Papers
The Genomic Architecture of Pregnancy-Associated Plasticity in the Maternal Mouse Hippocampus
Synopsis: NLP transformer models accurately identified 90% of pediatric injury cases from ED records, reducing manual review by over 80% and enabling faster, real-time surveillance for CHIRPP.
Abstract: Importance: Injury is a leading cause of morbidity and mortality among children worldwide. Prevention strategies rely on timely and accurate injury surveillance. Many national programs, including the Canadian Hospitals Injury Reporting and Prevention Program (CHIRPP), depend on manual review of emergency department (ED) medical records to track injury trends. Rising ED volumes have strained manual processes, delaying data analysis and compromising early detection of public health risks.
Venue: JAMA Network Open · Date: 2025-07-01
Authors: Devin Singh, Alper Celik, Evangeline W J Zhang, Eric Liu, Daniel Rosenfield
Safety and Efficacy of Very Low-Dose Multi-Nut Oral Immunotherapy in Children
Synopsis: Clinical and Translational Allergy, 2025. This study investigates the safety and efficacy of very low-dose oral immunotherapy for children with multiple nut allergies.
Abstract: ### Background:
Venue: Clinical and Translational Allergy · Date: 2025-06-11
Authors: Julia EM Upton, Carmen H Li, Alireza Berenjy, Alana Galper, Xiaojun Yin, Alper Celik, Lucy Duan, Samantha Wong, Christina M Ditlof, Jennifer A Hoang, Moshe Ben-shoshan, Akash Kothari, Lisa Hung, Mikhail Monteiro, Wut Hmone Phue, Theo J Moraes, Thomas
Assessing the diagnostic impact of blood transcriptome profiling in a pediatric cohort previously assessed by genome sequencing
Synopsis: NPJ Genomic Medicine, 2025. This study evaluates the utility of blood-derived RNA sequencing in refining genetic diagnoses in a pediatric cohort with rare genetic disorders.
Abstract: Despite advances in genome sequencing, many individuals with rare genetic disorders remain undiagnosed. Transcriptional profiling via RNA-seq can reveal functional impacts of DNA variants and improve diagnosis. We assessed blood-derived RNA-seq in the largely undiagnosed SickKids Genome Clinic cohort (n = 134), which has been subjected to multiple analyses benchmarking the utility of genome sequencing. Our RNA-centric analysis identifies gene expression outliers, aberrant splicing, and allele-specific expression. In one-third of diagnosed individuals (20/61), RNA-seq reinforced DNA-based findings. In 2/61 cases, RNA-seq revised diagnoses (EPG5 to LZTR1 in an individual with a Noonan syndrome-like disorder) and discovered an additional relevant gene (CEP120 in addition to SON in an individual with ZTTK syndrome). Additionally, ~7% (5/73) of undiagnosed cases had at least one plausible candidate gene identified. This study highlights both the benefits and limitations of whole-blood RNA profiling in refining genetic diagnoses and uncovering novel disease mechanisms.
Venue: NPJ Genomic Medicine · Date: 2025-06-11
Authors: Huayun Hou, Kyoko E. Yuki, Gregory Costain, Anna Szuto, Sierra Barnes, Arun K. Ramani, Alper Celik, Michael Braga, Meagan Gloven-Brown, Dimitri J. Stavropoulos, Sarah Bowdin, Ronald D. Cohn, Roberto Mendoza-Londono, Stephen W. Scherer, Michael Brudno, Christian R. Marshall, M. Stephen Meyn, Adam Shlien, J ames J. Dowling, Michael D. Wilson & Lianna Kyriakopoulou
Clinical utility analysis of the Hoxb8 mast cell activation test for the diagnosis of peanut allergy
Synopsis: Allergy, 2024. This study evaluates the diagnostic performance of the Hoxb8 mast cell activation test (Hoxb8 MAT) in a cohort of children and adolescents with peanut allergy, comparing it to established diagnostic methods.
Abstract: ### Background
Venue: Allergy · Date: 2024-09-28
Authors: Noemi Bachmeier-Zbären, Alper Celik, Robin van Brummelen, Nadine Roos, Melanie Steinmann, Jennifer A. Hoang, Xiaojun Yin, Christina M. Ditlof, Lucy Duan, Julia E. M. Upton, Thomas Kaufmann, Alexander Eggel, Thomas Eiwegger
Precision cut intestinal slices, a novel model of acute food allergic reactions
Synopsis: A novel ex vivo model using precision cut intestinal slices (PCIS) reproduces allergen-specific, IgE-mediated gut contractions. It enables evaluation of food allergy mechanisms and therapeutic effects, including antihistamines and oral immunotherapy.
