Biology subjects

Salomonis, N.

Publications and source records attributed to Salomonis, N..

At least 19 recordsLinked to original sources

bioRxiv2026

A Conversational Multi-Agent AI System for Integrated Multi-Omics Analysis and Biomedical Discovery

Single-cell and spatial omics offer unprecedented opportunities to decipher the mechanisms of disease, however, this process requires teams of experts, iterative trial-and-error and reasoning across modalities. Here we present LungChat (https://chat.lungmap.net), a conversational system for integrated multi-omics analysis and biomedical discovery, deployed as a hierarchical multi-agent architecture in which a supervisor decomposes natural-language questions into parallel, tool-grounded tasks spanning single-cell and spatial analyses, literature and clinical-trial synthesis, and drug repurposing. To predict new therapeutics, LungChat implements Direction-Aware Repurposing and Targeting (DART) to distinguish perturbations that reverse disease transcriptional programs from those that reinforce them, at the cell-type level, for safety prediction. Controlled architecture ablations showed that hierarchical orchestration improved grounded abstention and token efficiency and preserved strong performance on complex multi-step tasks. In pulmonary disease case studies, LungChat independently prioritized saracatinib for IPF through drug-connectivity screening, followed by DART-based cell-type analysis; the same compound has been evaluated in the STOP-IPF clinical trial (NCT04598919). The system also recovered fluticasone propionate, an established COPD therapy, through a single orchestrated analysis. This tissue-agnostic system provides a blueprint for verifiable agentic AI systems that support reproducible scientific discovery.

bioinformatics↗

bioRxiv2026

Single nucleus RNA sequencing of juvenile dermatomyositis skeletal muscle identifies altered angiogenic signaling

Juvenile dermatomyositis (JDM) is a chronic multisystem vasculopathy and inflammatory myopathy characterized by proximal muscle weakness, distinct rash, and risk of complications such as calcinosis cutis, skin ulceration, and mortality. Molecular insight from diagnostic muscle biopsy histology is limited, and the mechanistic pathoetiology of JDM remains poorly defined. We used single nuclei transcriptomics to assess muscle samples from patients with newly diagnosed treatment-naive JDM. As a control, we assessed muscle samples from patients with congenital (nemaline) myopathy (CM), a non-inflammatory disorder. A total of 25,794 high quality nuclei were analyzed and clustered into various muscle-resident or infiltrating cellular populations. JDM tissue was characterized by an enriched interferon (IFN) response signature across endothelial, stromal, and immune cell compartments. Endothelial and perivascular populations showed increased inflammatory and angiogenic programs. Intercellular communication inference analysis identified dysregulated vascular endothelial growth factor (VEGF)-related signaling involving endothelial, stromal, and myonuclear populations as a possible mechanism for myonuclear-driven modulation of the muscle microvasculature. Spatial RNA in situ hybridization supported increased expression of selected IFN responsive and angiogenesis signaling genes in JDM tissue. Collectively, these data provide a cell type-resolved view of treatment-naive JDM muscle and highlight vascular and IFN pathways for follow-up in larger cohorts.

genomics↗

bioRxiv2025

Bone Marrow Adipokine Mediates Hematopoietic Regeneration and Stem Cell Fitness

Bone marrow (BM) hematopoietic stem cells (HSCs) are exquisitely sensitive to cues from the BM microenvironment (ME), which is critical for their engraftment and regeneration following myeloablative stress. Retinoic acid signaling, acting on both HSCs and niche cells, has emerged as a central regulator of this process. Among ME components, BM adipocytes (BMAs), which can comprise up to 45% of BM volume and expand dramatically during the pancytopenic phase after myeloablation, play a previously underappreciated role in hematopoietic recovery. Here, we identify retinoid X receptor (RXR) signaling in BMAs as a key regulator of the adipokine Resistin, which promotes HSC self-renewal and functional fitness by activating NF-{kappa}B signaling. Conditional loss of RXR in adiponectin-expressing cells suppressed Resistin production, resulting in reduced NF-{kappa}B activity in HSCs, impaired self-renewal, and defective multilineage hematopoietic regeneration. Functionally, in vivo Resistin neutralization impaired hematopoietic reconstitution, whereas supplementation with either monomeric or dimeric Resistin enhanced HSC self-renewal and long-term lympho-hematopoietic reconstitution in an NF-{kappa}B-dependent manner. Together, these findings establish BMA-derived Resistin as an RXR-dependent, critical extrinsic regulator of HSC self-renewal and regenerative hematopoiesis, underscoring its essential role in lympho-myeloid reconstitution after myeloablation. Disclosures: The authors declare no relevant conflicts of interest.

