About

Zissimos Mourelatos, M.D., is a Professor of Pathology and Laboratory Medicine at the University of Pennsylvania's Perelman School of Medicine. He serves as an Attending Physician in Neuropathology at the Hospital of the University of Pennsylvania, as well as at Pennsylvania Hospital and Penn Presbyterian Medical Center. Dr. Mourelatos is the Director of the Division of Neuropathology and also the Fellowship Director for Neuropathology at the hospital. His research expertise focuses on the biology of ribonucleoproteins (RNPs) composed of small RNAs such as siRNAs, miRNAs, piRNAs, and mRNAs, as well as RNA dysregulation in the pathogenesis of neurodegeneration. He is involved in the development of RNA-based therapeutics for neurodegenerative diseases. His clinical expertise includes surgical neuropathology, particularly brain tumors, brain biopsies, muscle biopsies, and nerve biopsies. Dr. Mourelatos holds an M.D. from Aristotelian University of Thessaloniki's School of Medicine, obtained in 1991, and his work encompasses significant contributions to understanding RNA biology and neurodegenerative disease mechanisms.

Research topics

• Computer science
• Biology
• Reliability engineering
• Mathematical optimization
• Mathematics

Selected publications

• Plasma isomiRs as Candidate Biomarkers for Amyotrophic Lateral Sclerosis

  Neurology Genetics · 2026-03-10

  articleOpen accessSenior author

  Background and Objectives: There are no FDA-approved diagnostic biomarkers for amyotrophic lateral sclerosis (ALS). TDP-43 is a known cofactor in the cleavage of long premature microRNAs (miRNAs) into their short, mature products. isomiRs are miRNA variants that differ in their 5' and 3' end points and regulate distinct mRNA targets. In this study, we tested the hypotheses that circulating isomiR profiles differ in the context of TAR DNA-binding Protein pathology and that isomiRs are superior to miRNAs for classification of ALS. Methods: We obtained RNA from plasma samples of 14 patients with ALS and 14 age-matched and sex-matched controls for sequencing on a NextSeq 2000. Data were processed using Unique Molecular Identifier tools and a custom pipeline designed to match miRNA variant sequences without mismatches. Differential expression (DE) was identified using DEseq2 at FDR ≤ 0.1. XGBoost classifiers were built using a subset of (Model 1) isomiRs or (Model 2) miRNAs that were present above a median threshold in all sequencing batches. Parameters were tuned using grid search and 10-fold cross-validation while training to distinguish ALS samples from controls among a single large public data set. Models were then validated on in-house samples and 1 publicly available holdout data set. Results: Fourteen (0.2%), 355 (2.7%), and 14 (0.7%) isomiRs were differentially expressed in in-house plasma, public ALS plasma, and public ALS serum, respectively. One (0.1%), 94 (5.5%), and 13 (2.4%) miRNAs were differentially expressed, respectively. Model 1 accurately classified in-house ALS plasma and public ALS serum (area under the curve [AUC] = 0.87) and did not distinguish 40 of 41 Alzheimer disease samples from control plasma (GSE215789; AUC = 0.47) or 60 of 77 Parkinson disease samples from control whole blood (GSE180193; AUC = 0.55). In comparison, Model 2 using miRNAs performed worse on in-house plasma (AUC = 0.49). Discussion: Analyzing individual isomiRs may improve the performance of circulating noncoding RNAs as diagnostic biomarkers of ALS.

