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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.

The micro isolation (MISO) method combines microfluidics-based protein purification with cryo-EM grid preparation, enabling cryo-EM structure determination of soluble and membrane proteins starting from less than 1 µg of a target protein.

TRP channel TRPV6 is a regulator of Ca2+ homeostasis. Here, authors decipher the mechanism of TRPV6 inhibition by intracellular Mg2+ ions that bind to four sites around the intracellular pore entrance and lock the channel in the closed state.

Using electron cryomicroscopy, the structure of the rabbit RyR1 calcium channel is determined at 6.1 Å resolution in the closed state and 8.5 Å in the open state, revealing how calcium binding to the EF-hand of RyR1 regulates channel opening and facilitates calcium-induced calcium release.

Incomplete proteolysis of amyloid-β (Aβ) peptides by γ-secretases is linked to Alzheimer’s disease. Using cryo-EM and functional analyses, this study uncovers the γ-secretase – Aβ46 structure and unveils key interactions for efficient Aβ cleavage.

Here the structure of transposase from Tn3 family is reported in apo form and bound to the transposon ends. The activation of the transposase induces metamorphic refolding of the catalytic domain suggesting the family-specific regulation mechanism.

Fiolopodia are involved in cell migration and their attachment to the ECM is mediated by integrin receptors. Here the authors show that myosin X induced filipodia adhesion to fibronectin requires activity of myosin IIA at the filopodium base and formin at the tip to support force transmission through the actin core.

Resonant magnetic excitations are common in unconventional superconductors, but the mechanism for their formation is elusive. Using inelastic neutron scattering, this study finds similar excitations in the non-superconducting heavy-fermion metal CeB₆, suggesting common behaviour between the two ground states.

This article describes a time-resolved cryo-plunger that combines a droplet-based microfluidic mixer with a laser-induced generator of microjets that allows rapid reaction initiation and plunge-freezing of cryo-EM grids. A time resolution of 5 ms was achieved using this approach.

TCRen predicts TCR specificity by modeling the TCR–peptide–MHC structure and estimating the TCR–peptide interaction energy using a statistical potential. The use of structural information allows TCRen to generalize to unseen epitopes, such as cancer neoepitopes.

The authors report the structure of human oncochannel TRPV6 in complex with the plant derived phytoestrogen genistein. The structure provides insights into genistein binding in the channel pore, and how it acts as blocker and gating modifier, suggesting a mechanism of inhibition that can be explored for the structure-based drug design.

Neuberger et al. report the structure of human channel TRPV6 in complex with a cannabinoid inhibitor tetrahydrocannabivarin (THCV) and explore the pathway taken by the drug to reach binding sites in the portals that connect the membrane environment to the central cavity of the ion channel pore.

A multi-ancestry genome-wide association study for age at menarche followed by fine mapping and downstream analysis implicates 665 pubertal timing genes, such as the G-protein-coupled receptor 83 (GPR83) and other genes expressed in the ovaries involved in the DNA damage response.

High-resolution structures of the Photorhabdus luminescens TcA toxin subunit and the entire Tc toxin complex reveal important new insights into Tc complex structure and function.

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

Cryo-EM structures of the heat-activated TRP channel TRPV3 in lipid nanodiscs at different temperatures reveal a conformational wave involved in the gating process.

Similarities in cancers can be studied to interrogate their etiology. Here, the authors use genome-wide association study summary statistics from six cancer types based on 296,215 cases and 301,319 controls of European ancestry, showing that solid tumours arising from different tissues share a degree of common germline genetic basis.

Here, 3D nanofabrication and elasticity programming of monolithic soft microrobots equipped with magnetic springs with strain response at piconewton forces capable of deformation on micrometre length scales is demonstrated for applications in cell force sensing, cell manipulation and soft actuation.

A transcriptome-wide association study identifies associations of genetically predicted gene expression with breast cancer risk. This analysis finds 48 candidate genes implicated in breast cancer susceptibility, including 14 at novel loci.

A large-scale meta-analysis across eight biobank datasets identifies common genetic variants associated with mosaic loss of the X chromosome in female participants.

The first operation of the European X-ray free-electron laser facility accelerator based on superconducting technology is reported. The maximum electron energy is 17.5 GeV. A laser average power of 6 W is achieved at a photon energy of 9.3 keV.

Complex I is an enzyme of the respiratory chain, and is crucial to cellular energy production: it couples electron transfer between NADH and quinine to proton translocation. Here, structures are presented of the membrane domain of complex I from Escherichia coli, and of the entire complex I from Thermus thermophilus. It is proposed that conformational changes at the interface of the two main domains drive a particular 110-Å-long a-helix in a piston-like motion, tilting nearby transmembrane helices and causing proton translocation.

Divergent trends in biogeochemical constituents of the six largest rivers in the Arctic from 2003 to 2019 support multi-faceted changes on the Arctic landscape under global environmental change.

Over 170 susceptibility loci have been identified by genome-wide association studies in breast cancer. Here, the authors interrogated the role of risk-associated variants from non-breast tissue, and using expression quantitative trait loci, identify potential target genes of known breast cancer susceptibility variants, as well as 11 regions not previously known to be associated with breast cancer risk.

Crystal structure analysis of the Phd transcription factor bound to the DNA operator combined with biophysical studies reveal an interplay between intrinsically disordered regions and conditional cooperativity for operon binding and repression.

Ferroelectric orders hardly exist in liquid or ice state of water, despite its enormous molecular electrical polarizability. Here, Gorshunov et al. report incipient ferroelectricity in chains of interacting water molecules by placing them in the structural channels of a beryl crystal.