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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.

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.

T cells can recognise lipid antigen in the context of CD1d molecules. Here, the authors show that γδ T cell activation in response to CD1d differs from that of αβ T cells and determine the structure of a γδ T cell receptor that binds to CD1d independently of the presented lipid.

Lithium metal under extreme pressures shows a sequence of structural phase transitions. Here, the authors use neutron scattering and X-ray diffraction techniques under high pressure to expand the experimental phase diagram of lithium, showing an unexpected deviation from existing boundaries.

Elevated levels of IL-33 induce the production of autoantibodies through an unknown mechanism. Here, the authors show that IL-33 disrupts splenic architecture and germinal center organization, causing an expansion of antibody-secreting plasmablasts and plasma cells. In multiple mouse models of inflammation, administration of IL-33 exacerbates the pathology, increasing the production of autoantibodies, whereas IL-33 blockade reverses autoantibody production in a model of lung inflammation.

DNA damage can arise from natural cellular processes, but how cells prevent resulting mutations is unclear. Here, the authors show that the enzyme Polκ protects mouse tissues from mutations caused by endogenous guanine lesions, revealing how DNA repair and damage tolerance pathways cooperate to maintain genome integrity.

Synovial sarcoma (SS) is a difficult-to-treat cancer, driven by the fusion oncoprotein SS18::SSX. SS18::SSX alters the BAF (mammalian SWI/SNF) chromatin remodelling complex to create an oncogenic transcriptome. Here, the authors identify SS18::SSX-driven SMARCE1 SUMOylation as a therapeutic vulnerability in SS and show that SUMOylation inhibition stabilizes the cBAF complex, inducing cell death and sensitization of SS to chemotherapy.

Understanding synapse loss in Alzheimer’s disease has been hampered by a lack of human model systems. Here, the authors show that manipulation of physiological or pathological Aβ has differing effects on synapses in live human brain slice cultures.

McGeachan et al. observe oligomeric tau in synapses from individuals with progressive supranuclear palsy and provide evidence that tau pathology may spread through the brain via synapses.

Primary angle-closure glaucoma can cause blindness. Here, the authors study populations of Asian and European ancestries and find that genetic factors associated with darker irises and being far sighted increase the risk of developing the condition.

Activity in a set of parabranchial neurons in the mouse brain is increased during chronic pain, predicts coping behaviour, and can be modulated by circuits activated by survival threats.

Conducting a simulated turtlegrass herbivory experiment across 650 experimental plots and 13 seagrass meadows, the authors show that the negative effects of herbivory increase with latitude, driven by low levels of light insolation at high latitudes.

Crystal engineering is a powerful process for assembling complex materials but tends to require organic building blocks, which can limit stability. Here, the authors use inorganic polyoxometalates to assemble an all-inorganic metamorphic framework that can be switched between eight distinct states.

Computationally designed genetically encoded proteins can be used to target surface proteins, thereby triggering endocytosis and subsequent intracellular degradation, activating signalling or increasing cellular uptake in specific tissues.

Doudna and colleagues discuss recent advances in the targeted delivery of genome editors in vivo, offering a framework for the rational design of delivery systems.

A new version of nanorate DNA sequencing, with an error rate lower than five errors per billion base pairs and compatible with whole-exome and targeted capture, enables epidemiological-scale studies of somatic mutation and selection and the generation of high-resolution selection maps across coding and non-coding sites for many genes.

Experimental measurements of high-order out-of-time-order correlators on a superconducting quantum processor show that these correlators remain highly sensitive to the quantum many-body dynamics in quantum computers at long timescales.

Typical quantum error correcting codes assign fixed roles to the underlying physical qubits. Now the performance benefits of alternative, dynamic error correction schemes have been demonstrated on a superconducting quantum processor.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

Generating RNA sequences with improved function remains challenging. Here, authors present an RNA database for RNA structural and functional analysis. They use this database and the RNA generative models to identify RNA mutations that increase the thermostability of a bacterial ribosome.

DNA methylation loss has been observed in aging tissues and cancers for decades. Researchers from Van Andel Institute have now provided experimental evidence that this process is directly driven by cell division.

Colour code on a superconducting qubit quantum processor is demonstrated, reporting above-breakeven performance and logical error scaling with increased code size by a factor of 1.56 moving from distance-3 to distance-5 code.

Findings from an umbrella review of more than 100 meta-analyses suggest that screen time can have both positive and negative associations with educational and health outcomes for youth, but effect sizes are small.

This study reports that herbivory-induced volatiles can trigger plant–soil feedbacks that boost performance and yields of cereals in the field.

VCP/p97 is identified as a co-factor to the fusion oncoprotein ASPSCR1::TFE3. They co-localize on chromatin, co-dependent for enhancer looping and transcriptional regulation in alveolar soft part sarcomas and Xp11- rearranged renal cell carcinomas.