physiology↗

bioRxiv2025

Bridging the gap of late-gestation nephrogenesis using a non-human primate model

BackgroundHuman nephrogenesis is complete at 34-36 weeks gestation, with 60% of nephrons forming during the third trimester through lateral branch nephrogenesis (LBN). Currently, no mechanism exists for LBN as there are no late gestation human kidney transcriptional datasets. We hypothesized that a differentiated but dividing population of nephron progenitor cells (NPCs) would contribute to the amplification of nephrons in late gestation. We used the rhesus macaque, an established model of LBN, to help identify potential mechanisms. MethodsSingle-cell RNA-sequencing (scRNA-Seq) was performed on cortically-enriched fetal rhesus kidneys (n=9) from late second trimester and third trimester during LBN. This data was integrated with publicly available human scRNA-seq datasets from 8-18 weeks gestation kidneys (n=8) using state-of-the-art bioinformatics pipelines. Differentially expressed genes and ligand-receptor interactions were assessed and validated using RNAScopeTM on human and rhesus archival tissue. ResultsscRNA-Seq of 64,782 rhesus cells revealed 37 transcriptionally distinct cell populations, including 7,879 rhesus NPCs. Pseudotime analyses identified a late gestation-specific lineage branch of differentiated NPC in rhesus that was not observed in mid-gestation humans. Differential expression analyses identified increased SFRP1, FZD4, and TLE2 and decreased FZD7, SHISA2, SHISA3, and TLE4 within the late-gestation rhesus NPC compared to mid-gestation human NPC and increased SEMA3D within the rhesus ureteric bud (UB) tip, suggesting a compositional shift in WNT and SEMA signaling components within the naive NPC population during LBN. ConclusionThe rhesus macaque uniquely enables molecular studies of late-gestation primate nephrogenesis. Our study suggests the hypothesis that a transitional state of self-renewing NPCs supported by compositional shifts in key pathways may underlie the switch from branching phase nephrogenesis to lateral branch nephrogenesis and support ongoing nephron formation in late gestation. Translational statementNo transcriptional data exists for the late-gestation human kidney, during which 60% of the nephron endowment is formed through a primate-specific process called lateral branch nephrogenesis (LBN). In this study, we used single-cell RNA sequencing the late gestation rhesus macaque as a model for this developmental stage. Our findings suggest a potential mechanism for LBN, in which a transitional state of self-renewing nephron progenitor cells (NPCs) is supported by compositional shifts in key pathways, allowing for continued nephron formation in late gestation.

developmental biology↗

bioRxiv2024

Genotype-immunophenotype relationships in NPM1-mutant AML clonal evolution uncovered by single cell multiomic analysis

Acute myeloid leukemia (AML) is a multi-clonal disease, existing as a milieu of clones with unique but related genotypes as initiating clones acquire subsequent mutations. However, bulk sequencing cannot fully capture AML clonal architecture or the clonal evolution that occurs as patients undergo therapy. To interrogate clonal evolution, we performed simultaneous single cell molecular profiling and immunophenotyping on 43 samples from 32 NPM1-mutant AML patients at different stages of disease. Here we show that diagnosis and relapsed AML samples display similar clonal architecture patterns, but signaling mutations can drive increased clonal diversity specifically at relapse. We uncovered unique genotype-immunophenotype relationships regardless of disease state, suggesting leukemic lineage trajectories can be hard-wired by the mutations present. Analysis of longitudinal samples from patients on therapy identified dynamic clonal, transcriptomic, and immunophenotypic changes. Our studies provide resolved understanding of leukemic clonal evolution and the relationships between genotype and cell state in leukemia biology.

cancer biology↗

bioRxiv2024

m6A-mediated epi-transcriptomic dysregulation underlies synaptic dysfunction in fragile X syndrome

