Nature最新文献

T cell-based immunotherapies hold promise in treating cancer by leveraging the immune system’s recognition of cancer-specific antigens¹. However, their efficacy is limited in tumours with few somatic mutations and substantial intratumoural heterogeneity^2,3,4. Here we introduce a previously uncharacterized class of tumour-wide public neoantigens originating from RNA splicing aberrations in diverse cancer types. We identified T cell receptor clones capable of recognizing and targeting neoantigens derived from aberrant splicing in GNAS and RPL22. In cases with multi-site biopsies, we detected the tumour-wide expression of the GNAS neojunction in glioma, mesothelioma, prostate cancer and liver cancer. These neoantigens are endogenously generated and presented by tumour cells under physiologic conditions and are sufficient to trigger cancer cell eradication by neoantigen-specific CD8⁺ T cells. Moreover, our study highlights a role for dysregulated splicing factor expression in specific cancer types, leading to recurrent patterns of neojunction upregulation. These findings establish a molecular basis for T cell-based immunotherapies addressing the challenges of intratumoural heterogeneity.

Glaciers are indicators of ongoing anthropogenic climate change¹. Their melting leads to increased local geohazards², and impacts marine³ and terrestrial^4,5 ecosystems, regional freshwater resources⁶, and both global water and energy cycles^7,8. Together with the Greenland and Antarctic ice sheets, glaciers are essential drivers of present^9,10 and future^11,12,13 sea-level rise. Previous assessments of global glacier mass changes have been hampered by spatial and temporal limitations and the heterogeneity of existing data series^14,15,16. Here we show in an intercomparison exercise that glaciers worldwide lost 273 ± 16 gigatonnes in mass annually from 2000 to 2023, with an increase of 36 ± 10% from the first (2000–2011) to the second (2012–2023) half of the period. Since 2000, glaciers have lost between 2% and 39% of their ice regionally and about 5% globally. Glacier mass loss is about 18% larger than the loss from the Greenland Ice Sheet and more than twice that from the Antarctic Ice Sheet¹⁷. Our results arise from a scientific community effort to collect, homogenize, combine and analyse glacier mass changes from in situ and remote-sensing observations. Although our estimates are in agreement with findings from previous assessments^14,15,16 at a global scale, we found some large regional deviations owing to systematic differences among observation methods. Our results provide a refined baseline for better understanding observational differences and for calibrating model ensembles^12,16,18, which will help to narrow projection uncertainty for the twenty-first century^11,12,18.

arising from: J. Klunk et al. Nature https://doi.org/10.1038/s41586-022-05349-x (2022).

Klunk et al.¹ analysed ancient DNA from before, during and after the Black Death, and claimed that large allele frequency changes at immune genes in aggregate, and at four specific variants, reflected natural selection. These claims are unsupported for four reasons. First, the enrichment in immune genes disappears if an appropriate randomization test is carried out; second, after correcting an error in the estimation of allele frequencies, none of the four reported loci pass the original filtering thresholds; third, these filtering thresholds do not adequately correct for multiple testing, and even the original results were not statistically significant. Finally, we find no evidence of significant change in frequency of the ERAP2 variant rs2549794, either in the data reported by Klunk et al. or in published data for samples spanning 2,000 years.

SPO11 initiates meiotic recombination through the induction of programmed DNA double-strand breaks (DSBs)^1,2, but this catalytic activity has never been reconstituted in vitro^3,4. Here, using Mus musculus SPO11, we report a biochemical system that recapitulates all the hallmarks of meiotic DSB formation. We show that SPO11 catalyses break formation in the absence of any partners and remains covalently attached to the 5′ broken strands. We find that target site selection by SPO11 is influenced by the sequence, bendability and topology of the DNA substrate, and provide evidence that SPO11 can reseal single-strand DNA breaks. In addition, we show that SPO11 is monomeric in solution and that cleavage requires dimerization for the reconstitution of two hybrid active sites. SPO11 and its partner TOP6BL form a 1:1 complex that catalyses DNA cleavage with an activity similar to that of SPO11 alone. However, this complex binds DNA ends with higher affinity, suggesting a potential role after cleavage. We propose a model in which additional partners of SPO11 required for DSB formation in vivo assemble biomolecular condensates that recruit SPO11–TOP6BL, enabling dimerization and cleavage. Our work establishes SPO11 dimerization as the fundamental mechanism that controls the induction of meiotic DSBs.

Ultra-hot Jupiters, an extreme class of planets not found in our solar system, provide a unique window into atmospheric processes. The extreme temperature contrasts between their day- and night-sides pose a fundamental climate puzzle: how is energy distributed? To address this, we must observe the 3D structure of these atmospheres, particularly their vertical circulation patterns, which can serve as a testbed for advanced Global Circulation Models (GCM) e.g.¹. Here we show a dramatic shift in atmospheric circulation in an ultra-hot Jupiter: a unilateral flow from the hot star- facing side to the cooler space-facing side of the planet sits below an equatorial super-rotational jet stream. By resolving the vertical structure of atmospheric dynamics, we move beyond integrated global snapshots of the atmosphere, enabling more accurate identification of flow patterns and allowing for a more nuanced comparison to models. Global Circulation Models based on first principles struggle to replicate the observed circulation pattern³ underscoring a critical gap between theoretical understanding of atmospheric flows and observational evidence. This work serves as a testbed to develop more comprehensive models applicable beyond our Solar System as we prepare for the next generation of giant telescopes.