Digital Commons Network^™

Impact Of Common Variants On Brain Gene Expression From Rna To Protein To Schizophrenia Risk, Qiuman Liang, Yi Jiang, Annie W Shieh, Dan Zhou, Rui Chen, Feiran Wang, Meng Xu, Mingming Niu, Xusheng Wang, Dalila Pinto, Yue Wang, Lijun Cheng, Ramu Vadukapuram, Chunling Zhang, Kay Grennan, Gina Giase, Kevin P White, Junmin Peng, Bingshan Li, Chunyu Liu, Chao Chen, Sidney H Wang

The Brown Foundation: Institute of Molecular Medicine

Genetic variants influencing gene expression have been extensively studied at the transcriptional level. How these variants affect downstream processes remains unclear. We quantitated ribosome occupancy in prefrontal cortex samples from the BrainGVEX cohort and integrated these data with transcriptomic and proteomic profiles from the same individuals. Through cis-QTL mapping, we identified genetic variants associated with transcript level (eQTLs), ribosome occupancy (rQTLs), and protein level (pQTLs). Notably, only 34% of eQTLs have their effects propagated to the protein levels, suggesting widespread post-transcriptional attenuation. Using both a gene-based approach and a variant-based approach we identified omics-specific QTLs that associated with brain disorder …

Recombination Suppression Drives Expansion Of The Drosophila Dot Chromosome, Timothy J Stanek, Wilson Leung, Christopher D Shaffer, Ishtar Olaveja, Annabelle Laughlin, Jaquelyn Hester, Darwin Garrido, Emily K Oh, Maria Volski, Nistha Panda, Mia Mo, Ethan Cordes, Martin Dalling, Kacie Kershaw, Malcolm Arnott, Stephen Daly, Silvia Garcia Valenzuela, Paige Thompson, Kayla L Hastert, Destiny Sabb, Kathryn Karpinski, Meher Naaz Arora, Nicholas Rius, Larissa Lobello, Sebastian Jaramillo, Omkar Sonavane, Alice Herrmann, Laura K Reed, Sarah C R Elgin, Cindy Arrigo, Christopher E Ellison

Faculty, Staff and Student Publications

Genome size varies widely, even among closely related species, yet much less is known about chromosome size variation. Here we use the fourth chromosome of Drosophila, also known as the "Muller F element" or "dot chromosome", as a model to investigate chromosome-specific size expansion. The F element of most Drosophila species is small (∼1.3 Mb) and almost entirely heterochromatic, yet harbors approximately 80 protein-coding genes. Here, we study D. kikkawai, D. takahashii, D. ananassae, and D. bipectinata, whose F elements are 2- to 15-fold larger in size compared to D. melanogaster. Through manual gene curation and comparative genomic analysis, we …

Developmental Stage-Dependent Transcriptomic Responses To Neonatal Intraventricular Hemorrhage, Elizabeth Wallace-Anthony, Miriam Zamorano, Hemendra J Vekaria, Braden B Oldham, Kiara P Umpornpun, Scott D Olson, Stefano Berto, Brandon A Miller

Faculty, Staff and Student Publications

Neonatal intraventricular hemorrhage (IVH) is a major complication of preterm birth, yet how developmental stage influences the brain's response to injury remains unclear. We performed single-nucleus RNA sequencing on rat brains 24 h after IVH at postnatal day 2 (PND2) or day 5 (PND5) to define transcriptional responses across cell types. We identified 42 distinct cell populations and found that PND5 brains exhibited a markedly stronger immune and inflammatory response to IVH, with a threefold increase in differentially expressed genes compared to PND2. Microglia were the most perturbed cell type at both stages, showing increased oxidative stress and polarization toward …

Benchmarking Dna Foundation Models For Genomic And Genetic Tasks, Haonan Feng, Lang Wu, Bingxin Zhao, Chad Huff, Jianjun Zhang, Jia Wu, Lifeng Lin, Peng Wei, Chong Wu

Faculty, Staff and Student Publications

The rapid evolution of DNA foundation models promises to revolutionize genomics, yet comprehensive evaluations are lacking. Here, we present a comprehensive, unbiased benchmark of five models (DNABERT-2, Nucleotide Transformer V2, HyenaDNA, Caduceus-Ph, and GROVER) across diverse genomic and genetic tasks including sequence classification, gene expression prediction, variant effect quantification, and topologically associating domain (TAD) region recognition, using zero-shot embeddings. Our analysis reveals that mean token embedding consistently and significantly improves sequence classification performance, outperforming other pooling strategies. Model performance varies among tasks and datasets; while general purpose DNA foundation models showed competitive performance in pathogenic variant identification, they were less …

