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Neville, Ferguson et al. show that non-canonical Polycomb repressive complex 1.1-mediated gene silencing is antagonized by DOT1L and is required for the therapeutic efficacy of Menin and DOT1L inhibitors in mixed-lineage leukaemia.

The high-plasticity cell state (HPCS) is a critical hub that enables reciprocal transitions between cancer cell states, and targeting the HPCS may suppress cancer progression and eradicate treatment resistance.

The MOUNTAINEER phase 2 trial demonstrated the efficacy and safety of tucatinib (HER2-targeted TKI) and trastuzumab (anti-HER2 antibody) in patients with HER2 + , RAS wildtype unresectable or metastatic colorectal cancer that had progressed on chemotherapy, resulting in the approval of the regimen. Here, the authors report the updated analysis of the MOUNTAINEER trial.

The therapeutic relevance of telomere maintenance mechanisms in cancer, remains to be explored. Here, the authors integrate multi-omic data and functional readouts, generate a resource of telomere biology metrics and identify potential molecular vulnerabilities.

Using a non-human primate model, the authors identified the tissue sites of initial viral rebound after discontinuation of antiretroviral therapy, demonstrating that such rebound preferentially occurs in the gastrointestinal tract-associated lymphoid tissues.

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.

In a prespecified secondary analysis of the SURMOUNT-OSA trial, tirzepatide improved cardiometabolic outcomes in patients with moderate-to-severe obstructive sleep apnea and obesity.

Via high-throughput imaging and tracking over 140 million single mycobacteria, the authors show that drug- and strain-specific killing predict treatment outcomes, with potential to improve drug development and personalized therapy.

Following spinal cord injury, gamified physical therapy that incorporates closed-loop vagus nerve stimulation can aid restoration of arm and hand function.

Although the number of participants is important for phenotypic prediction accuracy in brain-wide association studies using functional MRI, scanning for at least 30 min offers the greatest cost effectiveness.

Mitochondrial DNA heteroplasmy associates with context-specific nuclear CpG methylation, supported by a cell model. Heteroplasmy–CpG scores relate to mortality and cardiovascular risk, though direction and mechanisms remain unclear.

By combining satellite observations with ground-based data and expert validation, this analysis demonstrates considerable misestimation of grassland extent and thereby carbon stock estimates in previous global assessments based on remote sensing.

DEAD-box helicase 6 (DDX6), the regulator of P-body assembly, is essential for the survival of acute myeloid leukemia (AML) cells. Here the authors report that DDX6 undergoes phase separation to preserve mRNA subsets in P-bodies, promoting branched-chain amino acid metabolism and chemoresistance in AML.

The early genetic evolution of uveal melanoma (UM) remains poorly understood. Here, the authors perform genetic profiling of 1140 primary UMs, including 131 small early-stage tumours, finding that most genetic driver aberrations have occurred by the time small tumours are biopsied; in addition, the15-gene expression profile discriminant score can predict the transition from low- to high-risk tumours.

How the brain adapts its representations to prioritize task-relevant information remains unclear. Here, the authors show that both monkey brains and deep learning models stretch neural representations along goal-relevant dimensions, with spike timing playing a key role.

Multi-ancestry genome-wide and transcriptome-wide association studies of aortic stenosis identify more than 200 independent risk loci and provide insights into its genetic architecture.

Here the authors show that tissue-resident memory and exhausted T cells in tumors are distinct populations that are shaped by relative presence or absence of TCR signals, suggesting that a tailored therapeutic strategy is needed to target each subset.

A benchmarking competition improves tools that predict how regulatory regions control gene expression.

High-depth sequencing of non-cancerous tissue from patients with metastatic cancer reveals single-base mutational signatures of alcohol, smoking and cancer treatments, and reveals how exogenous factors, including cancer therapies, affect somatic cell evolution.

TIRTL-seq is a high-throughput method for paired T cell receptor sequencing at the cohort scale.

The study presents an updated global inventory of glacial lake outburst floods, revealing a sharp rise in event frequency since the 1980s and a strong delayed link to climate warming, highlighting growing risks to downstream communities.

Together with an accompanying paper presenting a transcriptomic atlas of the mouse lemur, interrogation of the atlas provides a rich body of data to support the use of the organism as a model for primate biology and health.

This work presents a unified MS/MS spectral library of drugs and metabolites integrated with standardized pharmacologic metadata, enabling scalable, individualized profiling of drug exposure and metabolism directly from untargeted metabolomics data.

Clinical translation of cell products is impeded by the lack of clinically predictive potency assays. Here, the authors report a microfluidic system to evaluate patient-derived cells used in a clinical trial for osteoarthritis pain, and use the results and patient-matched clinical data to build prediction models, showing improved clinical prediction and higher correlative power with pain scores compared to 2D culture.

