Biology subjects

Deutsch, G.

Publications and source records attributed to Deutsch, G..

8 recordsLinked to original sources

bioRxiv2026

Lymphangiogenesis is Critical for Healing and Survival in a Murine Model of Laryngotracheal Injury

Objective: Lymphatic dysfunction has been implicated in exacerbating fibrosis in numerous diseases, yet the role of the lymphatic system in laryngotracheal injury has not previously been explored. This study aims to evaluate lymphatic vascular remodeling in a murine model of laryngotracheal stenosis (LTS) and determine how pharmacologic blockade of lymphangiogenesis impacts airway healing after mucosal injury. Methods: LTS was induced in C57BL6 mice using an established chemomechanical injury model. Lymphatic density was quantified using LYVE-1 immunohistochemistry. Mice were treated with the VEGFR-3-selective tyrosine kinase inhibitor SAR131675 to block lymphangiogenesis after injury. Outcomes assessed included survival, histopathology, immunohistochemistry, and Evans blue dye vascular leakage. Results: Laryngotracheal injury induced a substantial increase in subepithelial lymphatic vessel density concomitant with fibrotic remodeling. Pharmacologic inhibition of VEGFR-3 signaling with SAR131675 abrogated this lymphangiogenic response and resulted in markedly increased mortality, impaired epithelial repair with obstructive sloughing, increased edema, and persistent histopathologic evidence of tissue injury. A qualitative increase in pathologic fibrocellular remodeling was also observed, though with no measurable difference in lamina propria thickness. Conclusion: These findings establish lymphatic remodeling as an essential component of successful airway repair following mucosal injury. Lymphatic dysfunction is a common feature of known risk factors for LTS including diabetes, obesity, and prematurity, and can be exacerbated by positive pressure ventilation. Disruption of the lymphangiogenic response to airway injury may lead to stasis of pro-inflammatory factors that result in chronic inflammation, maladaptive remodeling, and pathologic tissue changes. The lymphatic vasculature is a viable target for future mechanistic study and potential therapeutic intervention following airway injury.

physiology↗

bioRxiv2026

Dissociable structural and molecular pathways of age-related change in sustained attention

Sustained attention, the capacity to maintain goal-directed attention over extended periods, declines with age but with substantial individual variability across cognitively unimpaired (CU) older adults. We sought to determine the contributions of microstructural deterioration of the superior longitudinal fasciculus (SLF), the principal white-matter tract coupling prefrontal and parietal nodes of the dorsal attention network, as well as markers of preclinical Alzheimers disease (AD) to individual differences in sustained attention in ageing. In 162 CU older adults (mean (SD) age = 73.0 (4.9), %F = 64.8) drawn from two Stanford ageing cohorts, we measured sustained attention using the gradual-onset Continuous Performance Task (gradCPT). Performance was indexed by a composite score (Att-Z) derived from discriminability (d') and response-time variability (RTV). We used diffusion MRI tractography to quantify SLF fractional anisotropy (FA) and mean diffusivity (MD) alongside two control tracts, the corticospinal tract (CST) and cingulum (CGC). NULISA multiplex plasma immunoassays were used to measured AD-related pathology (pTau-181, pTau-217), neuroaxonal injury (NfL), and astrocytic reactivity (GFAP; plasma subsample N = 146). Parallel mediation and commonality analyses tested whether structural and plasma biomarker pathways contribute independently to individual differences in sustained attention function. Older age was associated with lower Att-Z ({beta} = -0.315, p < 0.001). In simultaneous three-tract regression models, only SLF microstructure uniquely predicted Att-Z (FA: {beta} = +0.275, p < 0.001; MD: {beta} = -0.320, p < 0.001). SLF microstructure mediated the age-attention relationship (FA indirect {beta}unstandardised = -0.01, pboot <0.01, MD indirect {beta}unstandardised = -0.009 to -0.01, pboot <0.05). Plasma pTau-181 ({beta} = -0.212, pFDR < 0.03), pTau-217 ({beta} = -0.163, pFDR < 0.05), and NfL ({beta} = -0.156, pFDR < 0.05) were negatively associated with Att-Z and each mediated effects of age on performance (pTau-181 indirect {beta}unstandardised = -0.008, pboot < 0.01; pTau-217 indirect {beta}unstandardised= -0.006, pboot< 0.05; NfL indirect {beta}unstandardised = -0.011, pboot< 0.05), whereas GFAP showed no association with sustained attention in any model. SLF microstructure was negatively associated with age (FA {beta} = -0.207, p < 0.01; MD {beta} = +0.270, p < 0.001) but was not significantly associated with plasma biomarkers (all p > 0.10). In parallel mediation models, SLF microstructure and plasma pTau exhibited significant independent indirect effects on Att-Z (SLF FA indirect {beta}unstandardised= -0.010, pboot< 0.01; SLF MD indirect {beta}unstandardised = -0.009 to -0.010, pboot< 0.05; pTau-181 indirect {beta}unstandardised = -0.008 to -0.009, pboot< 0.01; pTau-217 indirect {beta}unstandardised= -0.006 to -0.007, pboot< 0.05). Effects of NfL were attenuated when combined in a model with pTau (indirect {beta}unstandardised = -0.005 to -0.008, pboot> 0.15), suggesting shared variance among these markers. These findings reveal multiple pathways that contribute to individual differences in sustained attention in ageing that are detectable before clinical impairment, including SLF white matter integrity -- which is linked to the structural disconnection of the dorsal attention network -- and preclinical AD pathology. The independence of these pathways identifies two separable biological targets for preserving attentional capacity in CU older adults.

