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Large-effect variants in autism remain elusive. Here, the authors use long-read sequencing to assemble phased genomes for 189 individuals, identifying pathogenic variants in TBL1XR1, MECP2, and SYNGAP1, plus nine candidate structural variants missed by short-read methods.

Deep brain stimulation tuned to cue-reactivity within the nucleus accumbens region reduced drug cravings, heralding an evocation-based programming strategy for opioid use disorder.

A streamlined blood test using mass spectrometry improves measurement of amyloid-β for early Alzheimer’s disease diagnosis, requiring less sample volume and reagents while maintaining high accuracy, sensitivity and strong agreement with brain imaging.

This paper reports the excess mortality estimated during the evolving consecutive waves of COVID-19 in countries participating in the European Mortality Monitoring Network (EuroMOMO) in 2020-2023 and how they compare to recent influenza seasons.

Using interviews, this paper establishes that experts agree government intervention is critical in enabling climate-resilient housing, given the transformative potential of regulatory reform, finance, and information services.

Newly emerging SARS-CoV-2 variants underscore the need for broad-spectrum antiviral solutions. This study shows a macrocyclic peptide inhibitor that locks the SARS-CoV-2 spike trimer into a “closed” conformation by engaging a conserved region, and demonstrates that intranasal administration of the peptide inhibitor protects against Omicron variants.

Sheep producers face growing expectations to produce more food, conserve biodiversity, stay profitable and cut emissions. The authors find that interventions work best when addressing underperforming environmental, economic, or psychological areas.

A single-cell epigenomic atlas of human immune cells highlights cell-type-specific features associated with genetic or environmental exposures.

Neural basis of decision-making is not fully understood. Here authors show that mouse prefrontal neurons encode history-specific rewards and choices. However, their influence is gated by task structure and timing, affecting decisions primarily in variable interval tasks and when temporal delays separate events.

An alternative mating system, termed parasex, produces progeny with high levels of genotypic diversity and is able to fulfil the roles of meiosis when it is absent in the fungal pathobiont Candida albicans.

There is a lack of effective therapies for patients with non-V600E BRAF mutant cancer. Here, the authors report limited response in a phase II trial investigating the combination of binimetinib (MEK inhibitor) and encorafenib (BRAF inhibitor) for the treatment of non-V600E BRAF mutant cancer and subsequently investigate resistance mechanisms and combination therapeutic strategies in patient-derived models.

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 cavity-array microscope is realized using intra-cavity lenses to create a two-dimensional array of over 40 modes, each coupled to a single atom in free-space.

Vassy, Dornisch and colleagues developed a genomics-based prostate cancer risk model to support a randomized clinical trial of precision screening in a national healthcare system.

Global Burden of Disease estimates show that between 1990 and 2023, the prevalence and burden of drug use disorders, inclusive of amphetamine, cannabis, cocaine and opioid use, have been increasing in high-income countries, particularly in the USA.

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.

Kinematic measurements of the Perseus galaxy cluster reveal two drivers of gas motions: a small-scale driver in the inner core associated with black-hole feedback and a large-scale driver in the outer core powered by mergers.

Systems of electron spins in nuclear-spin-rich hosts are gaining attention for quantum memory applications. Using spin ensemble studies, the authors propose transition metal ions in halide double perovskites as promising candidates, featuring long electron spin coherence and deterministic nuclear spin control.

T-cell–mediated rejection (TCMR) remains a major cause of kidney transplant failure with incompletely understood mechanisms. Here the authors use single-nucleus RNA sequencing, spatial transcriptomics and immunofluorescence to show that injured kidney epithelial cell states associate with poor transplant outcomes after T-cell–mediated rejection.

Lucerastat was well-tolerated, but did not reduce neuropathic pain, abdominal pain, or diarrhea compared with placebo. Lucerastat reduced biomarkers of Fabry Disease at 6 months, and these reductions were maintained at the 18-month interim analysis.

Proteomic data from natural isolates of Saccharomyces cerevisiae provide insight into how these cells tolerate aneuploidy (an imbalance in the number of chromosomes), and reveal differences between lab-engineered aneuploids and diverse natural yeasts.

In a phase 1b/2 trial, an off-the-shelf vaccine using gorilla adenoviral and modified vaccinia Ankara vectors with over 200 mutated peptides known to be present in persons with mismatch-repair-deficient tumors is safe and elicits neoantigen-specific T cells in individuals with Lynch syndrome.

The IKKα kinase was previously reported to promote metastasis. Here, the authors reveal that loss of IKKα function promotes colorectal cancer liver metastasis by expanding a CDH17⁺/CLDN2⁺ epithelial subpopulation characterized by tight junction stabilization and collective migration.

A platform using matched patient-derived lung tumouroids and healthy lung organoids enables accurate examination of patient responses to CAR T therapy and offers a faithful framework for improved CAR T design.

Genetic variants of TREX1, a negative regulator of type I interferon responses, have been linked previously to non-monogenic systemic lupus erythematosus (SLE). Here the authors analyze UK Biobank multi-omics data to show that, while a derived oligoprotein interferon signature associates with increased SLE risk, TREX1 variants do not.