Radiologist-Validated Automatic Lumbar T1-Weighted Spinal Mri Segmentation Tool Via An Attention U-Net Algorithm, Aryan Kalluvila, Ethan Wang, Michael C Hurley, Colbey Freeman, Jason M Johnson

Faculty, Staff and Student Publications

Background/Objectives: Spinal MRI segmentation has become increasingly important with the prevalence of disc herniation and vertebral injuries. Artificial intelligence can help orthopedic surgeons and radiologists automate the process of segmentation. Currently, there are few tools for T1-weighted spinal MRI segmentation, with most focusing on T2-weighted imaging. This paper focuses on creating an automatic lumbar spinal MRI segmentation tool for T1-weighted images using deep learning.

Methods: An Attention U-Net was employed as the main algorithm because the architecture has shown success in other segmentation applications. Segmentation loss functions were compared, focusing on the difference between BCE and MSE loss. Two board-certified …

Microbial Associations And Viruses On The Risk Of Celiac Disease (Mavric): A Longitudinal Post-Hoc Case-Cohort Study, Kristian F Lynch, Eric W Triplett, Heikki Hyöty, Angelica P Ahrens, Jutta E Laiho, Joseph F Petrosino, Richard E Lloyd, Daniel Agardh

Faculty, Staff and Students Publications

Celiac disease etiopathogenesis requires genetic predisposition and exposure to gluten, yet these factors alone are not sufficient. Larger longitudinal studies are needed to determine the role of time-varying infections and gut microorganisms. The aim was to design a celiac disease case-cohort longitudinal study using The Environmental Determinants of Diabetes in the Young (TEDDY) study. By age 3-years, persistent tissue transglutaminase autoantibodies (tTGA), i.e., celiac disease autoimmunity (CDA), was confirmed in 704 of the 6132 genetically at-risk TEDDY children. Celiac disease onset (CD-onset) was defined as the age CDA developed when followed by a biopsy-proven diagnosis. A competing risk analysis on …

Mecp2 Interacts With The Super Elongation Complex To Regulate Transcription, Jun Young Sonn, Wonho Kim, Marta Iwanaszko, Yuki Aoi, Yan Li, Guantong Qi, Luke Parkitny, Janice L Brissette, Lorin Weiner, Juan Botas, Ismael Al-Ramahi, Ali Shilatifard, Huda Y Zoghbi

Faculty, Staff and Students Publications

Loss-of-function mutations in methyl-CpG binding protein 2 (MECP2) cause Rett syndrome. While we know that MeCP2 binds to methylated cytosines on DNA, the full breadth of the molecular mechanisms by which MeCP2 regulates gene expression remains incompletely understood. Here, using a genetic modifier screen, we identify the super elongation complex, a P-TEFb–containing elongation factor that releases promoter-proximally paused RNA polymerase II, as a genetic interactor of MECP2. MeCP2 physically interacts with SEC subunits and directly binds AFF4, the scaffold of the SEC, via the transcriptional repression domain. Furthermore, MeCP2 facilitates the binding of AFF4 on a subset …

Outcomes After Flow Diversion For Ruptured Blood Blister-Like And Dissecting Aneurysms: A Single-Center Series, William W Wroe, Hussein A Zeineddine, Si Y Yu, Bridger H Freeman, Richard S Cook, Charles M Christensen, Peng Roc Chen, Sunil A Sheth, Spiros L Blackburn

Faculty, Staff and Student Publications

Background

Flow diverter (FD) use has become a popular method for treating intracranial aneurysms, but evidence in acutely ruptured blood blister-like and dissecting morphologies is limited. Furthermore, there is little evidence regarding the role of short-term follow-up imaging to assess aneurysm stability. This study is a single-center retrospective review of dissecting aneurysms treated by FD, with an analysis of short-term follow-up angiograms to guide post-treatment management.

Methods

Our single-center retrospective review included all patients from 2016 to 2024 with spontaneous subarachnoid hemorrhage from blood blister-like and dissecting aneurysms who underwent treatment with an FD. Outcomes included re-rupture, treatment failure, re-treatment, …

Correction: Perioperative Quality Initiative (Poqi) Consensus Statement On Perioperative Assessment Of Right Ventricular Function, Stephanie O Ibekwe, Jean Deschamps, Michael P W Grocott, Yafen Liang, Andrew Shaw, Tjorvi E Perry

Faculty, Staff and Students Publications

No abstract provided.