neuroscience↗

bioRxiv2026

Divergent Electrophysiological Responses in the Human Hippocampus During Verbal Memory Processing

The profile of electrophysiological responses in the human hippocampus (HPC) during verbal memory processing has remained complex and unclear. Here, we studied 26 patients implanted with intracranial electrodes across 187 HPC sites (50% left, 2-18 per patient). During memory encoding and retrieval, a subset of HPC responsive sites demonstrated increased ripple events, along with elevated high-frequency (HFA >50 Hz), and low-frequency (LFA 1-8 Hz) activity. A nearly equal number of sites showed no changes in ripple rate but increased LFA power and a delayed response-locked decrease in HFA power. More importantly, both successful encoding as well as recognition of remembered words were strongly associated with the coordination of the timing of LFA and HFA increases across the two clusters of responsive HPC sites. Using direct cortical electrical stimulations, we confirmed overlapping, but partially distinct, cortical connections to the functionally distinct HPC clusters. Our findings suggest a mesoscale mosaic functional organization within the human HPC where adjacent sites with divergent electrophysiological responses may have specialized roles during verbal memory processing. More importantly, our findings suggest that successful human memory depends on the coordination of the timing of low and high frequency local fields generated across these functionally divergent neuronal population sites.

neuroscience↗

bioRxiv2025

Single cell and spatial characterization of the human pancreas reveals drivers of beta cell dysfunction in cystic fibrosis

Cystic fibrosis (CF) causes severely damaged pancreas morphology and results in high rates of cystic fibrosis-related diabetes (CFRD), but the cellular pathways and regulatory programs driving CFRD pathogenesis in the pancreas are not understood. In this study, we performed single cell multiomic and spatial profiling of 2.04M cells in the pancreas from 23 non-disease and CF donors and defined regulatory programs and tissue niches of specific cell types and sub-types in CF. A high-mucin sub-type of ductal cells had relatively preserved abundance, altered localization and up-regulated stress, secretion and pro-fibrotic activity in CF, and conventional ductal cells showed evidence for transition to the high-mucin state. Increased inflammatory and fibrotic pathway activity in CF was linked to closer proximity and crosstalk between immune and stellate cells in specific niches. Beta cells had extensive genomic changes in CF, including increased stress and insulin secretion-related processes, and these changes were broadly distinct from those in type 1 and type 2 diabetes. Islets in CF preferentially localized near large adipose tissue and collagen structures, and both areas were strongly linked to beta cell loss in CF due to signaling from adipocytes, macrophages, stellate, and high-mucin ductal cells. Overall, our results reveal cellular drivers of pancreatic dysfunction in CF and offer new in-roads to preserving beta cells in CFRD.

genomics↗

bioRxiv2025

A multimodal imaging approach for imaging the metabolic changes resulting from bronchopulmonary dysplasia

Lung tissue is composed of various functional units, each essential for maintaining the intricate functions of the lung. Disruptions in the molecular and cellular mechanisms in the lung can cause tissue fibrosis, inflammation, and severe breathing difficulties, which are common in conditions such as bronchopulmonary dysplasia (BPD). BPDs molecular changes are not well understood, which hinders effective diagnosis and treatment. Here, we present a new multimodal imaging workflow for detailed molecular and metabolic characterization of tissues at multiple spatial scales. We applied a combined imaging approach using matrix-assisted laser desorption/ionization mass spectrometry imaging (MALDI-MSI) and ultrafast focused light-based imaging & photonics platform (U-FLIP) that included two-photon fluorescence (TPF), second harmonic generation (SHG), and stimulated Raman scattering (SRS). We also developed a hierarchical multimodal registration network (HiMReg) for the precise co-registration of each modality. This approach revealed previously unknown metabolic changes in distinct functional tissue units affected by BPD, including altered lipid distributions, reduced optical redox states, and specific collagen remodeling in bronchioles. Our findings evidenced alterations in lipid composition and metabolism of BPD-affected alveoli compared to healthy tissue, providing novel insights into disease pathophysiology. Our findings elucidate the intricate spatial and molecular complexity of BPD, building on prior research that did not provide the spatial resolution necessary to capture the nuances of metabolic alterations. This multimodal approach offers exceptional insights into disease exploration and could transform the way we study spatially heterogeneous conditions. By providing detailed maps of the metabolic shifts occurring in distinct tissue microanatomical features, the methods developed here could enable the discovery of new therapeutic avenues, making it highly attractive for the field of biomedical research.

