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Schizophrenia is a complex brain disorder with its underlying protein changes generally not well understood. Here, authors show widespread alterations in the prefrontal cortex, marked by reduced energy production and disrupted synaptic function.

Although antiretroviral therapies (ART) have expanded the life expectancy of patients with HIV, they are not curative due to the presence of latently infected cells. Here, the authors present IMC-M113V, a bispecific soluble TCR targeting the HIV peptide Gag_77-85 complexed to HLA-A*02:01 as an approach for targeting HIV reservoirs and test safety, tolerability and pharmacodynamics in a first-in-human clinical trial on 12 HLA-A*02:01-positive male individuals on ART.

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.

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.

89ZED88082A is a zirconium-89-labeled one-armed anti-CD8α antibody for the non-invasive whole-body visualization of CD8 + T-cells by positron emission tomography (PET). Here the authors report the results of a phase 2 study of 89ZED88082A for whole-body CD8 + T-cell PET imaging in patients with large B-cell lymphoma before and during CD19-directed CAR T-cell therapy.

Anti-phased changes in Antarctic Circumpolar Current strength between the Indian and Pacific sectors of the Southern Ocean occurred on orbital timescales over the past one million years, linked to glacial cycles and obliquity forcing, according to proxy records and modelling.

How aperiodic 1/f noise drives ripple activity in human brain and impacts on ripple detections is not fully understood. Here authors show that ripple detections should be driven by the 1/f noise, which indexes different brain states and cognitive demands.

Guided by density functional theory, a commercially viable refractory alloy is developed, which exhibits excellent room-temperature ductility and strength, and high strength at elevated temperatures.

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.

During development of eutherian females, one of the X-chromosomes is silenced. Here, authors show that alleles on the inactive X-chromosome are dynamically expressed along neural differentiation enhancing resilience of female neural tissue.

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.

The study shows that the HIV-1 Nef protein stabilizes actin, thereby preventing R12C release and priming of RIG-I–like receptors. HIV-1 containing a mutant Nef unable to bind the actinmodulating kinase PAK2, triggers enhanced interferon responses.

The impact of negative energy balance on dopamine transmission is unclear. Here, authors show that the ABA model disrupts dopamine transmission via loss of GABAergic control over VTA dopamine neurons contributing to the development of hyperactivity.

In honor of the fiftieth anniversary of Frank MacFarlane Burnet's presentation of the clonal selection theory, two of his former staff reminisce about their interactions with this Nobel prize–winning scientist.

Transcription factor osr2 is identified as a specific marker and regulator of mural lymphatic endothelial cell (muLEC) differentiation and maintenance, and muLECs and border-associated macrophages share functional analogies but are not homologous, providing an example of convergent evolution.

This study investigates long-term trajectories of post-traumatic-stress-disorder symptoms of World Trade Center responders (n = 12,822), revealing highly variable symptom trajectories and 10% of responders experiencing persistence or worsening of symptoms after 20 years.

Skill transfer depends on how tasks are structured, who is trained, and how they experience stress. This study demonstrates that individual differences in emotion-cognition traits and physiological responses shape divergent transfer trajectories.

Researchers studied the blood-based metabolome of over 23,000 people from ten ethnically diverse cohorts. They identified 235 metabolites associated with future risk of type 2 diabetes (T2D). By integrating genetic and modifiable lifestyle factors, their findings provide insights into T2D mechanisms and could improve risk prediction and inform precision prevention.

Age-related macular degeneration (AMD) is a common cause of vision loss with a large genetic risk in older individuals. Here, for a high-risk AMD subtype, the authors identify an association with a chromosome 10 risk region containing a long non-coding RNA.

IL-17A, a cytokine important for tissue repair, can impair healing when increased, contributing to keratinocyte dysfunction in type 2 diabetic wounds. Here, the authors show that IL-17A drives this dysfunction via JMJD3-mediated epigenetic changes, and that blocking this pathway improves wound healing.

Myotonic dystrophy type 1 affects both muscle and neuronal function, but its synaptic pathology is poorly understood. Here, the authors show that upregulation of FasII (NCAM1) in both pre- and postsynaptic cells synergistically drives neuropathological and behavioral DM1 phenotypes, which can be rescued by FasII knockdown or specific isoform modulation.

Neural progenitor cell transplantation shows promise for treating spinal cord injury. However, here, the authors show that graft-derived neurons form limited synaptic connections with host spinal motor circuits after injury, constraining functional motor recovery.

cellSTAAR advances noncoding rare variant association analysis by integrating single-cell genomics data.

