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Genome-wide analyses identify 30 independent loci associated with obsessive–compulsive disorder, highlighting genetic overlap with other psychiatric disorders and implicating putative effector genes and cell types contributing to its etiology.

Pulmonary large cell neuroendocrine carcinoma is an aggressive subtype of lung cancer. Here, the authors identify distinct subtypes based on genomic alterations and transcriptomic alterations.

Here the authors apply machine learning approaches to Alzheimer’s genetics, confirm known associations and suggest novel risk loci. These methods demonstrate predictive power comparable to traditional approaches, while also offering potential new insights beyond standard genetic analyses.

Laser-driven ultrafast tranmission electron microscopy (UTEM) approaches such as stroboscopic UTEM enable the study of ultrafast reversible processes at time resolutions at the femtosecond scale and beyond. This Primer focuses on stroboscopic UTEM, describing its experimental set-up and variants, and covers the various applications of this technique in condensed matter physics, including imaging structural dynamics, photo-induced near-field electron microscopy, attosecond-scale imaging, dark-field imaging and beyond.

Meta-analysis of genome-wide association studies on Alzheimer’s disease and related dementias identifies new loci and enables generation of a new genetic risk score associated with the risk of future Alzheimer’s disease and dementia.

Polygenic risk scores for Alzheimer’s disease derived from individuals of European ancestry can show improved performance in multiancestry settings after incorporating genome-wide association summary statistics from diverse populations.

Alterations in the tumour suppressor genes STK11 and/or KEAP1 can identify patients with advanced non-small-cell lung cancer who are likely to benefit from combinations of PD-(L)1 and CTLA4 immune checkpoint inhibitors added to chemotherapy.

Covalency in actinide–­ligand bonding is poorly understood compared to that in other parts of the periodic table due to the lack of experimental data. Here, pulsed electron paramagnetic resonance methods are used to directly measure the electron spin densities at coordinated ligands in molecular thorium and uranium complexes.

Stojanov et al. updated and internally validated a prediction model for the occurrence of post-operative shoulder stiffness following primary arthroscopic rotator cuff repair in Switzerland. Their findings support the development of further prediction models for an evidence-based and individualized decision-making in orthopedics.

Known genetic loci account for only a fraction of the genetic contribution to Alzheimer’s disease. Here, the authors have performed a large genome-wide meta-analysis comprising 409,435 individuals to discover 6 new loci and demonstrate the efficacy of an Alzheimer’s disease polygenic risk score.

Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.

Machine learning can be used to identify subtypes of psychiatric disease. Here the authors identified two neurostructural subgroups in schizophrenia, each showing reproducibility and generalizability across different collection locations and illness stages, using the SuStain algorithm.

In a phase 3 trial, selection of non-small cell lung cancer patients based on high blood-based tumor mutation burden did not improve clinical response to the checkpoint blockade inhibitor atezolizumab, as compared with standard of care platinum-based chemotherapy.

A quantitative morphological framework for the human thymus reveals the establishment of the lobular cytokine network, canonical thymocyte trajectories and thymic epithelial cell distributions in fetal and paediatric thymic development.

Progressive diseases tend to be heterogeneous in their underlying aetiology mechanism, disease manifestation, and disease time course. Here, Young and colleagues devise a computational method to account for both phenotypic heterogeneity and temporal heterogeneity, and demonstrate it using two neurodegenerative disease cohorts.

Andrew Morris, Mark McCarthy, Michael Boehnke and colleagues report a meta-analysis of genome-wide association studies for type 2 diabetes, including 26,488 cases and 83,964 controls from populations of European, east Asian, south Asian and Mexican and Mexican American ancestry. They identify seven loci newly associated with type 2 diabetes and examine the genetic architecture of disease across populations.

Tumor neoantigens versus tumor-associated antigens may have different functions in antitumor immunity depending on the strength of antigen recognition. Here the authors characterize CD8 T cell clones specific for TAA, neoantigens or viral antigens isolated from tumor and blood and show that neoantigen-specific clones have a higher structural avidity than TAA-specific ones and preferentially infiltrate tumors.

In this largest whole-exome sequencing study of epilepsies to date, the Epi25 Collaborative identified extremely rare variants that confer risk for diverse epilepsy subtypes, highlighting roles in synaptic transmission and neuronal excitability.

Deep optical imaging of a close quasar pair reveals a filamentary connection between them, providing insight into the transition between intergalactic and circumstellar media and a test of the cold-dark-matter cosmological theory.

The neoantigen discovery pipeline NeoDisc incorporates mass spectrometry immunopeptidomics data.

The randomized B-F1RST trial evaluating the clinical utility of blood tumor mutational burden as a predictor of benefit from atezolizumab in patients with advanced lung cancer did not meet its pre-specified primary objective, underscoring the need to further investigate the significance of bTMB as a relevant biomarker for patient selection.

