Digital Commons Network^™

Spectrum Of Coronary Artery Involvement With Multisystem Inflammatory Syndrome In Children Versus Kawasaki Disease., Simon Lee, Ashraf S. Harahsheh, Geetha Raghuveer, Michael A. Portman, Arash A. Sabati, Michael Khoury, Nagib Dahdah, Marianna Fabi, Supriya S. Jain, Audrey Dionne, Kyle Runeckles, Frederic Dallaire, Nadine F. Choueiter, Tyler H. Harris, Matthew D. Elias, Anji T. Yetman, Balasubramanian Sundaram, Luis M. Garrido-Garcia, Nilanjana Misra, Cedric Manlhiot, Pedrom Farid, Brian W. Mccrindle

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: There is significant overlap in clinical features between multisystem inflammatory syndrome in children (MIS-C) and Kawasaki disease (KD). We sought to compare the prevalence, severity, and associated factors for coronary artery (CA) involvement.

METHODS AND RESULTS: From January 1, 2020 through January 31, 2023, 1191 patients with MIS-C and 554 patients contemporaneously diagnosed with KD were enrolled into the International Kawasaki Disease Registry. Demographic and clinical features, laboratory values, maximum Z score in any CA branch +2.5 or greater) were determined separately for each diagnosis using multivariable logistic regression analyses. The prevalence of CA aneurysms was lower for MIS-C …

Lifespan Reference Curves For Harmonizing Multi-Site Regional Brain White Matter Metrics From Diffusion Mri, Alyssa H Zhu, Talia M Nir, Shayan Javid, Julio E Villalón-Reina, Amanda L Rodrigue, Lachlan T Strike, Greig I De Zubicaray, Katie L Mcmahon, Margaret J Wright, Sarah E Medland, John Blangero, David C Glahn, Peter Kochunov, Douglas E Williamson, Asta K Håberg, Paul M Thompson, Neda Jahanshad

Faculty, Staff and Student Publications

Age-related white matter (WM) microstructure maturation and decline occur throughout the human lifespan, complementing the process of gray matter development and degeneration. Here, we create normative lifespan reference curves for global and regional WM microstructure by harmonizing diffusion MRI (dMRI)-derived data from ten public datasets (N = 40,898 subjects; age: 3-95 years; 47.6% male). We tested three harmonization methods on regional diffusion tensor imaging (DTI) based fractional anisotropy (FA), a metric of WM microstructure, extracted using the ENIGMA-DTI pipeline. ComBat-GAM harmonization provided multi-study trajectories most consistent with known WM maturation peaks. Lifespan FA reference curves were validated with test-retest data …

A Cluster Randomized Trial Of A Multicomponent Clinical Care Pathway (Mccp) To Improve Masld Diagnosis And Management In Primary Care: Study Protocol, Kyler M Godwin, Larissa Grigoryan, Aaron P Thrift, Hao Duong, Fasiha Kanwal, Traber Giardina, Himabindu Kadiyala, Andrew Zimolzak, Kavish R Patidar, Hashem B El-Serag

Faculty, Staff and Students Publications

Background: Metabolic dysfunction associated steatotic liver disease (MASLD) is the most common chronic liver disorder in the world. Most patients with MASLD are undiagnosed, untreated and unreferred. Treatment depends on diagnosis and accurate staging of fibrosis risk, and therefore screening at the primary care setting coupled with consistent, timely, evidence-based, widely accessible, and testable management processes is critical. Randomized controlled trials of methods for screening, diagnosis, severity stratification, and referral are lacking. We previously validated the MASLD clinical care pathway (MCCP), a multistep algorithmic process geared to support primary care settings in screening, diagnosis, risk stratification, and suggested referral and …

Genome Announcement Of Four Parechovirus A3 Isolates From The United States Of America., Debarpan Dhar, Terry Fei Fan Ng, Christopher J. Harrison, Eric Rhoden, Bernardo A Mainou, Anjana Sasidharan, Katelyn E. Vandonge, Varun Chandra Boinpelly, Rangaraj Selvarangan

Manuscripts, Articles, Book Chapters and Other Papers

We report the complete genome sequences of four parechovirus-A3 (PeV-A3) isolates from Children's Mercy Kansas City (CMKC), United States of America (USA): PeV-A3-MO-12-CMKC/CSF/MO/USA/2012 (isolated in 2012 from cerebrospinal fluid), PeV-A3-8C-CMKC/CSF/MO/USA/2022/ (isolated in 2022 from cerebrospinal fluid), PeV-A3-9C-CMKC/CSF/MO/USA/2022 (isolated in 2022 from cerebrospinal fluid), and PeV-A3-11B-CMKC/Blood/MO/USA/2022 (isolated in 2022 from blood). Sequence analysis revealed multiple mutations throughout the genome of the PeV-A3 isolates in comparison to the prototypic PeV-A3 A308/99 reference sequence (AB084913). Several unique amino acid changes were observed in the PeV-A3 isolates from 2022 that were absent in the PeV-A3 isolate from 2012. Phylogenetic analysis comparison determined that the …

