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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.

Liu et al. report Chinese normative lifespan brain charts showing later neurodevelopmental milestones than those detected in Western cohorts. Individual deviations from these norms are valuable in assessing clinical risk and outcomes.

With combined phase-field simulations and experimental observations, the authors report the creation, evolution, and destruction of a polar skyrmion bag in a ferroelectric superlattice. The topological charge can be manipulated with applied potential.

Prime editing enables precise genetic modification but often suffers from unwanted byproducts. Here, authors show that the anti-CRISPR protein AcrIIA5 unexpectedly enhances prime editing efficiency while reducing unintended indels, offering an effective strategy to improve activity and specificity.

The methods for systematically profiling RNA composition of processing bodies (PBs) are limited. Here, the authors present PB-TRIBE-STAMP and LSM14A-TRIBE-ID, two RNA editing-based methods enabling systematic characterization of dynamic PB-RNAs association.

Zygotic genome activation coincides with extensive chromatin remodeling coordinated by maternal transcription factors. Here, by mapping accessible chromatin during early embryonic development of Xenopus tropicalis, the authors show how maternal factors E2f1 and Otx1 work together to control zygotic genome activation.

The gut-microbiota-derived aromatic amino acid metabolite 4-hydroxyphenylacetic acid (4HPAA) and its analogues have been shown to protect against obesity. In mice, 4HPAA exerts anti-obesogenic effects by modulating mucosal immunity and lipid uptake in the intestine.

Telomere shortening marks cellular aging and links to heart disease. Here, the authors show shared genetic loci between leukocyte telomere length and coronary artery disease, highlighting genes such as SH2B3 and pathways involved in DNA biosynthesis and telomere maintenance.

The introduction of ethylenediammonium diiodide reduces defects but also leads to severe hysteresis caused by excessive mobilized ions. Here, authors employ hydrazine monohydrochloride as a bulk passivator to mitigate such hysteresis, achieving maximum efficiency of 28.55% for tandem solar cells.

Wang and colleagues show that an AI-assisted designed peptide obstructs GSDMD pores and inhibits IL-1β and IL-18 release and pyroptosis.

β-Branched aromatic α-amino acids are valuable building blocks in natural products and pharmaceutically active compounds, but their synthesis is challenging due to the presence of two stereocenters. Here, the authors design phenylalanine ammonia lyases variants for the direct asymmetric synthesis of β-branched aromatic α-amino acids and reveal the reasons for enzyme’s inability to accept β-methyl cinnamic acid.

Anti-HER2 resistance causes treatment failure in HER2-positive breast cancers. Here the authors identify FGFR4 as one of the vulnerabilities of anti-HER2 resistant breast cancer and show that FGRR4 inhibition enhances sensitivity to anti-HER2 treatment in these resistant cells by triggering ferroptosis.

The laminar organization of macaque V1 cortex is similar to that seen in humans. Here the authors describe a single-cell RNA sequencing dataset of macaque V1 cortex cells.

Chronic insomnia is associated with cardiometabolic diseases. Here, in two clinical cohorts (n = 7,931), authors show that gut microbiota-bile acid axis may be an intervention target to attenuate the impact of chronic insomnia on cardiometabolic health.

Multivalent interactions are crucial in transcriptional regulation. Here, by integrating specific multivalent molecules into dCas9-based activators, the authors provide valuable strategies to refine CRISPRa applications and achieve highly efficient gene transcription.

Using animal models to mimic Parkinson’s disease can advance our understanding of pathogenesis. Here, the authors combine single-cell genomics with a primate model of parkinsonism to provide insights into neuronal vulnerability and resilience.

A human genome resolved at the haplotype level without a reference genome reveals previously undetected sequences.

The neural network Self2Self is applied here to denoising large astronomical images. On test images, it performs quickly and enhances the appearance of weak signals.

Intermodular recognition in polyketide synthase (PKS) is a key prerequisite for catalysis and assembly-line engineering. Here, the authors present a specific domain interaction between modules and an evolution-oriented strategy for PKS engineering derived from the enoylreduction module of azalomycin F.

The authors develop a metabolic engineering strategy for improving polyketide production of industrial interest and discovering new natural products in bacteria.

PAM constraints and off-target effects limit cytosine base editors in Streptomyces. Here, authors developed eSCBE3-NG-Hypa, a high-efficiency and -fidelity base editor recognizing NG PAM, achieving precise genetic modifications and enhanced avermectin production in an industrial S. avermitilis.

Here, the authors use single-molecule long-read sequencing to decipher the role of structural variations in high-altitude adaptation, finding evidence that an intergenic deletion down-regulates EPAS1 by disrupting a super-enhancer.

