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Lo and colleagues report that double-positive thymocytes from neonates express less Zap70 and show reduced Ca^2⁺/NFAT signaling compared to double-positive thymocytes from older thymi. This diminished Ca^2⁺ signaling alters negative selection for self-reactive TCRs, resulting in a cell-intrinsic temporal window for regulatory T versus conventional T cell development in the thymus.

Cells struggle to migrate on soft substrates, which don’t provide enough traction. Here, the authors show that rapid, cyclic changes in substrate rigidity allow cells to overcome this limitation and move quickly.

A phase 1/2 trial of dual-vector rAAVrh8 gene therapy for GM2 gangliosidosis, administered by bilateral intrathalamic, cisterna magna and intrathecal delivery found a dose-dependent biochemical correction of the disease.

A study of several longitudinal birth cohorts and cross-sectional cohorts finds only moderate overlap in genetic variants between autism that is diagnosed earlier and that diagnosed later, so they may represent aetiologically different conditions.

Perception can occur in the absence of report. Here, the authors use intracranial recordings to show that sequential sampling of sensory evidence in the ventral visual cortex supports perception beyond report.

Cationic polymers conventionally kill bacteria via physical membrane disruptions. Here, the authors report the development of carbon acid cationic polymers that show potent activity against multidrug-resistant strains in murine infection models and prevent bovine mastitis, and present evidence that these polymers translocate across bacterial membrane aided by N-heterocyclic carbene.

In the randomized phase 1b/2 Morpheus-Melanoma trial evaluating various neoadjuvant immune checkpoint inhibitor regimens in patients with resectable stage III melanoma, tobemstomig, an anti-PD-1/anti-LAG-3 bispecific antibody, showed the highest pathologic response rate with a better safety profile than the standard treatment approach of ipilimumab plus nivolumab.

Liang et al. estimate the prevalence of text modified by large language models in recent scientific papers and preprints, finding widespread use (up to 17.5% of papers in computer science).

A modeling approach to assess the global risk of Plasmodium falciparum histidine-rich protein 2 and 3 gene deletions identifies ten priority African countries for surveillance and could inform malaria control policies.

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.

Singla et al. report the secondary analysis of the Scaling Up Maternal Mental healthcare by Increasing access to Treatment (SUMMIT) trial.

An optical detection and analysis platform quantifies aggregate density, distribution and size in fluorescently labelled post-mortem human brain tissue.

CELLFIE, a CRISPR platform for optimizing cell-based immunotherapies, identifies gene knockouts that enhance CAR T cell efficacy using in vitro and in vivo screens.

Here the authors present a method to transform polygenic scores into disorder probabilities using only GWAS summary statistics, genotype data and a prior - no tuning sample is needed. The method enables individualized, well-calibrated predictions.

Two-qubit operations exceeding 99% fidelity have been demonstrated by silicon devices made with standard semiconductor tooling in a 300-mm foundry environment.

Here the authors reveal a study of 486,956 Han Chinese individuals showing that most people with genetic variants affecting drug response do not have the predicted adverse events, highlighting the challenges of implementing pharmacogenetics in clinical practice.

The Yamaji effect is a modulation of the electronic transport as the angle of an applied magnetic field is changed. This has been observed in a model cuprate and sheds light on the geometry of the Fermi surface and the nature of the pseudogap.

Over 20 species of geographically and phylogenetically diverse bird species produce convergent whining vocalizations towards their respective brood parasites. Model presentation and playback experiments across multiple continents suggest that these learned calls provoke an innate response even among allopatric species.

Genetic background, plasma metabolome and dietary data from 4,215 women and 1,490 men reveal 57 metabolites whose associations with dementia risk vary by APOE4 genotype and other risk variants.

UCHL5 is a deubiquitinating enzyme that cleaves Lys-48-linked polyubiquitin chains. Here, the authors discover through in-vivo CRISPR-Cas9 screens that Uchl5 is involved in immune evasion and modulation of extracellular matrix deposition in head and neck squamous cell carcinoma.

In a prospective study enrolling 1,222 patients from 22 emergency departments, a device using a machine-learning-based signature of blood mRNAs demonstrated clinically acceptable performance to diagnose bacterial and viral infections and to predict the all-cause need for critical care interventions within 7 days, with benchmark to established biomarkers and risk scores.

Lipid nanoparticles (LNPs) are a versatile class of clinically approved drug delivery vehicles, particularly for nucleic acid cargoes, but they often suffer from instability issues. Here, the authors report that the room temperature stability of small interfering RNA LNPs formulated with unsaturated ionizable lipids can be improved by inclusion of mildly acidic, antioxidant-containing buffers.

Prenatal stress triggers molecular dysregulations in fetal neuroimmune circuits, leading to altered mast cell and sensory neuron function, which predisposes offspring to develop eczema in response to otherwise harmless mechanical friction after birth.

Genome-wide and targeted perturbation of DNA methylation at centromeres affects CENP-A positioning and centromere structure, resulting in aneuploidy and reduced cell viability.

