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Parvalbumin (PV) interneurons in the dorsal striatum (DS) are fast-spiking GABAergic cells critical for feedforward inhibition and synaptic integration within basal ganglia circuits. Despite their well-characterized electrophysiological roles, their molecular identity remains incompletely defined. Using the Ribotag approach in Pvalb-Cre mice, we profiled the translatome of DS PV interneurons and identified over 2,700 transcripts significantly enriched (fold-change > 1.5) in this population. Our data validate established PV markers and reveal a distinct molecular signature of DS PV neurons compared to PV interneurons from the nucleus accumbens. Gene ontology analyses highlight prominent expression of genes related to extracellular matrix components, cell adhesion molecules, synaptic organization, ion channels, and neurotransmitter receptors, particularly those mediating glutamatergic and GABAergic signaling. Notably, perineuronal net markers were robustly expressed in DS PV interneurons and confirmed by immunofluorescence. Transcriptomic analysis of DS PV neurons following repeated d-amphetamine exposure identified Gm20683 as the only differentially expressed transcript between treated groups. Furthermore, RNAseq analysis of mice subjected to an operant behavior paradigm with two types of food reward (high-palatable diet or standard chow) identified over 1,000 and 100 genes enriched in DS PV neurons from standard and high-palatable masters, respectively. These findings provide a comprehensive molecular profile of DS PV interneurons, distinguishing them from other striatal PV populations, and reveal specific gene expression changes associated with psychostimulant exposure and reward-driven behaviors. Our findings deepen insight into the molecular mechanisms of PV interneuron activity in striatal circuits and their potential roles in neuropsychiatric, motor and reward-related disorders.

Tumor heterogeneity is a major determinant of tumor progression and therapeutic resistance, yet the contribution of metabolism to intratumoral heterogeneity still remains poorly explored. Here, we find that pyruvate dehydrogenase kinase-1 (Pdk1) expression defines metabolically distinct cancer cell populations in colorectal tumors. Image-based spatial single-cell phenotyping shows that Pdk1 ^high cells are associated with tumor progression in orthotopic models of colorectal cancer (CRC). Genetic ablation experiments demonstrate the role of Pdk1 ^high cells in tumor growth, 5-fluorouracil chemoresistance and tumor relapse. Mechanistically, we identify a link between Pdk1-driven metabolic states and specific cell phenotypes, where Pdk1 ^high cancer cells exhibit an EMT, stem cell-like phenotype characterized by increased interferon (IFN) signaling. Mitochondrial remodeling in Pdk1 ^high cells leads to the release of mitochondrial DNA to the cytosol and activation of IFN pathways, promoting Pdk1-driven phenotypes. Inhibition of IFN signaling impairs the tumorigenic and aggressive features of Pdk1 ^high cancer cells, thus establishing a functional connection between metabolic heterogeneity, cell-intrinsic IFN signaling and aggressive CRC.

The transcriptomic interaction between altered gravity and innate immunity remains largely unexplored. In this study, we established a novel dual-stress model combining 3 g hypergravity with lipopolysaccharide (LPS) immune challenge in 5 days post-fertilization (dpf) zebrafish ( Danio rerio ) larvae. RNA sequencing revealed that exposure to hypergravity alone induced no differentially expressed genes (DEGs), indicating a remarkable transcriptional resilience. In contrast, the addition of an immune challenge under hypergravity conditions triggered a substantial transcriptomic response involving 2,706 DEGs. Functional enrichment analyses identified significant alterations in pathways related to immune function, development, and circadian regulation. Targeted qPCR analyses further validated the expression patterns of selected genes. These findings suggest that while zebrafish larvae can effectively tolerate hypergravity alone, the combination of gravitational and immune stressors elicits profound molecular responses. This study provides new insights into the interplay between altered gravity and innate immunity using an animal model, contributing to future strategies aimed at safeguarding astronaut health and supporting space-based aquaculture systems.

Background: Glioblastoma (GBM) is a highly heterogeneous and vascularized malignancy in which the mesenchymal (MES) subtype is associated with poor prognosis, extensive macrophage infiltration and resistance to therapy. However, the signaling mechanisms integrating vascular remodeling with inflammatory tumor-macrophage crosstalk remain incompletely understood. Methods: We integrated magnetic resonance imaging-derived vascular phenotyping with transcriptomic analyses of human glioblastoma cohorts to identify molecular pathways associated with highly vascular tumors. Functional studies using glioblastoma cell lines, THP-1-derived macrophages and co-culture systems were performed to investigate the role of PI3K signaling in tumor-macrophage communication. Finally, an independent single-cell transcriptomic cohort of primary human glioblastoma was interrogated to determine whether the identified inflammatory programs were conserved in malignant cells from patient tumors. Results: Integrated imaging-transcriptomic analyses identified highly vascular glioblastomas as tumors enriched for the MES subtype, increased macrophage infiltration and activation of PI3K-associated signaling. Pharmacological inhibition of PI3K reduced the expression of macrophage-recruiting cytokines and impaired the ability of glioblastoma cells to educate macrophages toward an immunosuppressive phenotype. Reciprocally, tumor-educated macrophages enhanced inflammatory signaling, immune checkpoint expression and migratory capacity in glioblastoma cells, whereas IL-6 blockade attenuated these effects, identifying IL-6 as a key mediator of this bidirectional communication. To determine whether these inflammatory programs were conserved in human disease, we analyzed an independent single-cell transcriptomic dataset of primary glioblastomas. MES-like malignant cells exhibited the strongest inflammatory transcriptional programs among the four malignant transcriptional states, including higher NF-κB activation program scores and tumor-macrophage communication signature scores. At the tumor level, MES-like enrichment was positively associated with higher inflammatory program activity, supporting the clinical relevance of the proposed signaling axis. Conclusions: Together, our findings identify PI3K signaling as a central regulator integrating vascular remodeling with inflammatory tumor-macrophage communication in mesenchymal glioblastoma. These results provide a mechanistic framework linking PI3K signaling, macrophage education and the MES phenotype, and provide a rationale for therapeutic strategies aimed at disrupting inflammatory signaling within the glioblastoma microenvironment.

Triple-negative breast cancer (TNBC) is characterized by the absence of estrogen receptor (ER), progesterone receptor (PR), and HER2 expression on tumor cells. Compared to other breast cancer subty...