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Analysis of a placebo-controlled trial of a BCMA-targeting CAR-T cell therapy in patients with myasthenia gravis shows that CAR-T cell infusion selectively remodels the systemic immune environment, with elimination of BCMA-high plasma cells and activated plasmacytoid dendritic cells and changes in the autoreactive B cell repertoire.

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.

While antivirals like nirmatrelvir/ritonavir and molnupiravir are known to reduce severe COVID-19, their impact on cardiovascular outcomes is unclear. Here, the authors use a target trial emulation design to show that nirmatrelvir/ritonavir significantly lowers long-term cardiovascular risks among hospitalized patients, highlighting its potentials over molnupiravir for mitigating post-COVID-19 cardiovascular complications.

CD44 expressed by fibroblastic reticular cells in secondary lymphoid organs regulates trafficking of dendritic cells, and thus has an essential role in the priming of T cells and the adaptive immune response.

CD27 is a key T-cell costimulatory receptor, but efforts to target CD27 have been limited by the poor clinical efficacy of first-generation anti-CD27 antibodies. The authors here engineer higher-valency antibodies by more effectively engaging CD27 and selectively binding to FcγRIIB, which enhance anti-tumor activity.

Lai et al. use hospitalization records from the UK to examine associations between ambient temperature and changing temperature with all-cause and cause-specific hospitalizations. There is seasonal variation in associations with more pronounced effects in people living in deprived neighbourhoods and with low greenspace coverage.

Socializing at a young age helps to develop greater diversity in children’s microbiota, according to an analysis of baby-to-baby transmission of gut bacteria.

Antiviral treatment with nirmatrelvir-ritonavir has been associated with improved post-COVID outcomes. Here, the authors perform a retrospective cohort study using electronic health record data from Hong Kong to investigate the importance of timing of treatment.

The authors estimate genomic vulnerability for closely related species of rainbowfish. They find that narrow endemic species that have hybridized with a warm-adapted generalist show reduced vulnerability to climate change and that hybridization may facilitate evolutionary rescue for such species.

Natural hydrogen is generated through chemical and radioactive processes in the Earth’s crust, and could be an important future clean chemical feedstock and energy resource. This Review examines the processes of geological hydrogen generation, migration, accumulation and preservation that enable the development of exploitable reserves.

Childhood mortality is a global health problem. Plasma lipopolysaccharide levels, inflammatory stool biomarkers and proteomics were used in a nested case-cohort in sub-Saharan Africa and South Asia to predict mortality and decode immune mechanisms.

Baird et al. present the phase 2 PIONEER trial findings on the antitumor activity of combining aromatase inhibitor letrozole with megestrol in postmenopausal women with operable estrogen-receptor-positive human epidermal-growth-factor-receptor-2-negative breast cancer.

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.

Allogenic mesenchymal stem cells are engineered with three mRNAs to bind to multiple myeloma B cells while activating T cells for cancer therapy.

Understanding the mechanisms underlying the survival of drug tolerant persister cells following chemotherapy remains elusive. Here, multi-omics analysis and experimental approaches show that the germ-cell-specific H3K4 methyltransferase PRDM9 promotes metabolic rewiring in glioblastoma stem cells.

Developing treatments that withstand viral evolution is difficult. Here, the authors design ReconnAb-multimers: broad, highly potent therapeutics linking a non-neutralizing antibody, ACE2, and a multimerization domain to prepare for future pandemics.

Structural characterization of two influenza hemagglutinin stem antibodies reveals binding to non-competing epitopes and the evolution of antigenicity of the hemagglutinin stem, which is a target for developing broadly protective influenza vaccines.

A rainforest in southwest Ireland offers Rory Hodd the chance to discover unusual specimens of ferns and other flora.

In this study, the authors generated iPSC lines from more than 100 sporadic ALS cases, which recapitulated key disease phenotypes and enabled large-scale drug screening, identifying a promising combination therapy of baricitinib, memantine and riluzole.

Scaffold-guided bone regeneration is a promising treatment strategy for segmental defects, but clinical translation has been hindered, partially by mechanical function limitations. Here, Clark et al. describes a permanent printed polymer with a resorbable stem cell laden ceramic core for reconstructing segmental mandibular defects, which is tested in an ovine model.

This study uncovers a mechanism for innate immune memory in neurons, demonstrated by a more silent epigenetic structure of the Herpes Simplex Virus genome, resulting in a deep form of latent infection that is restricted for reactivation of the virus.

A neural implant with a subnanolitre-volume can provide year-long in vivo recordings in awake mice.

The authors assess the risk of overshoot beyond 1.5 °C warming, using three scenarios with minimal overshoot, brief overshoot and sustained overshoot. They show a risk of long-term Amazon dieback, which begins as early as 1.3 °C warming but is largely mitigated by reducing temperature below 1.5 °C.

Burden of major disease is projected to increase in England and many other countries. Here the authors model the impact of reducing eight known risk factors for disease burden, such as BMI and smoking, between 2023-2043 in England and report that reductions in risk factors may not substantially reduce the major illness burden by 2043 due to population ageing.

