A single-cell multiomic analysis identifies molecular and gene-regulatory mechanisms dysregulated in developing Down syndrome neocortex

Researchers used single-nucleus multiomic profiling (simultaneously measuring gene expression and chromatin accessibility) across 26 human mid-gestation brain samples to investigate how Down syndrome disrupts neocortical development at the molecular level. They found that DS brains have fewer neural progenitors and corticothalamic neurons but more intratelencephalic neurons, alongside accelerated neuronal differentiation. The analysis revealed broad disruptions in gene expression, chromatin accessibility, and cell-to-cell communication relevant to how neurons are generated, specified, and matured. Dysregulated gene-regulatory networks included those controlled by chromosome 21-encoded genes. The researchers also identified molecular pathways shared with other neurodevelopmental conditions and found that regions of altered chromatin in DS are enriched for genetic variants associated with the disorder via genome-wide association studies. Overall, the work maps the earliest molecular events in DS neocortical development, offering a resource for identifying potential therapeutic targets.

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Molecular and cellular processes disrupted in the early postnatal Down syndrome prefrontal cortex

Researchers examined why Down syndrome causes early cognitive, motor, and language impairments by investigating molecular disruptions in the prefrontal cortex during early postnatal life—a window critical for synapse formation and brain maturation. Using single-nucleus multiomic sequencing, they simultaneously measured gene expression and chromatin accessibility in Down syndrome versus typical brain tissue. They found broad dysregulation across both epigenetic and transcriptional levels, affecting metabolic and synaptic pathways, the progression of cells that produce myelin (oligodendrocyte lineage), and—most prominently—a strong neuroinflammatory signature. The resulting molecular atlas maps neuropathological changes at this key developmental stage, revealing that pathways associated with both neurodevelopment and neurodegeneration are disrupted together in Down syndrome. These findings help clarify the biological basis of intellectual disability in Down syndrome and point toward neuroinflammation as a potential therapeutic target.

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Mechanical load inhibits cancer growth in mouse and human hearts

The heart almost never develops primary tumors, and it also loses the ability to regenerate after birth — a coincidence that hints at shared underlying mechanisms. Researchers explored whether mechanical forces generated by the constantly beating heart might suppress tumor growth. Using mouse cancer models, lab-grown engineered heart tissues, and spatial transcriptomics of human cardiac metastases, they found that mechanical load directly reduces cancer cell proliferation within heart muscle. Analysis of human tissue showed that this mechanical pressure triggers changes in histone methylation and chromatin compaction, making proliferation-related genes less accessible. The protein Nesprin-2 was identified as a critical sensor translating physical force into these epigenetic changes. The findings explain why the heart's demanding mechanical environment acts as a natural barrier against cancer, and they open the possibility of exploiting mechanical stimulation as a therapeutic strategy in oncology.

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Mapping transcription factor functions in astrocytes using in vivo gain-of-function Perturb-seq

Researchers built a platform called iGOF–Perturb-seq to systematically study what transcription factors (TFs) do inside living brain tissue, specifically in astrocytes—cells critical to many brain functions. The approach combines high-throughput in vivo screening with single-cell transcriptomic readouts, allowing the team to profile the functional effects of roughly 1,000 TFs simultaneously. By analyzing the resulting data, they identified groups of TFs that work together, assigned roles to previously uncharacterized TFs, and predicted clusters linked to neurological disease. Applying the platform to a mouse model of neuroinflammation, they flagged Ferd3l as a promising therapeutic target; when Ferd3l was overexpressed specifically in astrocytes, Alzheimer's disease symptoms in mice were reduced. The work creates a broad resource for understanding gene regulation in the brain and offers a generalizable strategy for pinpointing therapeutic candidates in complex disease contexts.

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First genome loaded on a quantum computer

A team has taken an early step toward quantum genomics by encoding the genome of the hepatitis D virus — one of the smallest known viral genomes — onto a quantum computer. The work represents a proof-of-concept demonstration that genomic data can be represented within a quantum computing framework, laying groundwork for what researchers envision as a new field combining quantum computation with genomics. Because quantum computers can in principle process certain types of information exponentially faster than classical machines, the approach could eventually open new possibilities for genomic analysis, though the work is currently at a foundational stage.

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Reimagining human-centric drug development with new approach methodologies

High drug candidate failure rates in clinical trials point to a fundamental mismatch between traditional preclinical models and human physiology. This review examines how new approach methodologies (NAMs) — encompassing human-derived cell systems, microphysiological platforms (such as organ-on-a-chip devices), and AI-driven computational tools — could address that gap. The authors survey both biological and computational NAMs, exploring how combining them may improve the predictability and efficiency of drug development. They also consider recent regulatory shifts, notably the FDA Modernization Act 3.0, which formally opens the door to using NAMs alongside or instead of animal testing. Ethical frameworks guiding this transition are discussed, and the review proposes a roadmap for building a drug development infrastructure more firmly grounded in human biology, with the goal of producing safer, more effective therapies while reducing reliance on animal models.

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