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Despite extensive structural studies elucidating how antigens are anchored to antigen-presenting molecules and presented to T cells, little is known about the display mechanism of the lipid-antigen-presenting molecule CD1c. Here, by combining structural immunology, lipidomics, and biophysical analysis, the authors reveal that the CD1c binding cleft accommodates two different lipids, one of them with a bulky headgroup positioned sideways for display to T cells, rather than upwards, different from the conventional upright antigen-presentation mode

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.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

A haptic ring that has a soft multiaxis force-sensing skin capable of simultaneously detecting shear and normal force can provide a kinaesthetic force feedback of up to 6.5 N.

The anti-tuberculosis drug bedaquiline targets ATP synthase, but there is controversy about the precise mechanisms leading to mycobacterial death. Here, the authors show that the apparent ‘uncoupling’ activity of bedaquiline is, in fact, a redirection of electron flux to the CydAB oxidase, induced to mitigate the deleterious consequences of ATP synthase inhibition.

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.

The authors measure picosecond spin pumping in FeRh as a function of temperature by optical pump-THz emission spectroscopy. In the antiferromagnetic phase of FeRh enhanced spin pumping above the value measured in the ferromagnetic phase is observed.

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.

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.

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.

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.

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.

Adoptive cell therapies (ACT) hold promise for cancer immunotherapy, but optimization is still an ongoing process. Here the authors report CD4-targeted, nanoparticle-based artificial antigen-presenting cells that expand CD4⁺ T cells capable of lysing tumor cell lysis in vitro, and CD8⁺ T cells showing antitumor activity in a mouse melanoma model.

A dataset of 3D images from more than 200,000 human induced pluripotent stem cells is used to develop a framework to analyse cell shape and the location and organization of major intracellular structures.

Influenza B viruses are linked to significant morbidity and mortality, and yet their immunobiology is comparatively poorly understood. Here Menon et al identify influenza B virus-specific CD8⁺ T cell epitopes and characterise these in adults, children and the elderly.

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.

An analysis of 24,202 critical cases of COVID-19 identifies potentially druggable targets in inflammatory signalling (JAK1), monocyte–macrophage activation and endothelial permeability (PDE4A), immunometabolism (SLC2A5 and AK5), and host factors required for viral entry and replication (TMPRSS2 and RAB2A).

ImmuScope, a weakly supervised deep learning model capable of analysing multi- and single-allelic data, is introduced, facilitating interpretable neoantigen discovery and immune escape analysis.

In the dipolar XY model, quench dynamics from a polarized initial state lead to spin squeezing that improves with increasing system size, and two refinements show further enhanced squeezing and extended lifetime of the squeezed state by freezing its dynamics.

Multisystem inflammatory syndrome in children (MIS-C) onsets in COVID-19 patients with manifestations similar to Kawasaki disease (KD). Here the author probe the peripheral blood transcriptome of MIS-C patients to find signatures related to natural killer (NK) cell activation and CD8+ T cell exhaustion that are shared with KD patients.

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

Structural, biochemical and cellular analyses show that bacterial antigens can mimic gliadin epitopes involved in celiac disease being presented by HLA-DQ2.5 and recognized by T cells derived from patients.

Meta-analysis of 36,760 cases and 375,188 controls identifies 54 loci associated with susceptibility to cutaneous melanoma. Further analysis combining nevus count and hair color GWAS results provide insights into the genetic architecture of melanoma.

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.

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.

Chiea Chuen Khor, Tin Aung, Francesca Pasutto, Janey Wiggs and colleagues report a global genome-wide association study of exfoliation syndrome and a fine-mapping analysis of a previously identified disease-associated locus, LOXL1. They identify a rare protective variant in LOXL1 exclusive to the Japanese population and five new common variant susceptibility loci.

Wang et al. present T cell receptor sequencing of serial tumor and blood samples from TIL-treated patients with non-small cell lung cancer, identifying tumor-reactive clonotypes expressing dysfunctional programs in patients lacking clinical benefit.

A study leveraging transsynaptic tracing demonstrates rapid and extensive integration of human glioblastoma organoids into the mouse brain.

Binary stars with orbital periods of less than a day show magnetic activity beyond the saturation limit of single stars. This enhanced activity is probably driven by a large-scale α–ω dynamo during common-envelope evolution.

Sarcoma is a highly heterogeneous disease, which can be caused by a large variety of mutations. Here, the authors utilise multi-omics to characterise a cohort of 1,340 sarcoma tissue specimens to identify key somatic mutations and identify immune subtypes.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

Fine-mapping of causal variants and integration of epigenetic and chromatin conformation data identify likely target genes for 150 breast cancer risk regions.

Structures of the human calcium-sensing receptor can be bound into complex with G proteins from three different Gα subtypes while maintaining G-protein-binding specificity.

Tumour endothelial cell macropinocytosis is the dominant mechanism for nanoparticle entry into the tumour. Enhanced nanoparticle tumour accumulation may be due to upregulated macropinocytosis membrane ruffling compared with most healthy tissues.

Comprehensive integration of gene expression with epigenetic features is needed to understand the transition of kidney cells from health to injury. Here, the authors integrate dual single nucleus RNA expression and chromatin accessibility, DNA methylation, and histone modifications to decipher the chromatin landscape of the kidney in reference and adaptive injury cell states, identifying a transcription factor network of ELF3, KLF6, and KLF10 which regulates adaptive repair and maladaptive failed repair.

The changes that prostate cancer (PCa) induces in its microenvironment are not fully understood. Here the authors use single-cell RNA-seq and organoids to characterise how the microenvironment responds to PCa, and also identify tumour-associated epithelial cell states and club cells.

In a large trial of patients with recurrent high-grade gliomas, IL-13Rα2-targeting CAR-T cells were feasible to manufacture and well tolerated when delivered via intratumoral and/or intraventricular routes.

Cross-protective responses across all strains of influenza virus (IAV, IBV and ICV) are a key goal of universal vaccines against influenza. Kedzierska and colleagues identify cytotoxic T cells present in blood and lungs of healthy people that are directed against all strains of influenza virus.

Human leukocyte antigen (HLA) presents peptides to activate T cells, but many aspects in the T cell receptor (TCR)/HLA interaction remain unclear. Here the authors show, via structural data, that two TCRs differentially recognize the same tumour peptide/HLA complex and induce contrasting conformation changes of the peptide.

In a cynomolgus macaque model, CRISPR base editors delivered in lipid nanoparticles are shown to efficiently and stably knock down PCSK9 in the liver to reduce levels of PCSK9 and low-density lipoprotein cholesterol in the blood.

The immune response to the spike protein of SARS-CoV-2 has been relatively well studied, but less is known about other viral proteins. Here, the authors identify immunopeptides from seven structural and non-structural SARS-CoV-2 proteins presented to the immune system by HLA molecules and confirm T-cell responses against some of them in convalescent individuals.

A large-scale genetic analysis of type 1 diabetes identifies new susceptibility variants, highlights potential regulatory mechanisms and provides genetic support for therapeutic targets for immune intervention.

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.

Squamous cell lung cancer has dismal prognosis due to the dearth of effective treatments. Here, the authors perform an integrated proteogenomic analysis of the disease, revealing three proteomics-based subtypes and suggesting potential therapeutic opportunities.

It is hoped that quantum computers may be faster than classical ones at solving optimization problems. Here the authors implement a quantum optimization algorithm over 23 qubits but find more limited performance when an optimization problem structure does not match the underlying hardware.