Search

This study reports that de novo germline missense variants in SF3B1, distinct from the somatic variants frequently observed in cancer, cause a neurodevelopmental disorder and disrupt global RNA splicing.

Taveneau et al. leverage artificial-intelligence-driven protein design to create inhibitors that control RNA-targeting enzymes in cells, revealing a strategy to rapidly design off-switches for RNA-editing systems.

De novo and inherited dominant variants in genes encoding U4 and U6 small nuclear RNAs are identified in individuals with retinitis pigmentosa. The variants cluster at nucleotide positions distinct from those implicated in neurodevelopmental disorders.

This study presents a comprehensive modelling framework that jointly optimizes sequence and structure to generate de novo proteins with improved folding stability, providing large-scale experimental benchmarking across multiple computational design methods

Bessler et al. developed a human organoid model for H3.3K27M-altered diffuse midline glioma that recapitulates key tumor features and demonstrated its utility for modeling CAR T cell and microglia functions.

This study introduces an ion mobility–mass spectrometry method for de novo glycan structure identification, using a self-expanding database that reduces reliance on synthetic reference standards.

The combination of computational design, laboratory-based screening and biophysical validation enables the de novo generation of variable heavy-chain antibody fragments and antibodies that precisely target chosen disease-related molecules.

A machine-learning-based computational approach to probe pathway coessentiality reveals that complex II of the electron transport chain regulates de novo purine synthesis, and can be targeted to treat acute myeloid leukaemia.

Yan et al. use cryo-EM to obtain structures that reveal how DNMT3A2 and DNMT3L cooperate to read histone signals and bind chromatin, illustrating a mechanism that controls DNA methylation and shapes epigenetic regulation.

The authors show that regenerating liver requires de novo pyrimidine synthesis and it uses ammonia as precursors differentially as it traverses the liver zones. Tracing studies and spatial metabolomics reveal that assimilation periportally is via the urea cycle, and pericentrally through conversion into glutamine.

Bacteria evolving within humans employ strategies to overcome trade-offs. Here, the authors report that the cystic fibrosis-associated pathogen Burkholderia dolosa alternates phenotypes in vivo by accumulating successive de novo mutations.

Available wheat genomes are annotated by projecting Chinese Spring gene models across the new assemblies. Here, the authors generate de novo gene annotations for the 9 wheat genomes, identify core and dispensable transcriptome, and reveal conservation and divergence of gene expression balance across homoeologous subgenomes.

A method to label cultured human embryos finds chromosome segregation errors in placenta-fated cells.

Many pathogens encode transporters that extract heme directly from host proteins. In this study, the authors demonstrate the utility of de novo-designed proteins in understanding the mechanism behind this process and how it can be inhibited in pathogenic E. coli.

X-ray free electron lasers are increasingly available for use in macromolecular structure determination. Here, the authors describe the successful use of selenium single-wavelength anomalous diffraction data to calculate experimentally derived phases.

Analysis of more than 95% of each diploid human genome of a four-generation, twenty-eight-member family using five complementary short-read and long-read sequencing technologies provides a truth set to understand the most fundamental processes underlying human genetic variation.

Pharmacologic inhibition of dihydroorotate dehydrogenase (DHODH) shows limited efficacy in pancreatic ductal adenocarcinoma (PDAC) models. Here the authors find that targeting the anti-apoptotic protein BCL-XL synergizes with DHODH inhibition in promoting apoptosis in PDAC cells, patient-derived organoids, and PDAC mouse models.

Elevated ceramides have been implicated in endothelial dysfunction, preceding cardiometabolic diseases. Yet, direct in vivo evidence is lacking. Here we show that suppression of ceramides and S1P are causally linked to endothelial dysfunction contributing to cardiometabolic disease in obese mice

Cascadia is a mass spectrometry-based de novo sequencing model that uses a transformer architecture to handle data-independent acquisition data and achieves substantially improved performance across a range of instruments and experimental protocols.

Reconstructing the biosynthesis of complex natural products in yeast is challenging. Here the authors construct a yeast consortium with obligate mutualism aiming to alleviate metabolic promiscuity through the multicellular division of labor, similar to plants, for de novo synthesis of complex antiviral lignans.

Exome sequencing of 851 trios from more than 2,500 individuals finds 187 genes with de novo mutations that contribute to meningomyelocele (spina bifida) and highlights critical pathways required for neural tube closure.

An integrated analysis of de novo and inherited coding variants in 42,607 individuals with autism spectrum disorder identifies 60 risk genes of which five have not previously been associated with neurodevelopmental disorders.

