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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.

An automated workflow for scanning probe microscopy, steered by an active learning framework, can efficiently explore relationships between local domain structure and physical properties. Such a capability is demonstrated in a piezoresponse force microscopy experiment to guide measurements of ferroelectric materials.

Here, the authors describe the global distribution of crAssphage, its presence in Old-World and New-World primates, and its association with gut bacterial communities and dietary factors, providing insights into the origin, evolution and epidemiology of human gut crAssphage.

A framework combining combinatorial CRISPR knockout in breast, lung and oropharyngeal cancer in vitro models with public data identifies synthetic lethal interactions, such as perturbed KDM5C sensitizing cells to PARP7 inhibition.

Domain walls in van der Waals layered ferrielectric CuInP₂Se₆ exhibit piezoelectric response. This striking departure from traditional ferroelectric behavior is ascribed to a partially polarized antiferroelectric state, where the domain wall separates coexisting regions of ferrielectric and antiferroelectric phases.

The authors find the electric-field-driven motion of domain walls in the improper ferroelectric ErMnO₃, showing that they readily return to their initial position after having travelled distances exceeding 250 nm.

Proximity ferroelectricity is reported in wurtzite heterostructures, which enables polarization reversal in wurtzites without the chemical or structural disorder that accompanies elemental substitution.

A biased atomic force microscopy tip can write complex in-plane polar topologies in a model ferroelectric Pb_0.6Sr_0.4TiO₃ by means of a smart scan path design. Hence, on-demand generation, reading and erasing of tunable topologies is possible.

Ferroelectricity in hafnia-based systems seems to be correlated with oxygen vacancy dynamics, but the coupling of this and ferroelectric response is rarely studied. Here it is shown that Hf_0.5Zr_0.5O₂ can be antiferroionic, with antiferroelectric behaviour coupled to surface electrochemistry.

A sequencing chemistry that separates nucleotide identification from nucleotide incorporation achieves high accuracy.

High harmonics are generated from a thin film by leveraging the epsilon-near-zero effect. These kinds of harmonic are found to exhibit a pronounced spectral redshift as well as linewidth broadening caused by the time-dependency of this effect.

Dynamic mapping of charge motion across multiple length- and timescales is essential for understanding a variety of phenomena. Here, the authors introduce sparse scanning KPFM, which enables fast nanoscale charge mapping at 3 frames per second to track ion migration.

Ion migration is a plausible origin of material instability and photocurrent hysteresis in perovskite solar cells. Here, authors characterize photo-induced ion migration in perovskites by in situ laser illumination inside scanning electron microscope and observe long-range migration of halide ions.

Strain in thin films can increase piezoelectric properties, but crystallographic constraints may restrict the enhanced response to localized regions. Here, by combining strain and orientation engineering, a low-symmetry bridging phase of BiFeO₃ with enhanced piezoresponse is stabilized uniformly throughout the film.

By using a new deep learning architecture, Enformer leverages long-range information to improve prediction of gene expression on the basis of DNA sequence.

Genome-wide analyses identify common variants associated with 11 distinct neuropathology endophenotypes, providing insights into the mechanisms underlying the genetic risk of Alzheimer’s disease and related dementias.

Rationally designed polymer vesicles increase cytosolic delivery of cGAMP, activating the STING pathway and increasing the immunogenicity of the tumour microenvironment in in vivo murine models of melanoma and in human metastatic melanoma tissues.

Indium-doped cadmium oxide performs polarization switching on a subpicosecond timescale.

The authors summarize the data produced by phase III of the Encyclopedia of DNA Elements (ENCODE) project, a resource for better understanding of the human and mouse genomes.

This study finds that sST2 is a disease-causing factor for Alzheimer’s disease. Higher sST2 levels impair microglial Aβ clearance in APOE4⁺ female individuals. A genetic variant, rs1921622, is associated with a reduction in sST2 level and protects against AD in APOE4⁺ female individuals.