Stratified medicine promises to tailor treatment for individual patients, however it remains a major challenge to leverage genetic risk data to aid patient stratification. Here the authors introduce an approach to stratify individuals based on the aggregated impact of their genetic risk factor profiles on tissue-specific gene expression levels, and highlight its ability to identify biologically meaningful and clinically actionable patient subgroups, supporting the notion of different patient ‘biotypes’ characterized by partially distinct disease mechanisms.

A consensus cell type atlas for the fly brain provides both an intellectual framework and open-source toolchains for brain-scale comparative connectomics.

Semiconductor-based, non-optical DNA sequencing technologies such as Ion Torrent sequencing offer speed and cost advantages compared with alternative techniques. Cheng et al. demonstrate a protocol allowing the use of Ion Torrent technology to sequence DNA from chromatin immunoprecipitation experiments.

Proteomic prediction models developed using a large-scale dataset from the UK Biobank Pharma Proteomics Project were superior to clinical models for assessing the 10-year risk of 67 diseases across different types of pathology, including multiple myeloma, motor neuron disease, pulmonary fibrosis, celiac disease and dilated cardiomyopathy.

Cocaine-context associations rely on nucleus accumbens neuronal ensembles with engram-like properties unique to distinct stages of memory encoding. Here the authors show that ensemble reactivation parallels recall and selectively engages transcriptional plasticity programs.

The microbial metabolite trimethylamine (TMA), the precursor of TMAO, which is associated with adverse cardiometabolic outcomes, is shown to have beneficial metabolic and anti-inflammatory effects in the host in the context of obesity.

Garnet-type LLZO electrolytes are considered among the most promising solid-state electrolytes for all-solid-state batteries; however, numerous challenges need to be addressed before they are integrated into a cell. By precipitating amorphous zirconium oxide onto grain boundaries, increased ionic conductivity is observed and dendrite growth is suppressed.

Dengue is a major public health concern in the Americas, and the Caribbean can be a source for reintroduction and spread. Here, the authors use travel surveillance data and genomic epidemiology to reconstruct Dengue epidemic dynamics in the Caribbean from 2009-2022.

Zonal positioning in the liver determines whether the CTNNB1 oncogene can induce liver cancer.

Photometric recordings and optogenetic manipulation show that dopamine fluctuations in the dorsolateral striatum in mice modulate the use, sequencing and vigour of behavioural modules during spontaneous behaviour.

Single-nucleus and single-cell RNA sequencing plus spatial profiling with four methods of core biopsies from 60 patients with metastatic breast cancer reveal patient-specific gene expression programs of breast cancer metastases that are maintained across time, site of metastasis and spatial profiling method, with spatial phenotypes correlating with microenvironmental features.

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.

Klingelhuber, Frendo-Cumbo et al. develop a proteomic atlas elucidating the intracellular spatiotemporal changes in protein levels and localizations during human adipogenesis.

Hi-C methods for studying 3D genome structure typically require millions of cells and struggle with repetitive regions. Here, authors develop CiFi, combining 3C with PacBio HiFi sequencing, enabling chromatin analysis from as few as 60,000 cells and chromosome-scale assembly from small samples.

Treekitkarnmongkol, Katayama, Sankaran et al. identify RASH3D19 as a downstream target for KRAS signalling through miR-301a, which in turn leads to RAS activation and tumorigenesis. Targeting RASH3D19 inhibits growth of KRAS-mutant tumour cells in vivo.

Integrative analyses of transcriptome and whole-genome sequencing data for 1,188 tumours across 27 types of cancer are used to provide a comprehensive catalogue of RNA-level alterations in cancer.

In this study the authors consider the structural variants (SVs) present within cancer cases of the ICGC/TCGA Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium. They report hundreds of genes, including known cancer-associated genes for which the nearby presence of a SV breakpoint is associated with altered expression.

Integrating independent large-scale pharmacogenomic screens can enable unprecedented characterization of genetic vulnerabilities in cancers. Here, the authors show that the two largest independent CRISPR-Cas9 gene-dependency screens are concordant, paving the way for joint analysis of the data sets.

Head motion is an artifact in structural and functional MRI signals, and some traits or groups are more strongly correlated with motion than others. Here the authors describe a method to attribute a motion impact score to specific trait-functional connectivity relationships.

Using mouse pancreatic cancer models, Tsanov et al. show that reactivation of SMAD4 at metastatic sites promotes tumor growth in the lung through RUNX1 but restrains metastatic growth through KLF4 in the liver, influenced by organ-specific epigenetic states.

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.

Integrated multi-omic analyses using samples from the TRACERx study highlight cross-talk between DNA hypermethylation and genomic lesions in non-small cell lung cancer.