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Using generative AI, Insilico Medicine developed an oral PROTAC that potently inhibits and degrades PKMYT1, a synthetically lethal target in cancer, demonstrating high selectivity and strong antitumor efficacy in preclinical models.

In-depth characterization of adeno-associated virus (AAV)-mediated CRISPR delivery is still lacking. Here, the authors show high levels of integration into Cas9-induced double-strand breaks (DSBs) in therapeutically relevant genes in vivo.

This study defines the consequences of ARID1A and ARID1B loss in dedifferentiated or undifferentiated endometrial carcinoma, finding that altered SWI/SNF chromatin remodeler complex subtypes support oncogenesis, informing potential therapeutic opportunities.

Mutations in the chromatin modifier Chd7 have been associated with CHARGE syndrome and other developmental disorders. Here the authors show that Chd7 is required for the activation of genes essential for cerebellar granule cell differentiation, and that disrupting Chd7 leads to cerebellar hypoplasia in mice.

Using avian trait data and genomic data, the authors infer whether changes in net effective population size over time in response to climate change are correlated with multiple morphological and life history traits; they find that larger-bodied, slower-reproducing species with limited dispersal capacity are most sensitive to changes in warming and cooling climates.

How genome stability is maintained at regions of active transcription is currently not entirely clear. Here, the authors reveal an association between base excision repair factors and transcription elongation to modulate DNA repair.

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.

Nucleophosmin (NPM1) gene mutation induces a specific gene expression program leading to acute myeloid leukaemia. Here, the authors show that mutant NPM1 activates a HOXB locus-associated long non-coding RNA which is essential for its associated oncogenic transcriptional program and leukaemia development.

cfDNA fragmentomics is a potential clinically applicable method for identifying cancer. Here, the authors assess fragmentomics analysis methods and their application to commercial targeted sequencing panels.

Circulating tumor cell (CTC) clusters are much more likely to produce viable metastasis than single CTCs. Here the authors find that the transmembrane protein Plexin-B2 (PLXNB2) mediates homotypic and heterotypic CTC cluster formation, driving lung metastasis in breast cancer mouse models.

Highly protected areas help drylands stay productive under increasing aridity, delaying critical ecosystem thresholds and underscoring the need to expand protection to safeguard these vulnerable regions from climate change.

Understanding principles that govern protein association with extracellular vesicles should expand their potential as a therapeutic modality. Here, the authors show that by localizing proteins to the plasma membrane and lipid rafts, a variety of proteins can be preferentially loaded into extracellular vesicles.

Hydroazidation of alkenes provides a direct entry to alkyl azides which are prevalent structural motifs in medicine development and chemical biology probes. Here the authors report a photocatalytic anti-Markovnikov hydroazidation of alkenes enabled by cooperative ligand-to-metal charge transfer and hydrogen atom transfer.

Accurate spectral libraries are essential for analyzing data-independent acquisition (DIA) proteomics data. Here, the authors present Carafe, which trains on DIA data to build experiment-specific spectral libraries, boosting peptide detection across diverse datasets.

Garnet-type LLZO electrolytes are considered among the most promising solid-state electrolytes for all-solid-state batteries; however, numerous challenges need to be addressed before they are integrated into a cell. By precipitating amorphous zirconium oxide onto grain boundaries, increased ionic conductivity is observed and dendrite growth is suppressed.

This prespecified updated survival and exploratory subgroup efficacy analysis of the phase 3 DESTINY-Breast04 trial shows that trastuzumab deruxtecan treatment in patients with HER2-low metastatic breast cancer leads to continuous survival benefit irrespective of estrogen receptor or hormone receptor status.

Crystal structures of cyanobacterial protochlorophyllide oxidoreductases reveal the basis of the photocatalytic activities of this enzyme, through the role of its active site in enabling the light-driven reduction of protochlorophyllide.

Broad-spectrum vaccines have been proposed as a tool for rapid response to emerging infectious disease threats and are in pre-clinical development. Here, the authors use mathematical modelling to assess the potential impacts of broadly protective sarbecovirus vaccines for a hypothetical “SARS-X” outbreak.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Which combination of current genome sequencing and assembly approaches results in high-quality, complete diploid genome assemblies is determined.

Silicon carbide is a polymorphic material with over 250 known crystal structures. Here the authors show that such polymorphism can be used as a degree of freedom for engineering optically addressable and coherently interacting spin states, including many with room-temperature quantum coherence.

Chemical functionalization of graphene is a useful method for modulating its properties, although this is limited by a lack of control and resulting in poorly defined structures. Here the authors report the atomically precise chlorination of nanographenes and apply the methods to graphene nanoribbons.

Tuning the electronic properties of nanocatalysts by doping them with uniformly dispersed hetero-metal atoms is an effective way to improve catalytic performance. Here, the authors show that weakening the Cu–O bond energy in CuO nanocatalysts boosts the efficiency of NH₃ oxidation.

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.