Ribosomal translation is coupled to cotranslational protein folding, process assisted by dedicated chaperones. Here, authors present structures of the ribosome-bound yeast Hsp70 chaperone Ssb, identifying its ribosomal binding site and revealing its interactions with a model nascent chain.

Niche conservatism is a key assumption when planning non-native species management, but it is not always met. This study suggests that regional differences in niche conservatism are primarily transient and thus a matter of time.

In this study, Dahmane et al use a method called cryo-electron tomography to uncover new details of how tick-borne flaviviruses transform cells into virus factories.

The study reports the discovery of a persistent bow shock around a diskless magnetic accreting white dwarf, revealing a powerful energy-loss mechanism that challenges current models of accretion and compact binary evolution.

Understanding collective behaviour is an important aspect of managing the pandemic response. Here the authors show in a large global study that participants that reported identifying more strongly with their nation reported greater engagement in public health behaviours and support for public health policies in the context of the pandemic.

It remains unclear whether rRNA modifications can be naturally altered in response to antibiotics in bacteria. Here, the authors analyzed direct RNA nanopore sequencing data with an analytical pipeline Nanoconsensus, to investigate whether bacterial rRNA modifications are modulated upon exposure to various antibiotics.

This study assessed the durability of immunity in humans after vaccination with an MVA-based MERS vaccine. The data show that antibodies and T cells persist for at least two years, with the antibodies capable of cross-neutralizing MERS-CoV variants.

Here, the authors present genome-wide aDNA from 138 Early Bronze Age individuals from Lower Austria. Their findings point to a patrilocal society with non-strict female exogamic practices and long-distance genetic connections across Central Europe.

The xylosyltransferase isoenzymes XT1 and XT2 catalyze the first glycosylation step in the biosynthesis of proteoglycans. Now, bump-and-hole engineering of XT1 and XT2 enables substrate profiling and modification of proteins as designer proteoglycans to modulate cellular behavior.

How the complex interplay between multiple nutrients within the microenvironment dictates potential sites of metastatic cancer growth is explored.

This study identifies reproductive trajectories in the Finnish Twin Cohort, and shows that having either many or no live births is linked to faster biological aging and higher mortality risk, supporting the disposable theory of aging.

How landscapes are arranged affects soil pathogenic fungi worldwide. The authors reveal the global pattern and pronounced scale-dependency of landscape complexity and land-cover quantity on soil pathogenic fungal diversity.

More frequent fires in the North American boreal are causing shifts from conifer to deciduous forests. This study finds that when deciduous forests burn, their carbon losses are driven by weather, but are lower than in conifer forests, potentially dampening climate–fire feedbacks.

Antibodies against SARS-CoV-2 continue to evolve 6 to 12 months after infection in patients who have recovered from COVID-19, increasing in potency and breadth with time.

Wei et al. perform spatial transcriptomic profiling on synovial tissue biopsy samples from individuals with recent-onset rheumatoid arthritis, finding TGFβ signaling and fibrogenic fibroblast activation drive a treatment-refractory tissue phenotype.

Despite recent advances in targeting RAS, resistance to anti-RAS therapies limits their effectiveness in KRAS-mutant lung cancer. Here, the authors show that RAS inhibitors impair wild-type KRAS degradation, leading to its accumulation and resistance through mTOR, and demonstrate that targeting mTOR or amino acid transport can overcome this resistance.

Reactive carbon capture enables CO₂ conversion into valuable chemicals without the typically separate energy-intensive CO₂ recovery step. In this work, the authors suggest minimizing its performance trade-offs via indirect bicarbonate conversion within a porous solid electrolyte reactor.

Segmented Filamentous Bacteria (SFB) are understudied commensals that promote immune activation through their attachment to the intestinal epithelium. Here, Cruz et al. use cryo-electron microscopy and tomography to identify various surface structures and uncover a developmental transition at the SFB adhesive tip.

Hepatocyte organoids derived directly from human tissue enable long-term hepatocyte expansion and can be combined with portal mesenchyme and cholangiocyte organoids to form a donor-specific periportal liver assembloid system.

Bohlen and colleagues report that the E3 ubiquitin ligase CBL is necessary for the development, tolerance and activation of B cells in humans, unlike in mice where CBL deficiency results in loss of T cells.

Compiling data on floral introductions and European colonial history of regions worldwide, the authors find that compositional similarity of floras is higher than expected among regions once occupied by the same empire and similarity increases with the length of time the region was occupied by that empire.

Fungal parasites infect key nitrogen-fixing cyanobacteria during Baltic Sea blooms, drawing on carbon and nitrogen reserves. Here, authors find up to a fifth of newly fixed nitrogen is diverted to fungi in the cyanobacterium Dolichospermum, altering the fate of new nitrogen and trophic transfer.

Variants in the PSMC5 gene impair proteasome function and cellular homeostasis, altering brain development in children. This study reveals underlying molecular mechanisms contributing to this neurodevelopmental phenotype, and suggests therapeutic leads for neurodevelopmental proteasomopathies.

MAGPIE is a computational framework for co-registering spatially-resolved transcriptomics, metabolomics and tissue morphology for integrated downstream analysis. Case studies across lung, brain and breast reveal coordinated cross-modality molecular changes.