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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.

This report describes a nanobody targeting glycine receptor mGlyR that inhibits its ability to regulate G protein signaling and produces anti-depressant effects in mice providing an immunotherapy approach to potentially treat depression.

Estimates from the Global Burden of Disease study reveal declines in chronic respiratory disease mortality between 1990 and 2023—especially during the COVID-19 pandemic—but the burdens on people affected remain substantial.

Annunziato, Quan and Donckele et al. identify G3BP2 (Ras–GAP SH3 domain-binding protein 2) as a molecular glue-induced neosubstrate of the CRL4^CRBN E3 ubiquitin ligase. The CRBN–glue neosurface uses a molecular surface mimicry mechanism to recruit and degrade G3BP2 in a compound-dependent manner.

The meningeal compartment communicates with the brain to modulate homeostatic functions. Here, the authors demonstrate that natural killer (NK) cells and innate lymphoid cells (ILC) 1 shape synaptic neuronal transmission and affect mouse behavior.

Neuroimmune interactions are important in amyotrophic lateral sclerosis (ALS). Here the authors characterize the role of NK cells in mouse models of ALS, and in patient tissue.

The authors report long-lived pump-induced conductivity suppression in metallic Ti₃C₂ MXenes using ultrafast terahertz and reflectance spectroscopy. The effect is attributed to strong photothermal heating and slow heat dissipation.

New hominin fossils from the Grotte à Hominidés at Thomas Quarry I (ThI-GH) in Casablanca, Morocco, dated to around 773 thousand years ago are similar in age to Homo antecessor, yet are morphologically distinct.

A method to coherently manipulate excitons and perform all-optical logic operations using the valley degree of freedom in monolayer WS₂ is discussed.

How inflammation spreads from the skin to the joints in psoriatic disease is unclear. Here, the authors show that joint-resident fibroblasts can control differentiation of infiltrating skin-derived myeloid precursors that can become inflammatory macrophages.

Petrological studies along with volcano monitoring data relate the unusual 2019 explosive activity at Stromboli volcano (Italy) to deep magma recharges up to a few days prior the eruption and a direct link between deep and shallow magma reservoirs.

Mchantaf et al. explore HIV-1 persistence in five anatomical compartments in people living with HIV on successful Dolutegravir therapy. They find the highest levels of infection and viral transcription in lymph nodes, and that persistence is not associated with the selection of drug resistance mutations to Dolutegravir.

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.

Soil microorganisms play a crucial role in maintaining ecosystem functioning across diverse environments. This study shows that soil properties and specific microbial taxa jointly shape ecosystem functioning across European soils.

This work shows the two independent structures of cardiac amyloids formed by non-native atrial natriuretic peptide (ANP) dimers extracted from atrial fibrillation patients. These data point at dimeric ANP forms as the amyloidogenic species in vivo.

The adhesion of meningococci to endothelial cells relies on type IV pili, which induce the formation of long tubular structures on the host cell membrane. Here, the authors show that the tubular structures accumulate and trap host membrane-associated proteins, which facilitates their interaction with bacterial ligands and the activation of adhesion and signaling receptors.

A purpose-built implantable system based on biomimetic epidural electrical stimulation of the spinal cord reduces the severity of hypotensive complications in people with spinal cord injury and improves quality of life.

Reinforcement learning task-based behavioral and computational measures displayed low test–retest reliability at the individual level. Also in contrast to self-assessed personality measures, behavioral and computational measures were poor predictors of mental health measures, representing a challenge for computational psychiatry.

Chaperone-mediated autophagy declines with age in skeletal muscle of humans and mice, leading to muscle dysfunction characterized by impaired calcium homoeostasis and mitochondrial function.

A molecular glue induces CRBN homodimerization and degradation through degron mimicry, revealing a distinct glue mechanism and offering a tool to study CRBN biology.

In the proof-of-concept phase 2 ROME trial, comprehensive genomic profiling followed by molecular tumor board evaluation and randomization of patients with metastatic solid cancer to receive personalized therapy or standard of care led to a significantly higher objective response rate and longer progression-free survival in patients who received personalized therapy.

Elhan et al. show that ATG2A acts with DGAT2, the enzyme producing triacylglycerol (TAG), in lipid droplet growth. By delivering diacylglycerol to lipid droplets, ATG2A not only fuels TAG production but also promotes the recruitment of DGAT2 to droplet surfaces.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

The authors theoretically delineate the maximal increases in tree growth that can be expected from increases in plant intrinsic water-use efficiency, which increases with rising CO₂. They highlight environmental and physiological limits on growth in the context of experimental data.

Preclinical models are essential to study disease pathogenesis and test novel treatments. Here, a broad overview of metabolic dysfunction-associated steatotic liver disease and steatohepatitis-associated hepatocarcinoma preclinical models is provided, detailing main features, advances and limitations of in vitro and in vivo models, and how they translate to human disease.

