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Pathogenic BRCA2 truncating variants in heterozygosis drive distinct cancer-linked mechanisms. Here the authors show that one causes PARPi sensitivity and HR loss via haploinsufficiency, while another expresses a truncated protein that rewires transcription by hijacking PCAF, reducing H4 acetylation and NF-κB activity.

The authors demonstrate a proof-of-principle example of an NH-π hydrogen bond on the surface of an intrinsically disordered protein through detection of weak scalar couplings by NMR, supported by Molecular Dynamics simulation and DFT calculations.

A GRK-isoform immunoassay was used to quantify GPCR phosphorylation and evaluate the potency of GRK inhibitors in a controlled cellular system.

The small molecule Yoda1 is a crucial pharmacological tool for studying the ion channel PIEZO1. Here, Verkest et al. combine 3DMINFLUX nanoscopy, electrophysiology and mutagenesis to obtain unprecedented molecular insights into Yoda’s mode-of-action.

Here authors identify GluN2D-containing NMDA receptors on interneurons as a specific target for rapid antidepressant action. Blocking GluN2D restores stress-impaired plasticity and mimics the effects of ketamine with fewer side effects.

Here, the authors present the cryoEM structure of the sodium-translocating methyltransferase (Mtr) complex from Methanosarcina mazei. Along with providing catalytic insights, they identify MtrI, an unannotated small protein, bound to the Mtr complex in a redox-dependent manner.

Tree longevity is thought to increase in harsh environments, but global evidence of drivers is lacking. Here, the authors find two different pathways for tree longevity: slow growth in resource limited environments and increasing tree stature and/or slow growth in competitive environments.

Expression of TMPRSS2—a protease that activates SARS-CoV-2 for entry into cells—renders SARS-CoV-2 insensitive to chloroquine.

Highly pathogenic avian influenza H5N1 viruses cause mass mortality in birds and have infected over 50 mammalian species, including humans. Here, the authors report the use of a propagation-defective vesicular stomatitis virus replicon vaccine in captive birds, which provides protection against lethal H5N1 challenge.

Single-cell comparison of developing bat and mouse limbs reveals conservation of cell populations and gene expression patterns, and suggests repurposing of genes involved in proximal limb development for wing evolution.

This study characterizes the interaction between the clinical candidate anle138b and Aβ₄₀ fibrils in a lipid environment. The compound reduced fibril formation by approximately 75%, providing insights relevant to Alzheimer’s drug development.

Systematic base-editing and computational screens identify specific cysteine residues on VPS35 in the retromer complex as key sensors that decrease mitochondrial translation in response to reactive oxygen species signals.

A study by Kibe et al. of the translational landscape of HIV-1 reveals alternative translation events, including use of upstream and internal open reading frames, an RNA fold regulating gag-pol frameshifting and ribosome collisions, providing new targets for antivirals.

MERS-CoV is enzootic in dromedary camels, can spread to humans but undergoes limited onward transmission. Here, Schroeder et al. compare clinical isolates of MERS-CoV in vitro and show that the predominantly circulating recombinant lineage 5 possess a fitness advantage over parental lineage 3 and 4 due to reduced activation of innate immune signaling.

Prions are infectious agents that initiate transmissible spongiform encephalopathies. The study demonstrates that Prion proteins lower cellular oxidative stress via GPX8, remodel membrane lipids, and together with RAC3, sensitize cells to ferroptotic death, highlighting new therapeutic targets in prion diseases.

Decoding the role of inter-chromosomal DNA-DNA interactions remains challenging. Here, the authors use Micro-C to study the T. brucei genome architecture at high resolution and reveal an intricate network of inter-chromosomal transcription hub structures.

17β-oestradiol establishes an anti-ferroptotic state in female kidney tubules.

XPD is part of the TFIIH complex which plays major roles in transcription initiation and nucleotide excision repair (NER). Here the authors present a high-resolution crystal structure of the XPD-MAT1 interface and dissect the role of this interface in transcription and NER.

Heissmeyer and colleagues show that TCR stimulation-induced cell death is controlled by N⁶-methyladenosine (m⁶A) modification of Orai1 and Ripk1 mRNAs. m⁶A is deposited by a ‘writer’ complex of Wtap and the N⁶-methyltransferase and bound by the ‘reader’ protein Ythdf2. T cells lacking Wtap exhibit enhanced Ca²⁺ entry in response to TCR ligation and decreased survival due to activation-induced cell death.

CtBP is a transcriptional master co-repressor with oncogenic activity. Here, the authors use structural and biophysical methods to show that CtBP interacts with RAI2 through SLiMs that induce CtBP polymerization and inactivation.

The γ-TuRC plays a key role in regulated nucleation of microtubules (MTs). Here, the authors reveal how yeast γ-TuRC is assembled and activated by dimeric CM1 motifs in receptor protein Spc72 and how MT polymerase Stu2 binds to promote MT assembly.

Innate lymphoid cells (ILC) are involved with different immune responses. Here the authors show that Interferon regulatory factor 1 (IRF1) is important for intestinal ILC3 accumulation during Citrobacter rodentium infection and promotes release of the protective cytokine IL-22 and response to IL-23.

The authors use lineage tracing to map the fate of wild-type and Brca1^−/−;Trp53^−/− cells in the adult mouse mammary gland, identifying three layers of protection that limit the spread of mutant cells at the expense of allowing a minority of mutant cells to expand, which leads to field cancerization.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

Agonists of α2-adrenergic receptors could substantially improve the clinical efficacy of cancer immunotherapy.

MYCN amplification is common in neuroblastomas. Here the authors analyse the MYCN amplicon structure and its epigenetic regulation by integrating short- and longread genomic and epigenomic data and find two classes of MYCN amplicons in neuroblastomas, one driven by local enhancers and the other by hijacking of distal regulatory elements.

