Cell reports最新文献

Remapping is a fundamental feature of hippocampal contextual representations that underlies memory encoding and separation. Recently in Cell Reports, Tarcsay et al¹ have shown that experience determines remapping dynamics in context learning.

Human pluripotent stem cell (hPSC)-derived GABAergic neurons offer potential for treating neurological disorders by restoring disrupted inhibitory circuits, yet current differentiation methods show limited efficiency, purity, and subtype specificity. We present an approach for generating lateral/caudal ganglionic eminence (LGE/CGE) organoids (LCOs) from hPSC-derived brain organoids (BOs) without external signal induction. LCOs bud from the BO surface and are predominantly composed of LGE/CGE-type GABAergic neurons that mature into functional inhibitory neurons. LCOs and BOs exhibit distinct subtype compositions: LCOs contain both LGE-type neurons, with the capacity to form striatal medium spiny neurons, and abundant CGE-type neurons, whereas BOs contain fewer CGE-type neurons. Single-cell transcriptomic analysis reveals that LCOs closely resemble human embryonic LGE/CGE neurons at gestational weeks 12-13. We also developed a method to selectively enrich CXCR4⁺ CGE-type neurons from LCOs. This platform enables efficient generation of human LGE/CGE-type GABAergic neurons for disease modeling and cell therapy development.

Osteoarthritis (OA) is a prevalent age-related joint disorder with limited treatment options. Chronic activation of the innate immune response in chondrocytes plays a key role in OA progression. However, the underlying mechanisms remain incompletely understood. Here, we report that mitochondrial antiviral signaling protein (MAVS) exacerbates cartilage extracellular matrix (ECM) degradation in OA. MAVS activation is observed in chondrocytes from both OA patients and the destabilization of the medial meniscus (DMM) mouse model. Both constitutive and chondrocyte-specific MAVS knockout alleviate cartilage degradation, osteophyte formation, subchondral bone remodeling, and synovitis in DMM mice. Conversely, MAVS overexpression aggravates these OA phenotypes. Mechanistically, cytosolic accumulation of mitochondrial double-stranded RNA in chondrocytes triggers MAVS activation, leading to MAVS-nuclear factor κB-dependent ECM degradation by inducing matrix metalloproteinase 3 (MMP3) and MMP13. Pharmacologically blocking MAVS using L-lactate significantly attenuates ECM degradation and OA progression. These findings suggest that MAVS signaling is critical in OA pathogenesis and may be a potential therapeutic target for OA treatment.

Sensory cortices are not silent in the absence of sensory inputs but generate spontaneous activity intrinsic to the cortical circuit referred to as default-mode activity. Here, we report that spontaneous activity of excitatory and inhibitory neuronal types in layer 2/3 of the adult primary visual cortex (V1) exhibits quite stable default-mode local network architectures, which undergo rapid and selective restructuring following bilateral enucleation (EN), a model of adult-onset blindness. Spontaneous activity of both pyramidal (Pyr) and parvalbumin (PV) neurons rapidly and persistently increased following EN, but the default-mode network architecture of only Pyr rapidly rearranged and stabilized. Vasoactive intestinal peptide (VIP) neuronal network also restructured rapidly after EN, but their spontaneous activity increase was delayed. Somatostatin (SOM) neuronal network was quite stable. Our results indicate that adult-onset blindness rapidly and selectively modifies the stable default-mode local network architectures of V1, independent of increases in spontaneous activity, reflecting rapid adaptation to vision loss.

Cancer can recur when a subset of tumor cells, termed persister cells, survive therapy and re-enter the cell cycle. Through single-nucleus multi-omic profiling (single-nucleus RNA sequencing [snRNA-seq] and single-nucleus assay for transposase-accessible chromatin by sequencing [snATAC-seq]) of (1) non-malignant fallopian tubes and (2) treatment-naive and (3) neoadjuvant-chemotherapy-treated samples from patients with high-grade serous ovarian carcinoma (HGSOC), we identify a persister cell signature defining the chemotherapy-tolerant state. The chromatin features of the signature are detectable in residual tumors after treatment and in treatment-naive tumors from patients who later develop resistance. Further, the signature independently predicts chemotherapy response in metastatic HGSOC and patient-derived xenograft models. Cells enriched in the persister state display a subset of genes primed for expression before treatment, an altered cell cycle, and stress-response programs associated with poor clinical outcomes. These findings suggest that an intrinsic regulatory program primes tumor cells toward chemotherapy tolerance and reveal new vulnerabilities that can be targeted with chromatin-modifying agents to prevent cancer recurrence.