The site-selective functionalization of C(sp²)–H bonds is a powerful strategy for the synthesis of structurally diverse compounds with broad applicability. Here the authors show ruthenium-catalysed regiodivergent methods for the installation of silyl synthetic handles at both ortho and meta sites within arenes.

Computer-aided drug design has a high computational cost and a newly identified drug candidate might be unsuitable due to a range of drug properties. Lam and colleagues trained a model based on graph convolutional variational encoders that predicts a range of properties simultaneously to accelerate virtual screening.

A study reports whole-genome sequences for 490,640 participants from the UK Biobank and combines these data with phenotypic data to provide new insights into the relationship between human variation and sequence variation.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

The authors designed stapled antimicrobial peptides that have potent antibacterial activity in mice and limited toxicity.

Lindenhofer, Haendeler, Esk, Littleboy et al. perform whole-tissue lineage tracing in human cerebral organoids to reveal that a subpopulation of symmetrically dividing cells can adjust its lineage size depending on tissue demands.

Accounting for near-surface temperature gradients leads to estimates for annual CO₂ uptake in the North Atlantic that are 7% higher, based on a comparison of eddy covariance and bulk CO₂ measurements, which is consistent with theory, laboratory assessments and model analysis.

Primary open-angle glaucoma (POAG) is highly heritable, yet not well understood from a genetic perspective. Here, the authors perform a meta-analysis of genome-wide association studies in 34,179 POAG cases, identifying 44 previously unreported risk loci and mapping effects across multiple ethnicities.

The relationship between pathogenic germline variation, clonal hematopoiesis (CH) and risk of hematologic malignancy is explored in 731,835 individuals across 6 cohorts. Carriers of variants in certain genes show distinct patterns of CH and increased risk of CH progression to malignancy.

Cell type labelling in single-cell datasets remains a major bottleneck. Here, the authors present AnnDictionary, an open-source toolkit that enables atlas-scale analysis and provides the first benchmark of LLMs for de novo cell type annotation from marker genes, showing high accuracy at low cost.

Methyl-CpG-binding protein 2 (MeCP2) is phosphorylated in neurons in response to neuronal activity. Here, Li et al.show that it is also phosphorylated by aurora kinase B in neural progenitor cells, and cell cycle-dependent phosphorylation of MeCP2 regulates the balance between proliferation and differentiation via Notch signalling.

The authors show that DCAF1, a substrate receptor of CUL4 and EDVP E3 ligases, can be recruited by PROTACs to degrade the cancer drug target, WDR5. They also report the crystal structures of PROTAC ternary complexes that reveal a significant role for loops in DCAF1 substrate recognition, a potential mechanism behind the diverse substrate specificity of DCAF1.

A hybrid analogue–digital quantum simulator is used to demonstrate beyond-classical performance in benchmarking experiments and to study thermalization phenomena in an XY quantum magnet, including the breakdown of Kibble–Zurek scaling predictions and signatures of the Kosterlitz–Thouless phase transition.

Converting oxygen-rich biomass into fuels requires the removal of oxygen groups through hydrodeoxygenation. MoS₂ monolayer sheets decorated with isolated Co atoms bound to sulfur vacancies in the basal plane have now been synthesized that exhibit superior catalytic activity, selectivity and stability for the hydrodeoxygenation of 4-methylphenol to toluene when compared to conventionally prepared materials.

HLA-C expression levels correlate with immune responses to pathogens and autoimmunity, and vary in an allele-specific manner across individuals. Here the authors identify factors that drive differential expression of HLA-C allomorphs at the cell surface, and influence the structure of the peptide-binding cleft and diversity of peptides bound by HLA-C molecules.

A single-cell sequencing study using more than 30,000 tumour genomes from human ovarian cancers shows that whole-genome doubling is an ongoing mutational process that drives tumour evolution and disrupts immunity.

Despite the importance of osteoclast secretory lysosomes in bone digestion, the proteins that regulate them remain ill defined. Here, the authors identify Slc37a2 as a secretory lysosome sugar transporter that is required for maintenance of skeletal bone mass.

We present the complete 62,460,029-base-pair sequence of a human Y chromosome from the HG002 genome (T2T-Y) that corrects multiple errors in GRCh38-Y and adds over 30 million base pairs of sequence to the reference.

In a quantum simulation of a (2+1)D lattice gauge theory using a superconducting quantum processor, the dynamics of strings reveal the transition from deconfined to confined excitations as the effective electric field is increased.

Repeated vaccination is needed to maintain high levels of SARS-CoV-2 immunity in vulnerable populations, but there is concern that it could lead to immune exhaustion. Here, the authors assess the evidence for immune exhaustion following multiple SARS-CoV-2 vaccination three vulnerable population cohorts in Canada.