Biology subjects

Nichols, D. S.

Publications and source records attributed to Nichols, D. S..

8 recordsLinked to original sources

bioRxiv2026

Ethyl-iophenoxic acid as a serum biomarker for marsupial species in oral bait trials

Ethyl-iophenoxic acid (Et-IPA) is widely recognized as a useful biomarker to confirm oral bait consumption in eutherian species. In historical studies on marsupials, Et-IPA was rapidly eliminated from brushtail possums (Trichosurus vulpecula) and swamp wallabies (Wallabia bicolor) suggesting limited use for marsupial species. However, a 1 mg oral dose of Et-IPA was detectable in the marsupial Tasmanian devils (Sarcophilus harrisii) for [≥] 56 days suggesting the biomarker can be used in a devil bait vaccine program. To assess Et-IPA marking in off-target marsupials that may consume baits, we administered 1 mg oral doses of Et-IPA to brushtail possums, forester kangaroos (Macropus giganteus tasmaniensis), spotted-tailed quolls (Dasyurus maculatus) and eastern quolls (Dasyurus viverrinus). Liquid chromatography with tandem mass spectrometry was used to detect and quantify serum Et-IPA. Et-IPA was detected in the serum on day 2 but was not detected by day 14 in any of the species tested, including the two quoll species which are in the same carnivorous Dasyuridae family as the devils. The rapid elimination of Et-IPA in the marsupials included in this study suggests it is not useful as a biomarker for these species. Furthermore, rapid elimination in the kangaroos and possums suggests that Et-IPA is unlikely to accumulate in the food chain following distribution of Et-IPA-marked oral bait vaccines for Tasmanian devils. Short summary for non-expertsA recent study in Tasmanian devils (Sarcophilus harrisii) challenged the concept that ethyl iophenoxic acid (Et-IPA) is not a useful serum biomarker for marsupials. Using the same sensitive liquid chromatography-tandem mass spectrometry method we detected serum Et-IPA in four marsupial species on day two post-ingestion but by day 14, serum Et-IPA was undetectable. These findings indicate that Et-IPA is an unsuitable biomarker for these species and suggest that Et-IPA from devil bait vaccines is unlikely to bioaccumulate in the Tasmanian environment.

zoology↗

bioRxiv2025

Sustained Yap/Taz activation promotes aberrant alveolar epithelial cell differentiation and drives persistent fibrotic remodeling

YAP/TAZ signaling is required for initiation of lung alveolar repair, yet previous studies in idiopathic pulmonary fibrosis (IPF) predicted increased YAP/TAZ signaling in alveolar epithelial cells (AECs). We investigated whether persistent YAP/TAZ AEC signaling contributes to failed epithelial repair and persistent fibrotic remodeling. In IPF lungs, we identified increased YAP+/TAZ+ AECs and increased expression of YAP/TAZ transcriptional targets compared to donor control lungs. In human lung organoids, pharmacological YAP/TAZ activation resulted in phenotype shifts of AECs into aberrant transitional states. In mice with Yap/Taz activation (YTactive) resulting from deletion of Hippo-kinases Stk3/4 in alveolar-type 2 (AT2) cells, resulted in persistent fibrotic remodeling at 28- and 56-days post-bleomycin injury. Gene promoter activity associated with transitional cell markers (Krt19, Hopx, and Runx2) was increased in YTactive AT2 cells. Immunofluorescent staining showed a loss of AT2 associated Cebpa and increased Krt19 in YTactive lineage traced AT2 cells 28 days post-injury. Inhibition of Yap/Taz using Verteporfin resulted in improved lung repair in YTactive mouse lungs, including increased Cebpa and decreased Krt19+ transitional cells. These findings demonstrate sustained Yap/Taz activation drives abnormal alveolar repair and persistent fibrotic remodeling. Blocking aberrant persistent Yap/Taz activity promotes adaptive repair and has potential as a therapeutic strategy for PF.

molecular biology↗

bioRxiv2023

Image-based spatial transcriptomics identifies molecular niche dysregulation associated with distal lung remodeling in pulmonary fibrosis