Avian H15 influenza viruses are closely related to H7 viruses, but only 22 H15 sequences have been reported since 1987, suggesting both rarity and minimal antigenic variation. Here, we characterized a panel of mouse monoclonal antibodies (mAbs) raised against the A/wedge-tailed shearwater/Western Australia/2576/1979 ancestral strain, and a human mAb isolated from an H7N9 vaccinee. We found differences in binding and neutralization profiles against the ancestral strain and drifted strains of H15 isolated after 2008. mAbs exhibiting hemagglutination inhibition activity against the ancestral strain do not show binding to drifted strains, hinting at antigenic differences near the receptor binding site. We show that the mAbs protect in vivo and elucidate mAb-antigen interactions using negative stain and cryo-electron microscopy. The characterization of H15 antigenicity and the mechanisms of antibody-mediated neutralization expands our knowledge of this sparsely sampled avian influenza virus subtype and informs our understanding of immune pressures on viral surface glycoproteins.

Dumbrava et al. map a unified epigenetically primed persister state in high-grade serous ovarian carcinoma using single-nucleus multi-omics. Their work uncovers a chromatin-encoded tolerance program that precedes transcriptional change, revealing therapeutic options and motivating deeper spatiotemporal mapping of persister cells.

Phage genomes integrated within bacterial genomes, known as prophages, frequently encode proteins that provide defense against further phage infection. These proteins often function by altering the cell surface and preventing phages from attaching to their host receptor. Here, we describe prophage-encoded proteins that resemble FimU, a component of the Pseudomonas aeruginosa type IV pilus. These phage FimU proteins are incorporated into the pilus without altering its function, yet they mediate robust protection against infection by phages that bind to the tip of the pilus, where FimU is located. The phage FimU proteins and the phage tail proteins that likely interact with FimU are highly diverse, suggesting that evolution in this system is driven by phage versus phage competition. These phage FimU proteins represent an example of anti-phage defense mediated by the replacement of a bacterial cell surface component with a phage-encoded protein.

Triple-negative breast cancer (TNBC) is a prevalent breast cancer subtype with the lowest 5-year survival. Several factors influence outcomes, but their inherent molecular and cellular heterogeneity are increasingly acknowledged as crucial determinants. Here, we report on the spatio-molecular heterogeneity underlying TNBC tumors in a retrospective, treatment-naive cohort with differential prognoses (17 good prognoses [GPx] >15-year survival and 15 poor prognoses [PPx] <3-year survival]) profiled using GeoMx Digital Spatial Profiler. Analyses reveal that epithelial and microenvironment (TME) states are transcriptionally distinct between groups. Invasive GPx epithelia show an increase in immune transcripts, with a more immune-rich TME (via IF). PPx epithelia, in contrast, are more metabolically and translationally active, with a mesenchymal/fibrotic TME. Pre-cancerous epithelia in PPx exhibit a presence of aggressiveness, marked by increased EMT signaling and complement activity. We identify distinct epithelial gene signatures for PPx and GPx that can accurately classify diagnostic samples and likely inform therapy.

Mastitis threatens dairy cow health and public safety. While gut dysbiosis increases mastitis susceptibility, the mechanism is unclear. We hypothesized that gut dysbiosis exacerbates Staphylococcus aureus (S. aureus)-induced mastitis by reducing milk secretory immunoglobulin A (sIgA). In mice, vancomycin-induced gut dysbiosis reduced sIgA and IgA⁺ B cells in milk, gut, and Peyer's patches, impairing the blood-milk barrier and worsening mastitis, effects reversed by fecal microbiota transplantation. Dysbiosis specifically reduced intestinal M. intestinale abundance and GABA levels. Supplementing with M. intestinale or GABA restored sIgA, increased IgA⁺ B cells, and alleviated mastitis. We identified an NADP-specific glutamate dehydrogenase (GDH) in M. intestinale; a GDH-expressing E. coli-produced glutamate, elevating gut GABA, enhancing sIgA, and mitigating mastitis. Mechanistically, GABA activated the mTOR pathway to drive macrophage M2 polarization and B cell differentiation. Thus, M. intestinale-derived GABA boosts sIgA to protect against mastitis, offering novel prevention strategies.