Feasibility And Acceptability Of An Implementation Strategy To Enhance Use Of Classroom-Based Physical Activity Approaches In Elementary Schools: A Mixed Methods Study, Timothy J Walker, Derek W Craig, Christopher D Pfledderer, Matthew Lee, Kempson Onadeko, Emma E Saving, John B Bartholomew, Maria E Fernández

Faculty, Staff and Student Publications

Background: Classroom-based approaches are an evidence-based way to improve children's physical activity; however, they are inconsistently implemented in schools. We developed MAGIC (Movement for Academic Growth In Classrooms), a multifaceted implementation strategy that consists of leadership training, teacher training, and a monthly newsletter to improve use of classroom-based physical activity approaches. The purpose of this study is to examine the feasibility and acceptability of MAGIC among elementary school teachers and leaders.

Methods: We used an embedded, convergent mixed methods design. We provided the MAGIC implementation strategy to a partner elementary school. We then administered surveys to teachers to quantitatively examine …

Developing Ehealth Interventions To Improve Diabetes Management In Emerging Adulthood: Qualitative Formative Study, April Idalski Carcone, Deepika Baskar, Aishah Mahmood, Karen Macdonell, Susan Eggly, Samiran Ghosh, Colleen Buggs-Saxton, Steven J Ondersma, Deborah A Ellis

Faculty, Staff and Student Publications

Background: Emerging adulthood is a high-risk period during which many with type 1 diabetes demonstrate suboptimal diabetes management and glycemic control. There is a need for effective, scalable interventions designed specifically for this population. Technology-based approaches are readily accessible to this age group. Furthermore, interventions consistent with self-determination theory-which posits that the fulfillment of psychological needs for autonomy, self-efficacy, and relatedness promotes intrinsic motivation for change-may resonate well with emerging adults' developmental needs for establishing independence and autonomy, and growing their social network.

Objective: This study aimed to enhance the potential relevance, sustainability, and efficacy of 3 self-determination theory-informed mobile …

Met Overexpression Is Associated With Superior Immunotherapy Benefit In Advanced Non-Small Cell Lung Cancer, Hui Li, Lingzhi Hong, Pedro Rocha, Rafael Bach, Luisa M Solis Soto, Waree Rinsurongkawong, Bingnan Zhang, Haniel A Araujo, Yasir Y Elamin, Mehmet Altan, Claudio A Arrechedera, Jianling Zhou, Khaja B Khan, Wei Lu, Elliana Young, Carl M Gay, Tina Cascone, Lauren A Byers, Ferdinandos Skoulidis, George Blumenschein, Frank V Fossella, Anne Tsao, Marcelo V Negrao, Natalie Vokes, Jia Wu, Hai T Tran, Ignacio I Wistuba, J Jack Lee, Don L Gibbons, Ara A Vaporciyan, John V Heymach, Xiuning Le, Jianjun Zhang

Faculty, Staff and Student Publications

Background/objectives: MET overexpression is common in non-small cell lung cancer (NSCLC). The correlation between MET overexpression and immune checkpoint inhibitor (ICI) efficacy in NSCLC is underexplored.

Methods: In this retrospective observational cohort study, we curated a dataset of 279 stage IV NSCLC patients who received ICI treatment and had MET expression assessed by CLIA-certified immunohistochemistry (IHC) assay. MET expression was graded on a scale from 0 to 3+, with overexpression defined as 2+ or 3+. Clinicopathological features associated with MET expression were assessed using logistic regression. Overall survival (OS) and progression-free survival (PFS) were evaluated via Kaplan-Meier analysis and the …

Improving Diagnostic Accuracy In Preoperative Glioma Classification: Performance Of Knowledge-Enhanced Large Language Models Compared With Radiologists, Shuang Li, Xin Fang, Yuqi Jin, Yujiao Deng, Wei Hu, Bing Wu, Xiaobo Zhou, Guotai Wang, Kang Li, Qiang Yue

Faculty, Staff and Student Publications

Accurate preoperative MRI classification of gliomas is essential but challenging due to complex radiological features and inter-observer variability. This study evaluated three large language models (LLMs) for VASARI-based glioma classification compared to radiologist interpretations. We retrospectively analyzed 150 histopathologically confirmed gliomas (43 circumscribed astrocytic, 53 high-grade diffuse, 54 low-grade diffuse gliomas) using standardized MRI protocols. Three radiologists extracted VASARI features, while three LLMs (GPT-4, Claude3.5-Sonnet, Claude3.0-Opus) analyzed these features using standard input-output or knowledge-enhanced prompting incorporating diagnostic guidelines. Knowledge-enhanced prompting consistently outperformed standard prompting, improving diagnostic consistency (intra-model agreement: Sonnet κ = 0.91, Opus κ = 0.92, GPT-4 κ = …

