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Native top-down proteomics reveals epidermal growth factor receptor–estrogen receptor-alpha (EGFR–ER) signaling crosstalk in breast cancer cells and dissociation of nuclear transport factor 2 (NUTF2) dimers to modulate ER signaling and cell growth.

Pangenomic and epidemiological analyses reveal a genetic shift in U.S. Salmonella Hadar populations during 2019–20, driven by expansion of a lineage carrying a prophage-like element that likely arose in commercial poultry and spread to backyard flocks.

Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

PCNA–PAF15 has a key role in determining replisome dynamics during genome replication and protecting against genome instability.

In this study, the authors present optimization and efficacy testing of apolipoprotein-based lipid nanoparticles for delivering various nucleic acid therapeutics in vivo to immune cells and their progenitors in the bone marrow.

Cornell et al. show that target cells with low cortical tension induce macrophages to preferentially trogocytose, or engulf in small fragments, whereas target cells with high cortical tension tend towards phagocytosis.

Microhomology-mediated end joining (MMEJ) and mitotic DNA synthesis (MiDAS) are critical DNA repair pathways in mitosis. Here the authors show that CIP2A–TOPBP1 coordinate mitotic DNA repair through the regulation of factors required for MiDAS and MMEJ.

Reduced fitness of the tumor microenvironment is mediated by a long non-coding RNA expressed in tumors.

HMGCR is upregulated by E2F1, driving ferroptosis resistance by reducing oxidative damage triggered by T cell-based therapy. Notably, targeting HMGCR restores ferroptosis sensitivity in immune-refractory tumors, enhancing response to PD-1 blockade as well as adoptive T cell transfer therapy.

N-acetyltransferase 10 (NAT10) is an N⁴‐acetylcytidine (ac⁴C) writer, which catalyzes RNA acetylation at cytidine N⁴ position on RNAs. Here, the authors show that NAT10 catalyzes ac⁴C addition to a long non-coding RNA encoded by the oncogenic DNA virus Kaposi’s sarcoma-associated herpesvirus (KSHV), triggering viral lytic reactivation from latency, which promotes NAT10 recruitment of IFI16 mRNA, resulting in inflammasome activation.

RNAi therapy has huge potential but effective delivery to target location is a major issue. Here, the authors report on the delivery of RNAi to tumors using self-agglomerating nanohydrogels that can overcome the different delivery barriers and supply multiple RNAi payloads.

The role of protein UFMylation in cancer remains to be understood. Here the authors show that UFM1-specific ligase 1 and AKT positively regulate each other through UFMylation and phosphorylation in breast cancer cells, which could be therapeutically targeted by a cell-penetrating peptide through disrupting UFL1-AKT interaction.

Here the authors present NCATS-SM0225, a small molecule that inhibits ERAD and selectively kills cancer cells by binding VDACs, disrupting calcium homeostasis, and triggering the PERK-STIM1 pathway to degrade ERAD regulators.

In an arm of an ongoing multicenter phase 2 trial testing different therapies in patients with genetically profiled grade 2 or 3 meningiomas, treatment with an oral CDK4/6 inhibitor met the primary endpoint for progression-free survival at 6 months in patients with CDK or NF2 alterations.

Identifying jets originating from heavy quarks plays a fundamental role in hadronic collider experiments. In this work, the ATLAS Collaboration describes and tests a transformer-based neural network architecture for jet flavour tagging based on low-level input and physics-inspired constraints.

This study examines long-term changes in species richness across tropical forests in the Andes and Amazon. Hotter, drier and more seasonal forests in the eastern and southern Amazon are losing species, while Northern Andean forests are accumulating species, acting as a refuge for climate-displaced species.

Examining human brain organoids and ex vivo neonatal murine cortical slices demonstrates that structured neuronal sequences emerge independently of sensory input, highlighting the potential of brain organoids as a model for neuronal circuit assembly.

JWST’s COSMOS-Web survey is used to create an ultra-high-detail dark matter map, revealing hidden filaments, clusters and distant structures. By tracing features out to z = 2, this map shows how dark and luminous matter build the cosmic web across cosmic time.

Structure-specific endonucleases play an important role in several DNA repair pathways. Here the authors present structures of the endonuclease XPF-ERCC1 in complex with SLX4, SLX4IP, and DNA. Combined with functional analysis, these results provide insight into the mechanisms of XPF-ERCC1 recruitment and activation during DNA repair.

Affinity-proteomics platforms often yield poorly correlated measurements. Here, the authors show that protein-altering variants drive a portion of inter-platform inconsistency and that accounting for genetic variants can improve concordance of protein measures and phenotypic associations across ancestries.

DNA fork speed is considered as a potential regulator of stem cell fate. Here, the authors explore its role in radial glial cells (RGCs) during brain development and impacts on behaviour. Notably, an increase in fork speed induces RGCs detach from ventricular zone, mimicking outer-RGC like cells.

Scourzic et al. show that germinal centre B cells display an enhanced ability to reprogram to induced pluripotent stem cells compared to mature B cells. This ability indicates their higher plasticity level and is T follicular helper cell-dependent.

Here the authors show that transient cell cycle arrest reprograms CD8⁺ T cells into a highly energized state, increasing proliferation and antitumor activity and boosting efficacy of immunotherapies in cancer models.

Analysis combining multiple global tree databases reveals that whether a location is invaded by non-native tree species depends on anthropogenic factors, but the severity of the invasion depends on the native species diversity.