Fluid shear stress plays a role in medulloblastoma metastasis through a PIEZO2-actomyosin-GLUT1 signalling cascade.

Weldy et al. show that smooth muscle expression of the RNA editing enzyme ADAR1 regulates activation of the double-stranded RNA sensor MDA5 in a novel mechanism of atherosclerosis.

Centromeres play an essential function in faithful chromosome segregation. Here, the authors demonstrate the mechanism by which human cells dynamically modulate the activity of the Bloom’s syndrome helicase complex to safeguard centromere integrity throughout mitotic progression.

Authors measure plasma proteins in a cohort of hospitalised patients presenting to the emergency department with suspected infection, revealing six discrete host response clusters that were driven by pathogen exposure and organ dysfunction, and had distinct clinical characteristics, hospital courses, and responses to treatment.

Tergaonkar and colleagues identify a noncanonical interaction between the NF-κB transcription factor family member p52 and the ETS family member ETS1. They find that the p52–ETS1 complex is required for splenic germinal center B cell formation and T cell-dependent antibody responses.

Trained and validated on multimodal data from 14.5 million images from multicountry datasets, a foundation model is shown to increase diagnostic and referral accuracy of clinicians when used as an assistant in a trial involving 16 ophthalmologists and 668 patients.

Preventing endosomal damage sensing or using lipids that create reparable endosomal holes reduces inflammation caused by RNA–lipid nanoparticles while enabling high RNA expression.

Atropisomers are sterically hindered molecules whose formation typically proceeds via atropisomeric intermediates and encumbered transition states. Here, the authors report regio- and chemoselective nucleophilic aromatic substitution (S_NAr) reactions for the synthesis of heterobiaryl C─N atropisomers, via non-atropisomeric intermediates and transition states.

Boron-containing drug candidates have garnered increasing attention due to their pharmacological properties and application in boron neutron capture therapy. Here, the authors report a transition metal-free anti-addition of pinacolborane to alkynes, facilitated by the counteranion effect for the facile construction of bora-butenolide bioisosteres.

Understanding the cellular origins of cancers is crucial for improving diagnosis and treatment. Here, the authors utilize single cell chromatin accessibility data, patient whole-genome sequencing mutational profiles, and machine learning to predict the cell of origin for 37 cancer types, providing insights into cancer development and therapeutic strategies.

Primary angle-closure glaucoma is a leading cause of blindness. Here, the authors identify rare deleterious variants in UBOX5 as risk factors and implicate BIP ubiquitination as a potential disease mechanism.

Genome-wide association meta-analyses of attention-deficit/hyperactivity disorder symptom measures and clinical diagnoses identify new risk loci, highlight putative effector genes and yield improved polygenic risk scores.

Wamaitha and colleagues used the rhesus macaque to characterize the transcriptional and spatial mechanisms underlying ovarian reserve formation in prenatal life providing insights into the molecular processes governing ovarian follicle establishment.

The enzyme ABHD18 is shown to have a key role in cardiolipin metabolism in mitochondria, offering a potential route for a small-molecule treatment of the rare genetic disease Barth syndrome.

A Swedish study examined whether the risks of maternal and paternal suicide attempt differ during and after pregnancy and found a reversed sex difference in risk of suicide attempt during and after pregnancy compared with the general population.

In vivo gene editing hinges on identifying an ideal delivery vehicle from numerous candidates. Here, authors establish the GFP-on mouse model capable of translating successful adenine base editing to a fluorescent readout thus enabling the rapid evaluation of genome editing delivery vehicles.

Small cell lung cancer cells form functional synapses with glutamatergic neurons, receiving synaptic transmissions and deriving a proliferative advantage from these interactions.

A single dose of an adeno-associated virus vector encoding an HIV-1 broadly neutralizing antibody given shortly after birth results in persistent antibody expression and protection from infection in rhesus macaque models of human HIV-1 transmission through breastfeeding and sexual intercourse.

Chronic care manages long-term, progressive conditions, while acute care handles short-term ones. Here, authors show chronic conditions account for most of the global health burden, with 68% of DALYs and 93% of YLDs attributed to chronic care needs.

Transcriptional condensates concentrate gene regulatory proteins to control gene activation. Meyer et al. demonstrate that charge-mediated co-condensation of YAP and the oppositely charged transcriptional scaffold Med1 drives transcriptional activation.

Korobkina et al. show that ACLY in brown fat prevents metabolic overload in the tricarboxylic acid cycle, thus ensuring adequate thermogenesis by avoiding cellular stress.

Epigenome editing programs gene silencing without inducing DNA breaks but challenges in delivery into human cells limit its broader use. Here, the authors present the RENDER platform, which uses virus-like particles to enable CRISPR-based epigenome editing for durable gene silencing in human cells.

Using well-calibrated statistical methods the authors jointly analyze Undiagnosed Diseases Network genomes, identifying known and novel disease genes. Software is publicly available to support future cross-cohort rare disease discovery efforts.