Rescue Of The First Mitochondrial Membrane Carrier, The Mpic, By Tat-Mediated Protein Replacement Treatment, Samar Zabit, Orly Melloul, Michal Lichtenstein, Erin L. Seifert, Haya Lorberboum-Galski

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

The mitochondrial phosphate carrier (mPiC), encoded by the nuclear gene SLC25A3, is synthesized with an N-terminus mitochondrial targeting sequence (MTS), enabling its import into the mitochondria. mPiC imports inorganic phosphate (P_i) into the mitochondrial matrix for ATP production and other matrix phosphorylation reactions, as well as regulates mitochondrial Ca²⁺ uptake and buffering of matrix Ca²⁺. PiC also imports copper (Cu), crucial to COX subunit holoenzyme assembly. Variants in SLC25A3 exist and lead to mPiC deficiency (MPCD), cause a rare autosomal recessive disease with no current cure; patients with MPCD usually die within the first …

Relationship Between Maternal Iron Indices In The Second Trimester With Cord Blood Iron Indices And Pregnancy Outcomes: A Prospective Cohort Study, J.P. Akshaykirthan, Manjunath S. Somannavar, M.S. Deepthy, Umesh Charantimath, S. Yogeshkumar, Amaresh Patil, Mrutyunjaya B. Bellad, Richard Derman, Shivaprasad S. Goudar

Global Health Articles

Background/Objectives: Iron deficiency anemia in pregnancy poses risks to mothers and infants. This study aimed to correlate maternal iron indices in the second trimester with cord blood indices and pregnancy outcomes.

Methods: This prospective cohort study was nested within the RAPIDIRON Trial (Reducing Anaemia in Pregnancy in India) at Jawaharlal Nehru Medical College, Karnataka, India. A total of 292 pregnant women with moderate anemia who received oral iron supplementation were enrolled from April 2021 to May 2023. Maternal iron indices were measured at multiple time points and correlated with cord blood indices and pregnancy outcomes.

Results: Increased hemoglobin levels were …

Identifying Genetic Errors Of Immunity Due To Mosaicism, Elizabeth G Schmitz, Malachi Griffith, Obi L Griffith, Megan A Cooper

2020-Current year OA Pubs

Inborn errors of immunity are monogenic disorders of the immune system that lead to immune deficiency and/or dysregulation in patients. Identification of precise genetic causes of disease aids diagnosis and advances our understanding of the human immune system; however, a significant portion of patients lack a molecular diagnosis. Somatic mosaicism, genetic changes in a subset of cells, is emerging as an important mechanism of immune disease in both young and older patients. Here, we review the current landscape of somatic genetic errors of immunity and methods for the detection and validation of somatic variants.

What Are The Effects Of Time-Restricted Eating Upon Metabolic Health Outcomes In Individuals With Metabolic Syndrome: A Scoping Review, Rory J Heath, Jessie Welbourne, Daniel Martin

Peninsula Medical School

The primary objective of this scoping review (ScR) was to assess the breadth and type of evidence related to time-restricted eating (TRE) as an intervention to modify metabolic health outcomes in individuals with diagnosed metabolic syndrome (MetS), a major health challenge due to increasing prevalence and association with other chronic diseases. MetS comprises three or more of hypertension, hypercholesterolaemia, dyslipidaemia, dysregulated glucose homeostasis, and abdominal obesity. TRE, also known as time-restricted feeding (TRF), restricts food intake to specific time windows within a day, for example, a 10-h eating period between 10:00 and 20:00. Via multiple mechanisms, TRE interventions may provide …

Alzheimer’S Disease Protective Allele Of Clusterin Modulates Neuronal Excitability Through Lipid-Droplet-Mediated Neuron-Glia Communication, Xiaojie Zhao, Yan Li, Siwei Zhang, Ari Sudwarts, Hanwen Zhang, Alena Kozlova, Matthew J Moulton, Lindsey D Goodman, Zhiping P Pang, Alan R Sanders, Hugo J Bellen, Gopal Thinakaran, Jubao Duan

Duncan NRI Faculty and Staff Publications

Background: Genome-wide association studies (GWAS) of Alzheimer's disease (AD) have identified a plethora of risk loci. However, the disease variants/genes and the underlying mechanisms have not been extensively studied.

Methods: Bulk ATAC-seq was performed in induced pluripotent stem cells (iPSCs) differentiated various brain cell types to identify allele-specific open chromatin (ASoC) SNPs. CRISPR-Cas9 editing generated isogenic pairs, which were then differentiated into glutamatergic neurons (iGlut). Transcriptomic analysis and functional studies of iGlut co-cultured with mouse astrocytes assessed neuronal excitability and lipid droplet formation.

