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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.

Gram-negative bacteria use a multiprotein complex, LptB₂FGC, to transport lipopolysaccharides (LPS) to the outer membrane. Here, Fiorentino et al. present cryo-EM structures of the complex from Pseudomonas aeruginosa, revealing species-specific features and providing insights into LPS transport mechanisms.

Mass spectrometry (MS) is a powerful tool for the structural characterization of protein complexes. Here the authors offer a path for direct integration of MS and electron microscopy with a MS approach that enables grid deposition and structural preservation of gaseous protein complex ions.

Directly observing ultrafast single electron dynamics at the atomic scale remains a challenge. Here, the authors demonstrate ultrafast Coulomb blockade at selenium vacancies in WSe2/graphene heterostructures using lightwave-driven scanning tunneling microscopy.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Zhu et al. use machine learning to reveal complex insights into human strategic decision-making.

Here the authors provide an explanation for 95% of examined predicted loss of function variants found in disease-associated haploinsufficient genes in the Genome Aggregation Database (gnomAD), underscoring the power of the presented analysis to minimize false assignments of disease risk.

Alterations in the MAPK pathway are common in cancers, yet mutations are rarely found in patients. Here the authors find genomic amplifications of the PPP1CA gene in advanced and metastatic prostate cancer and identify a role for this phosphatase in the positive regulation of ERK signalling.

The family of two-dimensional materials is ever growing, but greater functionality can be realized by combining them together. Here, the authors report the direct synthesis of multijunction heterostructures made from graphene, tungsten diselenide and either molybdenum disulphide or molybdenum diselenide.

Networks of miniaturized magnetoelectric wireless implantable devices can be individually powered and controlled by a single transmitter, show power and transfer data efficiencies that scale with the number of receivers and be used for spinal cord stimulation and cardiac pacing in large animals.

Single-walled carbon nanotubes can be modified into bright and biocompatible agents for high resolution whole-animal imaging at wavelengths in the 1100–1700 nm region.

Nanoscale dimensions can lead to unique functional properties, often achieved via large-amplitude strains. Here, the authors use femtosecond X-rays to visualize light-induced strains in semiconductor nanocrystals, showing that they correspond to anisotropic ‘breathing modes’, which collapse after straining.

Sera from vaccinated individuals and some monoclonal antibodies show a modest reduction in neutralizing activity against the B.1.1.7 variant of SARS-CoV-2; but the E484K substitution leads to a considerable loss of neutralizing activity.

A single-cell approach is used to follow the heritable stochastic changes to DNA methylation that occur in primary chronic lymphocytic leukaemia and healthy B cells, allowing the tracing of cell lineage histories and evolution during treatment with ibrutinib.

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).

Endocisternal neural interfaces with wireless and magnetoelectrically powered electronics that approach brain and spinal cord targets through spaces filled with cerebrospinal fluid can perform recording and stimulation functions and devices can be removed after chronic implantation.

A study of the evolution of the SARS-CoV-2 virus in England between September 2020 and June 2021 finds that interventions capable of containing previous variants were insufficient to stop the more transmissible Alpha and Delta variants.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

G protein-coupled receptors and their effectors can now be released directly from a lipid bilayer using infrared irradiation for proteoform-level characterization by native top-down mass spectrometry. This represents a critical development for drug discovery, as the direct role of post-translational modifications in protein–protein and protein–drug interactions can be characterized.

Tomonaga-Luttinger liquid behavior has been observed within 1D defects in transition metal dichalcogenides. Here, using complementary experiments and engineered defects, the authors demonstrate the importance of graphene as a substrate and its role in the formation of this quasiparticle excitation in 2D WS₂.

Hominin fossils from the Ledi-Geraru Research Project area, Ethiopia, suggest that early Homo and Australopithecus species co-existed in the region more than 2.5 million years ago.

In this study, Aggarwal and colleagues perform prospective sequencing of SARS-CoV-2 isolates derived from asymptomatic student screening and symptomatic testing of students and staff at the University of Cambridge. They identify important factors that contributed to within university transmission and onward spread into the wider community.

Evidence is shown for a skyrmion-like texture in the layer polarization of the electronic wavefunctions of a twisted two-dimensional material. This provides support for theories that link this spatial texture to the topological properties.