The expansion of the white adipose tissue during obesity is accompanied by increased cellular stress, but factors that protect adipocytes from cell death are not well known. Here the authors report that the transcriptional co-activators YAP and TAZ are activated in adipocytes during obesity, which increases adipocyte survival through the proapoptotic factor BIM.

Two species of auxotrophic marine bacteria are shown to share precursors to synthesize the essential cofactor vitamin B₁₂, and such ligand cross-feeding may be a common phenomenon in the ocean and other ecosystems.

Sarcomas are a group of mesenchymal malignancies which are molecularly heterogeneous. Here, the authors develop an in vivo muscle electroporation system for gene delivery to generate distinct subtypes of orthotopic genetically engineered mouse models of sarcoma, as well as syngeneic allograft models with scalability for preclinical assessment of therapeutics.

Alternative lengthening of telomeres (ALT) is associated with a poor outcome in neuroblastoma. Here, the authors find that ALT is associated with mutated ATRX and/or reduced protein abundance, frequent telomeric repeat loci and heterochromatic telomeric chromatin.

A quantitative atlas of the transcriptomes, proteomes and phosphoproteomes of 30 tissues of the model plant Arabidopsis thaliana provides a valuable resource for plant research.

Glomerulonephritis is a frequent complication of autoimmune diseases, and involves aberrant activation of immune cells, but the underlying insights remain unclear. Here the authors use both patient data and a mouse glomerulonephritis model to show that increased type I interferon may expand a subset of pro-inflammatory T cells for subsequent kidney pathology.

Zuhra and Petrosino et al. report evidence that cyanide acts as a regulatory gasotransmitter in mammalian cells, where it is shown to affect cellular bioenergetics, most likely via protein S-cyanylation.

FR900359 (FR) is a Gq protein inhibitor depsipeptide isolated from an uncultivable plant endosymbiont and synthesized by non-ribosomal peptide synthetases. Here, the authors discover a cultivable bacterial FR producer and show that FrsA thioesterase domain catalyses intermolecular transesterification of the FR side chain to the depsipeptide core during biosynthesis, improving Gq inhibition properties.

Using bulk heart transcriptomics of rat models of right and left ventricle failure, Jurida et al. examined transcriptional changes in cardiomyocytes during the progression of heart failure and the overlap with transcriptomics from humans with chronic thromboembolic pulmonary hypertension (CTEPH), identifying more than 50 genes whose expression levels correlate with the severity of right heart disease.

A systems-level map of the Arabidopsis hormone signalling network, comprising more than 2,000 binary protein–protein interactions, reveals hundreds of interpathway contact points, many of which mediate crosstalk between different hormone pathways.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Using data from a single time point, passenger-approximated clonal expansion rate (PACER) estimates the fitness of common driver mutations that lead to clonal haematopoiesis and identifies TCL1A activation as a mediator of clonal expansion.

The mechanisms of intratumoral subtype heterogeneity in pancreatic ductal adenocarcinoma (PDAC) remain unclear. Here, the authors analyse PDAC tumours and preclinical models using multi-omics and imaging; they demonstrate that AP1 dichotomy influences tumor plasticity, heterogeneity, and immune response, with potential therapeutic implications.

Targeting the interaction between transcription factor TEAD and its co-repressor VGL4 is an attractive strategy to chemically modulate Hippo signaling. Here, the authors develop a proteomimetic with stabilized tertiary structure that inhibits the TEAD:VGL4 interaction in vitro and in cells.

The cellular functions of poly-SUMO chains of different compositions are not fully understood. Here, the authors characterize Arkadia/RNF111 as a SUMO-targeted ubiquitin ligase that recognizes proteins with hybrid SUMO1-capped SUMO2/3 chains and targets them for proteasomal degradation.

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.

Schneeberger, Kim, Geesdorf, Rajewsky, Heppner et al. tease IL-12 and IL-23 signaling apart in mouse models and human brain tissue to define a role for oligodendroglial and neuronal IL-12 signaling in neuroimmune crosstalk in Alzheimer’s disease.

Focusing on two ill-characterized subtypes of medulloblastoma (group 3 and group 4), this study identifies prevalent genomic structural variants that are restricted to these two subtypes and independently bring together coding regions of GFI1 family proto-oncogenes with active enhancer elements, leading to their mutually exclusive oncogenic activation.

The implementation of RNA viral transfection technology in multiple plant species allows transient expression or silencing of specific regulatory genes in various regulatory circuits to rapidly fine-tune multiple traits without modifying the genome.

Over half the world’s rivers dry periodically, yet little is known about the biological communities in dry riverbeds. This study examines biodiversity across 84 non-perennial rivers in 19 countries using DNA metabarcoding. It finds that nutrient availability, climate and biotic interactions influence the biodiversity of these dry environments.

Many natural products exist as families of structurally similar molecules, and therefore developing skeletal modifications of common intermediates offers flexible and powerful approaches for target synthesis. Here, the authors report a single-atom insertion into the framework of the benzenoid subfamily, providing access to the troponoid congeners.

The cryo-EM structure of the γ-tubulin ring complex (γ-TuRC) from Xenopus laevis provides insights into the molecular organization of the complex, and shows that actin is a structural component that is functionally relevant to microtubule nucleation.

Secondary lymphedema occurs frequently following oncologic surgery, but treatments are still lacking. Here the authors show, using both human samples and mouse models, that anti-CTLA4 mAb helps prevent edema and preserve lymphatic functions with corresponding expansion of T_reg cells, thereby hinting anti-CTLA4 as a potential treatment option.