Abstract: ### Background
Venue: Allergy · Date: 2023-05-04
Authors: Lisa Hung, Alper Celik, Xiaojun Yin, Kai Yu, Alireza Berenjy, Akash Kothari, Helena Obernolte, Julia EM Upton, Katrine Lindholm Bøgh, Gino R Somers, Iram Siddiqui, Martin Grealish, Fayez A Quereshy, Katherina Sewald, Priscilla PL Chiu, Thomas Eiwegger
Trio RNA sequencing in a cohort of medically complex children
Synopsis: Genome sequencing (GS) combined with RNA sequencing (RNA-seq) improves diagnosis of rare genetic disorders by clarifying splice variants. While RNA-seq added no new findings beyond GS, trio RNA-seq reduced manual review effort in variant filtering.
Abstract: Genome sequencing (GS) is a powerful test for the diagnosis of rare genetic disorders. Although GS can enumerate most non-coding variation, determining which non-coding variants are disease-causing is challenging. RNA sequencing (RNA-seq) has emerged as an important tool to help address this issue, but its diagnostic utility remains understudied, and the added value of a trio design is unknown. We performed GS plus RNA-seq from blood using an automated clinical-grade high-throughput platform on 97 individuals from 39 families where the proband was a child with unexplained medical complexity. RNA-seq was an effective adjunct test when paired with GS. It enabled clarification of putative splice variants in three families, but it did not reveal variants not already identified by GS analysis. Trio RNA-seq decreased the number of candidates requiring manual review when filtering for de novo dominant …
Venue: The American Journal of Human Genetics · Date: 2023-05-04
Authors: Ashish R Deshwar, Kyoko E Yuki, Huayun Hou, Yijing Liang, Tayyaba Khan, Alper Celik, Arun Ramani, Roberto Mendoza-Londono, Christian R Marshall, Michael Brudno, Adam Shlien, M Stephen Meyn, Robin Z Hayeems, Brandon J McKinlay, Panagiota Klentrou, Michael D Wilson, Lianna Kyriakopoulou, Gregory Costain, James J Dowling
[Link](https://www.cell.com/ajhg/fulltext/S0002-9297(23)
The Genomic Architecture of Pregnancy-Associated Plasticity in the Maternal Mouse Hippocampus
Synopsis: This study uses single nucleus RNA sequencing and snATAC-seq to explore cell type-specific transcriptional and epigenetic changes in the mouse hippocampus during and after pregnancy, providing insights into hormone-mediated brain plasticity.
Abstract: Pregnancy is associated with extraordinary plasticity in the maternal brain. Studies in humans and other mammals suggest extensive structural and functional remodeling of the female brain during and after pregnancy. However, we understand remarkably little about the molecular underpinnings of this natural phenomenon. To gain insight into pregnancy-associated hippocampal plasticity, we performed single nucleus RNA sequencing (snRNA-seq) and snATAC-seq from the mouse hippocampus before, during, and after pregnancy. We identified cell type-specific transcriptional and epigenetic signatures associated with pregnancy and postpartum adaptation. In addition, we analyzed receptor-ligand interactions and transcription factor (TF) motifs that inform hippocampal cell type identity and provide evidence of pregnancy-associated adaption. In total, these data provide a unique resource of coupled transcriptional and epigenetic data across a dynamic time period in the mouse hippocampus and suggest opportunities for functional interrogation of hormone-mediated plasticity.
Venue: eNeuro · Date: 2022-07-17
Authors: Alper Celik, Max Somer, Bharti Kukreja, Taiyi Wu, Brian T Kalish
X-linked myotubular myopathy is associated with epigenetic alterations and is ameliorated by HDAC inhibition
Synopsis: Drug screening in zebrafish identified valproic acid as a potent suppressor of X-linked myotubular myopathy (XLMTM) via HDAC inhibition. Validation in mice and patient samples revealed conserved epigenetic alterations, highlighting epigenetic modulation as a therapeutic strategy.
Abstract: X-linked myotubular myopathy (XLMTM) is a fatal neuromuscular disorder caused by loss of function mutations in MTM1. At present, there are no directed therapies for XLMTM, and incomplete understanding of disease pathomechanisms. To address these knowledge gaps, we performed a drug screen in mtm1 mutant zebrafish and identified four positive hits, including valproic acid, which functions as a potent suppressor of the mtm1 zebrafish phenotype via HDAC inhibition. We translated these findings to a mouse XLMTM model, and showed that valproic acid ameliorates the murine phenotype. These observations led us to interrogate the epigenome in Mtm1 knockout mice; we found increased DNA methylation, which is normalized with valproic acid, and likely mediated through aberrant 1-carbon metabolism. Finally, we made the unexpected observation that XLMTM patients share a distinct DNA methylation signature, suggesting that epigenetic alteration is a conserved disease feature amenable to therapeutic intervention.