physiology↗

bioRxiv2025

A Multimodal Spatial and Epigenomic Atlas of Human Adult Lung Topography

Developing high-resolution reference maps of disease-susceptible spatial niches is a critical step to mitigating the profound effects of lung disease. Here, we present an integrated multimodal single-nucleus human lung atlas (snHLA) profiling 746,047 nuclei from 49 mapped lung blocks spanning clinically relevant distal airways, alveoli, and interstitium across 11 healthy adults. Integrating snRNA-seq and SNARE-seq2, which co-assays chromatin accessibility and gene expression from the same nucleus, we resolved 70 molecularly distinct populations and captured 332,846 accessible chromatin regions, nominating new transcriptional regulators of human lung cell diversity. Spatial transcriptomics using MERFISH mapped 25 cell populations across 7 structural neighborhoods and multiplexed immunofluorescence localized cell subtypes and distal airway-defining protein markers, expanding and validating distinct lung structure-specific cell populations. This open access snHLA and companion Cell Type and Marker Gene Dictionary with anatomically aligned nomenclature delivers a foundational resource at an unprecedented resolution to interrogate the origins of lung pathophysiology.

cell biology↗

bioRxiv2024

IFNγ-Expressing Myeloid Cells Localize within Lipoproteinosis during Drug-Associated Pulmonary Alveolar Proteinosis occurring in Systemic Juvenile Idiopathic Arthritis

In the United States, approximately one in 1000 children are diagnosed with the autoinflammatory disease, Juvenile Idiopathic Arthritis (JIA). A subset of JIA cases manifests as Systemic JIA (sJIA), which is characterized by joint pain, fevers, rashes, and systemic inflammation. Severe pulmonary complications have not historically been associated with sJIA. Since 2010, inhibitors of interleukin-1 and interleukin 6 (IL-1i/IL-6i) are the recommended course of treatment for sJIA, yet recently studies show evidence of a severe drug hypersensitivity reaction implicating these medications in a subset of those treated. With this reaction, sJIA patients can develop severe lung disease, including pulmonary alveolar proteinosis (PAP). As this drug-associated lung disease has only recently been identified, the etiology of sJIA drug-associated PAP (sJIA-daPAP) is poorly understood. We used multiplexed ion beam imaging by time-of-flight (MIBI-TOF) to define the cellular immune infiltrate and describe pathological features of PAP in sJIA-daPAP patients. We found an enrichment of eosinophils, neutrophils, and M2 macrophages within regions of lipoproteinosis. These enriched subsets all upregulate IFN{gamma} within lipoproteinosis, a signature specific to sJIA-daPAP samples compared to non-sJIA-PAP samples. In a cellular neighborhood analysis, we identified that eosinophils, neutrophils and M2 macrophages frequently co-localize within the same cellular microenvironment, especially in lipoproteinosis regions. Therefore, this spatial coordination may be involved in clearance or persistence of lipoproteinosis in sJIA-daPAP. This study provides a comprehensive overview of sJIA-daPAP immune pathology and suggests cellular mechanisms that drive inflammation in sJIA patients experiencing pulmonary complications associated with delayed drug hypersensitivity during IL-1i/IL-6i treatment.

immunology↗

bioRxiv2023

A Trisomy 21 Lung Cell Atlas

Trisomy 21 (T21), resulting in Down Syndrome (DS), is the most prevalent chromosomal abnormality worldwide. While pulmonary disease is a major cause of morbidity and mortality in DS, the ontogeny of pulmonary complications remains poorly understood. We recently demonstrated that T21 lung anomalies, including airway branching and vascular lymphatic abnormalities, are initiated in utero. Here, we aimed to describe molecular changes at the single cell level in prenatal T21 lungs. Our results demonstrate differences in the proportion of cell populations and detail changes in gene expression at the time of initiation of histopathological abnormalities. Notably, we identify shifts in the distribution of alveolar epithelial progenitors, widespread induction of key extracellular matrix molecules in mesenchymal cells and hyper-activation of IFN signaling in endothelial cells. This single cell atlas of T21 lungs greatly expands our understanding of antecedents to pulmonary complications and should facilitate efforts to mitigate respiratory disease in DS.

developmental biology↗