  PublisherOA PDFDOI

• Author Correction: Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial

  Nature Medicine · 2025-06-11 · 3 citations

  erratumOpen access
  PublisherOA PDFDOI

• Uncertainty Quantification in Machine Learning Using an Ensemble Approach with Gaussian Process Regression

  SAE technical papers on CD-ROM/SAE technical paper series · 2025-03-31 · 3 citations

  articleSenior author

  <div class="section abstract"><div class="htmlview paragraph">Machine learning has witnessed widespread adoption across various domains, bringing about transformative changes in decision-making, trend prediction, task automation, and personalized experiences. Despite the remarkable predictive capabilities of machine learning models, the associated uncertainty in their predictions remains a critical concern. Uncertainty estimation plays a pivotal role in ensuring robust decision-making, going beyond mere outcome prediction to quantify the model's confidence and potential error. This paper first presents a review of existing uncertainty quantification techniques in machine learning, including Monte Carlo dropout and ensemble methods, highlighting their advantages in addressing uncertainty as well as their limitations. Then, it presents an efficient and fast novel technique for uncertainty quantification using a combination of the ensemble technique and Gaussian process regression providing an accurate estimation of uncertainty bounds. Due to its accuracy and efficiency, the proposed method is well-suited for real-time applications involving scalar or time series data. The advantages of the proposed method are demonstrated using a mathematical example and a vehicle dynamics example.</div></div>

  PublisherDOI

• Intracerebroventricular bivalent CAR T cells targeting EGFR and IL-13Rα2 in recurrent glioblastoma: a phase 1 trial

  Nature Medicine · 2025-06-01 · 57 citations

  articleOpen access
  PublisherOA PDFDOI

• MIWI arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis

  bioRxiv (Cold Spring Harbor Laboratory) · 2024-01-01 · 1 citations

  preprintOpen accessSenior authorCorresponding

  ABSTRACT N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using mouse MIWI (PIWIL1) as paradigm, we demonstrate that the NTRs are essential for spermatogenesis through the regulation of transposons and gene expression. Surprisingly, the loss of TDRD5 and TDRKH interaction with MIWI results in defective piRNA amplification, rather than an expected failure of piRNA biogenesis. We find that piRNA amplification is necessary for both transposon control and for sustaining levels of select, nonconserved, pachytene piRNAs that target specific mRNAs required for spermatogenesis. Our findings support the notion that the vast majority of pachytene piRNAs are dispensable, acting as autonomous genetic elements that rely for propagation on MIWI piRNA amplification. MIWI-NTRs also mediate interactions with TDRD6 that are necessary for chromatoid body compaction. Furthermore, MIWI-NTRs promote stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation. In summary, the NTRs underpin the diversification of MIWI protein function. Key points MIWI-NTRs coordinate interactions with TDRDs required for piRNA biogenesis to sustain piRNA amplification MIWI-NTRs are necessary for both transposon control and for sustaining levels of select pachytene piRNAs that target specific mRNAs required for spermiogenesis MIWI-NTRs mediate interactions with TDRD6 to compact the Chromatoid Body MIWI-NTRs underlie stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation

  PublisherOA PDFDOI

• Defining the True Native Ends of RNAs at Single-Molecule Level with TERA-Seq

  Methods in molecular biology · 2024-11-13

  articleOpen accessSenior author
  PublisherOA PDFDOI

• MIWI N-terminal arginines orchestrate generation of functional pachytene piRNAs and spermiogenesis

  Nucleic Acids Research · 2024-03-23 · 15 citations

  articleOpen accessSenior authorCorresponding

  N-terminal arginine (NTR) methylation is a conserved feature of PIWI proteins, which are central components of the PIWI-interacting RNA (piRNA) pathway. The significance and precise function of PIWI NTR methylation in mammals remains unknown. In mice, PIWI NTRs bind Tudor domain containing proteins (TDRDs) that have essential roles in piRNA biogenesis and the formation of the chromatoid body. Using mouse MIWI (PIWIL1) as paradigm, we demonstrate that the NTRs are essential for spermatogenesis through the regulation of transposons and gene expression. The loss of TDRD5 and TDRKH interaction with MIWI results in attenuation of piRNA amplification. We find that piRNA amplification is necessary for transposon control and for sustaining piRNA levels including select, nonconserved, pachytene piRNAs that target specific mRNAs required for spermatogenesis. Our findings support the notion that the vast majority of pachytene piRNAs are dispensable, acting as self-serving genetic elements that rely for propagation on MIWI piRNA amplification. MIWI-NTRs also mediate interactions with TDRD6 that are necessary for chromatoid body compaction. Furthermore, MIWI-NTRs promote stabilization of spermiogenic transcripts that drive nuclear compaction, which is essential for sperm formation. In summary, the NTRs underpin the diversification of MIWI protein function.