Peptides derived from non-ribosomal peptide synthetases (NRPS) are an important class of pharmaceutically relevant drugs. However, no general rules for the modification of NRPS or the generation of artificial NRPS are known. Now, a new strategy for the modification of NRPS has been developed that uses defined exchange units that are fused at specific positions connecting the condensation and adenylation domains.

The validation of inhibitors targeting PurF, a novel drug target for tuberculosis drug discovery, is described.

InstaNovo, a transformer-based model, and InstaNovo+, a multinomial diffusion model, enhance de novo peptide sequencing, enabling discovery of novel peptides, improved therapeutics sequencing coverage and detection of unreported organisms in proteomics studies

The non-coding RNA RNU4-2, which is highly expressed in the developing human brain, is identified as a syndromic neurodevelopmental disorder gene, and, using RNA sequencing, 5′ splice-site use is shown to be systematically disrupted in individuals with RNU4-2 variants.

Deep learning methods have been used to design proteins that can neutralize the effects of three-finger toxins found in snake venom, which could lead to the development of safer and more accessible antivenom treatments.

Metagenomic sequencing enhances microbiome analysis and understanding of microbial relationships but lacks tools for subspecies-level resolution. Here, authors present MAGinator, a tool that enables accurate profiling of microbiomes with strain-level information.

A study describes a direct computational approach without experimental optimization to design high-affinity proteins that bind small helical peptides.

Phase separation is being revealed as important in many biological processes. Most attempts to mimic and deconstruct this use engineered natural proteins. Now it is shown that de novo proteins can be designed from first principles to undergo liquid–liquid phase separation in cells, with the potential to organize multi-enzyme pathways.

Engineering the tunability of protein assembly in response to pH changes within a narrow range is challenging. Here the authors report the de novo computational design of pH-responsive protein filaments that exhibit rapid, precise, tunable and reversible assembly and disassembly triggered by small pH changes.

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.

The trRosetta neural network was used to iteratively optimise model proteins from random 100-amino-acid sequences, resulting in ‘hallucinated’ proteins, which when expressed in bacteria closely resembled the model structures.

De novo designed interleukin-4 mimetics were engineered that induce biased signaling activation and exhibit high thermal stability. These mimetics offer insight into cytokine signaling and can be directly incorporated into 3D-printed biomaterials

Differential sensing aims to mimic senses such as taste and smell through the use of synthetic receptors. Here, the authors show that arrays of de novo designed peptide assemblies can be used as sensor components to distinguish various analytes and complex mixtures.

Jiang et al. developed a computational method to design repeat proteins with multiple structured loops that are buttressed by extensive hydrogen bond networks. The designs were further functionalized into high-affinity peptide-binding proteins.

Separating different cell compartments from bulk gene expression data can be challenging. Here the authors present DECODER, which can perform de novo deconvolutions on non-negative matrices including microarray, RNA-seq and ATAC-seq data sets.

Methods to produce haplotype-resolved genome assemblies often rely on access to family trios. The authors present FALCON-Phase, a tool that combines ultra-long range Hi-C chromatin interaction data with a long read de novo assembly to extend haplotype phasing to the contig or scaffold level.

Tapioca is an ensemble machine learning framework for studying protein–protein interactions (PPIs) that facilitates integration of curve-based dynamic PPI data from thermal proximity coaggregation, ion-based proteome-integrated solubility alteration or cofractionation mass spectrometry data with static interaction data to predict PPIs in dynamic contexts.

PTPRK is a key protein in the transformation of normal to tumorigenic liver cells in obesity, providing fuel and lipids. Here, the authors show that genetic deletion of PTPRK in mice protects against fatty liver in an obesogenic diet and the development of liver cancer.

Innate IL-17-producing T cells—in particular, adipose γδ17 T cells—are enriched in molecular-clock genes, and the circadian expression of IL-17A and RORγt by these cells has a role in maintaining local homeostasis and regulating lipogenesis.

Coiled-coil assemblies have served as a rich resource for testing fundamental principles of protein structure and function. A semi-empirical design strategy now yields the first parallel hexamer, which also displays an internal channel that can be manipulated to direct assembly.

De novo fermentation and synthetic pathway construction for halogen-containing molecules remain relatively underexplored. Here, the authors report a mix-and-match co-culture platform to de novo generate a large array of halogenated tryptophan derivatives in E. coli from glucose.

A deep-learning-based strategy is used to design artificial luciferases that catalyse the oxidative chemiluminescence of diphenylterazine with high substrate specificity and catalytic efficiency.

Germline de novo mutations can impact individual fitness, but their role in human male infertility is understudied. Trio-based exome sequencing identifies many new candidate genes affecting male fertility, including an essential regulator of male germ cell pre-mRNA splicing.

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.