Organoid formation is driven by poorly understood intrinsic cellular properties and transcriptional programs that govern plasticity and differentiation. Deciphering these regulatory networks is essential for understanding normal tissue homeostasis and tumor initiation. Using a 3D organotypic model, which better recapitulates cell‐matrix interactions and biochemical cues, we performed a miRNA‐based screening strategy to identify key regulators of organoid initiation from human primary mammary epithelial cells. Our findings reveal that miR‐106a‐3p acts as a central modulator of mammary epithelial plasticity, enriching for stem/progenitor‐like cells (CD44 high /CD24 low phenotype), driving organoid expansion, fostering K14 + /K19 + lineage intermixing, and promoting branching morphogenesis characteristic of early ductal development. Further analysis revealed a core transcriptional network involving CBFB, NF‐YA, GATA3, and REST, which supports organoid‐forming potential. This regulatory program also induces a hybrid epithelial–mesenchymal transition (EMT) state, enhancing cellular plasticity while preserving organoid structural integrity. Extending these findings to cancer, we demonstrate that enforced expression of miR‐106a‐3p significantly increases tumoroid formation, suggesting that the tumor microenvironment, as modeled by 3D culture, promotes miR‐106a‐3p expression and functional relevance in tumorigenic processes. Collectively, these data indicate that miR‐106a‐3p drives a transient expansion of progenitor‐like states and orchestrates transcriptional reprogramming during organoid initiation, with broader implications for breast tissue homeostasis and pathophysiological remodeling in cancer.

Anterior Gradient 2 (AGR2) is an endoplasmic reticulum (ER)-resident protein that belongs to the protein disulphide isomerase (PDI) family, and whose expression and secretion are induced by stress. Extracellular (secreted) AGR2 has been proposed as a marker of ER stress-related proteostasis alterations. Cancer cells frequently overexpress intracellular AGR2 (iAGR2) and secrete extracellular AGR2 (eAGR2). These features are associated with tumour progression and may serve as potential biomarkers in epithelial ovarian cancer (EOC). To investigate the roles of both iAGR2 and eAGR2 in EOC, we first generated EOC cells overexpressing iAGR2 and secreting eAGR2. Antibodies blocking eAGR2 reduced the proliferation and migration of these overexpressing cells. Concurrently, supplementation of parental cells with recombinant eAGR2 partially rescued these properties, further supporting a functional extracellular role for AGR2 in EOC. Quantitative proteomics, complemented by analysis of the TCGA database, revealed that eAGR2 modulated the expression of proteins involved in autophagy. This suggests that eAGR2-induced signalling may enhance catabolic activity under stress conditions, thereby increasing nutrient availability and, in turn, facilitating protein synthesis. This was reflected in the increased translational activity observed in AGR2-overexpressing and eAGR2-stimulated cells. Our results highlight two distinct, compartmentalised roles for AGR2. Specifically, iAGR2 acts as an ER-resident PDI, enhancing protein folding and ER quality control. In a complementary manner, eAGR2 functions as a metabolic regulator that may relieve constraints on tumour cell aggressiveness by maintaining autophagic flux and promoting protein synthesis. Overall, these findings support a dual-compartment model in which iAGR2 couples ER proteostasis with the metabolic and translational stimulation mediated by eAGR2.

Microplastics and nanoplastics, collectively termed MNPs, are ubiquitous environmental pollutants that display diverse shapes, sizes, and polymer compositions. Although the biological effects of pristine microspheres at high concentrations have been widely studied, less is known about the immunotoxicological effects of environmentally relevant MNPs with irregular shapes and heterogeneous sizes (I-MNPs) at lower exposure levels. To address this gap, we leveraged the amphibian Xenopus laevis (X. laevis) as a comparative vertebrate model. Fully aquatic tadpoles are particularly well suited for studying waterborne pollutants because their post-embryonic development, including immune system maturation, occurs externally without maternal protection. Moreover, X. laevis shares a high degree of developmental and immunological conservation with humans. Using extensively characterized Nile Red-labeled polyethylene terephthalate (PET) I-MNPs, we found that waterborne exposure at concentrations as low as 0.1 μg/mL (580 particles) resulted in rapid accumulation within the intestine, blood, liver, and kidneys within 24 h. Chronic exposure (1 month) to PET I-MNPs at concentrations of 1 μg/mL (5,800 particles/mL) and 10 μg/mL (5.8*104 particles/mL) impaired macrophage function, weakened antiviral immunity, and reduced resistance to ranavirus (FV3) infection without inducing overt inflammation. Likewise, oral ingestion of environmentally relevant PET I-MNP doses similarly compromised macrophage function and antiviral defenses. Finally, we demonstrated that PET I-MNPs were efficiently internalized by macrophages in vivo and persisted for at least one week. Together, these findings identify macrophages as a key cellular target of environmentally relevant microplastic exposure and establish X. laevis as a powerful model for investigating the developmental immunotoxicity of plastic pollutants.​