The interplay between amyloid and tau pathology in Alzheimer’s disease is still not well understood. Here, the authors show that amyloid-related increased in soluble p-tau is related to subsequent accumulation of tau aggregates and cognitive decline in early stage of the disease.

Neuroinflammation is observed in Alzheimer’s disease. Here the authors show that 15 proteins related to inflammation found in CSF can potentially be used as a prognostic biomarker.

In Alzheimer’s disease (AD) tau and neurodegeneration have complex regional relationships. Here, the authors show neuronal hypometabolism discordant with tau burden defines functional resilience or susceptibility to Alzheimer’s pathology via limbic/cortical axes. Susceptible groups have faster cognitive decline and evidence of non-Alzheimer’s pathologies.

Alzheimer’s disease is heterogeneous in its neuroimaging and clinical phenotypes. Here the authors present a semi-supervised deep learning method, Smile-GAN, to show four neurodegenerative patterns and two progression pathways providing prognostic and clinical information.

Alzheimer’s disease has been associated with increased structural brain aging. Here the authors describe a model that predicts brain aging from resting state functional connectivity data, and demonstrate this is accelerated in individuals with pre-clinical familial Alzheimer’s disease.

Systematic characterization of longitudinal tau variability in human Alzheimer’s disease using an unbiased subtyping algorithm reveals four trajectories of tau deposition with distinct clinical features.

The KL-VS haplotype of the Klotho gene has been associated with reduced risk of Alzheimer’s disease and dementia. Here the authors show an association between the KL-VS haplotype and amyloid-dependent tau accumulation using PET data.

The BIN1 SNP rs744373 is associated with higher CSF tau and phosphorylated tau levels. Here the authors show, using PET imaging, that this SNP is associated with tau accumulation in the brain as well as impaired memory in older individuals without dementia.

In this study the authors identify a possible link between the gene FAM222A and brain atrophy. The protein it encodes is found to accumulate in plaques seen in Alzheimer’s disease, and functional analysis suggests it interacts with amyloid-beta.

Tau accumulation is associated with disease progression in Alzheimer’s disease. Here the authors use resting state fMRI and tau-PET to demonstrate that baseline connectivity in Alzheimer's disease is associated with tau spreading.

Whether Alzheimer’s disease originates in basal forebrain or entorhinal cortex remains highly debated. Here the authors use structural magnetic resonance data from a longitudinal sample of participants stratified by cerebrospinal biomarker and clinical diagnosis to show that tissue volume changes appear earlier in the basal forebrain than in the entorhinal cortex.

Late-onset Alzheimer's disease (LOAD) is a complex multi-factorial disorder. Here, the authors perform a data-driven analysis of LOAD progression, including multimodal brain imaging, plasma and CSF biomarkers, and find vascular dysfunction is among the earliest and strongest altered events.

Brain-iron elevation is implicated in Alzheimer’s disease (AD), but the impact of the metal on disease outcomes has not been analysed in a longitudinal study. Here, the authors examine the association between the levels of ferritin, an iron storage protein, in the cerebrospinal fluid (CSF) of AD patients and show that CSF ferritin levels predict AD outcomes.

Sun et al. report human lifespan changes in the brain’s functional connectome in 33,250 individuals, which highlights critical growth milestones and distinct maturation patterns and offers a normative reference for development, aging and diseases.

Several studies show that APOE-ε4 coding variants are associated with Alzheimer’s disease (AD) risk. Here, Zhou et al. perform fine-mapping of the APOE region and find AD risk haplotypes with non-coding variants in the PVRL2 and APOC1 regions that are associated with relevant endophenotypes.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

The tau protein is theorized to spread transneuronally in Alzheimers disease, though this theory remains unproven in humans. Our simulations of epidemic-like protein spreading across human brain networks support this theory, and suggest the spreading dynamics are modified by β-amyloid

An energy transduction mechanism across metal/semiconductor interfaces, which relies on electron–electron energy transfer rather than the transport of charge, is demonstrated through ultrafast infrared spectroscopy. This ballistic thermal injection process allows for extended modulation of plasmonic absorption in epsilon-near-zero media.