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In this study, authors employ fragment-based lead discovery to identify WRN inhibitors. The fragment hits reveal an additional allosteric pocket and uncover a previously uncharacterized structural conformation of the WRN helicase domain with unique orientations of the ATPase domains

The reconstitution of complex biological processes in cell-free systems can support the detailed characterisation of biochemical mechanisms which are difficult to probe in vivo. Here authors present an all-cell-free T7 phage cycle, consisting of cell-sized liposomes encapsulating a cell-free gene expression reaction and a phage receptor at the membrane.

Errors in oocyte division can cause infertility and birth defects. Here, authors combine a genetic strategy with a novel optochemical tool to show that spindle pole-localized F-actin is essential for proper meiotic spindle assembly and chromosome segregation.

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.

A nine-year transit-timing campaign has measured the extremely low masses and densities of four large planets orbiting the young star V1298 Tau, which are now predicted to contract and form a typical compact super-Earth and sub-Neptune system.

RNA oxidation is poorly characterized. Here, the authors introduce OAbSeq, a sequencing method that maps oxidized sites at nucleotide resolution and show guanosine oxidation proceeds via transient oxo8G to produce mainly abasic sites.

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.

Colloidal particles experience capillary interactions at liquid interfaces, but modifying these interactions is challenging as shape change is required. Here, the authors report polymer particles that change shape with polarised light, and therefore create flow patterns with unusual paths.

In patients with advanced cancer, the development of brain metastasis (BM) often signals a worsening prognosis with limited therapeutic options. Here, the authors assemble a large, open-source neuroimaging dataset of BM and perform spatial and morphological analysis which they use to develop a framework for function-sparing brain radiotherapy design.

JWST observations of the ultra hot Jupiter WASP 121 b reveal helium escaping for most of its orbit, forming two giant tails moving in opposite directions. The results show how stellar radiation modifies planetary atmospheres.

This study identifies key neurocognitive domains that distinguish patients with schizophrenia from healthy individuals using machine learning. Analyzing data from 1,304 participants, it demonstrates that verbal learning and emotion identification effectively classify conditions, promoting efficient neurocognitive profiling strategies.

This study demonstrates that the extracellular matrix (ECM) of the developing brain stabilizes recently born synapses. The authors identify a microglial metalloprotease that digests the ECM to increase the plasticity of these newborn synapses.

Respiration enhances cerebrospinal fluid flow through mechanical and autonomic pathways. Inhale length and diaphragm motion influence its displacement and net flow, identifying a modifiable, noninvasive mechanism relevant to brain homeostasis.

Cosgun et al. show that, in B cell leukemia, β-catenin expression is maintained at low levels through glycogen synthase kinase 3B (GSK3β)-mediated phosphorylation. Inhibition of GSK3β results in β-catenin–Ikaros–NuRD complex formation, leading to B-ALL cell death through MYC repression.

SWING is a versatile interaction language model that can learn the language of peptide and protein interactions.

Pilcher et al. present a single-cell transcriptomics-based immune atlas of participants with newly diagnosed multiple myeloma, reporting on the association of cell types, gene expression and intercellular interactions with disease progression phenotypes.

This study associates p53 loss and brain metastasis in breast cancer. Mechanistically, p53-null tumors recruit astrocytes that provide substrates for enhanced fatty acid synthesis via upregulated SCD1 expression, representing a targetable axis in the disease.

The origin and composition of stromal fibroblasts in the fibrotic CNS scar are unclear. Here, the authors demonstrate that pericytes and perivascular fibroblasts contribute to fibrotic scarring following spinal cord injury in mice in a region-dependent manner.

The hippocampus can replay long spatial sequences without ripples. When present, ripples cluster in spatially restricted zones as a function of replayed location that remap with barrier changes, implying a tagging role in consolidation.

Surgical sterilization alone cannot control global stray and feral domestic cat populations. Here, Godin et al. show that a single-dose injectable female sterilant administered before puberty safely and completely prevents pregnancy after maturity.

Core excitons are strongly localised excitonic states impacting x-ray absorption and resonant inelastic scattering (RIXS) spectra. Here, the authors demonstrate an application of free electron laser-driven ultrafast RIXS spectroscopy to study previously unclear aspects of core exciton-phonon interactions in graphite.

DNAJC12 variants cause parkinsonism. Here, the authors show that DNAJC12 stabilizes tyrosine hydroxylase, a crucial enzyme in dopamine synthesis, and identify key structural motifs for this interaction, explaining the pathogenesis of truncated variants.

A deep-learning-based de novo design strategy was developed that enables simultaneous scaffolding of three distinct epitopes derived from respiratory syncytial virus within small single-domain immunogens. Crystallographic analyses confirmed precise presentation of the designed motifs. The multiepitope constructs elicited enhanced cross-reactive and neutralizing antibody responses, demonstrating the potential of generative models for complex multisite protein engineering.

A histone ubiquitin-dependent regulatory hub governs stimulus-dependent heterochromatin propagation, with important implications for understanding mechanisms governing rapid changes in the epigenetic landscape in physiology and disease.