  PublisherOA PDFDOI

• Figure S1 from High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model

  2023-04-03

  preprintOpen access

  <p>Comparison of surface expression of CAR constructs used in these studies. T cells were transduced with indicated lentivirus at an MOI of 5. At day 8 of expansion, T cells were stained with anti-mouse antibody that recognizes the mouse scFv.</p>

  PublisherOA PDFDOI

• Data from High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model

  2023-04-03

  preprintOpen access

  <div>Abstract<p>The GD2 ganglioside, which is abundant on the surface of neuroblastoma cells, is targeted by an FDA-approved therapeutic monoclonal antibody and is an attractive tumor-associated antigen for cellular immunotherapy. Chimeric antigen receptor (CAR)–modified T cells can have potent antitumor activity in B-cell malignancies, and trials to harness this cytolytic activity toward GD2 in neuroblastoma are under way. In an effort to enhance the antitumor activity of CAR T cells that target GD2, we generated variant CAR constructs predicted to improve the stability and the affinity of the GD2-binding, 14G2a-based, single-chain variable fragment (scFv) of the CAR and compared their properties <i>in vivo</i>. We included the E101K mutation of GD2 scFv (GD2-E101K) that has enhanced antitumor activity against a GD2<sup>+</sup> human neuroblastoma xenograft <i>in vivo</i>. However, this enhanced antitumor efficacy <i>in vivo</i> was concomitantly associated with lethal central nervous system (CNS) toxicity comprised of extensive CAR T-cell infiltration and proliferation within the brain and neuronal destruction. The encephalitis was localized to the cerebellum and basal regions of the brain that display low amounts of GD2. Our results highlight the challenges associated with target antigens that exhibit shared expression on critical normal tissues. Despite the success of GD2-specific antibody therapies in the treatment of neuroblastoma, the fatal neurotoxicity of GD2-specific CAR T-cell therapy observed in our studies suggests that GD2 may be a difficult target antigen for CAR T-cell therapy without additional strategies that can control CAR T-cell function within the CNS. <i>Cancer Immunol Res; 6(1); 36–46. ©2017 AACR</i>.</p></div>

  PublisherDOI

• Figure S2 from High-Affinity GD2-Specific CAR T Cells Induce Fatal Encephalitis in a Preclinical Neuroblastoma Model

  2023-04-03

  preprintOpen access

  <p>Comparison of dissociation of GD2 and E101K IgG. SY5Y cells were incubated with mouse-IgG containing the variable domains from either the GD2 or E101K scFvs. Antibody was then allowed to dissociate in room temperature buffer for the indicated number of seconds, and bound antibody was then detected by flow cytometry using AF-647 labeled secondary antibody.</p>

  PublisherDOI

Recent grants

• NIH Grant R21NS072561

  NIH · $436k · 2013

• NIH Grant K08NS002199

  NIH · $357k · 2003

• Functional characterization of piRNPs

  NIH · $4.7M · 2005–2019

• NIH Grant R21NS053839

  NIH · $373k · 2007

• NIH Grant R01NS056070

  NIH · $1.4M · 2012

Frequent coauthors

• Zhen Hu

  University of Michigan–Dearborn

  53 shared

• Vijitashwa Pandey

  Oakland University

  48 shared

• David Gorsich

  United States Army

  38 shared

• Efstratios Nikolaidis

  32 shared

• Manolis Maragkakis

  National Institute on Aging

  29 shared

• Michael Kokkolaras

  McGill University

  27 shared

• Fadia Ibrahim

  Thomas Jefferson University

  26 shared

• Panagiotis Alexiou

  Central European Institute of Technology – Masaryk University

  26 shared

Education

• M.D.

  Aristotle University of Thessaloniki School of Medicine

  1991