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Analyses of snRNA genes in a French cohort of people with rare disorders, with validation through international collaboration, identify monoallelic and biallelic variants in RNU2-2 as frequent causes of neurodevelopmental disorders with epilepsy.

Bay et al. investigate upper respiratory mucosal transcriptomic profiles in critically ill COVID-19 patients infected with Omicron using an unsupervised clustering approach. Their study identifies two distinct immune response profiles, one characterised by enhanced innate and inflammatory activation compared with the other, highlighting the immune heterogeneity in severe COVID-19.

Zhang, Lahry, Cipurko et al. show that the microbial metabolites queuine and preQ₁ modify the same host tRNA. PreQ₁-tRNA reduces cell proliferation, slows tumour growth, decreases the translation of ribosomal proteins and is cleaved by IRE1 on the ER ribosome.

In the phase 1/2 TRIDENT-1 trial, treatment of patients with NTRK fusion–positive advanced solid tumors with the tyrosine kinase inhibitor repotrectinib—selective for ROS1, TRKA−C and ALK—was safe and resulted in durable systemic and intracranial clinical response.

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.

Metastasis of urothelial carcinoma remains incurable due to insufficient treatment options for advanced disease. Here, the authors combine whole exome sequencing and RNA-seq from metastatic biopsies, and show temporal evolution when compared with primary tumour.

Due to the delocalization of molecular orbitals, valence-shell spectroscopy does not allow distinction between individual atoms. Here, the authors show that for photoionization, the difference in mass—and hence recoil momentum—between atoms in a diatomic molecule allows site-selective emission to be observed.

Tuberculosis is a major global health threat. Here, the authors develop a single-cell drug discovery approach and identify a compound that tunes bacterial phenotypic variation. This enhances the activity of anti-tubercular drugs against the pathogen.

Basophils have been implicated in systemic lupus erythematosus (SLE), as evidenced by the fact that basophil-deficient mice do not develop the disease. Here, the authors demonstrate that PD-L1 and IL-4 expression in basophils promotes the pathogenic accumulation of follicular helper T cells in patients with SLE and murine models.

Targeted therapies matched to genomics improved progression-free survival when genomic alterations were classified as level I/II (according to ESCAT), and genomics should thus be driven by target actionability in patients with metastatic breast cancer.

A cavity optomechanics model accounting for the intrinsic dynamics of the interaction between plasmons and molecular vibrations reveals a parametric amplification mechanism that may provide an explanation for features recently observed in nonlinear Raman spectroscopy experiments.

The authors observe electron interference using the Auger electron emitted from an O₂ molecule ionized by a soft X-ray photon. The interference disappears when the location of the O⁺ can be determined from the final state observed.

Experimental observations in small-grained polycrystals suggest a new concept of considering metallic grain boundaries not as defects but as separate defect-containing lattices, providing a potential explanation for the deformation behaviour of nanocrystalline metals.

Borcoman and colleagues present the efficacy and safety results of the phase 2 PEVOsq basket trial investigating the combination of pembrolizumab with the epidrug vorinostat in patients with recurrent and/or metastatic squamous cell carcinoma.

High-affinity ligands were developed that specifically bind aggregated TDP-43, are selective over common co-pathologies, and possess pharmacokinetic profiles suitable for PET imaging to visualize TDP-43 pathology in the brains of patients.

The study reports the arrival of avian influenza H5N1 virus clade 2.3.4.4b into the Indian Ocean sub-Antarctic archipelagos of Crozet and Kerguelen. Using phylogeographic analyses, the virus likely came from the distant South Georgia islands.

Analysis of snRNA genes in individuals with rare disorders identifies de novo and recurrent variants in RNU5B-1 and RNU5A-1, in addition to previously unreported cases with pathogenic or likely pathogenic variants in RNU4-2.

Exploiting the full structuration of light fields for storing multiple degrees of freedom holds great promise for applications in classical and quantum optics. Here, the authors demonstrate the storage of spatio-polarization-patterned beams into an optical memory, and its retrieval at the single-photon level.

Genomic, transcriptomic and epigenetic analyses of malignant pleural mesothelioma identify molecular axes and specialized tumor profiles underlying intertumoral heterogeneity.

Sepsis induces a period of immunosuppression which can be problematic in the face of subsequent infectious challenge. Here the authors show the presence of PD-L1 expressing regulatory plasma cells that can inhibit T cells in a murine model and in patients with sepsis.

