modeling-dysplastic-functional-lung-alveolar-repair-after-influenza

Modeling Dysplastic and Functional Lung Alveolar Repair after Influenza Infection

Viral infection causes both acute and long-term damage to the lung alveolus, the specialized tissue structure responsible for gas exchange between the ...

National Institutes of Health

Myelodysplastic syndromes (MDSs) are stem cell disorders with risk of transformation to acute myeloid leukemia (AML). Gene expression profiling reveals transcriptional expression of GLI1, of Hedgehog (Hh) signaling, in poor-risk MDS/AML. Using a murine model of MDS we demonstrated that constitutive Hh/Gli1 activation accelerated leukemic transformation and decreased overall survival. Hh/Gli1 activation resulted in clonal expansion of phenotypically defined granulocyte macrophage progenitors (GMPs) and acquisition of self-renewal potential in a non-self-renewing progenitor compartment. Transcriptome analysis of GMPs revealed enrichment in gene signatures of self-renewal pathways, operating via direct Gli1 activation. Using human cell lines we demonstrated that in addition to canonical Hh signaling, GLI1 is activated in a Smoothened-independent manner. GLI1 knockdown or inhibition with GANT61 resulted in decreased proliferation and clonogenic potential. Our data suggest that GLI1 activation is frequent in MDS during disease progression and inhibition of GLI1 is an attractive therapeutic target for a subset of patients.

Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity.

Admixed populations are a resource to study the global genetic architecture of complex phenotypes, which is critical, considering that non-European populations are severely underrepresented in genomic studies. Here, we study the genetic architecture of BMI in children, young adults, and elderly individuals from the admixed population of Brazil.

Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes.

We introduce a phylogeny-aware framework for predicting linear B-cell epitope (LBCE)-containing regions within proteins. Our approach leverages evolutionary information by using a taxonomic scaffold to build models trained on hierarchically structured data. The resulting models present performance equivalent or superior to generalist methods, despite using simpler features and a fraction of the data volume required by current state-of-the-art predictors. This allows the utilization of available data for major pathogen lineages to facilitate the prediction of LBCEs for emerging infectious agents. We demonstrate the efficacy of our approach by predicting new LBCEs in the monkeypox (MPXV) and vaccinia viruses. Experimental validation of selected targets using sera from infected patients confirms the presence of LBCEs, including candidates for the differential serodiagnosis of recent MPXV infections. These results point to the use of phylogeny-aware predictors as a useful strategy to facilitate the targeted development of immunodiagnostic tools.

Phylogeny-aware linear B-cell epitope predictor detects targets associated with immune response to orthopoxviruses.

Neuromesodermal competent progenitors (NMCs) are located in the caudal epiblast near the node and primitive streak and give rise to spinal cord and somitic mesoderm during trunk and tail elongation. Their self-renewal depends on an autoregulatory loop involving Wnt3a and Fgf signaling, and the Tbxt and Cdx transcription factors, but the mechanisms underlying loop formation and the establishment of the niche are poorly understood. Here, we identify the zinc-finger transcription factors  and  () as essential regulators of NMC maintenance.  expression is controlled by Wnt, Fgf and retinoic acid signaling, and they cooperate with Tbxt, Tcf7 and Cdx2 to sustain a robust autoregulatory network that promotes high Wnt/Fgf and low retinoic acid activity in the niche. These factors bind a novel enhancer essential for  expression and feedback-loop integrity. Mechanistically, Sp5/8 regulate the dynamic exchange of activating and repressive Tcf complexes at Wnt-responsive enhancers. Our findings define a transcriptional module centered on Sp5/8 that stabilizes niche signaling and transcriptional circuitry essential for NMC fate decisions and trunk development.

Article	Year
Hedgehog/GLI1 activation leads to leukemic transformation of myelodysplastic syndrome in vivo and GLI1 inhibition results in antitumor activity. Oncogene\| PubMed ID: 30171262	2019
Admixture/fine-mapping in Brazilians reveals a West African associated potential regulatory variant (rs114066381) with a strong female-specific effect on body mass and fat mass indexes. International journal of obesity (2005)\| PubMed ID: 33633342	2021
Phylogeny-aware linear B-cell epitope predictor detects targets associated with immune response to orthopoxviruses. Briefings in bioinformatics\| PubMed ID: 39503522	2024
Sp Transcription Factors Establish the Signaling Environment in the Neuromesodermal Progenitor Niche During Axial Elongation. bioRxiv : the preprint server for biology\| PubMed ID: 40502200	2025

Francisco Lobo

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