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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.

A combination of biochemical, cell biological and electron microscopy analyses reveal a ‘nucleotide code’ that coordinates Lis1–dynein binding stoichiometry, which in turn governs Lis1’s ability to relieve dynein autoinhibition.

Histone-like HU proteins play roles in chromatin architecture and DNA-dependent processes in bacteria. Here, the authors describe the crystal structure of the DNA-binding domain of HU from Mycobacterium tuberculosis, and show that the pathogen’s growth can be inhibited using HU-targeting small molecules.

The nuclear clock transition of ^229mTh in ²²⁹Th:CaF₂ crystals is characterized as a function of doping concentration, temperature and time, demonstrating high reproducibility and identifying ideal operating characteristics of these crystals as nuclear clocks.

In this study, the authors develop a flavivirus vaccine strategy by introducing mutations into envelope glycoproteins resulting in structural changes that conceal the ADE-prone fusion loop epitope. They show that the Zika virus-specific construct protects mice against viral challenge and prevents ADE by Dengue virus.

Durable agonism of NPR1 achieved with a novel investigational monoclonal antibody could mirror the positive hemodynamic changes in blood pressure and heart failure identified in humans with lifelong exposure to NPR1 coding variants.

Bone marrow adipose tissue (BMAT) comprises over 10% of total fat mass but its systemic metabolic role is unclear. Here, the authors show that BMAT glucose uptake is not insulin or cold responsive; however, BMAT basal glucose uptake is higher than in white adipose tissue or skeletal muscle, underscoring BMAT’s potential to influence systemic glucose homeostasis.

Antibody drug conjugates (ADCs) with pyrrolobenzodiazepine (PBD) payloads are promising cancer therapeutics but are limited by toxicity. Here, the authors develop a HER2-targeted ADC (DHES0815A) with a reduced potency PBD payload that demonstrated promising preclinical efficacy and nonhuman primate tolerability, but culminated in a phase I clinical trial in patients with metastatic breast cancer which was terminated due to toxicity.

Feng et al. report a dynamic template-assisted strategy for depositing perovskite nanowire arrays across areas 12 times larger than the template itself, on diverse substrates. Large-area pixelated photodetectors with a responsivity of 1660A W⁻¹, detectivity of 3.9E14 Jones, and linear dynamic range of 160.3 dB are achieved.

Using data from the CoVPN 3008 study, the authors show that the neutralizing antibody correlate of risk holds in people living with HIV. However, the nAb correlate was weaker and shorter-lived in a vaccine-immunity versus hybrid-immunity population.

The Omicron variant evades vaccine-induced neutralization but also fails to form syncytia, shows reduced replication in human lung cells and preferentially uses a TMPRSS2-independent cell entry pathway, which may contribute to enhanced replication in cells of the upper airway. Altered fusion and cell entry characteristics are linked to distinct regions of the Omicron spike protein.

Molnupiravir is an antiviral that forces lethal error catastrophe in SARS-CoV-2 RNAs. Here, the authors confirm the mechanism of action of molnupiravir in humans using samples obtained from the UK’s AGILE phase IIa clinical trial investigating the antiviral efficacy of the drug against SARS-CoV-2. No treatment-associated SARS-CoV-2 mutations were identified.

Predicting recurrence risk in non small cell lung cancer can help to guide treatment decisions. Here, the authors use CT and PET imaging to develop predictive imaging subtypes, which can be integrated with existing ctDNA methods to predict recurrence.

Silicon-based photoelectrodes are attractive for solar fuel production, but suffer from vulnerability to corrosion. Using dielectric breakdown, a generic approach to improve the performance of metal-oxide semiconductor photoelectrodes is proposed.

Remaining drug-tolerant persistent (DTP) cancer cells limit the efficacy of targeted therapy in EGFR, ALK and KRAS mutant non-small cell lung cancer (NSCLC). Here, the authors show that focal adhesion kinase (FAK)-YAP signalling supports DTP cells promoting residual disease and targeting this pathway improved tumour response in NSCLC preclinical models.