Fragile X syndrome (FXS), the leading genetic cause of intellectual disability, arises from FMR1 gene silencing and loss of the FMRP protein. N6-methyladenosine (m6A) is a prevalent mRNA modification essential for post-transcriptional regulation. FMRP is known to bind to and regulate the stability of m6A-containing transcripts. However, how loss of FMRP impacts on transcriptome-wide m6A modifications in FXS patients remains unknown. To answer this question, we generated cortical neurons differentiated from induced pluripotent stem cells (iPSC) derived from healthy subjects and FXS patients. In electrophysiology recordings, we validated that synaptic and neuronal network defects in iPSC-derived FXS neurons corresponded to the clinical EEG data of the patients from which the corresponding iPSC line was derived. In analysis of transcriptome-wide methylation, we show that FMRP deficiency led to increased translation of m6A writers, resulting in hypermethylation that primarily affecting synapse-associated transcripts and increased mRNA decay. Conversely, in the presence of an m6A writer inhibitor, synaptic defects in FXS neurons were rescued. Taken together, our findings uncover that an FMRP-dependent epi-transcriptomic mechanism contributes to FXS pathogenesis by disrupting m6A modifications in FXS, suggesting a promising avenue for m6A- targeted therapies.

neuroscience↗

bioRxiv2024

The chromatin remodeler DEK promotes proliferation of mammary epithelium and is associated with H3K27me3 epigenetic modifications

The DEK chromatin remodeling protein was previously shown to confer oncogenic phenotypes to human and mouse mammary epithelial cells using in vitro and knockout mouse models. However, its functional role in normal mammary gland epithelium remained unexplored. We developed two novel mouse models to study the role of Dek in normal mammary gland biology in vivo. Mammary gland-specific Dek over-expression in mice resulted in hyperproliferation of cells that visually resembled alveolar cells, and a transcriptional profile that indicated increased expression of cell cycle, mammary stem/progenitor, and lactation-associated genes. Conversely, Dek knockout mice exhibited an alveologenesis or lactation defect, resulting in dramatically reduced pup survival. Analysis of previously published single-cell RNA-sequencing of mouse mammary glands revealed that Dek is most highly expressed in mammary stem cells and alveolar progenitor cells, and to a lesser extent in basal epithelial cells, supporting the observed phenotypes. Mechanistically, we discovered that Dek is a modifier of Ezh2 methyltransferase activity, upregulating the levels of histone H3 trimethylation on lysine 27 (H3K27me3) to control gene transcription. Combined, this work indicates that Dek promotes proliferation of mammary epithelial cells via cell cycle deregulation. Furthermore, we report a novel function for Dek in alveologenesis and histone H3 K27 trimethylation.

developmental biology↗

bioRxiv2024

Cholestasis alters polarization and suppressor function of hepatic regulatory T cells.

Fibrosing cholangiopathies, including biliary atresia and primary sclerosing cholangitis, involve immune-mediated bile duct epithelial injury and hepatic bile acid (BA) retention (cholestasis). Regulatory T-cells (Tregs) can prevent auto-reactive lymphocyte activation, yet the effects of BA on this CD4 lymphocyte subset are unknown. Gene regulatory networks for hepatic CD4 lymphocytes in a murine cholestasis model revealed Tregs are polarized to Th17 during cholestasis. Following bile duct ligation, Stat3 deletion in CD4 lymphocytes preserved hepatic Treg responses. While pharmacological reduction of hepatic BA in MDR2-/- mice prompted Treg expansion and diminished liver injury, this improvement subsided with Treg depletion. A cluster of patients diagnosed with biliary atresia showed both increased hepatic Treg responses and improved 2-year native liver survival, supporting that Tregs might protect against neonatal bile duct obstruction. Together, these findings suggest liver BA determine Treg function and should be considered as a therapeutic target to restore protective hepatic immune responses.

immunology↗

bioRxiv2024

Widespread variation in molecular interactions and regulatory properties among transcription factor isoforms