A blood-based DNA sequencing assay to infer tumor mutational burden in the absence of tumor biopsy predicts response to PD-L1 blockade in patients with non-small-cell lung cancer.

Some anticancer drugs target cell microtubules inhibiting mitosis and cell division. Here, the authors show that CRMP2 induces microtubule bundling and that this activity is regulated by the FER kinase, thus providing a rationale for targeting FER in combination with microtubule-targeting drugs.

Genetic associations with particular patterns of brain folding may provide insight into brain development and function. Here, the authors identify and replicate 388 genetic associations with brain sulcal morphology across 40,169 UK Biobank MRI scans, revealing insights into the processes guiding cortical development and genetic correlations with neuropsychiatric phenotypes.

Intermediate-length repeat expansions in ATXN-2 are the strongest genetic risk factor for ALS. Here, the authors combine patient-derived motor neurons and organoids with mouse models to dissect the pathogenic effects of ATXN2 intermediate expansions.

Species once considered extinct have now, through improved taxonomic knowledge and collection activities, been restored, with lessons for conservation policies both in Europe and globally.

Loss of BRCA1 or BRCA2 results in genomic instability; however most studies have focused on the role of these proteins in double-strand break repair. Here the authors coupled cell line genetics and whole genome sequencing to investigate the formation of base substitutions and short indels in BRCA1-deficient cells, revealing a role for translesion DNA synthesis regulated by 53BP1.

A machine learning model that uses longitudinal ctDNA metrics robustly predicts survival in two phase 3 trials of patients with metastatic NSCLC, which may improve therapy selection and risk stratification.

The accretion geometry of X-ray binary Cygnus X-3 is determined here from IXPE observations. X-ray polarization reveals a narrow funnel with reflecting walls, which focuses emission, making Cyg X-3 appear as an ultraluminous X-ray source.

Assessing the conservation status of 1,020 European marine fishes reveals half of large (>1.5 m) fishes are threatened with extinction and stock status diverges geographically: almost all Mediterranean stock is overfished, most northern European stock is not.

Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry. Here, Kandeil et al. show that the Western movement of this clade was followed by reassortment with viruses circulating in wild birds in North America which resulted in different genotypes exhibiting a wide range of disease severity in mammal models (mice, ferrets, chicken) ranging from asymptomatic disease to severe neurological pathology.

Prostaglandin E2 from the tumour microenvironment impairs interleukin-2 sensing by tumour-infiltrating lymphocytes, restricting proliferative response and promoting T cell death via metabolic impairment and ferroptosis. 

Though tractography is widely used, it has not been systematically validated. Here, authors report results from 20 groups showing that many tractography algorithms produce both valid and invalid bundles.

Small molecule activators of the energy sensing kinase AMPK are promising candidates as therapies for metabolic disease. Xiao et al. present the crystal structure of AMPK in complex with a small molecule activator, and show that the drug stabilizes interaction between the catalytic and carbohydrate-binding domains.

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology.

Viral infection of the respiratory system induces exuberant fibroblast activity, resulting in extensive remodelling of the extracellular matrix and cytokine release, which promote immune cell infiltration of the affected area at the expense of respiratory function.

An early cellular response to the occurrence of DNA double-strand breaks in mammals is the phosphorylation of the specialized histone variant H2A.X at Ser 139. The chromatin remodelling factor WSTF is found to phosphorylate H2A.X at another site, Tyr 142. Tyrosine phosphorylation has not been observed previously on histones.

Cross-correlation analysis of high-resolution spectra obtained as the exoplanet KELT-9b transited its host star reveals neutral and singly ionized atomic iron and singly ionized atomic titanium in the exoplanet’s atmosphere.

Evolutionarily conserved gene modules mediate neurodegenerative dementia in a variety of mouse models and in postmortem brain tissue from patients.

Magnetic hysteresis is observed in a dysprosocenium complex at temperatures of up to 60 kelvin, the origin of which is the localized metal–ligand vibrational modes unique to dysprosocenium.

Flow in the deep mantle is thought to create textures in the high-pressure mineral post-perovskite. Laboratory simulations of the transformation between lower-pressure perovskite and post-perovskite show that post-perovskite can also inherit textures from the perovskite phase, and vice versa.

The R2TP/PFDL co-chaperone facilitates assembly of RNA polymerase II and PI3-kinase-like kinases such as mTOR by a so far unknown mechanism. Here authors provide the cryo-EM structure of human R2TP, which shows how RPAP3 serves as a flexible platform to recruit HSP90 to diverse client proteins.

Traumatic brain injury is associated with changes to the metabolome. Here the authors show that acute traumatic brain injury has distinctive serum metabolic patterns which may suggest protective changes of systemic lipid metabolism aiming to maintain lipid homeostasis in the brain.

The results of the Fifth RNA-Puzzles contest highlights advances in RNA three-dimensional structure prediction and uncovers new insights into RNA folding and structure.