The human lung is structurally complex, with a diversity of specialized epithelial, stromal and immune cells playing specific functional roles in anatomically distinct locations, and large-scale changes in the structure and cellular makeup of this distal lung is a hallmark of pulmonary fibrosis (PF) and other progressive chronic lung diseases. Single-cell transcriptomic studies have revealed numerous disease-emergent/enriched cell types/states in PF lungs, but the spatial contexts wherein these cells contribute to disease pathogenesis has remained uncertain. Using sub-cellular resolution image-based spatial transcriptomics, we analyzed the gene expression of more than 1 million cells from 19 unique lungs. Through complementary cell-based and innovative cell-agnostic analyses, we characterized the localization of PF-emergent cell-types, established the cellular and molecular basis of classical PF histopathologic disease features, and identified a diversity of distinct molecularly-defined spatial niches in control and PF lungs. Using machine-learning and trajectory analysis methods to segment and rank airspaces on a gradient from normal to most severely remodeled, we identified a sequence of compositional and molecular changes that associate with progressive distal lung pathology, beginning with alveolar epithelial dysregulation and culminating with changes in macrophage polarization. Together, these results provide a unique, spatially-resolved characterization of the cellular and molecular programs of PF and control lungs, provide new insights into the heterogeneous pathobiology of PF, and establish analytical approaches which should be broadly applicable to other imaging-based spatial transcriptomic studies.

genomics↗

bioRxiv2023

Epithelial Yap/Taz are required for functional alveolar regeneration following acute lung injury

A hallmark of idiopathic pulmonary fibrosis (IPF) and other interstitial lung diseases is dysregulated repair of the alveolar epithelium. The Hippo pathway effector transcription factors YAP and TAZ have been implicated as essential for type 1 and type 2 alveolar epithelial cell (AT1 and AT2) differentiation in the developing lung, yet aberrant activation of YAP/TAZ is a prominent feature of the dysregulated alveolar epithelium in IPF. In these studies, we sought to define the functional role of YAP/TAZ activity during alveolar regeneration. We demonstrate that Yap and Taz are normally activated in AT2 cells shortly after injury, and deletion of Yap/Taz in AT2 cells led to pathologic alveolar remodeling, failure of AT2 to AT1 cell differentiation, increased collagen deposition, exaggerated neutrophilic inflammation, and increased mortality following injury induced by a single dose of bleomycin. Loss of Yap/Taz activity prior to a LPS injury prevented AT1 cell regeneration, led to intra-alveolar collagen deposition, and resulted in persistent innate inflammation. Together these findings establish that AT2 cell Yap/Taz activity is essential for functional alveolar epithelial repair and prevention of fibrotic remodeling.

cell biology↗

bioRxiv2023

Repetitive Sulfur Dioxide Exposure in Mice Models Post-Deployment Respiratory Syndrome

Soldiers deployed to Iraq and Afghanistan have a higher prevalence of respiratory symptoms than non-deployed military personnel and some have been shown to have a constellation of findings on lung biopsy termed post-deployment respiratory syndrome (PDRS). Since many of the deployers in this cohort reported exposure to sulfur dioxide (SO2), we developed a model of repetitive exposure to SO2 in mice that phenocopies many aspects of PDRS, including adaptive immune activation, airway wall remodeling, and pulmonary vascular disease (PVD). Although abnormalities in small airways were not sufficient to alter lung mechanics, PVD was associated with the development of pulmonary hypertension and reduced exercise tolerance in SO2 exposed mice. Further, we used pharmacologic and genetic approaches to demonstrate a critical role for oxidative stress and isolevuglandins in mediating PVD in this model. In summary, our results indicate that repetitive SO2 exposure recapitulates many aspects of PDRS and that oxidative stress may mediate PVD in this model, which may be helpful for future mechanistic studies examining the relationship between inhaled irritants, PVD, and PDRS.

pathology↗

bioRxiv2021

Ethyl-Iophenoxic acid as a serum marker for oral baiting of carnivorous marsupials

