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Martinez, J. S.

Publications and source records attributed to Martinez, J. S..

3 recordsLinked to original sources

Ensembling Unets, sparse representation and low dimensional visualization for rare chromosomal aberration detection in light microscopy images

AO_SCPLOWBSTRACTC_SCPLOWIn biological dosimetry, a radiation dose is estimated using the average number of chromosomal aberration per peripheral blood lymphocytes. To achieve an adequate precision in the estimation of this average, hundreds of cells must be analyzed in 2D microscopy images. Currently, this analysis is performed manually, as conventional computer vision techniques struggle with the wide variety of shapes showcased by chromosomes. The false discovery rate of current automated detection systems is high and variable, depending on small variations in data quality (chromosome spread, illumination variations ...), which makes using it in a fully automated fashion impossible. Automating chromosomal aberration is needed to reduce diagnosis time. Furthermore, an automated system can process more images, which improves confidence intervals around the estimated radiation dose. We build an object detection model to automate chromosomal aberration detection using recent advances in deep convolutional neural networks and statistical learning. We formulated the problem of rare aberration detection as a heatmap regression problem requiring the minimization of a sparsity-promoting loss to reduce the false alarm rate. Our Unet-based approach is analoguous to a one-stage object detector, and keeps the number of hyperparameters to a minimum. Finally, we demonstrate large performance improvements using an ensemble of checkpoints collected during a single run of training. A PCA-based strategy is used to provide cues for interpretation of our deep neural network-based model. The methodology is demonstrated on real, large, and challenging datasets depicting rare chromosomal aberrations and is favorably compared to a reference dosimetry technique.

bioinformatics↗

Human Digital Twin: Automated Cell Type Distance Computation and 3D Atlas Construction in Multiplexed Skin Biopsies

Mapping the human body at single cell resolution in three-dimensions (3D) is an important step toward a "digital twin" model that captures important structure and dynamics of cell-cell interactions. Current 3D imaging methods suffer from low resolution and are limited in their ability to distinguish cell types and their spatial relationships. We present a novel 3D workflow: MATRICS-A (Multiplexed Image Three-D Reconstruction and Integrated Cell Spatial - Analysis) that generates a 3D map of cells from multiplexed images and calculates cell type distance from endothelial cells and other features of interest. We applied this workflow to multiplexed data from sequential skin sections from younger and older donors (n=10; 33-72 years) with biopsies from ten anatomical regions with different sun exposure effects (mild, moderate-marked). Up to 26 sequential sections from each sample underwent multiplexed imaging with 18 biomarkers covering 12 cell types (keratinocytes (granular, spinous, basal), epithelial and myoepithelial cells, fibroblasts, macrophages, T helpers, T killers, T regs, neurons and endothelial cells, markers of DNA damage and repair (p53, DDB2) and cell proliferation (Ki67). Following cell classification, the tissue and classified cells were reconstructed into 3D volumes. A significant inverse correlation between DDB2 positive cells and age was found (corr= -0.78, adj. p=0.047). This suggests reduced capacity for repair in non-cancer older sun-exposed individuals. While absolute immune cell count did not differ by age or sun exposure, the ratio of T Helper/T Killer cells was positively correlated with age (corr=0.82, adj. p=0.048) This is the first such 3D study in skin and paves the way for cataloging more cell types and spatial relationships in aging and disease in skin and other organs.

cell biology↗

Controlled and Selective Photo-oxidation of Amyloid-β Fibrils by Oligomeric p-Phenylene Ethynylenes

Photodynamic therapy (PDT) has been explored as a therapeutic strategy to clear toxic amyloid aggregates involved in neurodegenerative disorders such as Alzheimers disease. A major limitation of PDT is off-target oxidation, which can be lethal for the surrounding cells. We have shown that a novel class of oligo-p-phenylene ethynylene-based compounds (OPEs) exhibit selective binding and fluorescence turn-on in the presence of pre-fibrillar and fibrillar aggregates of disease-relevant proteins such as amyloid-{beta} (A{beta}) and -synuclein. Concomitant with fluorescence turn-on, OPE also photosensitizes singlet oxygen under illumination through the generation of a triplet state, pointing to the potential application of OPEs as photosensitizers in PDT. Herein, we investigated the photosensitizing activity of an anionic OPE for the photo-oxidation of toxic A{beta} aggregates and compared its efficacy to the well-known but non-selective photosensitizer methylene blue (MB). Our results show that while MB photo-oxidized both monomeric and fibrillar conformers of A{beta}40, OPE oxidized only A{beta}40 fibrils, targeting two histidine residues on the fibril surface and a methionine residue located in the fibril core. Oxidized fibrils were shorter and more dispersed, but retained the characteristic {beta}-sheet rich fibrillar structure and the ability to seed further fibril growth. Importantly, the oxidized fibrils displayed low toxicity. We have thus discovered a class of novel theranostics for the simultaneous detection and oxidization of amyloid aggregates. Importantly, the selectivity of OPEs photosensitizing activity overcomes the limitation of off-target oxidation of currently available photosensitizers, and represents a significant advancement of PDT as a viable strategy to treat neurodegenerative disorders.

neuroscience↗