Streptovaricin C is an antibiotic containing a methylenedioxy bridge (MDB) moiety essential for its activity. Here, the authors show that a P450 monooxygenase StvP2 catalyses MDB formation, report its crystal structure in complex with the substrate, and elucidate mechanistic details of MDB formation.

The genome sequence and its analysis of the diploid wild wheat Triticum urartu (progenitor of the wheat A genome) represent a tool for studying the complex, polyploid wheat genomes and should be a valuable resource for the genetic improvement of wheat.

The tetronate ring appears in several natural products, but the biosynthetic path to this structure has proven elusive. Reconstitution of a polyketide assembly line and in vitro assays with a chemically synthesized intermediate now point to a single enzyme as catalyzing ring formation.

Intra-cell line heterogeneity remains to be characterized. Here, the use of single multi-omics on a large panel of human cell lines identifies copy number variation, epigenetic variation and extrachromosomal DNA distribution as the main contributors to intra-cell line heterogeneity.

Urethral repair can be carried out using hydrogels, but the harsh microenvironment hinders the repair. Here, the authors report the development of a 4D hydrogel dressing that can provide an early-vascularised and later-antifibrogenic microenvironment to assist in scarless reconstruction.

Li et al. show that the c-Myc-dependent splicing switch from ketohexokinase-C (KHK-C) to KHK-A activates phosphoribosyl pyrophosphate synthetase 1 (PRPS1), resulting in enhanced de novo nucleic acid synthesis and hepatocellular carcinoma formation.

Capsaicin prevents atherosclerotic plaque formation by activating TRPV1 cation channels, but its toxicity precludes its use in clinical settings. Here, Tang and colleagues use copper sulfide nanoparticles as a photothermal switch to locally and temporally activate TRPV1 in vascular smooth muscle cells and reduce plaque formation without apparent toxicity.

Electrosynthesis via two electron water reactions offers a promising method for decentralized H₂O₂ production, yet its mechanism remains unclear. Here, the authors address the challenge by using in-situ Raman and DEMS, and demonstrate 93% of H₂O₂ forms via the carbonate coupling route through a C₂O₆²⁻ intermediate.

Antibodies against SARS-CoV-2 S protein can provide a treatment strategy for COVID-19. Here, Guo et al. provide the crystal structure of a SARS-CoV2 neutralizing antibody isolated from a convalescent patient and highlight the therapeutic efficacy in a rhesus monkey model of an engineered version with optimized pharmacokinetic and safety profile.

Low-dose IL-2 treatment alters the abundance of regulatory T cells, IL-17-producing T cells and follicular helper T cells, but not of T helper type 1 and 2 cells, in patients with SLE.

High-quality genome sequence of cultivated peanut comprising 2.54 Gb with 20 pseudomolecules and 83,709 protein-coding gene models provides insights into genome evolution and the genetic mechanisms underlying seed size and leaf resistance in peanut.

The ability to grow at acidic pH is crucial for E. coli colonization of the host’s intestine. Here, the authors identify an acid-tolerance response system that is important for E. coli exponential growth at pH 4.2, survival in the mouse intestine, and production of 3-hydroxypropionate during fermentation.

Organic metal chalcogenides (OMCs) are organic-inorganic hybrid materials with continuous M-X (X = S, Se, Te) networks that are covalently connected by organic ligands. Here authors report a family of bimetallic OMCs synthesized via selective metal metathesis and oxidation transformation.

Dotti and colleagues present a CAR design featuring trans-acting CD28 and 4-1BB co-stimulation and shared CD3ζ-chain, which improved CAR-T cell metabolic and antitumor functions and avoided tumor escape through simultaneous targeting of two antigens.

Carbonates are known to exist in natural products, but their biosynthesis has not been linked to any enzymes. An unusual fungal Baeyer-Villiger monooxygenase CcsB is now revealed to catalyze an in-line carbonate formation via a two-step mechanism of oxygen atom insertions.

The efficacy of chimeric antigen receptor (CAR) T cells in solid tumor models is enhanced by interleukin-23 engineering.

This work shows that the biosynthesis of the polyether tetronasin involves an apparent enzyme-catalysed inverse-electron-demand hetero-Diels–Alder reaction to form an unexpected oxadecalin intermediate. A second enzyme then rearranges the oxadecalin to form the four-ringed tetronasin.

The COVID-19 pandemic has stopped many human activities, which has had significant impact on emissions of greenhouse gases. Here, the authors present daily estimates of country-level CO₂ emissions for different economic sectors and show that there has been a 8.8% decrease in global CO2 emissions in the first half of 2020.

It is challenging to characterize diverse transcript isoforms by short-read sequencing. Here the authors report full-length transcriptomes in rat hippocampus by hybrid-sequencing, predict isoform-specific translational status, and reconstruct open reading frames validated by mass spectrometry.