A Phase 1/2 Study Of Ds-1594 Menin Inhibitor In Relapsed/Refractory Acute Leukemias, Jayastu Senapati, Marina Konopleva, Ghayas C Issa, Elias Jabbour, Tapan Kadia, Courtney Dinardo, Gautam Borthakur, Naveen Pemmaraju, Nicholas J Short, Musa Yilmaz, Indraneel Deshmukh, Joie Alvarez, Sanam Loghavi, Guilin Tang, Hussein A Abbas, Michael Andreeff, Kapil Bhalla, Narasimha M Midde, Nabil Said, Amy Noyalis, Derek E Mires, Jing Ning, Lianchun Xiao, Farhad Ravandi, Guillermo Garcia-Manero, Hagop M Kantarjian, Naval G Daver

Faculty, Staff and Student Publications

Several menin inhibitors are in development targeting menin dependent leukemias, however available preclinical results show variable level of activity. We report the phase 1 portion (to establish a recommended phase 2 dose [RP2D]) and pharmacokinetic analysis of a phase 1/2 first-in-human clinical trial of DS-1594b menin inhibitor. Eligible patients included adults (≥ 18 years of age) with relapsed/refractory (R/R) acute myeloid leukemia (AML) or acute lymphoblastic leukemia (ALL) including but not restricted to those with KMT2A-rearrangement (r) or NPM1 mutation. Seventeen patients at a median of age 56 years (range, 19-82 years) were treated, 15 (88%) had R/R AML, and …

Soluble Immune Factor Profiles In Blood And Csf Associated With Lrrk2 Mutations And Parkinson's Disease, Roshni Jaffery, Yuhang Zhao, Sarfraz Ahmed, Jackson G Schumacher, Jae Ahn, Leilei Shi, Yujia Wang, Yukun Tan, Jiayin Zhang, Ken Chen, Hussein Tawbi, Jian Wang, Michael A Schwarzschild, Weiyi Peng, Xiqun Chen

Faculty, Staff and Student Publications

Mutations in LRRK2, a leading genetic cause of Parkinson's disease (PD), are linked to immune dysregulation, but the immune profiles in the periphery and central nervous system (CNS) remain incompletely defined. This study utilized a large cohort of serum samples (n = 651) and matched CSF samples (n = 129) from LRRK2 mutation carriers and non-carriers, with and without PD, to assess immune regulators using Luminex immunoassay. After correction for multiple comparisons, LRRK2 mutations were associated with significantly elevated serum levels of SDF-1 alpha and TNF-RII, while CSF markers such as BAFF, CD40L, and IL-27 were nominally reduced. Regardless of …

Human Plasma Proteomic Profile Of Clonal Hematopoiesis, Zhi Yu, Amélie Vromman, Ngoc Quynh H Nguyen, Art Schuermans, Linke Li, Thiago Rentz, Tetsushi Nakao, Shamsudheen K Vellarikkal, Md Mesbah Uddin, Abhishek Niroula, Gabriel Griffin, Michael C Honigberg, Amy E Lin, Christopher J Gibson, Daniel H Katz, Usman A Tahir, Shi Fang, Jacqueline S Dron, Michael Pan, Sara Haidermota, Shriienidhie Ganesh, Tajmara Antoine, Joshua Weinstock, Thomas R Austin, Ramachandran S Vasan, Gina M Peloso, Whitney Hornsby, Peter Ganz, Joann E Manson, Bernhard Haring, Charles Kooperberg, Alexander P Reiner, Joshua C Bis, Bruce M Psaty, Yuan-I Min, Adolfo Correa, Leslie A Lange, Wendy S Post, Jerome I Rotter, Stephen S Rich, James G Wilson, Benjamin L Ebert, Bing Yu, Christie M Ballantyne, Josef Coresh, Vijay G Sankaran, Alexander G Bick, Siddhartha Jaiswal, Robert E Gerszten, Nhlbi Trans-Omics For Precision Medicine, Peter Libby, Rajat M Gupta, Pradeep Natarajan

Faculty, Staff and Student Publications

Plasma proteomic profiles associated with subclinical somatic mutations in blood cells may offer insights into downstream clinical consequences. Here we explore these patterns in clonal hematopoiesis of indeterminate potential (CHIP), which is linked to several cancer and non-cancer outcomes, including coronary artery disease (CAD). Among 61,833 participants (3881 with CHIP) from TOPMed and UK Biobank (UKB) with blood-based DNA sequencing and proteomic measurements (1,148 proteins by SomaScan in TOPMed and 2917 proteins by Olink in UKB), we identify 32 and 345 proteins from TOPMed and UKB, respectively, associated with CHIP and most prevalent driver genes (DNMT3A, TET2, and ASXL1). These …