Non-tuberculosis mycobacteria M. abscessus (Mab) is an opportunistic pathogen increasingly causing diseases in humans, especially patients with immunocompromised conditions. We have developed the amphibian Xenopus as a comparative experimental organism to investigate pathogenesis and host resistance to Mab relevant for human health. We focused on a novel putative secondary metabolite pathway encoded in a gene cluster spanning MAB_0284c to 0305 that is related to Streptomyces pathways producing the secondary metabolites streptonigrin and nybomycin. We constructed an in-frame deletion of the MAB_0295 (phzC) gene and tested it in Xenopus tadpoles. We have shown that tadpoles, which have functional lungs and T cells, can serve as a reliable model for persistent Mab infection and pathogenesis. Our results suggests that tadpoles intraperitoneally infected with the ?phzC mutant exhibit reduced transcript levels of several pro-inflammatory cytokines (Il1b, tnfa, inos, ifng) in the liver and lungs as compared with WT Mab. Moreover, tail wound inoculation assay in tadpoles by intravital confocal microscopy reveals an impaired macrophage recruitment and decreased macrophage infection by ?phzC mutants compared to WT bacteria. These data underline the usefulness of Xenopus tadpoles as a novel model to identify genetic determinants of Mab immune-pathogenesis and suggests a role for this novel and uncharacterized pathway in Mab immune-pathogenesis. This study was funded by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health (R24-AI059830; R21 5R21AI166114) Veterinary and Comparative Immunology (VET)

The amphibian Xenopus immune system shares fundamental similarities with that of humans, making it a sensitive and reliable model for studying the impact of environmental toxicants on the developing immune system. Both species possess innate and adaptive immune components. Important signaling pathways and immunoregulatory cytokines are conserved between Xenopus and humans. Thus, the Xenopus model provides valuable insights into fundamental immunological processes and can help elucidate the impacts of environmental pollutants on human immune defenses against pathogens. Utilizing Xenopus as a relevant model for assessing human health implications, our research demonstrates that upon exposure to environmentally representative mildly weathered post-consumer polyethylene terephthalate microplastics (PET MPs), there is a rapid accumulation observed within tadpole intestine, liver, and kidneys, persisting over a week. This accumulation leads to compromised antiviral immunity and diminished resistance against viral infections. Preliminary data also suggest that PET MPs affect MHC-II expression and macrophage function. Ongoing investigations are delving into potential long-term immune deficits resulting from developmental exposure to PET MPs post-metamorphosis in adult frogs. These findings carry substantial significance, raising developmental immunotoxicity (DIT) concerns not only for aquatic vertebrates but also for human health. Institute of Allergy and Infectious Diseases (NIH/NIAID), as well as a Research Program Project P01ES035526 from the National Institute of Environmental Health Sciences,and a Pilot Project Grant from the Rochester Environmental Health Sciences Center (P30-ES01247). Veterinary and Comparative Immunology (VET)