Caveolae are mechanosensors and mutations of their coat proteins are implicated in muscle disorders, but molecular mechanisms are unclear. Here, the authors show that caveolae can regulate IL6/STAT3 signaling in muscle cells under stress, and that dystrophy related Cav3 mutant myotubes have reduced caveolae and upregulated IL6 signaling.

As quantum technologies attract more and more funding, Christophe Couteau and Snežana Lazić argue for a clear and accessible definition of the label ‘quantum’. This would help public and private investors to make the right choices.

Combined hepatocellular-cholangiocarcinomas (cHCC-CCA) are challenging to diagnose, as they exhibit features of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICCA). Here, the authors use deep learning to re-classify cHCC-CCA tumours into HCC or ICCA based on histopathology images.

How autophagy supports tumor cell metabolism is not fully clear. Here, the authors show that autophagy regulates lipid availability to support mitochondrial oxidative metabolism through mitochondria-endoplasmic reticulum contact sites, necessary for cell proliferation in AML.

This protocol qualitatively and quantitatively assesses the involvement of factors in the nucleolar structure. After siRNA-mediated depletion of factors of interest, dedicated software is used to analyze images of nucleoli to determine an index of nucleolar disruption, the iNo score.

Oaks can live hundreds of years. Comparative genomics using a high-quality genome sequence provides new insights that may explain tree longevity. Samples from branches and corresponding acorns also help quantify heritable somatic mutations.

Extensive oxidative potential measurements from across Europe analysed with the two most common assays, dithiothreitol and ascorbic acid, using a standardized protocol show the strong influence of site type and suggest pathways for mitigation strategies.

Strontium isotope analysis can be applied to animal and plant tissues to help determine their provenance. Here, the authors generate a strontium isoscape of sub-Saharan Africa using data from 2266 environmental samples and demonstrate its efficacy by tracing the African roots of individuals from historic slavery contexts.

Asthenozoospermia is a major cause of male infertility, and multiple morphological abnormalities of the flagella (MMAF) is a particularly severe form. Here, using whole-exome sequencing of 78 MMAF patients, the authors identify mutations in two WDR proteins, CFAP43 and CFAP44, and confirm that these proteins are required for flagellogenesis in mouse and Trypanosoma brucei.

Growth of the mammalian heart is controlled by Hippo signalling but how this is regulated is unclear. Here, the authors show that Fat4 (an atypical cadherin) acts upstream of Hippo signalling and Fat4 mutant mice have thicker myocardium, which is mediated by the scaffold Amot1 and transcription factor Yap1.

Combining a large-scale dataset of 23 ungulate species (in which newborns follow contrasting tactics of predator avoidance) with continuous-time stochastic movement models, the authors reveal that there are multiple dimensions of maternal movement behaviour and space use.

The nucleolus is a specialized functional domain of the nucleus where ribosome biogenesis is initiated and also implicated in a p53-dependent anti-tumor surveillance. Here the authors use a quantitative imaging approach to detail the role of each ribosomal protein on the structural integrity of the nucleolus and p53 homeostasis.

The SARS-COV-2 pandemic has put pressure on intensive care units, so that predicting severe deterioration early is a priority. Here, the authors develop a multimodal severity score including clinical and imaging features that has significantly improved prognostic performance in two validation datasets compared to previous scores.

It is not clear whether and how incoming HIV-1 Tat accumulates in uninfected cells. Here, Chopard et al. show that, in uninfected cells, incoming Tat is palmitoylated on Cys31 by DHHC-20, which increases its affinity for PI(4,5)P₂ and results in its accumulation at the plasma membrane.

The regulation of energy homeostasis by centrally-produced GLP-1 is not yet fully understood. Here, authors show that GLP-1 neuronal circuitry in the olfactory bulb reduces food intake and enhances insulin secretion in obese mice. The increase in insulin secretion is mediated by a GABA-dependent relay in the paraventricular hypothalamus and decreased sympathetic nerve activity.

Immune cells contribute to adverse remodeling following myocardial infarction. Here the authors show in mice and pigs that CD8⁺ lymphocytes release Granzyme B in the infarcted heart leading to cardiomyocyte death, enhanced inflammation and deterioration of cardiac function.

Analyses of 475 ancient horse genomes show modern horses emerged around 2200 bce, coinciding with sudden expansion across Eurasia, refuting the narrative of large horse herds accompanying earlier migrations of steppe peoples across Europe.