Brain Power Comparison Between Microgravity And Head-Down Tilt Bed Rest: An Electroencephalography Approach, María Sevilla-García, Adrián Quivira-Lopesino, Pablo Cuesta, Sandra Pusil, Ricardo Bruña, Patrique Fiedler, Fernando Maestu, Ana Maria Cebolla, Guy Cheron, Katharina Brauns, Alexander C Stahn, Michael E Funke

Faculty, Staff and Student Publications

This study examines neurophysiological changes in microgravity by comparing EEG data from two ground analog 60-day head-down tilt bed rest (HDBR) experiments (ESA/DLR “Cocktail” and “RSL”) and the NEUROSPAT experiment in space. The primary objective was to determine whether HDBR could effectively model spaceflight’s impact on the human brain’s EEG signal. In the HDBR dataset, increases in relative delta (2–4 Hz) (p <  0.01) and theta (4–8 Hz) (p <  0.001) power bands were observed during a two-month HDBR experiment, predominantly in the left temporal and parieto-occipital regions. Conversely, the NEUROSPAT dataset showed a significant increase in beta (12–30 Hz) (p <  0.05) power in the left somatosensory cortex during in-flight conditions, suggesting a potential adaptation to disrupted proprioceptive input and motor control in microgravity. The contrasting findings between the two datasets indicate that while HDBR can simulate some aspects of microgravity, it may not serve as a model for all central nervous system changes, especially those related to proprioception and motor functions. This highlights the need for further research, including larger sample sizes, consistent EEG recording conditions, and integration of additional physiological and cognitive markers to fully understand the effects of prolonged microgravity.

Accelerating Digital Mental Health: The Society Of Digital Psychiatry's Three-Pronged Road Map For Education, Digital Navigators, And Ai, John Torous, Kathryn Taylor Ledley, Carla Gorban, Gillian Strudwick, Julian Schwarz, Soumya Choudhary, Margaret Emerson, Michelle Patriquin, Allison Dempsey, Jason Bantjes, Laura Ospina-Pinillos, Jennie Hornick, Shruti Kochhar

Faculty, Staff and Student Publications

Digital mental health tools such as apps, virtual reality, and artificial intelligence (AI) hold great promise but continue to face barriers to widespread clinical adoption. The Society of Digital Psychiatry, in partnership with JMIR Mental Health, presents a 3-pronged road map to accelerate their safe, effective, and equitable implementation. First, education: integrate digital psychiatry into core training and professional development through a global webinar series, annual symposium, newsletter, and an updated open-access curriculum addressing AI and the evolving digital navigator role. Second, AI standards: develop transparent, actionable benchmarks and consensus guidance through initiatives like MindBench.ai to assess reasoning, safety, and …

Delphi Panel On Neuromodulation As A Treatment Strategy For Dry Eye Disease: Unlocking The Potential Of Natural Tear Production, Esen Akpek, Lyndon Jones, Kelly K Nichols, Lisa M Nijm, Stephen Pflugfelder

Faculty, Staff and Students Publications

Purpose: Chronic tear deficiency, through reduced production and/or increased evaporation, is regarded as a root cause of dry eye disease (DED). The goal of treating DED is restoration of the tear film ultimately resulting in ocular surface homeostasis. Multiple therapeutic prescription drugs to manage DED exist with varying speed of onset, overall magnitude of efficacy, and tolerability. Neuromodulation is an emerging treatment modality offering direct stimulation of natural tear production. A modified Delphi study was conducted to explore the role of neuromodulation as a treatment for DED.

Methods: Twenty DED experts participated in three rounds of structured electronic Delphi questionnaires. …

Prior Incarceration And Dental Insurance Trajectories Throughout Older Adulthood, A Testa, L Mijares, D B Jackson, V Maroufy, R Samper-Ternent, A C Neumann, R Mungia, K T Ganson, J M Nagata, T Oates

Faculty, Staff and Student Publications

Objectives: This study examines the relationship between prior incarceration and dental insurance trajectories throughout older adulthood.

Methods: A nationally representative sample of adults aged 55 y and older who participated in the 2012-2020 Health and Retirement Survey was analyzed (n = 6,383). Group-based trajectory modeling was used to identify distinct patterns of dental insurance coverage across the 8 survey waves. Multinomial logistic regression was used to assess the association between prior incarceration and dental insurance trajectory group membership.