Understanding deregulation of biological pathways in cancer can provide insight into disease etiology and potential therapies. Here, as part of the PanCancer Analysis of Whole Genomes (PCAWG) consortium, the authors present pathway and network analysis of 2583 whole cancer genomes from 27 tumour types.

BPTF is known to regulate chromatin accessibility and self-renewal in mammary epithelial stem cells. Here, the authors discover that BPTF inhibition delays tumor formation, re-activates ERα expression, increases sensitivity to tamoxifen treatment, and inhibits metastatic development.

A common mechanism by which cancer cells acquire resistance to chemotherapeutics is through the overexpression of efflux pumps, but platinum anticancer agents that crosslink DNA and interact with proteins are poor efflux pump substrates. Here, the authors design dual warhead drug conjugates by tethering a platinum pharmacophore to the doxorubicin backbone, which exhibit the activity of both parent anticancer compounds and can overcome drug efflux effectively due to covalent binding to intracellular biomolecules.

Little Red Dots (LRDs) are a high-redshift galaxy population with unclear nature. Here, authors show CANUCS-LRD-z8.6, a spectroscopically confirmed LRD, hosting an active galactic nucleus, and its properties provide insights for early black hole and galaxy formation.

This study demonstrates that 16p11.2 hemideletion, a genetic deletion linked to neurodevelopmental disorders, affects male and female mice differently, altering specific striatal neuronal circuits and driving sex-specific behavioral changes.

VRACs are ubiquitously expressed osmosensitive ion channels assembled from LRRC8A-E subunits. Here, the authors determine the structures of a LRRC8A:D VRAC using cryo-EM and identified that these channels are gated by lipids inside the channel pore.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

The authors present DNA-Diffusion, a generative AI framework that designs synthetic regulatory elements with tunable cell-type specificity. Experimental validation demonstrates their ability to reactivate AXIN2 expression, a leukemia-protective gene, in its native genomic context.

Variants in NOS1AP can cause monogenic nephrotic syndrome. Here, the authors show that disrupting the intergenic NOS1AP splice isoform that is more prevalent in podocytes leads to monogenic kidney disease responsive to RAAS inhibition.

Exercise has considerable health benefit, including modulation of the immune system. Here the authors compare the molecular make-up of peripheral blood immune cells at resting state and upon a single bout of two different aerobic exercise modes by proteomics and show that although both exercise modes trigger similar changes, the effect is more pronounced after high intensity interval training.

The authors report an enhancement of the superconducting onset temperature in nanometer-thin YBa₂Cu₃O₇-δ films grown on substrates with nanofaceted surfaces. They theoretically show that the enhancement is mainly driven by electronic nematicity and unidirectional charge density waves, and further suggest that the nanofacets themselves may promote these effects.

By performing a CAR-adapted base-editing screen of phosphatidylinositol-3-kinase delta (PI3Kδ, PIK3CD), Bucher et al. identify mutations affecting endogenous PI3K–AKT signaling that enhances CAR T cell antitumor potency.

Sensory experience transforms endogenously structured cortical networks with diverse and unreliable visual responses into reliable representations. This process is proposed to involve the alignment of feedforward and recurrent networks.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Here, authors investigate how gut microbiota contribute to defensive behaviours in honeybees, finding evidence that gut-associated bacteria affect aversive learning and memory of sting extension reflex.

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 variability in clinical outcomes of SARS-CoV-2 infection is partly due to deficiencies in production or response to type I interferons (IFN). Here, the authors describe a FIP200-dependent lysosomal degradation pathway, independent of canonical autophagy and type I IFN, that restricts SARS-CoV-2 replication, offering insights into critical COVID-19 pneumonia mechanisms.

Water-vapor interfaces have been studied with many techniques, yet open questions persist about their electronic and molecular structure. Here, the authors demonstrate the application of soft x-ray second harmonic generation to study the water surface by leveraging attosecond pulses at the LCLS and a flat liquid sheet microjet, providing insights on the H-bond structure.

Genome-wide CRISPRi screens for modulators of androgen receptor (AR) protein levels using live-cell quantitative endogenous AR fluorescence reporters identify PTGES3 as a new regulator of AR stability and function in prostate cancer.

Quantifying ecosystem dynamics is critical in the face of rapid environmental change. This study uses airborne eDNA to quantify changes in organism abundances across the tree of life and reveal a regional decline in biodiversity over three decades.

Machine learning can be used to identify subtypes of psychiatric disease. Here the authors identified two neurostructural subgroups in schizophrenia, each showing reproducibility and generalizability across different collection locations and illness stages, using the SuStain algorithm.

The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

Here, the authors present archaeology of the Namorotukunan site in Kenya’s Turkana Basin that demonstrates adaptive shifts in hominin tool-making behaviour spanning 300,000 years and increasing environmental variability. They contextualize these findings with paleoenvironmental proxies, dating, and geological descriptions.

Perceptual abilities can be improved by training, up to certain limits. Martin et al. show that vagus nerve stimulation in mice boosts performance on an auditory task via cholinergic modulation, beyond the level achieved by training alone.

This study reveals that excitatory–inhibitory imbalance in Alzheimer’s disease is diverse including both impaired long-range synaptic integration and altered local excitability, with distinct links to β-amyloid and tau pathology.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.