Most human Transcription factors (TFs) genes encode multiple protein isoforms differing in DNA binding domains, effector domains, or other protein regions. The global extent to which this results in functional differences between isoforms remains unknown. Here, we systematically compared 693 isoforms of 246 TF genes, assessing DNA binding, protein binding, transcriptional activation, subcellular localization, and condensate formation. Relative to reference isoforms, two-thirds of alternative TF isoforms exhibit differences in one or more molecular activities, which often could not be predicted from sequence. We observed two primary categories of alternative TF isoforms: "rewirers" and "negative regulators", both of which were associated with differentiation and cancer. Our results support a model wherein the relative expression levels of, and interactions involving, TF isoforms add an understudied layer of complexity to gene regulatory networks, demonstrating the importance of isoform-aware characterization of TF functions and providing a rich resource for further studies.

systems biology↗

bioRxiv2023

A potential acoustic role for CFTR ion channel in conductive hearing loss

Loss-of-function mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene cause cystic fibrosis (CF). The middle ear and eustachian tube could be adversely affected in CF. In this study, we provide evidence of the role of CFTR function in conductive hearing. We developed an in-situ model to determine CFTR dependent fluid secretion in the middle ear using native mouse auditory capsule. A unique middle ear-on-a-chip was developed to address the functional and molecular basis of conductive hearing impairment. Using single-cell transcriptomics, middle ear cell composition and the associated transcriptomic signature were compared between CF and WT groups. A specialized subset of epithelial cells expressed CFTR with an overlapping signature with secretory epithelial cells. Genes related to ciliogenesis, hearing and ossification were significantly altered in CF mice middle ear. Our data suggest that CF middle ear may be at higher risk for conductive hearing loss.

cell biology↗

bioRxiv2023

Temporal dynamics and genomic programming of plasma cell fates

Affinity-matured plasma cells (PCs) of varying lifespans are generated through a germinal center (GC) response. The developmental dynamics and genomic programs of antigen-specific PC precursors remain to be elucidated. Using a model antigen, we demonstrate biphasic generation of PC precursors, with those generating long-lived bone marrow PCs preferentially produced in the late phase of GC response. Clonal tracing using scRNA-seq+BCR-seq in spleen and bone marrow compartments, coupled with adoptive transfer experiments, reveal a novel PC transition state that gives rise to functionally competent PC precursors. The latter undergo clonal expansion, dependent on inducible expression of TIGIT. We propose a model for the proliferation and programming of precursors of long-lived PCs, based on extended antigen encounters followed by reduced antigen availability.

immunology↗

bioRxiv2023

Quantifying tumor specificity using Bayesian probabilistic modeling for drug target discovery and prioritization

In diseases such as cancer, the design of new therapeutic strategies requires extensive, costly, and unfortunately sometimes deadly testing to reveal life threatening "off target" effects. A crucial first step in predicting toxicity are analyses of normal RNA and protein tissue expression, which are now possible using comprehensive molecular tissue atlases. However, no standardized approaches exist for target prioritization, which instead rely on ad-hoc thresholds and manual inspection. Such issues are compounded, given that genomic and proteomic data detection sensitivity and accuracy are often problematic. Thus, quantifiable probabilistic scores for tumor specificity that address these challenges could enable the creation of new predictive models for combinatorial drug design and correlative analyses. Here, we propose a Bayesian Tumor Specificity (BayesTS) score that can naturally account for multiple independent forms of molecular evidence derving from both RNA-Seq and protein expression while preserving the uncertainty of the inference. We applied BayesTS to 24,905 human protein-coding genes across 3,644 normal samples (GTEx and TCGA) spanning 63 tissues. These analyses demonstrate the ability of BayesTS to accurately incorporate protein, RNA and tissue distribution evidence, while effectively capturing the uncertainty of these inferences. This approach prioritized well-established drug targets, while deemphasizing those which were later found to induce toxicity. BayesTS allows for the adjustment of tissue importance weights for tissues of interest, such as reproductive and physiologically dispensable tissues (e.g., tonsil, appendix), enabling clinically translatable prioritizations. Our results show that BayesTS can facilitate novel drug target discovery and can be easily generalized to unconventional molecular targets, such as splicing neoantigens. We provide the code and inferred tumor specificity predictions as a database available online (https://github.com/frankligy/BayesTS). We envision that the widespread adoption of BayesTS will facilitate improved target prioritization for oncology drug development, ultimately leading to the discovery of more effective and safer drugs. Code and Data AvailabilityThe BayesTS code and inferred tumor specificities are available at (https://github.com/frankligy/BayesTS), along with the scripts for reproducing the results in the study and instructions on retraining the model. The training data is available at Synapse (https://www.synapse.org/#!Synapse:syn51170082/files/).