ContextEthyl-Iophenoxic acid (Et-IPA) has been widely used as a bait biomarker to determine oral bait consumption by vertebrate wildlife species. Oral bait vaccines have been delivered to numerous wildlife species to protect them from disease. The Tasmanian devil (Sarcophilis harrisii), the largest extant carnivorous marsupial species, is threatened by the transmissible cancers known as devil facial tumour disease (DFTD). Development of a protective DFTD vaccine is underway, and an oral bait has been proposed to deliver the vaccine in the wild. The bait delivery system requires a biomarker that can be detected for several months post-consumption in Tasmanian devils. AimTo determine the suitability of Et-IPA as a bait biomarker in the Tasmanian devil. MethodTwo Tasmanian devils were fed 50 mg Et-IPA (4.5 to 7.1 mg Et-IPA/kg bodyweight). Liquid chromatography with tandem mass spectrometry (LC-MS/-MS) was used to directly measure Et-IPA in baseline serum samples and samples collected on days 1, 14, 26 and 56 post-baiting. Key resultBoth devils retained serum Et-IPA concentrations at two orders of magnitude above negative control sera when this study concluded. ConclusionsEt-IPA is a useful bait biomarker for Tasmanian devils and can be included in future DFTD bait vaccine field trials to determine bait vaccine uptake.

zoology↗

bioRxiv2020

The role of CLV signalling in the negative regulation of mycorrhizal colonisation and nitrogen response of tomato

Plants form mutualistic nutrient acquiring symbioses with microbes, including arbuscular mycorrhizal fungi. The formation of these symbioses is costly and plants employ a negative feedback loop termed autoregulation of mycorrhizae (AOM) to limit arbuscular mycorrhizae (AM) formation. We provide evidence for the role of one leucine-rich-repeat receptor like kinase (FAB), a hydroxyproline O-arabinosyltransferase enzyme (FIN) and additional evidence for one receptor like protein (SlCLV2) in the negative regulation of AM formation in tomato. Reciprocal grafting experiments suggest that the FAB gene acts locally in the root, while the SlCLV2 gene may act in both the root and the shoot. External nutrients including phosphate and nitrate can also strongly suppress AM formation. We found that FAB and FIN are required for nitrate suppression of AM but are not required for the powerful suppression of AM colonisation by phosphate. This parallels some of the roles of legume homologs in the autoregulation of the more recently evolved symbioses with nitrogen-fixing bacteria leading to nodulation. This deep homology in the symbiotic role of these genes suggests that in addition to the early signalling events that lead to the establishment of AM and nodulation, the autoregulation pathway might also be considered part of the common symbiotic toolkit that enabled plants to form beneficial symbioses. HighlightWe describe the role of CLV signalling elements in the negative regulation of arbuscular mycorrhizal symbioses of tomato, including influencing nitrate but not phosphate suppression of mycorrhizal colonisation.

plant biology↗

bioRxiv2020

Age-related expression of SARS-CoV-2 priming protease TMPRSS2 in the developing lung

The SARS-CoV-2 novel coronavirus global pandemic (COVID-19) has led to millions of cases and hundreds of thousands of deaths around the globe. While the elderly appear at high risk for severe disease, hospitalizations and deaths due to SARS-CoV-2 among children have been relatively rare. Integrating single-cell RNA sequencing (scRNA-seq) of the developing mouse lung with temporally-resolved RNA-in-situ hybridization (ISH) in mouse and human lung tissue, we found that expression of SARS-CoV-2 Spike protein primer TMPRSS2 was highest in ciliated cells and type I alveolar epithelial cells (AT1), and TMPRSS2 expression was increased with aging in mice and humans. Analysis of autopsy tissue from fatal COVID-19 cases revealed SARS-CoV-2 RNA was detected most frequently in ciliated and secretory cells in the airway epithelium and AT1 cells in the peripheral lung. SARS-CoV-2 RNA was highly colocalized in cells expressing TMPRSS2. Together, these data demonstrate the cellular spectrum infected by SARS-CoV-2 in the lung epithelium, and suggest that developmental regulation of TMPRSS2 may underlie the relative protection of infants and children from severe respiratory illness.

developmental biology↗