Results: We identified a putative causal SNP of CLU that impacted neuronal chromatin accessibility to transcription-factor(s), with …

Patterns Of Associations With Epidemiologic Factors By High-Grade Serous Ovarian Cancer Gene Expression Subtypes., Lindsay J Collin, Kara L Cushing-Haugen, Kathryn L Terry, Ellen L Goode, Anna H Wu, Holly R Harris, Naoko Sasamoto, Daniel W Cramer, Francesmary Modugno, Esther Elishaev, Zhuxuan Fu, Kirsten B Moysich, Peter A Fasching, Celeste Leigh Pearce, Usha Menon, Aleksandra Gentry-Maharaj, Simon A Gayther, Nicolas Wentzensen, Marc T Goodman, Joshy George, Aline Talhouk, Michael S Anglesio, Susan J Ramus, David D L Bowtell, Shelley S Tworoger, Joellen M Schildkraut, Penelope M Webb, Jennifer A Doherty

Faculty Research 2025

BACKGROUND: Ovarian high-grade serous carcinomas (HGSC) comprise four distinct molecular subtypes based on mRNA expression patterns, with differential survival. Understanding risk factor associations is important to elucidate the etiology of HGSC. We investigated associations between different epidemiologic risk factors and HGSC molecular subtypes.

METHODS: We pooled data from 11 case-control studies with epidemiologic and tumor gene expression data from custom NanoString CodeSets developed through a collaboration within the Ovarian Tumor Tissue Analysis consortium. The PrOTYPE-validated NanoString-based 55-gene classifier was used to assign HGSC gene expression subtypes. We examined associations between epidemiologic factors and HGSC subtypes in 2,070 cases and 16,633 …

Artificial Intelligence-Based Virtual Staining Platform For Identifying Tumor-Associated Macrophages From Hematoxylin And Eosin-Stained Images, Arpit Aggarwal, Mayukhmala Jana, Amritpal Singh, Tanmoy Dam, Himanshu Maurya, Tilak Pathak, Sandra Orsulic, Kailin Yang, Deborah Chute, Justin A Bishop, Farhoud Faraji, Wade M Thorstad, Shlomo Koyfman, Scott Steward, Qiuying Shi, Vlad Sandulache, Nabil F Saba, James S Lewis, Germán Corredor, Anant Madabhushi

Faculty, Staff and Students Publications

Background: Virtual staining is an artificial intelligence-based approach that transforms pathology images between stain types, such as hematoxylin and eosin (H&E) to immunohistochemistry (IHC), providing a tissue-preserving and efficient alternative to traditional IHC staining. However, existing methods for translating H&E to virtual IHC often fail to generate images of sufficient quality for accurately delineating cell nuclei and IHC+ regions. To address these limitations, we introduce VISTA, an artificial intelligence-based virtual staining platform designed to translate H&E into virtual IHC.

Methods: We applied VISTA to identify M2-subtype tumor-associated macrophages (M2-TAMs) in H&E images from 968 patients with HPV+ oropharyngeal squamous cell …

Examining Demographic, Geographic, And Temporal Patterns Of Melanoma Incidence In Texas From 2000 To 2018: Retrospective Study, Kehe Zhang, Madison M Taylor, Jocelyn Hunyadi, Hung Q Doan, Adewole S Adamson, Paige Miller, Kelly C Nelson, Cici Bauer

Faculty, Staff and Student Publications

Background: Melanoma currently ranks as the fifth leading cancer diagnosis and is projected to become the second most common cancer in the United States by 2040. Melanoma detected at earlier stages may be treated with less-risky and less-costly therapeutic options.

Objective: This study aims to analyze temporal and spatial trends in melanoma incidence by stage at diagnosis (overall, early, and late) in Texas from 2000 to 2018, focusing on demographic and geographic variations to identify high-risk populations and regions for targeted prevention efforts.

Methods: We used melanoma incidence data from all 254 Texas counties from the Texas Cancer Registry (TCR) …

Longitudinal Profiling Of Circulating Tumor Dna Reveals The Evolutionary Dynamics Of Metastatic Prostate Cancer During Serial Therapy, Yuehui Zhao, Naveen Ramesh, Ping Xu, Emi Sei, Min Hu, Shanshan Bai, Patricia Troncoso, Ana M Aparicio, Christopher J Logothetis, Paul G Corn, Nicholas E Navin, Amado J Zurita

