Cell reports最新文献

Although macaques and marmosets are both primates of choice for studying the brain mechanisms of cognition, they differ in key aspects of anatomy and behavior. Interestingly, a recent connectomic analysis revealed that strong top-down projections from the prefrontal cortex to the posterior parietal cortex, present in macaques and important for executive function, are absent in marmosets. Here, we propose a consensus mapping that bridges the two species' cortical atlases and allows for direct area-to-area comparison of their connectomes, which are then used to build comparative computational large-scale modeling of the frontoparietal circuit for working memory. The macaque model exhibits resilience against distractors, a prerequisite for normal working memory function. By contrast, the marmoset model predicts a sensitivity to distractibility commonly observed behaviorally in this species. Surprisingly, this contrasting trend can be swapped by rescaling intrafrontal and frontoparietal connection weights and offers a credible prediction to the marmoset's behavior in this specific task.

Noise correlations-synchronized firing fluctuations among neurons-critically influence sensory processing, yet their regulatory mechanisms remain unclear. We investigated how V1 inhibitory neuron subtypes regulate noise correlations and visual encoding in mice using optogenetics and electrophysiology. Suppression of parvalbumin-positive (PV⁺) or somatostatin-positive (SOM⁺) neurons increased noise correlations, whereas suppression of vasoactive intestinal peptide-positive (VIP⁺) neurons decreased them, reflecting their distinct inhibitory roles. These changes correlated with altered orientation-discrimination performance. Our linear regression model, integrating noise correlations with neuronal discriminability, successfully predicted individual animals' behavioral performance, demonstrating their synergistic influence on visual perception. These findings elucidate how inhibitory circuits regulate noise correlations and sensory processing, indicating potential therapeutic targets for sensory-processing disorders.

Glioblastoma is the most aggressive and deadly form of brain cancer. Here, we leverage our human organoid tumor transplantation (HOTT) co-culture system to explore how extrinsic cues modulate glioblastoma cell types and behavior. HOTT recapitulates core features of major patient tumor cell types and key aspects of neural cell-enriched tumor microenvironment (nTME) gene programs. Our exploration of patient TME interactions preserved in HOTT highlights four receptor-ligand interactions of interest. We knock down all four of these genes in the HOTT microenvironment. We observe that knocking down nTME PTPRZ1, a receptor tyrosine phosphatase implicated in cancer cell migration, results in an increased fraction of mesenchymal cells, enrichment of epithelial-to-mesenchymal gene programs, and an elevated tumor microtube length in co-cultured primary patient tumors. This phenotype is not mediated by PTPRZ1's catalytic activity, suggesting a mechanism of tumor cell fate driven by nTME PTPRZ1, highlighting the strengths of the HOTT system.

Trisomy 21 (T21) gives rise to Down syndrome (DS), the most commonly occurring chromosomal abnormality in humans. T21 affects nearly every organ and tissue system in the body, predisposing individuals with DS to congenital heart defects, autoimmunity, and Alzheimer's disease, among other co-occurring conditions. Here, using multi-omic analysis of plasma from more than 400 people, we report broad metabolic changes in the population with DS typified by increased bile acid levels and protein signatures of liver dysfunction. In a mouse model of DS, we demonstrate conservation of perturbed bile acid metabolism accompanied by liver pathology. Bulk RNA sequencing revealed widespread impacts of the Dp16 model on hepatic metabolism and inflammation, while single-cell transcriptomics highlighted cell types associated with these observations. Modulation of dietary fat profoundly impacted gene expression, bile acids, and liver pathology. Overall, these data represent evidence for altered hepatic metabolism in DS that could be modulated by diet.

Chronic kidney disease (CKD) is projected to become the fifth leading cause of mortality by 2040. Tubular senescence drives kidney fibrosis, but current treatments do not target senescent cells. Here, we identify nicotinamide-N-methyltransferase (NNMT) as a critical mediator of tubular senescence and kidney fibrosis. Human CKD microarrays link NNMT to senescence and fibrosis transcriptomic signatures, and diabetic kidney disease (DKD) biopsies show NNMT protein associating with p21, fibrosis, and kidney function decline. Spatial transcriptomics in human biopsies demonstrates that NNMT-positive tubules are senescent, fibrotic, and surrounded by a pro-inflammatory microenvironment. Importantly, this pattern is conserved in aged and DKD mice, mimicking early-stage CKD features. Mechanistically, NNMT overexpression in tubular epithelial cells exacerbates senescence and partial epithelial-to-mesenchymal transition, while selective NNMT inhibition in senescent kidney cells, organoids, and in vivo is protective. Altogether, these findings position NNMT as a promising therapeutic target to reduce tubular senescence and fibrosis in early CKD.