Results: Four dental insurance trajectories were identified: persistent dental insurance (30.0%), intermittent high insurance (16.4%), intermittent low insurance (20.4%), and no …

Predicting The Response Of Triple Negative Breast Cancer To Neoadjuvant Systemic Therapy Via Biology-Based Modeling And Habitat Analysis, Casey E Stowers, Chengyue Wu, Clinton Yam, Jingfei Ma, Gaiane M Rauch, Thomas E Yankeelov

Faculty, Staff and Student Publications

Despite being the standard-of-care treatment, neoadjuvant therapy (NAT) attains a complete response only in approximately half of the patients with triple negative breast cancer. Thus, methods to predict and optimize patient response to NAT are needed. Previously, we employed patient-specific MRI data to calibrate a biology-based mathematical model that describes cell movement, proliferation, and death due to drug at the tumor level and cell proliferation at an image voxel level. We now extend our approach by using MRI data to group voxels into "habitats" whereby tumor cells of a habitat share the same proliferation. With this approach, we now calibrate …

Impact Of Atrial Fibrillation, Diabetes Mellitus, And Obesity On Outcomes With Aspirin Avoidance And Hemocompatibility With A Left Ventricular Assist Device: An Analysis From The Aries-Hm3 Trial, Nir Uriel, Ivan Netuka, Ulrich P Jorde, Francis D Pagani, Jason N Katz, Jean M Connors, Peter Ivak, Daniel Zimpfer, Yuriy Pya, Jennifer Conway, Finn Gustafsson, Sriram Nathan, Anna Mara Scandroglio, Christopher Hayward, David A D'Alessandro, Morgan Collins, Nicholas Dirckx, Mandeep R Mehra

Faculty, Staff and Student Publications

Background: The ARIES-HM3 trial demonstrated the safety and effectiveness of aspirin elimination from the antithrombotic regimen after HeartMate 3 (HM3) left ventricular assist device (LVAD) implantation. We explored the interaction of atrial fibrillation, diabetes mellitus, and obesity (AF/DM/Ob) with aspirin elimination on hemocompatibility-related adverse events at 1-year postimplant.

Methods: This prospective, double-blind, placebo-controlled trial randomized patients with an HM3 LVAD implant to receive aspirin (100 mg/d) or placebo, in addition to a vitamin K antagonist. The primary endpoint was survival free of nonsurgical (>14 days postimplant) hemocompatibility-related adverse events, including stroke, pump thrombosis, bleeding, and arterial peripheral thromboembolism at …

Loss Of Idh1 And Idh2 Mutations During The Evolution Of Metastatic Chondrosarcoma, William Cross, Iben Lyskjær, Christopher Davies, Abigail Bunkum, Ana Maia Rocha, Tom Lesluyes, Fernanda Amary, Roberto Tirabosco, Cristina Naceur-Lombardelli, Mariam Jamal-Hanjani, Charles Swanton, Nischalan Pillay, Simone Zaccaria, Adrienne M Flanagan, Peter Van Loo

Faculty, Staff and Student Publications

Driver mutations in IDH1 and IDH2 are initiating events in the evolution of chondrosarcoma and several other cancer types. Here, we present evidence that mutant IDH1 is recurrently lost in metastatic central chondrosarcoma. This may reflect either relaxed positive selection for the mutant IDH1 locus, or negative selection for the hypermethylation phenotype later in tumor evolution. This finding highlights the challenge for therapeutic intervention by mutant IDH1 inhibitors in chondrosarcoma.

Transcription-Replication Collisions Trigger High-Fidelity Replication Reset, Matthew B Cooke, Kobie T Welch, Laura Deus Ramirez, Katelin M Hagstrom, Alice X Wen, Jennifer A Halliday, Susan M Rosenberg, Christophe Herman

Faculty, Staff and Students Publications

Double-stranded DNA ends arise from external agents or cellular processes like transcription-replication collisions (TRCs), threatening genome stability. Here, we performed genomic CRISPRi screens to uncover DNA end formation factors in Escherichia coli. We discovered that translation-transcription decoupling causes DNA end formation through a TRC-dependent pathway, which is lethal when DNA end processing by RecBCD is disrupted, but not when recombination is disrupted. We find that TRCs cause replisome stalling followed by "rear-ending" from trailing replisomes which generates free DNA ends, rather than strand breaks. Surprisingly, these DNA ends are resolved through a process we call "replication reset", where the stalled …

Waiting Room And Hallway Care For Older Adults: A Qualitative Study With Emergency Nurses And Technicians, Sarah J Nessen, Ari B Friedman, Annika R Bhananker, K Jane Muir, Anita N Chary

Faculty, Staff and Students Publications

Background: Emergency Department (ED) crowding places older ED patients at risk for adverse outcomes. Crowding often necessitates ED waiting room and hallway care, but there has been limited research on approaches to care for older adults in these settings. Frontline clinician insights can inform best practices for older adults in the context of the ongoing ED crowding crisis. Our objective was to describe the experiences of emergency nurses and technicians in providing waiting room and hallway care for older adults.

