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Biology subjects

Harris, P. D.

Publications and source records attributed to Harris, P. D..

4 recordsLinked to original sources

Multiparameter-based photosynthetic state transitions of single phytoplankton cells

Phytoplankton are a major source of primary production. Their photosynthetic fluorescence uniquely reports on their type, physiological state and response to environmental conditions. Changes in phytoplankton photophysiology are commonly monitored by bulk fluorescence spectroscopy, where gradual changes are reported in response to different perturbations such as light intensity changes. What is the meaning of such trends in bulk parameters if their values report ensemble averages of multiple unsynchronized cells? To answer this, we developed an experimental scheme that enables acquiring multiple fluorescence parameters, from multiple excitation sources and spectral bands. This enables tracking fluorescence intensities, brightnesses and their ratios, as well as mean photon nanotimes equivalent to mean fluorescence lifetimes, one cell at a time. We monitored three different phytoplankton species during diurnal cycles and in response to an abrupt increase in light intensity. Our results show that we can define specific subpopulations of fluorescence parameters for each of the phytoplankton species and in response to varying light conditions. Importantly, we identify the cells undergo well-defined transitions between these subpopulations that characterize the different light behaviors. The approach shown in this work will be useful in the exact characterization of phytoplankton cell states and parameter signatures in response to different changes these cells experience in marine environments, which will be useful in monitoring marine-related effects of global warming. Significance StatementUsing three representatives of red-linage phytoplankton we demonstrate distinct photophysiological behaviors at the single cell level. The results indicate cell wide coordination into discrete cell states. We test cell state transitions as a function of light acclimation during diurnal cycle and in response to large intensity increases, which stimulate distinct photoprotective response mechanisms. The analysis was made possible through the development of flow-based confocal detection at multiple excitation and emission wavelengths monitoring both pigment composition and photosynthetic performance. Our findings show that with enough simultaneously recorded parameters per each cell, the detection of multiple phytoplankton species at their distinct cell states is possible. This approach will be useful in examining the response of complex natural marine populations to environmental perturbations.

biophysics↗

Identification and Quantification of Within-Burst Dynamics in Singly-Labeled Single-Molecule Fluorescence Lifetime Experiments

Single-molecule spectroscopy has revolutionized molecular biophysics and provided means to probe how structural moieties within biomolecules spatially reorganize at different timescales. There are several single-molecule methodologies that probe local structural dynamics in the vicinity of a single dye-labeled residue, which rely on fluorescence lifetimes as readout. Nevertheless, an analytical framework to quantify dynamics in such single-molecule single-dye fluorescence bursts, at timescales of microseconds to milliseconds, has not yet been demonstrated. Here, we suggest an analytical framework for identifying and quantifying within-burst lifetime-based dynamics, such as conformational dynamics recorded in single-molecule photo-isomerization related fluorescence enhancement. After testing the capabilities of the analysis on simulations, we proceed to exhibit within-burst millisecond local structural dynamics in the unbound -synuclein monomer. The analytical framework provided in this work paves the way for extracting a full picture of the energy landscape for the coordinate probed by fluorescence-lifetime based single-molecule measurements.

biophysics↗

MNPmApp: An image analysis tool to quantify mononuclear phagocyte distribution in mucosal tissues

Mononuclear phagocytes (MNPs) such as dendritic cells and macrophages perform key sentinel functions in mucosal tissues and are responsible for inducing and maintaining adaptive immune responses to mucosal pathogens. Positioning of MNPs at the mucosal epithelial interface facilitates their access to luminally-derived antigens and may regulate MNP function through soluble mediators or surface receptor interactions. Therefore, accurately quantifying the distribution of MNPs within mucosal tissues as well as their spatial relationship with other cells is important to infer functional cellular interactions in health and disease. In this study, we developed and validated a MATLAB-based tissue cytometry platform, termed "MNP mapping application" (MNPmApp), that performs high throughput analyses of MNP density and distribution in the gastrointestinal mucosa based on digital multicolor fluorescence microscopy images and that integrates a Monte Carlo modeling feature to assess randomness of MNP distribution. MNPmApp identified MNPs in tissue sections of the human gastric mucosa with a specificity of 98.3 {+/-} 1.6% and a sensitivity of 76.4 {+/-} 15.1%. Monte Carlo modeling revealed that mean MNP-MNP distances were significantly lower than anticipated based on random cell placement, whereas MNP-epithelial distances did not significantly differ from those of randomly placed cells. Interestingly, H. pylori infection had no significant impact on MNP density or distribution with regards to MNP-epithelial distances or MNP-MNP distances in gastric tissue. Overall, our analysis demonstrates that MNPmApp is a useful tool for unbiased quantitation of MNPs and their distribution at mucosal sites.

immunology↗

Multi-parameter photon-by-photon hidden Markov modeling

Single-molecule Forster resonance energy transfer (smFRET) is a unique biophysical approach for studying conformational dynamics in biomacro-molecules. Photon-by-photon hidden Markov modelling (H2MM) is an analysis tool that can quantify FRET dynamics of single biomolecules, even if they occur on the sub-millisecond timescale. However, dye photophysical transitions intertwined with FRET dynamics may introduce artefacts. Here, we introduce multi-parameter H2MM (mpH2MM), which assists in identifying FRET dynamics based on simultaneous observation of multiple experimentally-derived parameters. We show the importance of using mpH2MM to decouple FRET dynamics caused by conformational changes from photophysical transitions in confocal-based smFRET measurements of a DNA hairpin, the maltose binding protein, MalE, and the type-III secretion system effector, YopO, from Yersinia species all exhibiting conformational dynamics ranging from the sub-second to microsecond timescales. Overall, we show that using mpH2MM facilitates the identification and quantification of biomolecular sub-populations and their origin.

biophysics↗