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Coagulation factor IX (FIX) contributes to hemostasis through both plasma activity and binding to extravascular collagen IV. Here, the authors show that collagen binding of albumin-fused hyperactive FIX can be engineered to tailor the pharmacokinetics, distribution, and functional properties in mice for tailored short- or long-term hemophilia B therapy.

Khetarpal et al. show that the metabolic regulator PGC-1α is essential in heart muscle cells for exercise-driven cardiac growth, and that suppression of the stress-induced myokine GDF15 is required to enable cardiomyocyte adaptations to training.

Elephant endotheliotropic herpesvirus (EEHV) haemorrhagic disease is a major threat for juvenile Asian elephants. This study reports a proof-of-concept trial that evaluates the safety and immunogenicity of a vaccine against EEHV.

Palmitoylation at C64 in stimulator of interferon genes (STING) is reported and, along with engagement of C91, is involved in dynamic cross talk with C148 to alter STING oligomer states and ultimately control STING activation.

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.

CRAF is one of three RAF-family kinases and is mutated in cancer and RASopathies. Jang et al. report structural and mechanistic studies of CRAF/MEK1/14-3-3 complexes that explain distinct features of CRAF regulation.

In this study, Weber et al., investigate the long-term survival and integration of human stem cell-derived neural progenitors into the stroke-injured mouse brains. They report grafted cells integrate into host circuits and mediate repair through graft-host crosstalk via neurexin, neuregulin, neural cell adhesion molecules, and SLIT signalling pathways.

Deltex E3s modify ADP-ribosylated targets with ubiquitin, creating a hybrid modification whose readers remains unknown. Here, the authors synthesise a non-hydrolysable probe that mimics the modification and identify RNF114 as an interactor. RNF114 binds tightly to this modification and further elongates it with a K11-linked ubiquitin chain.

A report from the first 2,000 newborns enrolled in the Early Check program, which offered genome screening covering 198 genes associated with early-onset diseases, shows the feasibility and potential clinical utility of the approach, leading to 28 true positive results.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

Computational methods are becoming an increasingly important part of biological research. Using the Rosetta framework as an example, the authors demonstrate how community-driven development of computational methods can be done in a reproducible and reliable fashion.

Predictive protein design and experiments are combined to develop anisotropic bifaceted protein nanomaterials using pseudosymmetric hetero-oligomeric building blocks.

Metformin is under clinical trial for brain neuroprotection but how it may work is poorly understood. Here, the authors show that metformin helps myelin formation by human oligodendrocytes and improves mitochondrial action in all brain cells.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

This study reveals that an outer membrane protein from the predator Bdellovibrio bacteriovorus forms a pentameric assembly that traps a lipid monolayer within. This allows the discovery of two superfamilies, distributed across a wide range of bacteria, likely to adopt a similar architecture.

Induced proximity by molecular glues is a strategy that leverages the recruitment of proteins to facilitate their modification or degradation. Here the authors present unbiased quantitative proteomic, biochemical and computational workflows that uncover hundreds of CRBN molecular glue targets using recombinant protein and cell lysate.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.

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.

Acyl-CoA oxidases, which play important roles in primary and secondary metabolism, are not known to be regulated by ATP. Here, the authors uncover the mechanism whereby ATP binds to an acyl-CoA oxidase, enhancing its affinity for its FAD cofactor and stimulating its enzymatic activity.

Phosphorylation of residues in the N-terminal tail of histone H3 signals different biological outcomes. High-resolution NMR analyses now reveal a mechanistic hierarchy of H3 phosphorylation events, whereby phosphorylation of Ser10 impedes the phosphorylation of Thr6 and Thr11 by PKC and Chk1, respectively. Because both enzymes also target Ser10, this establishes an autoinhibitory feedback loop on H3 tails.

How cyclins contribute to CDK1 substrate specificity during cell division is poorly understood. Here, the authors show that a phosphate-binding pocket in cyclin B1 is critical for accurate CDK1 substrate phosphorylation ensuring mitotic fidelity.

Chromatin “breathing” at DNA lesions is controlled by different waves of histone ADP-ribosylation.

The autophagy protein p62 undergoes liquid-liquid phase separation but how this is regulated is unclear. Here, the authors report that the histone chaperone DAXX interacts with p62 in the cytoplasm to drive its phase separation.

