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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.

Cancer cells respond differently to inhibitors of Poly (ADP-ribose) polymerase. Here the authors reveal that ovarian cancer cells with higher cellular NADP+ levels are more sensitive to clinically relevant PARP1 inhibitors and show that NADP+ act as an endogenous inhibitor of PARP enzymes.

Currently polyamide membranes fabricated by interfacial polymerization are limited by inherently negative charge as well as narrow charge tailoring window restricting the application of these membranes. Here, the authors report a facile ionic liquid-decoupled bulk/interfacial diffusion strategy to fabricate polyamide membranes which can transform on-demand from inherently negative to highly positive and near-neutral charge.

Mudskippers are amphibious fishes that have adapted to live on mudflats. Here, the authors sequence the genomes of four different mudskipper species and highlight genetic changes that may have had an evolutionary role in the water-to-land transition of vertebrates.

Here, the authors show a causal role for gut bacteria-derived metabolites tryptamine and phenethylamine in contributing to insulin resistance and the development of metabolic syndrome in patients with irritable bowel syndrome and type 2 diabetes.

Many thrombolytic agents depend on plasminogen, leading to D-dimer accumulation. Here, Tang et al. report a plasminogen-independent thrombolytic enzyme that degrades blood clots and D-dimer without plasminogen.

CXXC domain proteins bind to CpG DNA sequences and influence chromatin modification. Xuet al.report crystal structures of the CXXC protein CFP1, a component of the SETD1 histone H3K4 methyl transferase complex, and study the molecular mechanisms of DNA-binding specificity.

Tumour-associated macrophages (TAMs) facilitate malignant growth of glioblastoma (GBM). Here, the authors show that TAMs support glioma stem cell renewal via paracrine signalling to the pleiotrophin receptor PTPRZ1 and that blocking this axis results in increased survival of tumour-bearing animals.

Tools to investigate a wide range of 3D microenvironmental parameters are important for understanding and controlling cell fate. Here, the authors develop hydrogels with orthogonal biochemical gradients and use this screening system to identify microenvironments that induce mesenchymal stem cell chondrogenesis.

The integration of genome sequencing, genome re-sequencing, QTL mapping and gonadal transcriptome data reveals that the sex chromosome has undergone rapid turnover in three closely related species of the family Scatophagidae.

The application of the LCC variant of polyethylene terephthalate (PET) hydrolase for industrial degradation of PET has been hindered by the 10% of nonbiodegradable PET. Here, the authors use a computational strategy to engineer TurboPETase which outperforms other PETase variants and achieves nearly complete depolymerization of the postconsumer PET bottles at a high, industrially relevant, level of solids loading.

Single-cell transcriptomics of human lung tissue from individuals with tuberculosis identifies signatures of inflammation, apoptosis and senescence affecting immune, epithelial and endothelial cells linked with long-term pulmonary impairment.

This study identifies Basal-B cells as a transient cell state during prostate homeostasis and androgen-mediated regeneration. These cells exist in humans and increase in number with prostatitis and inflammation.

The authors show that adriamycin induces global changes on chromatin conformation associated with phase transitions mediated through Histone H1.

The mechanisms behind how vascular repair is regulated after ischemic stroke are yet to be elucidated. Here, the authors describe that a circular RNA interacts with FTO to promote vascular repair following stroke in mice and primates via mediating m6 A modification.

Carbon materials are promising for perovskite solar cells but suffer from poor interfacial energy level alignment. Now, Zhang et al. show that Ti atomically dispersed in reduced graphene reduces energy losses improving device performance.

The polarly localized BASL protein controls asymmetric cell division during stomatal lineage development in Arabidopsis. Here, the authors show that BASL polarization depends on PRAF/RLD proteins that interact with GNOM and suggest a role for endosomal trafficking in establishing polarity.

3D culture systems can provide critical insights into cellular behaviour. Here, the authors study the binding timescale of dynamic crosslinks and the conjugation stability of cell-adhesive ligands in cell–hydrogel network interactions to evaluate the impact on stem cell behaviour, mechanosensing and differentiation.

Cyclized or folded single-chain polymeric nano-objects are generally produced with low efficiency. Here, the authors have scaled up the preparation of supramolecular single-chain nanogels by RAFT polymerizations and applied the dynamic supramolecular single-chain nanogels to regulate cell behaviours at varying scales.

Here, the genome sequence of the tiger tail seahorse is reported and comparative genomic analyses with other ray-finned fishes are used to explore the genetic basis of the unique morphology and reproductive system of the seahorse.

Polarization-dispersive imaging spectrometer enables simple, fast and reliable circular dichroism measurement for single chiral nanostructures.

The authors demonstrate that carnitine palmitoyltransferase 1A (CPT1A) expression is reduced in glioma stem cells (GSCs) in comparison with non-stem tumor cells. CPT1A overexpression promotes mitochondrial fusion and GSC differentiation by increasing the phosphorylation of dynamin-related protein 1 (Drp1) at Ser-637, thus impairing GSC-derived xenograft growth and prolonging survival in tumor-bearing mice. These results suggest that CPT1A could be a molecular target for GSC differentiation therapy.

Chen et al. perform single-cell analysis and identify transcriptomic remodelling in epithelial cells, macrophages, T cells, fibroblasts and endothelial cells, which together regulate prostate cancer progression.

Pu-erh tea displays cholesterol-lowering properties. Here, Huang et al. show that this is mostly due to the action of a pigment in Pu-erh tea that induces changes in certain gut microbiota and bile acid levels, thus modulating the gut-liver metabolic axis.

While producing renewable fuel is crucial for a sustainable energy economy, there is still a need for active and durable materials capable of efficient fuel generation and utilization. Here, authors demonstrate a triple-conductive oxide as an oxygen electrode for H₂ or electricity production.

Electrolyte design is crucial for lithium metal battery development. Here the authors report an electrolyte with a compact solvation structure on the nanometre scale that facilitates fast interfacial reaction kinetics and improves battery performance.