Biology subjects

El-Achkar, T. M.

Publications and source records attributed to El-Achkar, T. M..

21 records · Page 2Linked to original sources

bioRxiv2020

The orchestrated cellular and molecular responses of the kidney to endotoxin define the sepsis timeline

Clinical sepsis is a highly dynamic state that progresses at variable rates and has life-threatening consequences. Staging patients along the sepsis timeline requires a thorough knowledge of the evolution of cellular and molecular events at the tissue level. Here, we investigated the kidney, an organ central to the pathophysiology of sepsis. Single cell RNA sequencing revealed the involvement of various cell populations in injury and repair to be temporally organized and highly orchestrated. We identified key changes in gene expression that altered cellular functions and can explain features of clinical sepsis. These changes converged towards a remarkable global cell-cell communication failure and organ shutdown at a well-defined point in the sepsis timeline. Importantly, this time point was also a transition towards the emergence of recovery pathways. This rigorous spatial and temporal definition of murine sepsis will uncover precise biomarkers and targets that can help stage and treat human sepsis.

bioinformatics↗

bioRxiv2019

A precision medicine approach uncovers a unique signature of neutrophils in patients with brushite kidney stones

BackgroundWe have previously found that papillary histopathology differs greatly between calcium oxalate and brushite stone formers (SF); the latter have much more papillary mineral deposition, tubular cell injury and tissue fibrosis. MethodsIn this study, we applied unbiased orthogonal "omics" approaches on biopsied renal papillae and extracted stones from patients with brushite or calcium oxalate (CaOx) stones. Our goal was to discover stone type-specific molecular signatures to advance our understanding of the underlying pathogenesis. ResultsBrushite SF did not differ from CaOx SF with respect to metabolic risk factors for stones, but did exhibit increased tubule plugging in their papillae. Brushite SF had upregulation of inflammatory pathways in papillary tissue, and increased neutrophil markers in stone matrix compared to those with CaOx stones. Large-scale 3D tissue cytometry on renal papillary biopsies showed an increase in the number and density of neutrophils in the papillae of brushite vs. CaOx patients, thereby linking the observed inflammatory signatures to the neutrophils in the tissue. To explain how neutrophil proteins appear in the stone matrix, we measured neutrophil extracellular trap (NET) formation, NETosis, and found it significantly increased in the papillae of brushite compared to CaOx patients. ConclusionsWe show that increased neutrophil infiltration and NETosis is an unrecognized factor that differentiates brushite and CaOx SF, and may explain the markedly increased scarring and inflammation seen in the papillae of brushite patients. Given the increasing prevalence of brushite stones, the role of neutrophil activation in brushite stone formation requires further study.

pathology↗

bioRxiv2019

A Multimodal and Integrated Approach to Interrogate Human Kidney Biopsies with Rigor and Reproducibility: The Kidney Precision Medicine Project

Comprehensive and spatially mapped molecular atlases of organs at a cellular level are a critical resource to gain insights into pathogenic mechanisms and personalized therapies for diseases. The Kidney Precision Medicine Project (KPMP) is an endeavor to generate 3-dimensional (3D) molecular atlases of healthy and diseased kidney biopsies using multiple state-of-the-art OMICS and imaging technologies across several institutions. Obtaining rigorous and reproducible results from disparate methods and at different sites to interrogate biomolecules at a single cell level or in 3D space is a significant challenge that can be a futile exercise if not well controlled. We describe a "follow the tissue" pipeline for generating a reliable and authentic single cell/region 3D molecular atlas of human adult kidney. Our approach emphasizes quality assurance, quality control, validation and harmonization across different OMICS and imaging technologies from sample procurement, processing, storage, shipping to data generation, analysis and sharing. We established benchmarks for quality control, rigor, reproducibility and feasibility across multiple technologies through a pilot experiment using common source tissue that was processed and analyzed at different institutions and different technologies. A peer review system was established to critically review quality control measures and the reproducibility of data generated by each technology before being approved to interrogate clinical biopsy specimens. The process established economizes the use of valuable biopsy tissue for multi-OMICS and imaging analysis with stringent quality control to ensure rigor and reproducibility of results and serves as a model for precision medicine projects across laboratories, institutions and consortia.

scientific communication and education↗