Venue: Acta Neuropathologica · Date: 2022-07-17
Authors: Jonathan R Volpatti, Mehdi M Ghahramani-Seno, Mélanie Mansat, Nesrin Sabha, Ege Sarikaya, Sarah J Goodman, Eric Chater-Diehl, Alper Celik, Emanuela Pannia, Carine Froment, Lucie Combes-Soia, Nika Maani, Kyoko E Yuki, Gaëtan Chicanne, Liis Uusküla-Reimand, Simon Monis, Sana Akhtar Alvi, Casie A Genetti, Bernard Payrastre, Alan H Beggs, Carsten G Bonnemann, Francesco Muntoni, Michael D Wilson, Rosanna Weksberg, Julien Viaud, James J Dowling
Variants in ASPH cause exertional heat illness and are associated with malignant hyperthermia susceptibility
Synopsis: Rare pathogenic variants in the ASPH gene were identified as a new genetic cause of susceptibility to exertional heat illness and malignant hyperthermia, validated through CRISPR-edited cells and zebrafish models.
Abstract: Exertional heat illness (EHI) and malignant hyperthermia (MH) are life threatening conditions associated with muscle breakdown in the setting of triggering factors including volatile anesthetics, exercise, and high environmental temperature. To identify new genetic variants that predispose to EHI and/or MH, we performed genomic sequencing on a cohort with EHI/MH and/or abnormal caffeine-halothane contracture test. In five individuals, we identified rare, pathogenic heterozygous variants in ASPH, a gene encoding junctin, a regulator of excitation-contraction coupling. We validated the pathogenicity of these variants using orthogonal pre-clinical models, CRISPR-edited C2C12 myotubes and transgenic zebrafish. In total, we demonstrate that ASPH variants represent a new cause of EHI and MH susceptibility.
Venue: Nature Communications · Date: 2022-06-13
Authors: Yukari Endo, Linda Groom , Alper Celik, Natalia Kraeva, Chang Seok Lee, Sung Yun Jung, Lois Gardner, Marie-Anne Shaw, Susan L Hamilton, Philip M Hopkins, Robert T Dirksen, Sheila Riazi, James J Dowling
One size does not fit all - lessons learned from a multiple-methods study of a resident wellness curriculum across sites and specialties
Synopsis: A brief stress-reduction curriculum (SMART-R) did not significantly reduce perceived stress in junior medical residents, with subgroups like female residents and those with lower self-efficacy reporting greater distress—highlighting the need for tailored wellness interventions.
Abstract: Background: There is growing recognition that wellness interventions should occur in context and acknowledge complex contributors to wellbeing, including individual needs, institutional and cultural barriers to wellbeing, as well as systems issues which propagate distress. The authors conducted a multiple-methods study exploring contributors to wellbeing for junior residents in diverse medical environments who participated in a brief resilience and stress-reduction curriculum, the Stress Management and Resiliency Training Program for Residents (SMART-R).
Venue: BMC Medical Education · Date: 2021-11-13
Authors: Deanna Chaukos, Jonathan P Zebrowski, Nicole M Benson, Alper Celik, Emma Chad-Friedman, Aviva Teitelbaum, Carol Bernstein, Rebecca Cook, Afia Genfi, John W Denninger
Basophil activation test shows high accuracy in the diagnosis of peanut and tree nut allergy: The Markers of Nut Allergy Study
Synopsis: The basophil activation test (BAT) accurately predicted peanut and tree nut allergies in children, outperforming standard IgE testing and potentially reducing the need for risky oral food challenges.
Abstract: Background: Peanut and tree nut allergies are the most important causes of anaphylaxis. Co-reactivity to more than one nut is frequent, and co-sensitization in the absence of clinical data is often obtained. Confirmatory oral food challenges (OFCs) are inconsistently performed.
Venue: Allergy · Date: 2021-06-01
Authors: Lucy Duan, Alper Celik, Jennifer A Hoang, Klara Schmidthaler, Delvin So, Xiaojun Yin, Christina M Ditlof, Marta Ponce, Julia E M Upton, Jean-Soo Lee, Lisa Hung, Heimo Breiteneder, Chiara Palladino, Adelle R Atkinson, Vy H D Kim, Alireza Berenjy, Maria Asper, David Hummel, Samantha Wong, Mara Alexanian-Farr, Ahuva Magder, Sharon R Chinthrajah, Kaori Mukai, Mindy Tsai, Kari Nadeau, Stephen J Galli, Arun K Ramani, Zsolt Szepfalusi, Thomas Eiwegger
Modeling the conversion between specific IgE test platforms for nut allergens in children and adolescents
Synopsis: This study models the conversion between different specific IgE testing platforms for nut allergens in pediatric populations, aiming to improve diagnostic consistency and clinical decision-making.