bioinformatics↗

bioRxiv2022

Guided construction of single cell reference for human and mouse lung

Accurate cell type identification is a key and rate-limiting step in single cell data analysis. Single cell references with comprehensive cell types, reproducible and functional validated cell identities, and common nomenclatures are much needed by the research community to optimize automated cell type annotation and facilitate data integration, sharing, and collaboration. In the present study, we developed a novel computational pipeline to utilize the LungMAP CellCards as a dictionary to consolidate single-cell transcriptomic datasets of 104 human lungs and 17 mouse lung samples and constructed "LungMAP CellRef" and "LungMAP CellRef Seed" for both normal human and mouse lungs. "CellRef Seed" has an equivalent prediction power and produces consistent cell annotation as does "CellRef" but improves computational efficiency and simplifies its utilization for fast automated cell type annotation and online visualization. This atlas set incorporates 48 human and 40 mouse well-defined lung cell types catalogued from diverse anatomic locations and developmental time points. Using independent datasets, we demonstrated the utility of our CellRefs for automated cell type annotation analysis of both normal and disease lungs. User-friendly web interfaces were developed to support easy access and maximal utilization of the LungMAP CellRefs. LungMAP CellRefs are freely available to the pulmonary research community through fast interactive web interfaces to facilitate hypothesis generation, research discovery, and identification of cell type alterations in disease conditions.

bioinformatics↗

bioRxiv2022

CellDrift: Inferring Perturbation Responses in Temporally-Sampled Single Cell Data

Cells and tissues respond to perturbations in multiple ways that can be sensitively reflected in alterations of gene expression. Current approaches to finding and quantifying the effects of perturbations on cell-level responses over time disregard the temporal consistency of identifiable gene programs. To leverage the occurrence of these patterns for perturbation analyses, we developed CellDrift (https://github.com/KANG-BIOINFO/CellDrift), a generalized linear model-based functional data analysis method capable of identifying covarying temporal patterns of various cell types in response to perturbations. As compared to several other approaches, CellDrift demonstrated superior performance in the identification of temporally varied perturbation patterns and the ability to impute missing time points. We applied CellDrift to multiple longitudinal datasets, including COVID-19 disease progression and gastrointestinal tract development, and demonstrated its ability to identify specific gene programs associated with sequential biological processes, trajectories, and outcomes.

bioinformatics↗

bioRxiv2021

LungMAP Portal Ecosystem: Systems-Level Exploration of the Lung

An improved understanding of the human lung necessitates advanced systems models informed by an ever-increasing repertoire of molecular omics, cellular, imaging and pathological datasets. To centralize and standardize information across broad lung research efforts we expanded the LungMAP.net website into a gateway portal. This portal connects a broad-spectrum of research networks, bulk and single-cell multi-omics data and a diverse collection of image data that span mammalian lung development and disease. The data are standardized across species and technologies using harmonized data and metadata models that leverage recent advances including those from the Human Cell Atlas, diverse ontologies, and the LungMAP CellCards initiative. To cultivate future discoveries, we have aggregated a diverse collection of single-cell atlases for multiple species (human, rhesus, mouse), to enable consistent queries across technologies, cohorts, age, disease and drug treatment. These atlases are provided as independent and integrated queriable datasets, with an emphasis on dynamic visualization, figure generation and reference-based classification of user-provided datasets (Azimuth). As this resource grows, we intend to increase the breadth of available interactive interfaces, data portals and datasets from LungMAP and external research efforts.

systems biology↗

bioRxiv2021

Balance between protective and pathogenic immune responses to pneumonia in the neonatal lung enforced by gut microbiota.