Pseudovirus-based SARS-CoV-2 spike deep mutational scanning is used to measure how mutations across the spikes affect ACE2 binding, cell entry or escape from human sera, producing data that could enable better prediction of viral evolution.

T-cell enrichment has attracted great interest but currently fails to fully replicate the complex natural immune interactions. Here, the authors report on magnetic polymerised antigen-presenting cells that mimic natural interactions to isolate rare tumour-reactive T cells, offering a platform for enhancing cancer immunotherapy and neoantigen discovery.

A global network of researchers was formed to investigate the role of human genetics in SARS-CoV-2 infection and COVID-19 severity; this paper reports 13 genome-wide significant loci and potentially actionable mechanisms in response to infection.

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.

Although the number of participants is important for phenotypic prediction accuracy in brain-wide association studies using functional MRI, scanning for at least 30 min offers the greatest cost effectiveness.

Serological analysis and infection outcomes of participants in the multi-center, prospectively enrolled OCTAVE cohort, comprising 2,686 participants with immune-suppressive diseases who recieved two COVID-19 vaccines, reveals specific clinical phenotypes that might benefit from specific COVID-19 therapeutic strategies.

Metagenomic next-generation sequencing has the potential to support diagnosis of unknown infections as it can identify all potential pathogens without requiring a prior suspected cause. Here, the authors develop and clinically validate a metagenomics-based assay for common and novel respiratory viral pathogens.

RNA-binding proteins orchestrate the post-transcriptional co-regulation of subsets of mRNAs that encode functionally related proteins, thereby contributing to the coordination of gene expression in eukaryotes. Understanding the dynamics of such ribonucleoprotein structures might provide insights into some complex diseases and the regulation of gene expression during development.

Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

A longitudinal evolutionary analysis of 126 lung cancer patients with metastatic disease reveals the timing of metastatic divergence, modes of dissemination and the genomic events subject to selection during the metastatic transition.

In this Stage 2 Registered Report, Buchanan et al. show evidence confirming the phenomenon of semantic priming across speakers of 19 diverse languages.

Topological antiferromagnetic states are generated and spatially reconfigured in free-standing crystalline membranes of haematite through strain design.

There has been a drastic increase in detection of lung nodules, many of which are precancers, preinvasive, minimally invasive or sometimes invasive lung cancers. Here, Hu et al. perform multi-region exome sequencing to discern the evolutional trajectory from precancers to invasive lung cancers.

In Drosophila, long noncoding RNAs (lncRNAs) are expressed most highly in male germline cells. Here the authors report the subcellular distributions of approximately 600 Drosophila lncRNAs in male reproductive tissues, indicating potential involvement in spermatogenesis, fertility and evolution.

Granulomatous/sarcoid-like lesions have been reported in patients treated with immune checkpoint inhibitors (ICIs). Here the authors report the occurrence of “nodal immune flare”, an apparent radiological cancer progression in the nodes characterized by the absence of cancer and the presence of non-caseating granulomas, in patients with non-small cell lung cancer following neoadjuvant ICI treatment.

GWAS have enhanced our understanding for the genetic basis of breast cancer, but the majority of them were performed for European ancestry populations. Here, the authors use a cross-ancestry approach and report seven new variants associated with breast cancer risk among women of African ancestry.

Two doses of the coronavirus disease 2019 vaccine ChAdOx1 nCoV-19 boost antibody responses and functions in phase 1/2 trial participants.

An optimized design of free-space silicon nanoantennas combines high quality factor and low mode volume, reducing the trade-off between these parameters.

This study presents a predictive equation for total energy expenditure derived from doubly labelled water measurements. Applying this equation to two large datasets (the National Diet and Nutrition Survey and National Health and Nutrition Examination Survey) shows that the misreporting of total energy intake is greater than 50%, with important implications for macronutrient availability.