Methods: This qualitative study used individual, semi-structured interviews with a purposive sample of 20 ED nurses and technicians at a …

Multimodal Cardiac Imaging Of Immune-Mediated Complications Post Heart Transplantation: A Contemporary Review, Bruno Bezerra Lima, Tam T Doan, Atilla Feher, James C Wilkinson, Marvin W Kronenberg, Chloe Carr, Malek Nayfeh, Tania Ruiz, Luke L Laws, Melissa Lou Silva, John A Wells, Leandro Slipczuk, Emily T Lippincott, John J Carr, Kaushik Amancherla, Cameron Henry, David Parra, Kelly Schlendorf, Quinn S Wells, Sean G Hughes, Jonathan Soslow

Faculty, Staff and Students Publications

Heart transplantation significantly enhances survival and quality of life for patients with end-stage heart failure. Despite advances in surgical and postoperative care, immune-mediated complications, acute graft rejection and cardiac allograft vasculopathy (CAV), remain major barriers to long-term success. Acute rejection predominantly affects early posttransplant survival, whereas CAV becomes a leading cause of mortality in later years. The gold standards for diagnosis, endomyocardial biopsy for rejection and coronary angiography for CAV, are invasive and imperfect. Noninvasive multimodality imaging is increasingly used to complement or, in selected scenarios, defer invasive testing. Echocardiography with strain detects early myocardial dysfunction when ejection fraction is …

Investigating The Neuronal Role Of The Proteasomal Atpase Subunit Gene Psmc5 In Neurodevelopmental Proteasomopathies, Sébastien Küry, Janelle E Stanton, Geeske M Van Woerden, Amélie Bosc-Rosati, Tzung-Chien Hsieh, Lise Bray, Marielle Oloudé, Cory Rosenfelt, Marie Pier Scott-Boyer, Victoria Most, Tianyun Wang, Jonas J Papendorf, Charlotte De Konink, Wallid Deb, Virginie Vignard, Maja Studencka-Turski, Thomas Besnard, Anna M Hajdukowicz, Franziska G Thiel, Sophie Wolfgramm, Laëtitia Florenceau, Silvestre Cuinat, Sylvain Marsac, Yann Verrès, Audrey Dangoumau, Léa Poirier, Ingrid M Wentzensen, Annabelle Tuttle, Cara Forster, Johanna Striesow, Richard Golnik, Damara Ortiz, Laura Jenkins, Jill A Rosenfeld, Alban Ziegler, Clara Houdayer, Dominique Bonneau, Erin Torti, Amber Begtrup, Kristin G Monaghan, Sureni V Mullegama, Catharina M L Nienke Volker-Touw, Koen L I Van Gassen, Renske Oegema, Mirjam S De Pagter, Katharina Steindl, Anita Rauch, Ivan Ivanovski, Kimberly Mcdonald, Emily Boothe, Andrew Dauber, Janice Baker, Noelle Andrea V Fabie, Raphael A Bernier, Tychele N Turner, Siddharth Srivastava, Kira A Dies, Lindsay C Swanson, Carrie Costin, Alali Abdulrazak, Rebekah K Jobling, John Pappas, Rachel Rabin, Dmitriy Niyazov, Anne Chun-Hui Tsai, Karen Kovak, David B Beck, May Christine V Malicdan, David R Adams, Lynne Wolfe, Rebecca D Ganetzky, Colleen C Muraresku, Davit Babikyan, Zdeněk Sedláček, Miroslava Hančárová, Andrew T Timberlake, Hind Al Saif, Berkley Nestler, Kayla King, M J Hajianpour, Gregory Costain, D'Arcy Prendergast, Chumei Li, David Geneviève, Antonio Vitobello, Arthur Sorlin, Christophe Philippe, Tamar Harel, Ori Toker, Ataf Sabir, Derek Lim, Mark J Hamilton, Lisa J Bryson, Elaine Cleary, Sacha Weber, Trevor L Hoffman, Anna M Cueto-González, Eduardo F Tizzano, David Gómez-Andrés, Marta Codina-Solà, Athina Ververi, Efterpi Pavlidou, Alexandros Lambropoulos, Kyriakos Garganis, Marlène Rio, Jonathan Levy, Sarah J Langas, Anne M Mcrae, Mathieu K Lessard, Maria Daniela D'Agostino, Isabelle De Bie, Meret Wegler, Rami Abou Jamra, Susanne B Kamphausen, Viktoria Bothe, Lorraine Potocki, Eric Olinger, Yves Sznajer, Elsa Wiame, Michelle L Thompson, Molly C Schroeder, Catherine Gooch, Raphael A Smith, Arti Pandya, Larissa M Busch, Uwe Völker, Elke Hammer, Kristian Wende, Benjamin Cogné, Bertrand Isidor, Jens Meiler, Clémentine Ripoll, Stéphanie Bigou, Frédéric Laumonnier, Peter W Hildebrand, Evan E Eichler, Kirsty Mcwalter, Peter M Krawitz, Florence Roux-Dalvai, Ype Elgersma, Julien Marcoux, Marie-Pierre Bousquet, Arnaud Droit, Jeremie Poschmann, Andreas M Grabrucker, Francois V Bolduc, Stéphane Bézieau, Frédéric Ebstein, Elke Krüger