While modern clinical practices like cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure, mirroring current clinical practices, interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system as assessed by single-cell proteomic and transcriptomic analyses of the pulmonary immune response. Early-life antibiotic exposure rendered newborn macaques susceptible to bacterial pneumonia, mediated by profound changes in neutrophil senescence, inflammatory signaling, and macrophage dysfunction. Pathogenic reprogramming of pulmonary immunity was reflected by a hyperinflammatory signature in all pulmonary immune cell subsets. Distinct patterns of immunoparalysis, including dysregulated antigen presentation in alveolar macrophages, impaired costimulatory function in T helper cells, and dysfunctional cytotoxic responses in natural killer (NK) cells, were coupled with a global loss of tissue-protective, homeostatic pathways in lungs of dysbiotic newborns. Fecal microbiota transfer corrected the broad immune maladaptations and protected against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity. Gut microbiota promote balance between pathways driving tissue repair and inflammatory responses, thereby leading to clinical recovery from infection in infants. One sentence summaryGut microbiota promote clinical recovery by reinforcing the balance between regenerative pathways driving tissue homeostasis and inflammatory responses limiting pathogens in infected neonatal lungs.

immunology↗

bioRxiv2021

Gain-of-function cardiomyopathic mutations in RBM20 rewire splicing regulation and re-distribute ribonucleoprotein aggregates within processing bodies

RNA binding motif protein 20 (RBM20) is a key regulator of alternative splicing in the heart, and its mutation leads to malignant dilated cardiomyopathy (DCM). To understand the mechanism of RBM20-associated DCM, we engineered isogenic human induced pluripotent stem cells (iPSCs) with heterozygous or homozygous DCM-associated missense mutations in RBM20 (R636S) as well as RBM20 knockout (KO) iPSCs. iPSC-derived engineered heart tissues made from these cell lines recapitulated contractile dysfunction of RBM20-associated DCM and revealed greater dysfunction with missense mutations than KO. Analysis of RBM20 RNA binding by eCLIP revealed a gain-of-function preference of mutant RBM20 for 3' UTR sequences that are shared with amyotrophic lateral sclerosis (ALS) and processing-body associated RNA binding proteins (FUS, DDX6). Deep RNA sequencing revealed that the RBM20 R636S mutant has unique gene, splicing, polyadenylation and circular RNA defects that differ from RBM20 KO, impacting distinct cardiac signaling pathways. Splicing defects specific to KO or R636S mutations were supported by data from R636S gene-edited pig hearts and eCLIP. Super-resolution microscopy verified that mutant RBM20 maintains limited nuclear localization potential; rather, the mutant protein associates with cytoplasmic processing bodies (DDX6) under basal conditions, and with stress granules (G3BP1) following acute stress. Taken together, our results highlight a novel pathogenic mechanism in cardiac disease through splicing-dependent and -independent pathways that are likely to mediate differential contractile phenotypes and stress-associated heart pathology.

cell biology↗

bioRxiv2021

A potent myeloid response is rapidly activated in the lungs of premature Rhesus macaques exposed to intra-uterine inflammation

Intrauterine inflammation/infection (IUI), which is present in up to 40% of premature births, leads to elevated levels of pro-inflammatory mediators and microbial products within the amniotic fluid, which come in close contact to fetal mucosae. Yet, knowledge on the fetal mucosal responses to IUI exposure remains limited. To address these questions, we used a non-human primate model of IUI, in which pregnant Rhesus macaques received intra-amniotic (IA) LPS, compared with IA saline. We found that IA LPS exposure induced a robust and rapid inflammation of the fetal lung, but not the intestine. This inflammatory response was characterized by high levels of pro-inflammatory cytokines in the lung and the alveolar wash, and a potent myeloid cell response, dominated by neutrophils and monocytes/macrophages. scRNAseq analyses of fetal lungs showed that the infiltrating (neutrophils and inflammatory monocytes) and the resident (alveolar and interstitial macrophages) myeloid cells exhibited transcriptional profiles consistent with exposure to TLR ligands, as well as to cytokines, notably IL-1 and TNF. However, blocking IL-1 signaling or TNF, alone or simultaneously by administering inhibitors intra-amniotically and subcutaneously to the dam only partially blunted fetal lung inflammation. Together, our novel data indicate that the fetal innate immune system can mount a rapid multi-factorial mucosal innate response to IUI, responding both to direct signaling by bacterial products and to indirect cytokine-mediated pathways of activation. These data thus provide more mechanistic insights into the association between IUI exposure and the post-natal lung morbidities of the premature infant.

immunology↗