Multimodal DNA methylation and transcriptome profiling of single glioma cells links tumor cell transcriptional states to epigenetics via interaction with PRC2 and shows that these states are heritable and important for tumor plasticity.

Examination of the viral E1 hexameric helicase structure finds that a loop of each subunit becomes attached to a nucleotide and remains associated with it during the next six steps of translocation, thereby escorting a single nucleotide through the channel.

Here, the authors show that post-translational molecular signatures of human skeletal muscle in response to acute or chronic aerobic and resistance exercise are distinct, potentially dictating the differential physiologic adaptations to different exercise modes.

Chemical disequilibrium is a known biosignature, and it is important to determine the conditions for its remote detection. A thermodynamical model coupled with atmospheric retrieval shows that a disequilibrium can be inferred for a Proterozoic Earth-like exoplanet in reflected light at a high O₂/CH₄ abundance case and signal-to-noise ratio of 50.

Inbreeding depression has been observed in many different species, but in humans a systematic analysis has been difficult so far. Here, analysing more than 1.3 million individuals, the authors show that a genomic inbreeding coefficient (FROH) is associated with disadvantageous outcomes in 32 out of 100 traits tested.

Coenzyme Q (CoQ) is a lipid made in the inner mitochondrial membrane with antioxidant roles throughout the cell, but regulation of its cellular distribution is unclear. Here the authors identify two proteins that have reciprocal CoQ trafficking functions to help coordinate CoQ localization in yeast.

Combining a published dataset of stable carbon isotopes from herbivore tooth enamel with multidecadal Landsat estimates of C₃ woody cover across 30 African ecosystems, the authors show that there is little relationship between intrataxonomic variation in δ¹³C enamel and vegetation structure, leading them to recommend a community-level approach for making vegetation inferences.

Moiré patterns and flat bands usually occur in multilayer materials with a small interlayer twist angle, but this can cause detrimental lattice reconstruction. Now, flat bands are shown in a bilayer with large twist angle and structural rigidity.

Analysis of blood pressure data from the Million Veteran Program trans-ethnic cohort identifies common and rare variants, and genetically predicted gene expression across multiple tissues associated with systolic, diastolic and pulse pressure in over 775,000 individuals.

This study estimates the reproductive potential of fish in globally distributed coral reef sites. The results show substantial gains in reproductive potential can be achieved through the 30 × 30 conservation target, particularly for the important fisheries family, Serranidae, demonstrating the possible benefit of protection to population replenishment.

Climate change affects agricultural productivity. New systematic global agricultural yield projections of the major crops were conducted using ensembles of the latest generation of crop and climate models. Substantial shifts in global crop productivity due to climate change will occur within the next 20 years—several decades sooner than previous projections—highlighting the need for targeted food system adaptation and risk management in the coming decades.

Genetic and testing data from England show that the SARS-CoV-2 variant of concern B.1.1.7 has a transmission advantage over other lineages.

Post-international travel quarantine has been widely implemented to mitigate SARS-CoV-2 transmission, but the impacts of such policies are unclear. Here, the authors used linked genomic and contact tracing data to assess the impacts of a 14-day quarantine on return to England in summer 2020.

Self-rectifying magnetoelectric metamaterials with nonlinear responses generate electrical pulse sequences that enable precisely timed remote neural stimulation and restoration of sensory motor responses in vivo.

Phylogenetic analysis of trait heritability (PATH) applies phylogenetic correlations to single-cell lineage tracing data, quantifying cell state plasticity and transition probabilities. PATH offers insights into cell state heritability and transition dynamics in cancers.

Stable isotope and community faunal analysis of early hominid environments in the lower Awash Valley (Ethiopia) and Turkana Basin (Kenya/Ethiopia) reveal environmental change and divergence coincident with the emergence of the genus Homo (approx. 2.8 Ma).

Native mass spectrometry, HDX-MS and MD simulations define the mechanism for how LPS binding to the Gram-negative outer membrane complex LptDE opens the LptD lateral exit gate and how thanatin impairs transport across the periplasm.

Point defects in 2D semiconductors have potential for quantum computing applications, but their controlled design and synthesis remains challenging. Here, the authors identify and fabricate a promising quantum defect in 2D WS₂ via high-throughput computational screening and scanning tunnelling microscopy.