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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.

Infective endocarditis (IE) is an understudied biofilm-associated infection. Here, analyses of preclinical and clinical data reveal that the Fsr quorum sensing (QS) system of Enterococcus faecalis is a negative regulator of IE pathogenesis.

Newly developed mouse models that enable cell-specific analyses of proteostasis dynamics across the lifespan of the mice reveal key aspects of neuronal proteostasis with ageing.

Ramaglia and colleagues show that aberrant formation of B cell-rich lymphoid structures in the brain meninges is associated with high CXCL13:BAFF ratios. Inhibiting the kinase BTK reduces the lymphotoxin signaling needed to sustain such structures, lowers CXCL13:BAFF ratios and reduces cortical tissue injury.

Anti-tumor functions of low-avidity T cells are often suboptimal. Here the authors show that genetic disruption of TIGIT in TCR-engineered T cells enhances their anti-tumor activity against pancreatic and other gastrointestinal cancers by increasing TCR signal strength.

A cluster-randomized controlled trial found that using an electronic system for symptom monitoring of patient-reported outcomes during treatment led to sustained improvements in emergency visits, quality of life and delayed deterioration of physical function in patients with metastatic cancer.

Targeting two distinct steps of the transcription process yields synergistic antibiotics that kill non-replicating Mycobacterium tuberculosis and reduce drug resistance.

Cancer immunotherapy benefits from antibody-lectin chimeras that block glyco-immune checkpoints.

A greater diversity of crops at the national level increases the temporal stability of total national harvest, reflecting markedly lower frequencies of years with sharp harvest losses.

The role of astrocytes in Alzheimer’s disease pathology remains insufficiently characterized. Here, the authors show that aggravated astrocyte response to Aβ causes brain inflammation, and amyloid and tau co-morbidity, driven by aberrant induction of δ secretase.

IL-6 blockade represents a promising therapeutic approach for the treatment of osteoarthritis (OA), although durable effects have yet to be explored in clinical trials. Here, the authors report the results of a phase I randomized clinical trial testing the efficacy and safety of PPV-06, an anti-IL-6 active immunotherapy able to modulate the activity of circulating IL-6 in patients with knee OA.

An implantable vagus nerve-targeted device safely reduces disease activity and joint damage in rheumatoid arthritis, offering a new nondrug treatment for patients who do not respond to or cannot tolerate medication.

Zonal positioning in the liver determines whether the CTNNB1 oncogene can induce liver cancer.

Single-cell transcriptomics studies on human and mouse non-small cell lung cancer and conditional knockout mouse models show that IL-4 from bone marrow basophils drives the development of granulocyte-monocyte progenitors to myeloid cells that suppress antitumour immunity.

CD163 is a macrophage scavenger receptor central to the clearance of haptoglobin-hemoglobin (HpHb) complexes and the resolution of inflammation. In a remarkable example of near-simultaneous scientific progress, three complementary studies published in Nature Communications^1–3 have resolved the near-atomic resolution structure of the full extracellular domain of human CD163 complexed with HpHb, primarily utilizing cryo-electron microscopy (cryo-EM). The most significant and unified conclusion emerging from this trio of papers is that CD163’s scavenging activity is fundamentally dependent on its ability to form functional multimers.

Both environmental factors and genetic factors influence human immunity. Albert and colleagues leverage data from the Milieu Intérieur Consortium to comprehensively describe the effects of lifestyle, environment and genetics on human innate and adaptive immunity.

Matriptase, a transmembrane serine protease, has been implicated in breast cancer since its discovery, but the mechanisms of this implication have not been elucidated. Here the authors show that matriptase abrogation in vivoaffects c-Met signalling and the growth of breast cancer cells.

Single-cell RNA sequencing and imaging of macrophages in human non-small cell lung cancer and in a mouse model of lung adenocarcinoma show that tissue-resident macrophages have a key role in early tumour progression.

Dysregulation of synovial fibroblasts is thought to be an important step in the pathogenesis of rheumatoid arthritis. Here the authors implicate α2-6 sialylation in this process by studying the glycome of these cells in patients and in a mouse model of inflammatory joint disease.