The authors present a novel channel rhodopsin variant with enhanced Ca²⁺ conductance in megakaryocytes and platelets.

BMAL1–HIF2α heterodimer was recently shown to modulate circadian variations in myocardial injury. Here, the authors show that BMAL1 can form a heterodimer with HIF2α in clear cell renal cell carcinoma, contributing to tumor progression and response to HIF2α antagonist drugs.

Designed novel protein nanoparticle technology integrates antibody targeting and responds to changes in environmental conditions to release protected molecular cargoes, opening new applications for precision medicine.

Elena De Vita and Rebecca Page reflect on the unique properties of phosphate, an essential building block with versatile functions in living systems. Modulating protein phosphorylation is an effective therapeutic strategy, with emerging approaches highlighting the continuous development in this area of drug discovery.

Genetic analyses of ancestrally diverse populations show evidence of heterogeneity across ancestries and provide insights into clinical implications, highlighting the importance of including ancestrally diverse populations to maximize genetic discovery and reduce health disparities.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Developmental and epileptic encephalopathies are devastating neurological disorders. Here, the authors establish a cohort of patients with variants in the gene DENND5A and use human stem cells to discover a disease mechanism involving altered cell division.

Therapeutic proteins are often conjugated with polymers, but separating the conjugate from unconjugated protein and free polymer is a major challenge. Here, the authors discover that proteins conjugated to charged or zwitterionic polymers maintain solubility in 100% ammonium sulfate, greatly simplifying purification.

Recent studies have shown that energy transfer photoenzymes can be engineered to promote stereocontrolled [2 + 2] cycloadditions; however, existing systems rely on ultraviolet light and display limited photochemical efficiencies. A generation of thioxanthone-containing photoenzymes now harnesses visible light to drive challenging photochemical conversions with high efficiencies and selectivities.

RH5, which is part of the trimeric RCR-complex essential for invasion, is a vaccine candidate for malaria. Here, Williams et al. show that monoclonal antibodies targeting each of the three proteins in the RCR-complex can work together to more effectively block the invasion of red blood cells by Plasmodium falciparum and design a combination vaccine candidate.

The flagship paper of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes Consortium describes the generation of the integrative analyses of 2,658 cancer whole genomes and their matching normal tissues across 38 tumour types, the structures for international data sharing and standardized analyses, and the main scientific findings from across the consortium studies.

A pan-cancer genomic analysis reports the effects of structural variations on chromatin domains (TADs). Most TAD disruptions do not result in appreciable changes in expression of nearby genes.

Padi and Godek et al. solve cryo-electron microscopy structures of protein phosphatase 2A (PP2A):B55 bound to p107 and Eya3, which, together with nuclear magnetic resonance dephosphorylation experiments, show how PP2A:B55 recruits specific substrates and how it achieves efficient dephosphorylation of phosphosites with high cellular fidelity.

Collagen proteins assemble into trimers from distinct monomers with high specificity, yet the molecular basis for this specificity remains unclear. Here the authors demonstrate the crucial role of conserved C-terminal domain cysteine residues and calcium in homotrimeric procollagen assembly.

Modifications enhancing degradation resistance and albumin affinity enabled the delivery of an siRNA conjugate silencing MMP13 to guinea pig and murine arthritic joints, improving therapeutic outcomes following intravenous administration.

Deep learning methods have been used to design proteins that can neutralize the effects of three-finger toxins found in snake venom, which could lead to the development of safer and more accessible antivenom treatments.

The tetrameric neuraminidase (NA) of influenza virus H1N1 requires calcium at the centre of the tetramer for its activity. Substitutions that alter binding of NA to central calcium contribute to H1N1 virus diversification and adaptation over time.

Access to defined human glycans is crucial for biomedical research. Here, authors report Glycocarriers, a mammalian cell-based method for the sustainable and scalable production of O-, N-glycans, and glycosaminoglycans in various formats including free glycans, glycopeptides, and multimer glycomodules.

Ultrafast breaking of the molecular symmetry is a key process in photochemistry. Here the authors show direct observation during internal conversion of a heterocyclic molecule using Coulomb explosion imaging supported by simulations.

Hepatitis E virus exists in two forms in patients: naked and quasi-enveloped. Using a new imaging method, the authors found that these forms enter cells through different pathways, directed by interaction of the capsid protein with integrin beta 1.