By combining satellite observations with ground-based data and expert validation, this analysis demonstrates considerable misestimation of grassland extent and thereby carbon stock estimates in previous global assessments based on remote sensing.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Humanity’s Last Exam, a multi-modal benchmark at the frontier of human knowledge, is designed to be an expert-level closed-ended academic benchmark with broad subject coverage.

Single-cell RNA sequencing and assay for transposase-accessible chromatin using sequencing profiling of human retinal samples from diverse ancestries create an epitranscriptomic atlas characterizing over 130 cell types. Integration with genome-wide association study and expression quantitative trait loci data provides further insights into gene regulation and disease etiology.

This study shows that optimally sized nanocarriers reach Duchenne muscular dystrophy muscle primarily through transcytosis, where they can deliver tamoxifen to improve muscle health and strength in mice.

Intracellular redox state orchestrates a self-reinforcing circuit connecting hypoxia inducible factor 1α-dependent signalling with post-translational regulation of the metabolic enzyme isocitrate dehydrogenase 1 to govern intestinal stem cell fate.

The proteasome is essential for protein degradation, but its complexity can be lost in vitro. Here, the authors use in-situ cross-linking mass spectrometry and structural modeling to reveal compartment-specific interactions and previously uncharted structural heterogeneity and dynamics.

Atherosclerosis is the leading cause of death worldwide. Here, the authors show that defective vascular smooth muscle cell tafazzin promotes mitochondrial dysfunction and atherosclerosis, highlighting tafazzin as a potential therapeutic target.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

Here the authors introduce INSPECT, a live-cell imaging method for mapping protein interactions. They reveal how Cdc42–FMNL locks cell polarity while Rac1–ROCK triggers turning, exposing the intrinsic program that drives spontaneous cell migration.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.

Mecp2 deficiency underlies Rett syndrome, a genetic disorder presenting with chronic low-grade inflammation of unknown origin. Here, the authors show that Mecp2 is a central regulator of the onset, breadth and nature of nucleic acid immunity.

The HTLV-1 capsid (CA) domain of Gag was resolved to 3.4 Å resolution and reveals insights into immature lattice stabilization, the varying lattice curvatures and distances from the membrane, and the dispensable nature of inositol hexakisphosphate (IP6) for immature particle assembly.

Haines et al. developed an MEK–RAF molecular glue called IK-595 that blocks MAPK pathway activation in RAS-mutant and BRAF-mutant cancer cells. IK-595 exhibited high tolerability and strong antitumor effects in preclinical models across cancer types.

Fanjiang Kong, Zhixi Tian, Xingliang Hou, Baohui Liu and colleagues report the cloning and functional characterization of J, the locus underlying the long-juvenile (LJ) trait that has enabled tropical cultivation of soybean. They show that J, an ortholog of Arabidopsis ELF3, downregulates the expression of E1, thereby promoting flowering under short-day conditions.

Determinants of WEE1 inhibitor sensitivity in cancer cells are largely undefined. Here, the authors show that WEE1 inhibitors beyond their cell cycle perturbing effects also lead to paradoxical activation of the integrated stress response kinase GCN2.

Murphy et al. reveal a unifying pathogenetic mechanism according to which diverse mutations in the muscle-specific ribosomal protein RPL3L cause severe neonatal dilated cardiomyopathy, establishing a framework for interpreting the growing spectrum of RPL3L variants.

This study discovers human SERF2 as a key partner in stress granule formation by binding specific RNA G-quadruplexes. SERF2 and these RNAs provide a detailed structural model of protein-RNA interactions driving liquid-liquid phase separation in condensates.

Glioblastoma (GBM) is characterized by a high degree of heterogeneity and plasticity due to interplay with neural developmental programs. Here, the authors develop a model of GBM by introducing sequential oncogenic mutations in human neural stem cells and using this, identify INSM1 as a driver of a neural progenitor gene network promoting tumorigenesis.

The mechanism(s) controlling CD8+ virtual memory T cell (TVM) development are still under investigation. Here, using uninfected or IAV-challenged Ikzf3-deficient mice, the authors identify the transcription factor Aiolos as a negative regulator of TVM cell development by repressing Eomes and IL-15/STAT5 signaling.

The balance between radial progenitors and intermediate precursors to generate upper-layer neurons during the development and evolution of the cerebral cortex is mediated by members of the tuberous sclerosis complex.

Here, the authors show that ZBTB16, SALL4 and SOX3 regulate mouse stem cell renewal and sperm production through a three-dimensional interacting chromatin network that maintains undifferentiated spermatogonia and primes genes for spermatogonia development and meiosis.

Microglial states throughout remyelination are incompletely understood. Here, the authors show that microglia form several states during the early stages of remyelination that coalesce into a partially resolved state that is dysregulated with age.

cAMP export by ABCC4 is critical for localized signaling. Here, the authors revealed that PKA activation drives ABCC4 to the plasma membrane and organizes a PDZ-dependent protein network with actin cytoskeleton and scaffolds, like SCRIB, that stabilize the transporter and optimize cAMP efflux. Furthermore, the authors show that the potent ABCC4 inhibitor Ceefourin 2 disrupts this network, revealing a non-canonical mechanism of ABCC4 inhibition.

The therapeutic relevance of telomere maintenance mechanisms in cancer, remains to be explored. Here, the authors integrate multi-omic data and functional readouts, generate a resource of telomere biology metrics and identify potential molecular vulnerabilities.