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The authors took a multimodal approach to characterize the differential transcriptome and epigenetic landscape between distinct regions of the embryonic mouse forebrain, revealing many unexplored presumptive promoter-enhancer interactions.

Tumor-associated macrophages can restrict antitumor responses. Barreira da Silva and colleagues demonstrate that the intracellular enzyme QPCTL supports recruitment of immunomodulatory macrophages to the tumor microenvironment and its targeting can enhance tumor control.

Understanding conserved functional genomic properties between human and mouse provides important context for mouse model studies. Here, the authors present a genome-wide conservation score integrating epigenomic, transcription factor binding, and transcriptomic data from mouse and human genomes.

The assembly of the genome of the koala provides insights into its adaptive biology and identifies gene expansions that contribute to its ability to detoxify eucalyptus-derived compounds and perceive plant secondary metabolites.

Federated learning (FL) algorithms have emerged as a promising solution to train models for healthcare imaging across institutions while preserving privacy. Here, the authors describe the Federated Tumor Segmentation (FeTS) challenge for the decentralised benchmarking of FL algorithms and evaluation of Healthcare AI algorithm generalizability in real-world cancer imaging datasets.

The evolutionarily conserved SARS-CoV-2 spike’s S2 subunit provides the foundation for its usage as an immunogen in vaccines. Here, the authors use a simulation-driven approach to design S2-only immunogens stabilized in the closed prefusion conformation.

Single-cell data analysis is challenging due to inherent noise and sparsity. Here, authors introduce scMINER, a mutual information-based integrative tool to enhance clustering and reveal regulatory networks and hidden biological drivers by transforming scRNA-seq expression into activity profiles.

Different functional variants in ADH1B (and elsewhere) in Europeans and Africans strongly affect risk for alcohol dependence. Dependence only partly genetically correlates with consumption, with strong correlations to other psychiatric disorders.

Sexual interactions with males shorten the lifespan of the opposite sex in several species, including Caenorhabditis elegans, but the mechanisms are not fully understood. Here the authors use transcriptomic profiling in C. elegans to systematically identify the genetic pathways involved in male-induced demise, which include upregulation of a conserved ion channel that regulates fat metabolism.

Ribonucleotide reductase (RNR) catalyzes the conversion of ribonucleotides to deoxyribonucleotides, which is an essential step in DNA synthesis. Here the authors use small-angle X-ray scattering, X-ray crystallography, and cryo-electron microscopy to capture active and inactive forms of the Bacillus subtilis RNR and provide mechanistic insights into a convergent form of allosteric regulation.

Patient-derived xenografts provide a resource for basic and translational cancer research. Here, the authors generate multiple pediatric high-grade glioma xenografts, use omics technologies to show that they are representative of primary tumours and use them to assess therapeutic response.

Viral pathogen load in cancer genomes is estimated through analysis of sequencing data from 2,656 tumors across 35 cancer types using multiple pathogen-detection pipelines, identifying viruses in 382 genomic and 68 transcriptome datasets.

Human brain structure changes throughout the lifespan. Brouwer et al. identified genetic variants that affect rates of brain growth and atrophy. The genes are linked to early brain development and neurodegeneration and suggest involvement of metabolic processes.

Mutation of the C-terminal extension of 5′-aminolevulinate synthase 2 (ALAS2) is the molecular cause for X-linked protoporphyria, but the underlying mechanism is unclear. Based on crystal structures and MD simulations of ALAS2, the authors here show how the C-terminal extension regulates ALAS2 activity.

The CDK4/6 inhibitor ribociclib holds promise in cancer therapy but how cell cycle inhibitory drugs affect the anti-tumor immune response remains a question. Here authors show that poor response of early-stage estrogen receptor positive breast cancers to ribociclib is caused by changes in the immune cell composition and cancer-cell-immune-cell communication in the tumors rather than intrinsic cancer cell resistance to cell cycle inhibition.

Analyses of the TRACERx study unveil the relationship between tissue morphology, the underlying evolutionary genomic landscape, and clinical and anatomical relapse risk of lung adenocarcinomas.

In individuals diagnosed with age-related macular degeneration in one eye, a deep learning model can predict progression to the ‘wet’, sight-threatening form of the disease in the second eye within a 6-month time frame.

A library of fluorogenic dyes enables the measurement of protein unfolding for a large range of proteins.

Hoang et al. developed a deep-learning framework called ENLIGHT–DeepPT that predicts therapy response based on imputed transcriptomics and shows predictive power across patient cohorts and cancer types.

The blooming alga Emiliania huxleyi and its viruses are a model for density-dependent virulent dynamics. However, Knowles et al. show that this host–virus system exhibits temperate dynamics at natural host densities, in a manner dependent on host physiology.

Genetic code expansion and reprogramming require orthogonal tRNAs. Methods have now been developed for the automated generation of chimeric orthogonal tRNAs and discovery of their cognate synthetases. These approaches have been used to discover new orthogonal pairs for efficient non-canonical amino acid incorporation.

Guide RNA folding affects functionality of CRISPR-Cas transcriptional control systems. Here, the authors report computational gRNA design together with creation of synthetic CRISPRa promoters for orthogonal expression control and demonstrate the application in pteridine and human milk oligosaccharide production in E. coli.

Tracking of individual place cells in mouse CA1 shows that representational drift is not influenced by changes in environment or behaviour, and is lower for more excitable place cells.

The effects of pesticides on individual species could propagate into additional community-wide and ecosystem-level effects. Here the authors use a mesocosm experiment to test how a diverse array of herbicides and insecticides disrupt aquatic community structure and ecosystem function.

Comprehensive genomic and transcriptomics analyses of more than 1,300 cases of childhood T-lineage acute lymphoblastic leukaemia identify 15 distinct subtypes that are associated with specific outcomes.

