize a mutant MALT1 carried by an immunodeficient patient.

Here the authors isolate monoclonal antibodies specific for Plasmodium vivax apical membrane antigen 1, and characterize the epitope of one antibody that inhibits invasion of reticulocytes and hepatocytes, and reduces liver infection in a mouse model.

Hermes is a member of the eukaryotic hAT DNA transposon superfamily. Its transposase forms a ring-shaped tetramer of dimers to provide sufficient number of DNA binding BED domains to locate its transposon left-end in genomic DNA and facilitate the subsequent interaction with the right-end.

Autophagosome tethering compounds (ATTECs) are small molecule degraders hijacking the autophagy system. Here, the authors show that current ATTEC ligands did not bind to their designated targets but establish good ligandability of ATG8 isoforms through fragment screening and docking.

While static structures can provide insight into T cell receptor (TCR) antigen specificity, this often fails and auxiliary information is needed. Here the authors show, by focusing on an HLA-A3-bound neoantigen and its WT counterpart, the allosteric formation of a peptide-dependent dynamic gate that permits selective TCR recognition of a neoantigen.

Accounting for the diurnal cycle in low clouds more than doubles estimated aerosol radiative warming in the southeast Atlantic, according to radiative transfer modelling and satellite observations.

Sarcoma is a highly heterogeneous disease, which can be caused by a large variety of mutations. Here, the authors utilise multi-omics to characterise a cohort of 1,340 sarcoma tissue specimens to identify key somatic mutations and identify immune subtypes.

Eph receptor tyrosine kinases and their ephrin ligands mediate cell-cell communication. Here, the authors assess the structure and dynamics of the EphA2 intracellular region and uncover complex effects of phosphorylation within the linker region between EphA2 kinase and SAM domains.

BRCA1 and BRCA2 are well known breast cancer predisposition genes, however, many variants have not yet been classified for their pathogenicity. Here, the authors analyse a large combined cohort to provide evidence of variant pathogenicity.

A phage-derived peptide selectively binds to the Frizzled 7 CRD resulting in disruption of the dimer interface and impairing Wnt/β-catenin stem signaling in intestinal organoids.

Knottin is a cystine knot peptide. Here, the authors develop a knottin-based tracer for positron emission tomography and demonstrate its ability to detect cancer and idiopathic pulmonary fibrosis through selective binding to integrin αvβ₆.

The exosome complex contains two catalytic subunits which degrade RNA in either a distributive (Rrp6) or a processive (Rrp44) manner—previous structures indicated how RNA could be directed to Rrp44, but the path taken to Rrp6 was unclear; here the location of the Rrp6 catalytic domain and the RNA 3′ end are determined and it is found that the RNA lies in an opposite orientation from that of the Rrp44-containing exosome structure, suggesting that the fate of an RNA may be influenced by the manner in which cofactors present it.

This study found that a prebiotic intervention was well-tolerated and safe, beneficially changed the microbiome, decreased inflammation and a marker of neurodegeneration, with possible clinical effects in Parkinson’s disease (PD) patients. This study offers the rationale for further investigations using prebiotic fibers in PD.

Self-assembly enables complex structures to be fabricated from a few relatively simple components, but requires a detailed understanding of how the constituents may interact. Here, the authors report the rational assembly and crystallographic characterization of a fullerene-protein superstructure.

Identification of specificity from antibody sequence is challenging especially when different clonotype lineages recognise antigens similarly in a process of convergence. Here using TREM2 reactive antibodies in rats as an example the authors characterise convergent antibodies and identify similarities in recognition between different lineages.

A cross-ancestry meta-analysis of genome-wide association studies identifies association signals for stroke and its subtypes at 89 (61 new) independent loci, reveals putative causal genes, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as potential drug targets, and provides cross-ancestry integrative risk prediction.

Orthoreovirus σNS, essential for forming viral replication factories, has RNA chaperone activity that requires the association of σNS dimers into filamentous structures stabilized by domain-swapping interactions of the flexible N-terminal arms.

A design pipeline is presented whereby binding proteins can be designed de novo without the need for prior information on binding hotspots or fragments from structures of complexes with binding partners.

Calcium-independent phospholipase A₂β (iPLA₂β) is involved in many physiological and pathological processes but the underlying mechanisms are largely unknown. Here, the authors present the structure of dimeric iPLA₂β, providing insights into the regulation of its activity and cellular localization.

AspH catalyses hydroxylation of asparagine and aspartate residues in epidermal growth factor-like domains (EGFDs). Here, the authors present crystal structures of AspH with and without substrates and show that AspH uses EFGD substrates with a non-canonical disulfide pattern.

Several β-secretase (BACE) inhibitors exhibit unexplained ocular toxicity in preclinical studies. Here the authors generate a clickable photoaffinity probe to interrogate off-targets in cells and animals, and identify inhibition of cathepsin D as a driver of ocular toxicity.

The voltage-sensing domain of Ci-VSP regulates the enzymatic activity of its PTEN-like phosphatase domain. New structural and functional data identify a gating loop that controls access to the enzyme's active site and is coupled to voltage sensor movements.

Here, the X-ray crystal structure of the β₁ adrenergic receptor, a G-protein-coupled receptor, bound to four small molecules that either act as full agonists or partial agonists is solved. The structures show that agonist binding induces a contraction of the catecholamine-binding pocket relative to the antagonist-bound receptor. This work reveals the pharmacological differences between different ligand classes, which should facilitate the structure-based design of new drugs with predictable efficacies.

Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.

The authors present structures of plant polerovirus ^NRTD proteins that protrude from the viral capsid and show that the purified ^NRTD can inhibit insect transmission and act as a bioinsecticide, providing a blueprint for control of related viruses.

Azacitidine (AZA) response in myelodysplastic neoplasms is unpredictable. Here, the authors show in a phase 2 trial that while global methylation changes did not differ by response, baseline and initial CpG methylation differences in HSPCs predicted AZA response.

Anti-integrin therapy inhibits lymphocyte trafficking in ulcerative colitis. Here Mennillo et al. use single-cell and spatial -omics to show modulation of mononuclear phagocytes and other networks, identifying gene sets related to treatment response.

VRC01-class bNAbs against the CD4 binding site of HIV-1 Env are targets of vaccine design. Here, the authors structurally characterized germline versions of the VRC01-class bNAb, BG24, bound to Env. They reveal mechanisms of germline binding, informing the design of VRC01-class targeting immunogens.

Approaches have been devised to increase the discovery rate of intrabodies but often these yield results that aren’t functional in cells. Here the authors engineer and optimise an autonomous and disulphide-free human VH domain for intracellular expression, and they identify several VH domain binders against eIF4E.

MLKL is regarded as an executor of the necroptotic inflammatory cell death pathway. Here authors show, by introducing a mutation into mouse MLKL representing a frequently occurring human single nucleotide polymorphism, that MLKL mutations could critically alter the inflammatory response and the clearance of Salmonella from organs upon infection.