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POLG mutations impair mitochondrial DNA replication and cause diverse mitochondrial diseases. Here, the authors show that structural differences in the POLγB subunit between humans and mice modulate mutation severity.

Fittipaldi et al. examined how heterogeneity affects social cognition in populations over 50 years old by using advanced neuroimaging techniques and social cognition assessments in a diverse sample of over 1,000 adults across nine countries.

Interplay of enzyme PqsE and transcription factor RhlR controls the virulence of Pseudomonas aeruginosa. Here, the authors show that complex formation with PqsE stabilizes RhlR in a soluble active state. PqsE/RhlR complex structures provide a basis for drug discovery against this important pathogen.\

Clinical studies have suggested that the therapeutic potential of polyclonal convalescent plasma is highest in the first days of symptoms. Here, the authors present results from a pooled analysis of two clinical trials in COVID-19 outpatients that did not provide conclusive evidence in favor of convalescent plasma.

Progranulin-deficieny results in gangliosidosis due to reduced lysosomal lipids (BMP) required for ganglioside degradation. Lysosomal ganglioside accumulation may contribute to neuroinflammation and neurodegeneration susceptibility observed in FTD.

To improve annotation in non-targeted metabolomics studies, authors develop a Multiplexed Chemical Metabolomics (MCheM) platform, combining post-column derivatization with integrated data processing. MCheM enables feature-resolved chemical tagging across complex mixtures, which provides orthorgonal chemical information about unknown metabolites.

Mutations in the ADD domain of ATRX protein lead to severe mental retardation. Now the importance of this domain for targeting ATRX to heterochromatin is examined; ADD simultaneously recognizes unmethylated lysine 4 and trimethylated lysine 9 of histone H3, making it a combinatorial reader. This readout is enhanced by interaction with HP-1, forming a tripartite network that may bridge adjacent nucleosomes.

Using a globally distributed standardized aerial sampling of fungal spores, we show that the hyperdiverse kingdom of fungi follows globally highly predictable spatial and temporal dynamics, with seasonality in both species richness and community composition increasing with latitude.

African Trypanosomes have developed elaborate immune evasion mechanisms. Here, the authors present the cryoelectron microscopy structures of a trypanosome surface receptor with human complement C3 and C3b, revealing several modes of complement interaction.

Whole-genome sequencing data from more than 2,500 cancers of 38 tumour types reveal 16 signatures that can be used to classify somatic structural variants, highlighting the diversity of genomic rearrangements in cancer.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

The cryo-electron microscopy structure of the human adenosine A₁ receptor in complex with adenosine and heterotrimeric G_i2 protein provides molecular insights into receptor and G-protein selectivity.

Correlating aromatic carbons attached to fluorine with meta-position hydrogens in fluorine-labelled phenylalanines can yield two-dimensional correlations with narrow linewidths in large proteins. Adapting phenylalanine-tRNA synthetase increases the incorporation rate, while expanding the genetic code enables site-specific incorporation of fluorinated phenylalanine. The resulting HC_F-transverse relaxation-optimized spectroscopy can illuminate protein dynamics and drive multiplexed drug discovery campaigns.

A report from the Australian Acute Care Genomics programme shows that the integration of rapid whole-genome sequencing and multi-omic analyses informs diagnoses and treatment decisions in a prospective cohort of 290 critically ill infants and children.

Sebastian Bonhoeffer, Christos Petropoulos and colleagues report a systems analysis of the fitness landscape of HIV-1 protease and reverse transcriptase. They use a dataset of over 70,000 virus samples, isolated from HIV-1 subtype B infected individuals, assayed for in vitro replicative capacity alone or under drug selection.

Adverse climatic conditions are commonly reported to shape asylum migration, but their effect relative to other drivers is unknown. Here the authors compare climatic, economic, and political factors as predictors of future asylum flows to the EU and find that war and repression are the most important factors.

SNAIL promotes tumour metastasis through inducing epithelial to mesenchymal transition (EMT). Here the authors report that SNAIL bypasses senescence and regulates cell cycle progression to promote pancreatic carcinogenesis and this is independent of EMT induction.

Saturation genome editing characterizes BAP1 variants and their association with disease presentation. A phenome-wide association analysis in the UK finds that BAP1 variants identified as deleterious in the study are associated with higher serum IGF-1 levels.

High spatiotemporal precision tracking using 3D MINFLUX shows that nuclear import and export occur in overlapping regions of the central pore, providing insight into transport across the nuclear pore complex.

In this large interventional, randomized controlled trial, structured and individualized exercise in patients with metastatic breast cancer led to lower levels of fatigue and improved health-related quality of life.

Some biological reactions can require thermodynamically unfavourable electron transfer processes, the occurrence of which are not yet fully understood. Here, the authors provide the structural basis of energy transduction during the reductive activation of B12-dependent methyltransferases.

Peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS) is a heterogeneous and aggressive type of T-cell lymphoma. Here, the authors perform single-cell analyses of human and murine PTCL-NOS tumors, and identify a subtype defined by the loss of SMARCB1 that could be targeted with HDAC-inhibitor combination therapies.

Volta phase-plate cryo-electron microscopy reveals the structure of the full-length calcitonin receptor in complex with its peptide ligand and Gα_sβγ.