Abstract: Background: Multiplex tests allow for measurement of allergen-specific IgE responses to multiple extracts and molecular allergens and have several advantages for large cohort studies. Due to significant methodological differences, test systems are difficult to integrate in meta-analyses/systematic reviews since there is a lack of datasets with direct comparison. We aimed to create models for statistical integration of allergen-specific IgE to peanut/tree nut allergens from three IgE test platforms.
Venue: The Journal of Allergy and Clinical Immunology · Date: 2021-05-01
Authors: Jennifer A Hoang, Alper Celik, Christian Lupinek, Rudolf Valenta, Lucy Duan, Ruixue Dai, May G Brydges, Aimée Dubeau, Claire Lépine, Samantha Wong, Mara Alexanian-Farr, Ahuva Magder, Padmaja Subbarao, Julia E M Upton, Klara Schmidthaler, Zsolt Szépfalusi, Arun Ramani, Thomas Eiwegger
General decapping activators target different subsets of inefficiently translated mRNAs
Synopsis: Pat1, Lsm1, and Dhh1 selectively regulate decapping of inefficiently translated yeast mRNAs, with distinct and overlapping targets. The Dcp2 C-terminal domain mediates both positive and negative regulation, and loss of these factors alters genome-wide expression indirectly.
Abstract: The Dcp1-Dcp2 decapping enzyme and the decapping activators Pat1, Dhh1, and Lsm1 regulate mRNA decapping, but their mechanistic integration is unknown. We analyzed the gene expression consequences of deleting PAT1, LSM1, or DHH1, or the DCP2 C-terminal domain, and found that: i) the Dcp2 C-terminal domain is an effector of both negative and positive regulation; ii) rather than being global activators of decapping, Pat1, Lsm1, and Dhh1 directly target specific subsets of yeast mRNAs and loss of the functions of each of these factors has substantial indirect consequences for genome-wide mRNA expression; and iii) transcripts targeted by Pat1, Lsm1, and Dhh1 exhibit only partial overlap, are generally translated inefficiently, and, as expected, are targeted to decapping-dependent decay. Our results define the roles of Pat1, Lsm1, and Dhh1 in decapping of general mRNAs and suggest that these factors may monitor mRNA translation and target unique features of individual mRNAs.
Venue: eLife · Date: 2018-12-06
Authors: Feng He, Alper Celik, Chan Wu, Allan Jacobson
High-Resolution Profiling of NMD Targets in Yeast
Synopsis: This study outlines RNA-Seq methods to identify transcripts regulated by the NMD pathway in yeast, revealing around 900 transcripts upregulated upon NMD inactivation.
Abstract: Contemporary high-throughput sequencing methods, notably RNA-Seq, permit the systematic identification and characterization of transcripts whose levels change significantly in response to altered biological states. We have described methods for the application of this methodology to a definition of the transcripts regulated by the NMD pathway in the yeast Saccharomyces cerevisiae. In short, we outline methods for growing cells of wild-type or NMD-deficient yeast, isolating RNA from the different strains, depleting rRNA from each sample, preparing and sequencing the respective RNA-Seq libraries, and employing multiple software packages to characterize the resulting sequence reads meaningfully. Our experimental approach has identified approximately 900 transcripts that are commonly upregulated when yeast NMD is inactivated (Celik, Baker, He, & Jacobson, 2017).
Venue: Methods in Enzymology · Date: 2018-08-09
Authors: Feng He, Alper Celik, Richard Baker, and Allan Jacobson
[Link](https://linkinghub.elsevier.com/retrieve/pii/S0076-6879(18)
High-resolution profiling of NMD targets in yeast reveals translational fidelity as a basis for substrate selection
Synopsis: This study provides a comprehensive catalog of yeast transcripts targeted by NMD, revealing that most are protein-coding mRNAs with low translational efficiency and suboptimal codon usage, offering new insights into NMD targeting mechanisms.
Abstract: Nonsense-mediated mRNA decay (NMD) plays an important role in eukaryotic gene expression, yet the scope and the defining features of NMD-targeted transcripts remain elusive. To address these issues, we reevaluated the genome-wide expression of annotated transcripts in yeast cells harboring deletions of the UPF1, UPF2, or UPF3 genes. Our new RNA-seq analyses confirm previous results of microarray studies, but also uncover hundreds of new NMD-regulated transcripts that had escaped previous detection, including many intron-containing pre-mRNAs and several noncoding RNAs. The vast majority of NMD-regulated transcripts are normal-looking protein-coding mRNAs. Our bioinformatics analyses reveal that this set of NMD-regulated transcripts generally have lower translational efficiency and higher ratios of out-of-frame translation. NMD-regulated transcripts also have lower average codon optimality scores and higher transition probability to nonoptimal codons. Collectively, our results generate a comprehensive catalog of yeast NMD substrates and yield new insights into the mechanisms by which these transcripts are targeted by NMD.
Venue: RNA · Date: 2017-05-23
Authors: Alper Celik, Feng He, Richard Baker, Allan Jacobson