Biology subjects

Davidson, B. R.

Publications and source records attributed to Davidson, B. R..

4 recordsLinked to original sources

bioRxiv2025

Real time evaluation of the liver microcirculation by whole organ machine perfusion within an MRI system

ObjectivesMachine perfusion of organs outside of the body is a growing area of research with significant applications in the fields of organ preservation and transplantation, but more widely it offers a new approach to study disease processes and to evaluate new therapeutics and devices. Magnetic Resonance Imaging (MRI) allows for non-invasive assessment of organ structure and function, enabling quantitative measurement of tissue perfusion and microstructure. In this study, we demonstrate that MR imaging sequences can be obtained from machine-perfused porcine livers using a modified perfusion rig for MR compatibility and highlight the quantitative measures that can be obtained through this methodology. Materials and Methods7 porcine livers were retrieved fresh from the abattoir using a previously published protocol and following transport in cold preservative underwent perfusion with oxygenated autologous blood inside a 3T clinical MRI scanner using a custom modified perfusion rig. Multiple MR imaging sequences were acquired: T2-weighted imaging, Diffusion Weighted Imaging and Dynamic Contrast Enhanced imaging following injection of Gadolinium dye into the portal vein and hepatic artery. Histological analysis was performed to assess preservation injury to the liver. Control samples for histology were obtained from livers with similar preservation periods but preserved in standard cold storage on ice (Static Cold Storage). ResultsConcurrent MR imaging and machine perfusion were successfully performed, allowing dynamic measurement of tissue perfusion to be obtained in ex vivo livers, including calculation of gadolinium contrast enhancement curves and Apparent Diffusion Coefficient maps. Segmentation of vessels down to a radius of 0.45mm allowed detailed morphological analysis of the vascular network, including extraction of clinically relevant parameters such as vessel tortuosity. Histological evaluation showed better preservation of the hepatic acinar structure in perfused than non-perfused livers. ConclusionsOur results demonstrate that MR imaging of machine-perfused organs enables high-resolution quantitative evaluation of whole-organ vascular morphology and flow dynamics. This platform provides opportunities to study vascular pathology in diseased human organs and evaluate novel therapeutic interventions, with particular relevance for drug-delivery strategies.

physiology↗

bioRxiv2025

Anticlustering for Sample Allocation To Minimize Batch Effects

High throughput sequencing is a powerful tool for processing large amounts of DNA and RNA samples in batches. Proper experimental design and statistical methods are required to mitigate systematic technical factors due to differences in batches ("batch effects"), as data variation due to these non-biological factors can mask actual biological differences. We propose using anticlustering as an automated method to assign samples to balanced batches. Anticlustering effectively negates differences in (numeric and/or categorical) covariates among batches, and implements user-defined restrictions on the number of batches, the number of samples per batch, and whether to assign certain samples to the same batch ("must-link constraints"). A simulation study shows that anticlustering is better at achieving balance among batches than previous approaches. An application from the UCSF-Stanford Endometriosis Center for Discovery, Innovation, Training and Community Engagement ("ENACT", https://enactcenter.org/) is presented as a real-life example. In the application, multiple samples provided by an individual had to be processed on the same batch, so that comparisons among different samples of the same patient were not diluted by batch effects. The novel Two Phase Must Link (2PML) anticlustering algorithm realized the must-link restrictions while simultaneously obtaining balance among batches regarding disease stage, menstrual cycle phase, case versus control sample, and clinical site. All methods presented here are accessible via the free and open source R package anticlust (https://cran.r-project.org/package=anticlust). An interactive visualization and web-based batch assignment tool are made available in the Rshiny app "anticlust" (https://anticlust.org/).

bioinformatics↗

bioRxiv2024

A Multiomics, Spatiotemporal, and Single Cell Atlas for Mapping Cell-Type-Specific Dysregulation at the Maternal-Fetal Interface

The placenta, the first organ to functionally mature, undergoes disordered development in many pregnancy complications. Molecular investigations have been hampered by the extreme cellular heterogeneity of the placenta, and this complexity is further exaggerated at the maternal-fetal interface where maternal and fetal cells co-mingle. We generated the paired single nucleus epigenomes and transcriptome for each of [~]200,000 cells at the human maternal-fetal interface from early pregnancy to term. These data identified cell-type-specific transcriptional regulatory programs and uncovered key transcription factors driving the lineage differentiation of placental cytotrophoblasts. Integrating spatial single cell proteomics profiling, we localized the observed cell types in situ, and characterized the dynamic stages and distinct features of endothelial cells of maternal spiral arteries remodeled by extravillous cytotrophoblasts. Integrative analyses of the single cell data across gestation enabled fine-mapping of the developmental trajectories of cytotrophoblasts and decidual stromal cells, and defining the signature molecular profiles of known and novel cell (sub)types. To demonstrate clinical value, we integrated the reference single cell data with large-scale population genomes from pregnancy complications and identified the most vulnerable maternal and fetal cell types in preeclampsia, preterm birth, and miscarriage. This study presents the most comprehensive placental and decidual single cell resource across gestation to date, reveals new insights into the drivers of normal human placentation, and uncovers the cellular basis of dysfunction associated with common pregnancy complications.

genomics↗

bioRxiv2022

Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted by metastasis

CD8+ T cell responses are critical for anti-tumor immunity. While extensively profiled in the tumor microenvironment (TME), recent studies in mice identified responses in lymph nodes (LN) as essential; however, the role of LN in human cancer patients remains unknown. We examined CD8+ T cells in human head and neck squamous cell carcinomas, regional LN, and blood using mass cytometry, single-cell genomics, and multiplexed ion beam imaging. We identified progenitor exhausted CD8+ T cells (Tpex) that were abundant in uninvolved LN and clonally related to terminally exhausted cells in the TME. After anti-PD-L1 immunotherapy, Tpex in uninvolved LN reduced in frequency but localized near dendritic cells and proliferating intermediate-exhausted CD8+ T cells (Tex-int), consistent with activation and differentiation. LN responses coincided with increased circulating Tex-int. In metastatic LN, these response hallmarks were impaired by immunosuppressive cellular niches. Our results identify important roles for LN in anti-tumor immune responses in humans.

immunology↗