Employing a candidate gene approach, Mancina et al. identify a genetic variant of the Pleckstrin and Sec7 domain-containing 3 (PSD3) gene that reduces susceptibility to fatty liver disease. Functional studies in vitro and in vivo demonstrate that targeting PSD3 protects against fatty liver disease.

Activation of the growth factor Trunk patterns the Drosophila embryonic termini but how this is regulated is unclear. Here, Johnson et al.report that Trunk is cleaved intracellularly by Furin proteases, and its extracellular accumulation is then mediated by the perforin-like protein Torso-like.

Magnetic fields in stellar upper atmospheres are key to understanding stellar activity and its planetary effects. Here, the authors study chromospheric magnetic fields in three M-dwarf stars using spectropolarimetric observations, finding fields reaching hundreds of Gauss with complex height-dependent structures.

The authors analyze rare coding variants in 1990 individuals with congenital kidney anomalies, finding diagnostic variants in 14.1% of cases. They identify two new causal genes, ARID3A and NR6A1, along with 38 candidate genes, providing evidence for shared genetics with other developmental disorders.

Stem cell differentiation is controlled by manipulating RNA condensates.

The dynamic behavior of supported metal nanoparticles under reaction conditions plays a crucial role in determining their catalytic performance. Here, time-resolved XRD, PDF, and modulation techniques provide direct evidence of hydrogen-induced breathing and detachment of Pt nanoparticles from an alumina support, uncovering reversible, size-dependent dynamics in both gas and liquid phases.

Hole spin qubits in germanium are well suited for fast, electrically driven gates with high fidelity, but scaling to large qubit arrays remains challenging. Here the authors demonstrate a 10-spin qubit array with gate fidelities exceeding 99%, revealing mechanisms for uniform and scalable qubit control.

Cellular forces shaping cells and tissues during development are well understood, but their dynamic material properties less so. Here, the authors use Brillouin microscopy to map cell material properties in developing fruit fly embryos, revealing dynamic, fate-specific modulation.

There has been considerable interest in using magnons for information processing. Such ‘magnonic’ devices will require magnetic patterning analogous to the lithographic patterns of integrated circuits. Here, Levati, Vitali and coauthors present one possible approach to this, demonstrating laser induced changes in the perpendicular magnetic anisotropy of Yttrium Iron Garnet.

The advantage of living in cities compared with rural areas with respect to height and BMI in children and adolescents has generally become smaller globally from 1990 to 2020, except in sub-Saharan Africa.

A genome-wide association study including over 76,000 individuals with schizophrenia and over 243,000 control individuals identifies common variant associations at 287 genomic loci, and further fine-mapping analyses highlight the importance of genes involved in synaptic processes.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

Researchers demonstrate a terahertz quantum cascade laser operating in a regime of active mode-locking by modulating its bias current with a radiofrequency synthesizer. This technique allows coherent sampling of the terahertz electric field as well as control over the laser's carrier–envelope phase shift.

Asymmetric cell division often requires alignment of the mitotic spindle to cortical polarity cues. Here the authors show that cortical Wnt signaling induces formation of a complex between NuMA/dynein microtubule motors, LRP6 and β-catenin that promotes asymmetric division.

Whole-genome sequencing, transcriptome-wide association and fine-mapping analyses in over 7,000 individuals with critical COVID-19 are used to identify 16 independent variants that are associated with severe illness in COVID-19.

Epidemiological methods are used to show that the Great Fear of 1789, a series of peasant insurrections in rural revolutionary France, was driven by deliberate political action rather than spontaneous fear.

The application of partitioned polygenic scores to data from cohorts of patients identifies two distinct subtypes of MASLD with different cardiometabolic risk profiles.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

Methylthio-alkane reductases are recently discovered enzymes that can produce methanethiol and small hydrocarbons from methylated sulfur compounds. Now the cryo-EM structure of a methylthio-alkane reductase complex is solved, revealing large metalloclusters previously observed only within nitrogenases.

The heterogenous nature of rheumatoid arthritis renders the prediction of responsiveness to biological treatments difficult. Here the authors analyze bulk RNA-seq data from the STRAP trial (n = 208) to build a machine-learning model for predicting responses to etanercept, tocilizumab and rituximab with AUCs around 0.75 to potentially assist in therapy planning.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Dietary n-6 PUFAs enhance adipose tissue expandability through the PPARγ–LPCAT3 membrane remodelling axis.

Dengue and chikungunya are an increasing public health concern in Europe, and Italy is particularly affected. Here, the authors analyse travel-related cases and outbreaks in Italy from 2006 to 2023 and assess current transmission risks.