Astrocytes not only play a central role in orchestrating the brain's microenvironment but also are tightly connected to neurodegenerative processes. Hence, unraveling astrocytes' intercellular pathways can give important insight into disease-spreading mechanisms. Here, we describe a distinct form of actively migrating cellular vehicles, which we have named zombosomes. Zombosomes shed from astrocytes but retain their adhesive and motile properties, even though they lack nuclei. They share protein markers with their parental astrocytes, including highly packed vimentin, and are loaded with intact organelles. Importantly, zombosomes act as disease couriers, transferring α-synuclein aggregates from one cell to another, and have the capacity to infiltrate and induce pathology in cerebral organoids. Human brain sections show scattered vimentin-rich zombosomes with no attachments to nearby astrocytes, which contain deposits of aggregated α-synuclein. Taken together, our findings represent an interaction pathway between distant cells through "live" vehicles that when misused, may cause propagation of Parkinson's disease pathology.

Legionella pneumophila, the etiological agent of legionnaires' disease, establishes its intracellular niche through the Dot/Icm type IVB secretion system, which translocates ∼300 effector proteins into host cells. Efficient secretion of many effectors requires the IcmS and IcmW chaperones, which interact with both substrates and the type IV coupling protein DotL. A prior model proposed that IcmSW are released from substrates during translocation by transfer to the C terminus of DotL and then recycled to the cytoplasm. This model predicts an excess cytoplasmic pool of IcmSW and their dissociation from DotL. We tested these predictions using quantitative stoichiometric analysis of Dot/Icm components and DotL-chaperone fusion constructs. IcmSW were present at levels comparable to DotL, and a DotL-IcmW-IcmS fusion fully complemented an ΔicmS ΔicmW mutant for intracellular replication. These findings refute the recycling model and support an updated "anchored chaperone" model, wherein IcmSW remain stably associated with DotL during substrate translocation.

Working memory (WM) relies on efficient coding strategies to overcome its limited capacity, yet how the brain adaptively organizes WM representations to maximize coding efficiency based on environmental structure remains largely unknown. In our study, participants remembered a sequence of gratings defined in a two-dimensional feature space where we manipulated directional consistency, revealing enhanced performance for structured (consistent direction) vs. non-structured (inconsistent direction) contexts, particularly for individuals with lower WM capacity. Magnetoencephalography analyses uncovered dissociable neural bases: consistent sequences engaged anterior temporal and medial frontal cortices for abstract directional representations during maintenance, while inconsistent sequences preferentially reactivated item-specific representations in parietal regions. These neural patterns predicted behavioral performance, establishing a neural efficiency principle wherein the brain adaptively switches between relational and item-based coding strategies, mitigating WM constraints. These findings advance our understanding of how structures shape WM organization, offering insights into cognitive flexibility and neural resource allocation in complex environments.

Fibroblasts are abundant structural cells with an emerging immune-sentinel role in the wound healing process, though its functional significance remains incompletely explored. By utilizing an oral injury model that heals rapidly, we identify murine PI16⁺ reticular fibroblasts to be enriched in interleukin-33 (IL-33), an alarmin cytokine, and demonstrate that Il33 deletion in fibroblasts impairs oral wound healing. Single-cell RNA sequencing analysis points to regulatory T (Treg) cells, which respond to IL-33 by upregulating the expression of macrophage migration-inhibitory factor (MIF) and transforming growth factor β1 (TGF-β1). Mechanistically, MIF promotes monocyte recruitment, which facilitates angiogenesis, whereas TGF-β1 is linked to early macrophage transition to a pro-resolving phenotype. Importantly, human oral mucosa harbors IL-33⁺PI16⁺ fibroblasts in the reticular layer of connective tissue, and Treg cells express MIF and TGFB1 in regenerating human oral mucosa. These results unveil a crucial role of IL-33-expressing oral fibroblasts for modulating inflammation in healing wounds via Treg cell activation.

The septotemporal axis of the hippocampus separates it into domains with unique molecular, cellular, downstream connectivity, and behavioral profiles, and yet very little is known about the ontogenesis of these highly specialized subcircuits. Here, we use viral tracing, optogenetic-assisted patch clamping, chemogenetics, and behavior in mice to examine changes in domain-defined hippocampus efferent projections from postnatal day (P)10 to P60. We find distinct anatomical and synaptic developmental signatures in ventral and intermediate CA1 downstream connectivity, with unique contributions to the prelimbic and infralimbic subregions of the medial prefrontal cortex (mPFC). Juvenile inhibition of the ventral and intermediate CA1-mPFC pathways leads to opposing modulation of adult cognitive flexibility, establishing a sex- and pathway-specific sensitive period preceding the stabilization of CA1-mPFC synaptic transmission. Our data elucidate domain- and target-defined postnatal maturation of hippocampus efferents, indicating juvenility as a CA1-mPFC sensitive period with crucial implications for early life influences on adult cognition.