The practice of clinical research is strictly regulated by law. During submission and review processes, compliance of such research with the laws enforced in the country where it was conducted is not always correctly filled in by the authors or verified by the editors. Here, we report a case of a single institution for which one may find hundreds of publications with seemingly relevant ethical concerns, along with 10 months of follow-up through contacts with the editors of these articles. We thus argue for a stricter control of ethical authorization by scientific editors and we call on publishers to cooperate to this end. We present an investigation of the ethics and legal aspects of 456 studies published by the IHU-MI (Institut Hospitalo-Universitaire Méditerranée Infection) in Marseille, France. We identified a wide range of issues with the stated research authorization and ethics of the published studies with respect to the Institutional Review Board and the approval presented. Among the studies investigated, 248 were conducted with the same ethics approval number, even though the subjects, samples, and countries of investigation were different. Thirty-nine (39) did not even contain a reference to the ethics approval number while they present research on human beings. We thus contacted the journals that published these articles and provide their responses to our concerns. It should be noted that, since our investigation and reporting to journals, PLOS has issued expressions of concerns for several publications we analyze here. This case presents an investigation of the veracity of ethical approval, and more than 10 months of follow-up by independent researchers. We call for stricter control and cooperation in handling of these cases, including editorial requirement to upload ethical approval documents, guidelines from COPE to address such ethical concerns, and transparent editorial policies and timelines to answer such concerns. All supplementary materials are available.

Unlike conventional T cells, which express a highly diverse repertoire of dimeric αβ T-cell receptors (TCRs) restricted by classical, polymorphic MHC class I molecules (MHC-Ia), a distinct group of T cells—collectively termed “innate-like T (iT) cells”—exhibits limited TCR diversity and depends instead on nonclassical, nonpolymorphic MHC class I molecules (MHC-Ib) for their development and function. While mounting evidence supports the role of iT cells as pivotal regulators and effectors in both innate and adaptive immune responses, many aspects of their biology remain incompletely understood. In humans, iT cells represent a significant fraction of the total T cell population, and evolutionarily conserved subsets have also been identified in other mammals and amphibians. Moreover, the expanding catalog of nonpolymorphic MHC-Ib genes and lineages—distinct from polymorphic MHC-Ia genes—across jawed vertebrate genomes suggests a broader and potentially more integral role for MHC-Ib molecules in T cell function and immune surveillance. In this review, we explore the immunological significance of MHC-Ib molecules and iT cells through an evolutionary lens, highlighting recent advances that shed light on their contributions to immune homeostasis and defense.

In natural environments, hosts frequently experience infections from multiple pathogenic species or strains, significantly influencing disease dynamics. Despite shared susceptible hosts and overlapping distributions, the impacts of coinfections by the two most threatening global amphibian pathogens, Batrachochytrium dendrobatidis (Bd) and Ranavirus (Rv), remain largely understudied. This study offers new insights into how simultaneous and sequential exposures to Bd and Rv influence disease outcomes in an amphibian host under controlled experimental conditions. Our findings reveal that the sequence and timing of pathogen exposure can lead to contrasting outcomes. Animals previously exposed to Rv displayed the highest mortality following Bd infection, whereas simultaneous exposure to both pathogens resulted in higher survival than single infections. These findings suggest that priority effects, driven by differences in the timing and order of pathogen exposure, can exacerbate disease severity in amphibian populations, particularly in communities with persistent, sublethal Rv infections. This study highlights the critical role of pathogen interactions in shaping disease dynamics and emphasizes the importance of integrating coinfections into wildlife disease management strategies to mitigate biodiversity crises in amphibians and beyond.

The possibilities of combining several degrees of freedom inside a unique material have recently been highlighted in their dynamics and proposed as information carriers in quantum devices where their cross-manipulation by external parameters such as electric and magnetic fields could enhance their functionalities. An emblematic example is that of electromagnons, spin-waves dressed with electric dipoles, that are fingerprints of multiferroics. Point-like objects have also been identified, which may take the form of excited quasiparticles. This is the case for magnetic monopoles, the exotic excitations of spin ices, that have been recently proposed to carry an electric dipole, although experimental evidences remain elusive. Presently, we investigate the electrical signature of a classical spin ice and a related compound that supports quantum fluctuations. Our in-depth study clearly attributes magneto-electricity to the correlated spin ice phase distinguishing it from extrinsic and single-ion effects. Our calculations show that the proposed model conferring magneto-electricity to monopoles is not sufficient, calling for higher-order contributions.