Previous studies on astrocyte development have led to controversial results due to a lack of pertinent tools. Here, authors analyze large numbers of astrocyte clones generated by nearby cortical progenitors using the MAGIC Markers strategy and ChroMS 3D imaging, and show that clonally-related astrocytes organize in a non-stereotyped manner and that cortical astrocyte subtypes are not intrinsically specified.

A combination of hardware developments has increased the achievable spatial resolution in 7 Tesla human neuroimaging to about 0.4 mm.

Distinct membrane interaction dynamics between the two non-visual arrestin subtypes uncover new mechanistic insights into arrestin activation and highlight the essential role of membrane engagement.

Tissue-resident effector memory T cells respond rapidly after reencountering antigen. Masopust and colleagues show that memory CD8⁺ T cells also induce the release of chemokines, then recruit more memory cells to the site of infection.

Some anesthetics despite being generally associated with sedation, can also increase brain activity—a phenomenon called paradoxical excitation. The authors identified dozens of compounds that generally decrease neuronal activity, but increase activity in the caudal hindbrain of zebrafish.

Here, the authors apply genome-scale metabolic network reconstructions to metagenomic data obtained from human vaginal swabs to identify bacterial vaginosis-associated bacterial metabolic interactions, and validate in vitro microbial metabolites implicated in host estrogen receptor binding.

Genomic studies often lack representation from diverse populations, limiting equitable insights. Here, the authors show that the BIG Initiative captures extensive genetic diversity and reveals ancestry-linked health disparities in a community-based Mid-South cohort.

The photoreceptor cilium contains an exclusive group of proteins responsible for capturing light and eliciting a visual response. Here, the authors show that the tectonic complex plays a role in the barrier that prevents unsolicited protein entry into the cilium.

Many pathogens manipulate ubiquitin-mediated signaling to evade host cell defense. Here, the authors characterize the structure and enzymatic activity of a deubiquitylase domain from the causative pathogen of scrub typhus, providing evidence for a distinct mechanism of ubiquitin chain selectivity.

It remains unclear how rapid antibiotic switching affects the evolution of antibiotic resistance in individual patients. Here, Chung et al. combine short- and long-read sequencing and resistance phenotyping of 420 serial isolates of Pseudomonas aeruginosa collected from the onset of respiratory infection, and show that rare resistance mutations can increase by nearly 40-fold over 5–12 days in response to antibiotic changes, while mutations conferring resistance to antibiotics not administered diminish and even go to extinction.

Hydroxysteroid 17-beta-dehydrogenase 13 (HSD17B13) is a hepatic lipid droplet-associated enzyme that is upregulated in patients with non-alcoholic fatty liver disease. Here, the authors report crystal structures of HSD17B13 and its complexes with two series of inhibitors.

Paediatric therapy-related myeloid neoplasms (tMN) have a dismal prognosis and have not been comprehensively profiled. Here the authors characterise the molecular landscape of 84 paediatric tMN patients, and find that, unlike adult tMNs, these do not emerge from pre-existing clones and that MECOM dysregulation is frequent.

Net-zero bioplastics are possible when combined with high recycling rates. This study presents a mixed polyester recycling process integrated with monomer separation and purification for both fossil- and bio-based plastics. Techno-economic and life cycle analyses confirm its environmental and commercial advantages, advancing the path toward circular, low-emission polyester plastics.

Fine-tuning the RoseTTAFold structure prediction network on protein structure denoising tasks yields a generative model for protein design that achieves outstanding performance on a wide range of protein structure and function design challenges.

DNA Ligase IV (LigIV) catalyzes nick sealing of DNA double-strand break substrates during non-homologous end-joining. Here the authors present the crystal structures of two human LigIV DNA-bound catalytic states, which provide insights into its catalytic mechanism and the molecular basis of LIG4 syndrome causing disease mutations.

By studying cortical activity patterns during prey capture and spontaneous behavior in marmosets, the authors identify distinct subnetworks defined by reliable spike timing correlations. These subnetworks emerge during prey capture, with each potentially playing different roles in controlling reaching movements.

An analysis of 2,954 genomes from 38 cancer subtypes identified 19,166 retrotransposition events in 35% of samples. Aberrant LINE-1 retrotranspositions can lead to the deletion of tumor-suppressor genes as well as the amplification of oncogenes.

A critical goal in functional genomics is evaluating which non-coding elements contribute to gene expression, cellular function, and disease. Here the authors present a CRISPRi-based method using truncated guides disrupts transcription factor binding and enhancer activity across thousands of sites, expanding CRISPRi targeting scope for functional genomics and enabling efficient screening of repeated genomic elements

Cas12i is a genome editing platform with compact size that fits in AAV vector with short 43-mer gRNA, absence of tracrRNA, ability to process pre-crRNA, and high specificity. Here the authors present an unbiased mutational scanning approach to engineer Cas12i, which shows low activity in mammalian cells, and identify single substitutions that significantly improve indel activity.

Transferrin receptor (TfR) and CD98hc are increasingly used to enable more effective drug delivery to the central nervous system. Here, the authors reveal comprehensive and distinct brain cellular and whole body biodistribution patterns of TfR- and CD98hc-binding molecules.

A population-scale map of gene expression in primary human microglia provides a systematic exploration of microglia diversity and how age, sex, pathology, cortical anatomy and common germline genetic variation influence the microglia transcriptome.

Pose estimation in combination with an anatomically constrained model allows inferring skeletal kinematics in rodents.

A genetically encoded FRET-based optical sensor generated from a computational design approach can monitor hippocampal glycine levels in brain tissue to determine differences between spines and shafts and changes induced by high- and low-frequency stimulation.