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AlphaGenome, a deep learning model that inputs 1-Mb DNA sequence to predict functional genomic tracks at single-base resolution across diverse modalities, outperforms existing models in variant effect prediction and enables comprehensive genomic analysis.

The evolutionary dynamics of aneuploidy in solid tumors are challenging to study. Here the authors introduce a method, ALFA-K, which estimates karyotype fitness and predicts emergent karyotypes before experimental detection, and test its performance on synthetic and empirical data.

This study shows that TE, an inferotemporal (IT) cortex subregion, displays stronger neural plasticity than TEO, another IT subregion, during learning of a challenging visual categorization task in primates, to which both areas contribute.

A global synthesis of >600 studies finds that across agro-ecosystems, grasslands and forests in temperate and tropical zones, increasing plant diversity has a consistently positive effect on plant performance and the suppression of antagonists.

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.

Proxy records from Lake Baikal show that rapid cooling coincided with Northern Hemisphere ice sheet expansion 2.7 million years ago, a change accompanied by a transition to open steppe ecosystems.

Five-year survival data and biomarker analysis of the PRADO extension cohort of the phase 2 OpACIN-neo trial, in which patients with high-risk stage III melanoma received neoadjuvant ipilimumab and nivolumab and underwent pathologic response-directed surgery and adjuvant therapy, show 71% event-free survival and 88% overall survival, with tumor mutational burden, IFNγ signature and PD-L1 expression associated with favorable outcomes.

Amoung the e-mails sent to the debate in the first week is the following, which asks the question "The fossil record-adequate for what?"

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.

Agricultural drought linked to past and current growing-season soil moisture is rising in Europe, southern Africa, northern South America and western North America and may persist until 2100, according to climate reanalyses and model simulations.

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.

Rider, Grantham, Smith, Watson et al. integrate multiomic data from patients with psoriasis using dimensionality reduction and machine learning techniques. This approach identifies biological relationships between genetic background, clinical features and disease severity, providing insight into disease variability across individuals.

Yashinskie, Zhu and colleagues show that p53 activation triggers increased synthesis and accumulation of phospholipids, with enhanced activation of autophagy and lysosomal catabolism programmes and increased reliance on lipid headgroup recycling.

Climate change can alter when and how animals grow, breed, and migrate, but it is unclear whether this allows populations to persist. This global study shows that shifts in seasonal timing are key to helping vertebrate species maintain population growth under global warming.

WGS data were used from 347,630 individuals with European ancestry in the UK Biobank to obtain high-precision estimates of coding and non-coding rare variant heritability for 34 complex traits and diseases.

Researchers discovered five phases of brain rewiring across the lifespan. The eras of childhood, adolescence, adulthood, early aging, and late aging each have characteristic rewiring of structural connections across the whole brain.

How is specific ribosomal RNA expression precisely controlled in the malaria parasite? Dr. Couble et al. show that a switch between distinct energy-generating pathways during parasite development directly impacts the accessibility to rDNA chromatin.

FAME is a biobank-scale method that tests whether the effect of an SNP on a quantitative trait is modulated by an individual’s polygenic background. FAME can also be used to estimate of the proportion of variance explained by such marginal epistasis effects

cSplotch compares spatial transcriptomics data across ages and regions of mouse colon tissue.

How inflammation spreads from the skin to the joints in psoriatic disease is unclear. Here, the authors show that joint-resident fibroblasts can control differentiation of infiltrating skin-derived myeloid precursors that can become inflammatory macrophages.

The sequential recruitment of a thalamocortical transcriptional cascade enables memory maintenance over long timescales.

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.

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.

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.

Grussu et al. use co-localised MRI and histology data to design a practical MRI technique for cell size and density measurement in liver tumours in vivo. The method provides non-invasive proxies of histological properties that are associated to cell proliferation, that explain tumour volume and that distinguish liver tumour types.

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

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.

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

Kalia et al. investigate metabolic changes in Alzheimer’s disease (AD) using blood metabolomics, and show that lysophosphatidylcholines are associated with early amyloidosis in AD as measured by P-tau181 and P-tau217.

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.

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.

Futrell and Hahn argue that languages can be understood as codes that minimize predictive information; that is, they express approximately independent features systematically and locally.

Climate models cannot match long-term observed changes in the tropical Pacific zonal sea surface temperature gradient, implying that model responses to increasing radiative forcing from atmospheric greenhouse gases are diverging from the real world.

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.

Accurate segmentation of ischemic stroke lesions from brain MRI is crucial for timely diagnosis and treatment planning. Here, the authors present DeepISLES, an AI ensemble for stroke MRI analysis that outperforms previous methods and matches expert radiologist performance in identifying stroke lesions.

The MiDAC complex regulates gene expression through histone deacetylation. Here, the authors identify a recurrent MIDEAS mutation that disrupts an auto-inhibitory loop, elevating deacetylase activity and causing a multisystem developmental disorder.

A study in rats proposes a mechanism for how the brain maps the surrounding environment, including places it has never seen, by alternating left and right forward sweeps in successive theta cycles.

The authors identify thousands of genetic variants affecting RNA splicing in primary human chondrocytes and link several of them to osteoarthritis risk using genome editing and computational approaches.

DNA damage threatens genome stability, but its dynamics in living systems remain difficult to track. Here, the authors engineer MCPH1-based protein probes that specifically recognize γH2AX, enabling real-time visualization and mapping of DNA damage across diverse cellular and organismal contexts.

Electrochemical modulation of fluorophores enables regulating their emission states, facilitating spectral unmixing of up to four fluorophores with similar spectral characteristics. This method is readily applicable to multicolour STED imaging, effectively expanding a single imaging channel to four channels.

This research identifies local field potential markers associated with obsessive–compulsive disorder symptoms in patients during provocation. Key findings reveal increased delta and alpha power in specific brain regions, correlating with symptom severity and suggesting potential biomarkers for targeted interventions.

Shotgun metagenomic sequencing (using the MinION platform) of mock microbial communities and faecal samples from healthy and ill preterm infants can be used to identify pathogens and their antimicrobial resistance gene profiles in real time, indicating the potential for translation into clinical settings.

COVID-19 can be associated with neurological complications. Here the authors show that markers of brain injury, but not immune markers, are elevated in the blood of patients with COVID-19 both early and months after SARS-CoV-2 infection, particularly in those with brain dysfunction or neurological diagnoses.

Across 13 longitudinal studies (3,737 adults), the authors show that brain atrophy parallels memory loss, with a stronger coupling in later life. APOE ε4 increases decline, yet genetic risk does not modify the brain–memory relationship.

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.

Resistance to first line treatment is a major hurdle in cancer treatment, that can be overcome with drug combinations. Here, the authors provide a large drug combination screen across cancer cell lines to benchmark crowdsourced methods and to computationally predict drug synergies.

Deposition of tau protein aggregates occurs during aging and Alzheimer disease. Here, the authors show that tau burden in the anterior-temporal memory network is associated with disrupted fMRI connectivity and functional isolation of the hippocampus from other memory network components.

This study describes the integrative analysis of 111 reference human epigenomes, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression; the results annotate candidate regulatory elements in diverse tissues and cell types, their candidate regulators, and the set of human traits for which they show genetic variant enrichment, providing a resource for interpreting the molecular basis of human disease.

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