Multi-ancestry genome-wide analyses identify 95 loci associated with post-traumatic stress disorder and implicate candidate genes, pathways and neurobiological systems underlying its pathophysiology.

Wastewater-based surveillance tends to focus on specific pathogens. Here, the authors mapped the wastewater virome from 62 cities worldwide to identify over 2,500 viruses, revealing city-specific virome fingerprints and showing that wastewater metagenomics enables early detection of emerging viruses.

Ferroptosis is an iron-dependent lipid peroxidation-mediated form of cell death that holds promise for targeting treatment-resistant cancer cells. Here, the authors show that AMPK-mediated lipid droplet dynamics modulates the response to ferroptosis inducers in melanoma.

Genomic analyses applied to 14 childhood- and adult-onset psychiatric disorders identifies five underlying genomic factors that explain the majority of the genetic variance of the individual disorders.

This work challenges the view of nucleation governing halide perovskite grain morphology, showing that most additives act post-nucleation by boosting ion mobility across grain boundaries, triggering grain coarsening, similar to post-processing effects.

How the brain represents high-level musical meaning is unclear. Here, the authors reconstruct heard music from fMRI data and show that both music- and text-derived semantic features are predictive of activity in the auditory cortex.

Promising clinical activity of Claudin (CLDN) 18.2-directed CAR-T cell therapy in patients with gastric cancer has been recently reported, however gastrointestinal toxicities have also been described. Here the authors recapitulate the on-target off-tumor toxicity of CLDN18.2-directed CAR-T cells due to gastric mucosa damage in preclinical models, suggesting an AND-gate strategy targeting CLDN18.2 and mesothelin to overcome CAR-T cell toxicity

T-cell acute lymphoblastic leukemia is a highly aggressive disease with varying recurrence rates. Here, the authors build a single cell transcriptomic atlas of childhood T-cell acute lymphoblastic leukaemia (T-ALL). They identified a distinctive cancer cell state that correlates with high risk, treatment refractory T-ALL.

Genome-wide association analyses of post-traumatic stress disorder and its symptom subdomains in individuals of European and African ancestry provide insights into its relationship with anxiety and depressive disorders and identify potential candidates for drug repositioning.

Using generative AI, Insilico Medicine developed an oral PROTAC that potently inhibits and degrades PKMYT1, a synthetically lethal target in cancer, demonstrating high selectivity and strong antitumor efficacy in preclinical models.

Here, as part of the Sherlock-Lung study, the authors profile the microbiomes of 940 lung cancers in never smokers finding no significant associations with demographic and clinical features, suggesting lung bacteria are unlikely to have a sizable role in lung cancer.

Hydrogen oxidation in alkaline media is limited by slow reaction kinetics. Here, the authors develop a family of bimetallic catalysts by theoretical analysis and reveal that RuIr achieves superior activity and durability through synergistic adsorption of hydrogen and hydroxyl intermediates.

The global burden of Metabolic syndrome is incompletely characterized. Here the authors report a systematic review and modelling study showing that global metabolic syndrome prevalence doubled from 2000 to 2023, now affecting 1.54 billion adults (31.0% of women, 25.7% of men), with higher rates in women, urban areas, and high-income countries, with disparities across regions.

Somatic instability plays a role in Huntington’s disease. Here, the authors show that lowering HTT levels by transcriptional repression suppresses somatic instability. This can also be done without affecting HTT levels by direct CAG repeat binding.

A phase I trial of cerebellar deep brain stimulation to enhance chronic post-stroke motor rehabilitation supports the safety and feasibility of the approach while providing encouraging evidence of motor improvements.

The structural mechanism of a natively isolated GRP94 folding intermediate tethered to a CCDC134-bound translocon is described, revealing how the nascent chain remodels the translocon to control N-glycosylation by OST.

In this study of more than 6500 emergency department patients, symptoms consistent with Long COVID are reported by 38.9% of SARS-CoV-2 test-positive and 20.7% of test-negative patients three months after their visit. A documented SARS-CoV-2 infection increased the risk fourfold of reporting Long COVID symptoms.

Some patients experience long-lasting symptoms after coronavirus disease (COVID-19). Here the authors report the clinical and laboratory parameters in patients with post-COVID-19 syndrome from a prospective observational cohort study.