Biology subjects

Sanders, P.

Publications and source records attributed to Sanders, P..

4 recordsLinked to original sources

bioRxiv2025

Systematic cross-study assessment of RNA-Seq experimental workflows for plasma cell-free transcriptome profiling

Plasma cell-free RNA (cfRNA) is a promising source of non-invasive biomarkers, but its clinical translation is hindered by technical challenges and a lack of protocol standardization, which compromises reproducibility and comparability across studies. There is a need for a systematic evaluation of existing cfRNA-Seq workflows to understand the drivers of technical variability. Here, we address this gap by performing a comprehensive cross-study analysis of 2,166 cfRNA-Seq samples from 15 published studies and an in-house generated dataset, applying a uniform bioinformatics pipeline to enable a controlled comparison of experimental workflows. Our analysis reveals that the donor phenotype typically explains a negligible fraction of the transcriptomic variation, whose main determinants are technical - principally protocol choice, genomic DNA contamination levels and library diversity. Remarkably, this technical noise is so profound that variation within plasma cfRNA samples exceeds that found across a wide range of human tissues. Finally, we demonstrate that critical pre-analytical factors are often confounded with patient phenotypes, jeopardizing the validity of biomarker discovery efforts. Our work serves as a comprehensive benchmark of current cfRNA-Seq methodologies and provides evidence-based guidelines to improve experimental design. By highlighting the dominance of controllable technical factors, we offer a path towards more robust and reproducible cfRNA research.

bioinformatics↗

bioRxiv2021

Exploring Parallel MPI Fault Tolerance Mechanisms for Phylogenetic Inference with RAxML-NG

Phylogenetic trees are now routinely inferred on large scale HPC systems with thousands of cores as the parallel scalability of phylogenetic inference tools has improved over the past years to cope with the molecular data avalanche. Thus, the parallel fault tolerance of phylogenetic inference tools has become a relevant challenge. To this end, we explore parallel fault tolerance mechanisms and algorithms, the software modifications required, and the performance penalties induced via enabling parallel fault tolerance by example of RAxML-NG, the successor of the widely used RAxML tool for maximum likelihood based phylogenetic tree inference. We find that the slowdown induced by the necessary additional recovery mechanisms in RAxML-NG is on average 2%. The overall slowdown by using these recovery mechanisms in conjunction with a fault tolerant MPI implementation amounts to 8% on average for large empirical datasets. Via failure simulations, we show that RAxML-NG can successfully recover from multiple simultaneous failures, subsequent failures, failures during recovery, and failures during checkpointing. Recoveries are automatic and transparent to the user. The modified fault tolerant RAxML-NG code is available under GNU GPL at https://github.com/lukashuebner/ft-raxml-ng Contact: lukas.huebner@{kit.edu,h-its.org};, alexey.kozlov@h-its.org, hespe@kit.edu, sanders@kit.edu, alexandros.stamatakis@hits.org Supplementary information: Supplementary data are available at bioR{chi}iv.

bioinformatics↗

bioRxiv2020

In vivo progressive degeneration of Huntington's disease patient-derived neurons reveals human-specific pathological phenotypes

Research on neurodegenerative disorders has been hampered by the limited access to patients brain tissue and the absence of relevant physiological models with human neurons, accounting for the little success of clinical trials. Moreover, post-mortem samples cannot provide a detailed picture of the complex pathological mechanisms taking place throughout the course of the disease. This holds particularly true for Huntingtons disease (HD), an incurable inherited brain disorder marked by a massive striatal degeneration due to abnormal accumulation of misfolded huntingtin protein. To characterize progressive human neurodegeneration in vivo, we transplanted induced pluripotent stem cell-derived human neural progenitor cells (hNPCs) from control (CTR-hNPCs) and HD patients (HD-hNPCs) into the striatum of neonatal wild-type mice. Implanted human cells were examined by immunohistochemistry and electron microscopy, and chimeric mice were subjected to behavioral testing. Most grafted hNPCs differentiated into striatal neurons that sent axonal projections to their natural targets and established synaptic connections within the host basal ganglia circuitry. HD-hNPCs first showed developmental abnormalities characterized by an increased proliferation and accelerated medium spiny neuron (MSN) differentiation, mimicking the initial striatal hypertrophy of child mutant huntingtin (mHTT) carriers. HD human striatal neurons progressively developed mHTT oligomers and aggregates, which primarily targeted mitochondria, endoplasmic reticulum and nuclear membrane to cause structural alterations. Five months after transplantation, selective death of human MSNs and striatal degeneration altered mouse behavior, suggesting disease propagation to non-mutated host cells. Histological analysis and co-culture experiments revealed that HD-hNPCs secreted extracellular vesicles containing soluble mHTT oligomers, which were internalized by mouse striatal neurons triggering cell death. Finally, in vivo pharmacological inhibition of the exosomal secretory pathway through sphingosine-1 phosphate receptor functional antagonism, limited the spreading of apoptosis within the host striatum. Our findings cast new light on human neurodegeneration, unveiling cell and non-cell autonomous mechanisms that drive HD progression in patients.

neuroscience↗

bioRxiv2017

Abundance and diversity of the fecal resistome in slaughter pigs and broilers in nine European countries

EFFORT groupHaitske Graveland, Alieda van Essen, Bruno Gonzalez-Zorn, Gabriel Moyano, Pascal Sanders, Claire Chauvin, Julie David, Antonio Battisti, Andrea Caprioli, Jeroen Dewulf, Thomas Blaha, Katharina Wadepohl, Maximiliane Brandt, Dariusz Wasyl, Magdalena Skarzynska, Magdalena Zajac, Hristo Daskalov, Helmut W Saatkamp, Katharina D.C. Stark.\n\nAbstractAntimicrobial resistance (AMR) in bacteria and associated human morbidity and mortality is increasing. Use of antimicrobials in livestock selects for AMR that can subsequently be transferred to humans. This flow of AMR between reservoirs demands surveillance in livestock as well as in humans. As part of the EFFORT project (www.effort-against-amr.eu), we have quantified and characterized the acquired resistance gene pools (resistomes) of 181 pig and 178 poultry farms from nine European countries, generating more than 5,000 gigabases of DNA sequence, using shotgun metagenomics. We quantified acquired AMR using the ResFinder database and a database constructed for this study, consisting of AMR genes identified through screening environmental DNA. The pig and poultry resistomes were very different in abundance and composition. There was a significant country effect on the resistomes, more so in pigs than poultry. We found higher AMR loads in pigs, while poultry resistomes were more diverse. We detected several recently described, critical AMR genes, including mcr-1 and optrA, the abundance of which differed both between host species and countries. We found that the total acquired AMR level, was associated with the overall country-specific antimicrobial usage in livestock and that countries with comparable usage patterns had similar resistomes. Novel, functionally-determined AMR genes were, however, not associated with total drug use.

microbiology↗