Inherited mitochondrial DNA mutations can result in diverse clinical phenotypes. Here, the authors characterise a heteroplasmic tRNA^Ala mutation (m.5019A>G) in mice and demonstrate that macrophages carrying this mutation display altered function and metabolism in vitro, along with increased type I IFN release following LPS challenge in vivo.

Immune aging fosters multimorbidity and compromises control of infection and cancer. In a phase 1 randomized controlled trial in middle-aged adults, Denk and colleagues administer the mitophagy inducer urolithin A and profile cellular and metabolic aspects of immune aging.

Analysis of soundscape data from 139 globally distributed sites reveals that sounds of biological origin exhibit predictable rhythms depending on location and season, whereas sounds of anthropogenic origin are less predictable. Comparisons between paired urban–rural sites show that urban green spaces are noisier and dominated by sounds of technological origin.

Artificial intelligence is driving rapid growth in electricity demand, straining grid reliability and infrastructure. This study demonstrates a software-based method that allows data centres to adjust workloads in response to real-time grid signals, reducing power use and supporting grid stability without hardware modifications.

A free-living trial in people with overweight or obesity found that minimally processed diets led to greater weight loss and cardiometabolic improvements than ultraprocessed diets following UK healthy eating guidelines at 8 weeks.

Aerosol deposition onto the surface of the ocean has been underestimated, suggesting that aerosol lifetimes over the ocean are longer than previously appreciated, according to a global compilation of cosmogenic beryllium isotope data.

Here the authors show that lung epithelial, fibroblast, and endothelial cells retain an imprint of influenza A infection, including increased MHCI/II expression and that re-infection is quickly controlled by a localized antiviral response acting before memory T cells are required.

Hepatitis C virus (HCV) variability and its phenotypic consequences aren’t well studied in relation to viral replication fitness and disease severity. Here, the authors identify a replication-enhancing domain in non-structural protein 5A, linking high replication fitness to severe disease outcomes, with implications for understanding HCV pathogenesis in immunocompromised patients.

Some pathogens manipulate host ferroptosis, a type of programmed cell death, for pathogenesis. Here, the authors show that Pseudomonas aeruginosa uses a quorum sensing metabolite to induce ferroptosis in macrophages through a methylation pathway.

The neural mechanisms driving seizure development in peritumoral brain regions remain incompletely defined. Here, using patient tissue, glioma mouse model, and computational simulation, the authors identify early pathological activities that are predictive of tumor-associated seizures.

BPTF is known to regulate chromatin accessibility and self-renewal in mammary epithelial stem cells. Here, the authors discover that BPTF inhibition delays tumor formation, re-activates ERα expression, increases sensitivity to tamoxifen treatment, and inhibits metastatic development.

Large-scale genome-wide analyses identify hundreds of genetic loci associated with hypothyroidism and thyroid hormone levels, demonstrating the potential of using polygenic risk scores to predict disease onset and progression.

Translation of evidence about dementia risk into effective public health policy is a challenge. In this Consensus Statement, Demnitz-King and colleagues present 56 policy recommendations for dementia prevention, providing policymakers with a foundation for designing and implementing evidence-based dementia prevention strategies, prioritizing clear communication, targeted intervention and sustained research investment.

A single dose of the anti-sporozoite monoclonal antibody CIS43LS can achieve durable, sterile protection against Plasmodium falciparum infection.

Chronic infection with SARS-CoV-2 leads to the emergence of viral variants that show reduced susceptibility to neutralizing antibodies in an immunosuppressed individual treated with convalescent plasma.

A revised draft is imminent, a new job for Michael Bloomberg, and a trip into the New York Times archives.

A patient with newly diagnosed glioblastoma was safely treated with neoadjuvant nivolumab, relatlimab and ipilimumab before maximal resection, with comprehensive immune profiling showing the induction of overall immune activation early during treatment. The patient had no definitive evidence of recurrence at 17 months after treatment.

LYMTACs are heterobifunctional small molecules that take advantage of lysosomal membrane proteins to degrade membrane targets via relocalization and lysosomal degradation, offering a modular approach to drug otherwise intractable membrane proteins.

Pathogenic variants in UNC13A underlie a novel neurodevelopmental syndrome, with three subtypes defined by distinct genotypes with varying clinical and functional impacts characterized in cellular and animal models.

Aarrestad et al. show that, in contrast to psychedelics, the nonhallucinogenic psychoplastogen tabernanthalog promotes neuroplasticity through 5-HT_2AR activation without immediately increasing extracellular glutamate levels or immediate early gene expression.

Ward et al. utilise electronic health records to identify groups of adults (who had received a second booster dose of a COVID-19 vaccine) at elevated risk of COVID-19 death.

Analysis of eukaryotic gene sequences using a relaxed molecular clock methodology indicate that eukaryotes emerged 3.0–2.25 billion years ago as a result of mitochondrial endosymbiosis with complex archaea that already possessed an elaborated cytoskeleton, membrane trafficking, endomembrane, phagocytotic machinery and a nucleus.