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Volume 23 Issue 1, January 2026

Squidiff predicts transcriptomic responses to perturbations

A micro-etching-style network of illuminated grids streams inward and gradually becomes organic, forming a cell-like shape that reflects Squidiff’s diffusion-based denoising and semantic control that enables the prediction of continuous cell-state transitions under differentiation and perturbations.

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Image: Mark Mazaitis, Nascent Studio LLC. Cover design: Thomas Phillips

Editorial

  • We highlight some of the Nature Methods team’s favorite papers published in 2025, reflecting on some trends and new technology developments.

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This Month

  • Not all conferences offer childcare, but when they do, these scientists, who are also mothers, rejoice. The toys are pretty good, too.

    • Vivien Marx
    This Month
  • The jellyfish Clytia hemisphaerica has long been established as a model for studying embryogenesis and gametogenesis because of its transparency, simple tissue architecture and evolutionary position. With the recent development of efficient transgenesis, this jellyfish is now poised for tackling systems-level questions in comparative neuroscience and regeneration.

    • Julian O. Kimura
    • Brandon Weissbourd

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    This Month
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Correspondence

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Research Highlights

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Technology Feature

  • Since the chance discovery of nanobodies in the late 1980s, their uses and applications have kept growing. Researchers are now exploring new ways to harness nanobody versatility.

    • Vivien Marx

    Collection:

    Technology Feature
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News & Views

  • TIRTL-seq is an innovative method that allows efficient and cost-effective identification of αβ TCR clones from millions of T cells with the aid of a pairing algorithm called T-SHELL, which provides high accuracy and throughput in sequencing paired TCR clones.

    • Mary Melissa Roland
    • Alok V. Joglekar
    News & Views
  • DynamicAtlas is a new open-source tool for incorporating gene expression and tissue shape changes into a single atlas with a continuous developmental timeline.

    • Miriam Osterfield
    News & Views
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Research Briefings

  • Modeling cellular responses to developmental and chemical cues is essential for understanding disease progression and informing therapeutic strategies, yet it often demands extensive experimental screening. We have developed a conditional diffusion model called Squidiff, which enables the in silico prediction of single-cell transcriptomic responses to both developmental signals and perturbations.

    Research Briefing
  • We introduce the Cryo-EM Image Evaluation Foundation (Cryo-IEF) model, which has been pretrained on 65 million particle images in an unsupervised manner. Cryo-IEF excels in diverse cryogenic electron microscopy data-processing tasks; it automates the complex workflow and makes this technology more accessible and robust.

    Research Briefing
  • We developed SmartEM, a method that integrates machine learning directly into the image acquisition process of an electron microscope. By allocating imaging time in a specific manner — scanning quickly at first, then rescanning only critical areas more slowly — we are able to accelerate the mapping of neural circuits up to sevenfold without sacrificing accuracy.

    Research Briefing
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Analysis

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