A longitudinal study of clinically unimpaired individuals reveals that Lewy body pathology measured in vivo is associated with worse smell and cognitive functions and predicted subsequent cognitive decline and progression to Parkinson’s disease or dementia with Lewy bodies.

Here, the authors solve a series of cryo-EM structures of the Swi2/Snf2 family transcription regulator Mot1 to show how this remodeler uses energy to displace the transcription initiation factor TBP from its gene promoters.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Here the authors identify PHF3 SPOC domain as a reader of the phosphorylated RNA polymerase II (Pol II) C-terminal domain. They show that PHF3 clusters with Pol II complexes in cells, drives phase separation of Pol II in vitro, and regulates neuronal gene expression and neuronal differentiation.

Proteins are inserted into the outer mitochondrial membrane by the mitochondrial sorting and assembly machinery, two structural forms of which are presented here, suggesting the mechanism involved.

Chordoma is a rare often incurable malignant bone tumour. Here, the authors investigate driver mutations of sporadic chordoma in 104 cases, revealing duplications in notochordal transcription factor brachyury (T), PI3K signalling mutations, and mutations in LYST, a potential novel cancer gene in chordoma.

A proteomics approach using MS2 as an RNA tag is used to provide snapshots of nascent preribosomal particles from budding yeast, thus allowing the determination of the stage-specific order in which 70 ribosome-assembly factors associate with pre-rRNA domains.

Here the authors determined several cryo-EM structures of the human Elongator complex, which modifies anticodons of tRNAs. The structural work is complemented by functional analyses to understand this clinically relevant cellular machine at the molecular level.

Sensory processing can be influenced by non-sensory signals. Here, the authors demonstrate that, in the primary olfactory cortex, odour-responsive neurons acquire multiple non-sensory signals through learning, improving odor decoding and discrimination.

Eitan et al. discovered genetic variants in the 3′UTR for the gene encoding IL-18 receptor that protect against ALS. The variant 3′UTR destabilizes the mRNA and dampens microglia NF-κB signaling and neurotoxicity, thus emphasizing the value of noncoding genetic association studies.

A computationally designed antigen based on the receptor binding domain of the spike protein of sarbecoviruses elicits broad humoral responses against severe acute respiratory syndrome viruses in mice, rabbits and guinea pigs.

Hereditary ATTR amyloidosis has diverse disease manifestations. Using cryo-EM it was possible to reveal, that the phenotypic variations arise from the circumstances under which the amyloid fibrils are formed, rather than from different fibril morphologies.

Wang et al. report on an inhibitor of the lysine methyltransferase KMT9 with cellular activity. The inhibitor blocks proliferation of androgen-resistant prostate cancer cells, opening therapeutics avenues to treat this type of cancer.

Using human cerebrospinal fluid proteomics, the authors found that proteins associated with Aβ pathology in Alzheimer disease were mainly expressed in glial cells, whereas those associated with tau tangle were linked to metabolism and mainly expressed in neurons.

Here the authors show that, upon embryo implantation, signaling triggers a large-scale rearrangement of protein–RNA interactions. Phosphorylated LIN28A reassembles onto the 3′ untranslated region termini of pluripotency-associated mRNAs, where it converges with the binding of poly(A)-binding protein and drives selective mRNA decay.

New simulations find that one of Antarctica’s largest ice shelves, the Filchner–Ronne, may be less vulnerable to climate change than previously thought. Melting of the ice shelf initially decreases for many decades, and only increases when global warming exceeds approximately 7 °C.

Mas et al introduce in-cyclo NMR to quantify all states and kinetic steps of Hsp70 chaperones ATPase cycle. In-cyclo NMR will enable studies of other molecular machines at an unprecedented level of detail.

The fundamental processes of protein insertion and translocation at the outer membrane are mediated by Omp85 proteins. Here the authors report structures of the translocase FhaC, showing that the critical L6 loop adopts a conformation similar to that of related insertases; establishing a common structural basis for Omp85 function.

SCF–FBXO31 scans proteins for C-terminal amidation and marks them for subsequent proteasomal degradation.

A computational deep learning approach is used to design synthetic proteins that target the neosurfaces formed by protein–ligand interactions, with applications in the development of new therapeutic modalities such as molecular glues or cell-based therapies.

The alkaloids crocagins are derived from a ribosomal peptide through a series of enzymatic post-translational modifications. A combination of biochemistry and structural biology techniques has now been used to elucidate this biosynthetic pathway, propose a mechanism for the formation of the tetracyclic core structure and enable genome mining for related natural products.

Mapping the metabolic effects of drugs helps define their mode of action.

A novel multi-omics workflow, combining gut microbiome metagenomics, metatranscriptomics and metabolomics, enabled the identification of the microbial pathways responsible for the degradation of the immunomodulatory drug 5-ASA in the gut of patients with inflammatory bowel disease.

A massively parallel assay developed to map the essential photosynthetic enzyme rubisco showed that non-trivial biochemical changes and improvements in CO₂ affinity are possible, signposting further enzyme engineering efforts to increase crop yields.

The structure and function of the MCR activation complex from Methanococcus maripaludis were revealed, demonstrating its ATP-dependent ability to activate MCR and form methane while uncovering a unique electron transfer pathway involving iron–sulfur clusters similar to the nitrogenase cofactor intermediates.