The utility of CRISPR-based technologies could be enhanced with the ability to control the spatial and temporal expression of gRNAs. Here the authors design a tRNA scaffold for highly specific gRNA production from a Pol II promoter.

Wood density is an important plant trait. Data from 1.1 million forest inventory plots and 10,703 tree species show a latitudinal gradient in wood density, with temperature and soil moisture explaining variation at the global scale and disturbance also having a role at the local level.

Advances have been made in thin-film piezoelectrics; however, the linearity of electric-field-induced strain with frequency and temperature still requires improvement. Here, by growing interlocked monoclinic and tetragonal polar nanoregions in (K,Na)NbO₃ thin films, highly linear strains of up to 1.1% are reported at frequencies up to 10⁵ Hz.

The enteric nervous system integrates microbial cues to regulate gut function. Using an optogenetic gut culture model, authors show lineage- and frequency-specific neuronal control of immune responses and barrier integrity, shaped by gut microbes.

The bird hand is thought to derive from the second, third and fourth digits of an ancestral five-digit hand. However, the three-fingered hand of theropod dinosaurs, which are the closest extinct relatives of birds, are thought to derive from the first, second and third digits. The discovery of a small, primitive herbivorous theropod from the Jurassic period of China with a stub of the first digit alongside more developed second, third and fourth digits, sheds light on this problem.

The synthesis of crystalline 2D polymers typically relies on reversible dynamic covalent reactions, but achieving 2D polymers through irreversible carbon-carbon coupling reactions remains a formidable challenge. Here, the authors present an on-liquid surface synthesis method for constructing diyne-linked 2D polymers.

Li et al. characterize overlapping and divergent metabolic requirements of human and murine NK cells in response to activation, with a focus on serine metabolism

Using pancreatic organoids and genetic mouse models, Antonucci et al. show that cellular stress activates an NRF2–EZH2 epigenetic axis leading to metabolic reprogramming and subsequent malignant transformation of KRAS-mutant benign lesions.

The metabolic dependencies of androgen receptor (AR)-driven growth in prostate adenocarcinoma are largely unknown but could represent a therapeutic target when hormonal manipulations fail. Here the authors demonstrate that the mitochondrial pyruvate carrier (MPC) is transcriptionally regulated by AR and that MPC inhibition suppresses tumour growth in hormone-responsive and castrate-resistant conditions.

The cortex fuels essential physiological processes with glucose-derived carbon, while gliomas fuel their aggressiveness by rerouting glucose carbon pathways and scavenging alternative carbon sources such as environmental amino acids, providing a potential therapeutic target.

CDK4/6 inhibitors have improved outcomes for patients with ER+ breast cancer, however, those with loss of RB1 function often fail to respond. Here, the authors identify a vulnerability of ER + /RB1- breast cancer on PRMT5 and via dual blockade of ER and PRMT5 therapeutically target this in patient-derived xenograft models.

Transancestral GWAS meta-analysis in 160,420 individuals identifies 139 loci associated with refractive error, including myopia. Newly identified genes implicate pathways involved in eye growth and light signaling cascades.

Embryonic stem cells for chicken and seven other avian species are derived.

Electrochemical CO_x reduction to multi-carbon products is hindered by low energy efficiency, in part due to sluggish ion transport across charge-selective membranes used in electrolysers. Here the authors use a porous, non-charge-selective separator that enhances ion transport and improves performance for CO electrolysis.

Tuft cells constitutively express IL-25 to sustain ILC2 homeostasis in the intestine, but mechanisms driving IL-25 secretion have been unclear. Here, Feng et al. find that tuft cells express IL-17RB, which is required to regulate the bioavailability of IL-25 and to restrain the activation of ILC2s during homeostasis.

There are no robust methods for systematically identifying mutation-specific synthetic lethal (SL) partners in cancer. Here, the authors develop a computational algorithm that uses pan-cancer data to detect mutation-andcancer-specific SL partners and they validate a novel SL interaction between mutant IDH and loss of ACACA in leukaemia.

Terrestrial ecosystem productivity is widely accepted to be nutrient limited. A series of standardized nutrient addition experiments, carried out on grasslands on five continents, suggests aboveground grassland productivity is commonly limited by multiple nutrients, including potassium and micronutrients.

How can the brain improve memory for an experience after it has occurred? Halpern et al. use intracranial EEG to show that, even while processing current experiences, people reactivate old ones and re-encode them, turning thoughts into memories.

International trade links regions of production and consumption. Analyses with a multiregional input–output model based on trade data reveal that much of East Asia’s aerosol radiative forcing is tied to consumption in developed countries.

ATRX inactivation occurs often in IDH-mutant gliomas and has been associated with immune dysfunction. Here, using preclinical models of glioma, the authors show that ATRX inactivation promotes innate immune signalling in response to double stranded RNA-based innate immune agonists, an effect that is masked in IDH-mutant tumours, presenting a therapeutic vulnerability.