Nonheme Fe enzymes with open coordination sites hold the potential for advancing new-to-nature reactions. Here a plant-derived nonheme Fe enzyme, 1-aminocyclopropane-1-carboxylic acid oxidase, is evolved and repurposed to catalyze 1,3-nitrogen migration reactions, enabling the enantioselective synthesis of noncanonical amino acids.

The complement cascade is increasingly recognized in the brain. Here, with MERFISH, the authors showed developmentally regulated brain endogenous expression of complement genes and a potential role of the alternative pathway in brain development.

Tan et al. identify PRDM16 as a key repressor of fibrotic switching in smooth muscle cells and show that its downregulation in atherosclerosis drives smooth muscle cells toward a synthetic fate, promoting fibrous plaques.

Thomas Bugge and colleagues report that the matriptase protease initiates an epidermal kallikrein proteolytic cascade in mice lacking Spink5, which encodes the serine protease inhibitor LEKTI. Loss of matriptase rescued some features of excessive proteolytic degradation of corneodesmosomes and inflammatory activation in LEKTI-deficient mice, which are a model of human Netherton syndrome.

We report on the oxidative cross-coupling of organoboron reagents and amino acids via pyridoxal biocatalysis to produce non-canonical amino acids, uncovering stereoselective, intermolecular free-radical transformations.

Tan and colleagues discuss recent advances in spatial omics and computational models that inform the classification and clinical relevance of cellular neighborhoods in cancer.

Pancreatic cancer progression is driven by a switch from HNF4G-driven transcriptional activity in primary disease to FOXA1-mediated transcription in the metastatic setting.

The phase-out of coal will require targeted strategies. New research assesses the retirement vulnerability of coal plants in the USA based on similarity to plants with announced retirements. The findings highlight strategies to guide and accelerate phase-out.

Shale gas and oil production and prospective development are increasing, but methods for shale extraction (‘fracking’) have been met with opposition. This study shows that informed discourse around shale development focussed on risks or doubts about benefits in a similar manner across the US and UK.

Neuroimmune communication in Alzheimer’s disease (AD) is poorly understood. Here, the authors show that CD103–CD8+ resident memory T cells induce neurotoxicity and neuroinflammation in AD via the granzyme K–PAR-1 axis.

Here, the authors investigate the effect of perioperative levosimendan on postoperative subclinical heart failure, evaluated via NT-proBNP measurements in cardiac risk patients undergoing noncardiac surgery, and show no significant difference between levosimendan and placebo on the postoperative maximum NT-proBNP release.

Plasma proteomics plays a key role in advancing clinical research and biomarker discovery. Here, the authors show in a large MSCoreSys multicenter benchmark study that DIA outperforms DDA, delivering robust, precise, and reproducible label-free protein quantification across sites.

The transcription factor Ikaros is required for lymphopoiesis. Busslinger and colleagues show Ikaros positively regulates genes encoding pre-BCR signal transducers and thereby promotes pro-B to pre-B cell progression and proliferation.

In this single-arm phase 2 trial in patients with HR⁺HER2⁻ advanced breast cancer, treatment with the HER3-targeting antibody–drug conjugate paritumab deruxtecan led to encouraging objective response rates, and comprehensive exploratory analyses indicate potential biomarkers of response.

A systemically administered peptide (CARSKNKDC) that homes to injured tissues, has inherent ability to promote wound healing. Here, the authors show that this peptide binds to syndecan-4 and activates ARF6 to trigger re-epithelialisation and the naturally occurring wound repair pathway.

SARS-CoV-2 main protease (Mpro) directly activates coagulation by cleaving factors VII and XII, showing a broader protease specificity and revealing a novel mechanism linking COVID-19 infection to thrombosis.

Phytoplankton are important primary producers. Here the authors investigate phytoplankton physiological changes associated with bloom phases and mixing regimes in the North Atlantic, finding that stratification and deep mixing shape accumulation rates by altering physiology and viral production.

Membrane proteins are essential for any cell but difficult to fold. Here, the authors show that the EMC acts as a chaperone for membrane proteins. They dissect client recognition and provide a molecular mechanism that underlies this EMC function.