Faculty, Staff and Students Publications

Neurodevelopmental proteasomopathies are a group of disorders caused by variants in proteasome subunit genes, that disrupt protein homeostasis and brain development through poorly characterized mechanisms. Here, we report 26 distinct variants in PSMC5, encoding the AAA⁺ ATPase subunit PSMC5/RPT6, in individuals with syndromic neurodevelopmental conditions. Combining genetic, multi-omics and biochemical approaches across cellular models and Drosophila, we unveil the essential role of proteasomes in sustaining key cellular processes. Loss of PSMC5/RPT6 function impairs proteasome activity, leading to protein aggregation, disruption of mitochondrial homeostasis, and dysregulation of lipid metabolism and immune signaling. It also compromises synaptic balance, neuritogenesis, and neural progenitor …

Current Status And Future Directions For The Use Of Artificial Intelligence In Pediatric Critical Care Nephrology, Sameer Thadani, Christopher M Horvat, Christin Silos, Bronwyn Sutherland, Kristin Dolan, Jin Chen, Ayse Akcan-Arikan, Javier A Neyra

Library Staff Publications

Artificial intelligence (AI) has the potential to significantly improve the practice of medicine. However, its application in pediatric critical care nephrology remains underdeveloped. This scoping review investigates the current state of AI/machine learning (ML) algorithms developed and implemented in the field of pediatric critical care nephrology over more than two decades (2000-2024). We identified 24 articles related to commonly encountered pathologies including acute kidney injury (AKI), electrolyte and acid-base imbalances, fluid management, and dialysis. Twenty (80%) of these articles focused on AKI (prediction and/or detection) and only two articles (4%) investigated the impact of implemented AI/ML models on clinical care …

Leaping Between Branches: Hybridisation And The Tangled Evolutionary History Of True Lemurs, Giacomo Mercuri, Giovanni Merici, Kyle Kai-How Farh, Lukas F K Kuderna, Jeffrey Rogers, Tomàs Marques-Bonet, Giuseppe Donati, Riccardo Percudani, Cristian Capelli

Faculty, Staff and Students Publications

The true lemurs (genus Eulemur) are a genetically diverse and spatially widespread group of species inhabiting most of Madagascar's forests. Including 12 recognized species, the genus can be divided into four major evolutionary groups: E. rubriventer, E. mongoz, the Brown Lemur Species Complex (BLSC), and the coronatus-macaco-flavifrons complex (CMFC), although monophyly for the CMFC is not always supported. Recent genome-based studies highlighted topological and chronological differences between nuclear and mitochondrial phylogenies of true lemurs, which could be explained by events of hybridisation. In order to reconstruct the evolutionary history of the genus, we test for gene-flow between Eulemur clades using …

Optimizing Lower Intensity Triplet Therapy In Acute Myeloid Leukemia: A Practical Guide, Wei-Ying Jen, Curtis A Lachowiez, Jennifer Marvin-Peek, Jessica K Altman, Musa Yilmaz, Jacqueline S Garcia, Yasmin Abaza, Nicholas J Short, Joshua F Zeidner, Naval G Daver, Andrew H Wei, Ghayas C Issa, Courtney D Dinardo

Faculty, Staff and Student Publications

Venetoclax-based doublets with azacitidine or low dose cytarabine are the standard of care for the treatment of acute myeloid leukemia (AML) in older patients or those unfit for intensive chemotherapy. However, some patients do not attain complete remission, and over time, most patients relapse. Frontline triplet therapy incorporating a targeted therapy (FLT3, IDH or menin inhibitor) is an emerging treatment concept under investigation for this population. Initial triplet regimens have yielded encouraging composite complete remission and measurable residual disease negativity rates, enabling the transition to allogeneic stem cell transplantation for eligible patients. While effective, triplets are associated with myelosuppression and …