Faculty, Staff and Student Publications

Treatment decisions in metastatic castration-resistant prostate cancer are mostly guided by clinical variables, but efforts to molecularly monitor the disease remain hampered by challenges in acquiring tumor tissue repeatedly. In this study, we simultaneously profiled the genome copy number and exome in longitudinal plasma circulating tumor DNA (ctDNA) acquired before, during, and upon progression to serial treatments with androgen signaling inhibitors and taxane chemotherapy from 60 patients with metastatic castration-resistant prostate cancer (2-10 samples per patient). The genomic data were used to delineate the clonal substructure and evolutionary dynamics of each patient, and an evolutionary dynamic index was developed to …

Efficacy And Safety Of Larotrectinib In Patients With Trk Fusion Gastrointestinal Cancer, Changsong Qi, Lin Shen, Thierry Andre, Hyun Cheol Chung, Timothy L Cannon, Elena Garralda, Antoine Italiano, Damian T Rieke, Tianshu Liu, Domnita-Ileana Burcoveanu, Natascha Neu, Chiara E Mussi, Rui-Hua Xu, David S Hong, Alexander Drilon, Jordan Berlin

Faculty, Staff and Student Publications

Background: Larotrectinib is the first-in-class, highly selective TRK inhibitor with demonstrated efficacy in various TRK fusion solid tumours. We report the efficacy and safety of larotrectinib in patients with TRK fusion gastrointestinal (GI) cancer.

Methods: Patients with TRK fusion GI cancer from NAVIGATE (NCT02576431) were included. Response was independent review committee (IRC)-assessed per RECIST v1.1.

Results: As of July 2023, 44 patients were enrolled. Tumour types included colorectal (CRC; n = 26), pancreatic (n = 7), cholangiocarcinoma (n = 4), gastric (n = 3), and one each of appendiceal, duodenal, oesophageal and hepatic cancers. Of the 26 patients …

Genomic Characterization Of High-Grade Serous Ovarian Carcinoma Reveals Distinct Somatic Features In Black Individuals, Katherine A Lawson-Michod, Jeffrey R Marks, Lindsay J Collin, David A Nix, Natalie R Davidson, Chad D Huff, Yao Yu, Aaron Atkinson, Courtney E Johnson, Lucas A Salas, Lauren C Peres, Casey S Greene, Joellen M Schildkraut, Jennifer A Doherty

Faculty, Staff and Student Publications

Black individuals experience worse survival after a diagnosis of high-grade serous ovarian carcinoma (HGSC) than White individuals and are underrepresented in ovarian cancer research. To date, the understanding of the molecular and genomic heterogeneity of HGSC is based primarily on the evaluation of tumors from White individuals. In the present study, we performed whole-exome sequencing on HGSC samples from 211 Black patients to identify significantly mutated genes and characterize mutational signatures, assessing their distributions by gene expression subtypes. The occurrence and frequency of somatic mutations and signatures by self-reported race were compared with historic data from The Cancer Genome Atlas …

Crispr/Ncas9-Edited Cd34+ Cells Rescue Mucopolysaccharidosis Iva Fibroblasts Phenotype, Angélica María Herreno-Pachón, Andrés Felipe Leal, Shaukat Khan, Carlos Javier Alméciga-Díaz, Shunji Tomatsu

Department of Pediatrics Faculty Papers

Mucopolysaccharidosis (MPS) IVA is a bone-affecting lysosomal storage disease (LSD) caused by impaired degradation of the glycosaminoglycans (GAGs) keratan sulfate (KS) and chondroitin 6-sulfate (C6S) due to deficient N-acetylgalactosamine-6-sulfatase (GALNS) enzyme activity. Previously, we successfully developed and validated a CRISPR/nCas9-based gene therapy (GT) to insert an expression cassette at the AAVS1 and ROSA26 loci in human MPS IVA fibroblasts and MPS IVA mice, respectively. In this study, we have extended our approach to evaluate the effectiveness of our CRISPR/nCas9-based GT in editing human CD34+ cells to mediate cross-correction of MPS IVA fibroblasts. CD34+ cells were electroporated with the CRISPR/nCas9 system, …

Mrn-Ctip, Exo1, And Dna2-Wrn/Blm Act Bidirectionally To Process Dna Gaps In Parpi-Treated Cells Without Strand Cleavage, Isabelle M Seppa, Mithila Tennakoon, Jessica Jackson, Celia D Rouault, Sumedha Agashe, Vladislav O Sviderskiy, Mangsi Limbu, Erica Lantelme, Alice Meroni, Priyanka Verma, Alessandro Vindigni, Et Al.

2020-Current year OA Pubs

Single-stranded DNA (ssDNA) gaps impact genome stability and PARP inhibitor (PARPi) sensitivity, especially in BRCA1/2-deficient tumors. Using single-molecule DNA fiber analysis, electron microscopy, and biochemical methods, we found that MRN, CtIP, EXO1, and DNA2-WRN/BLM resect ssDNA gaps through a mechanism different from their actions at DNA ends. MRN resects ssDNA gaps in the 3'-to-5' direction using its pCtIP-stimulated exonuclease activity. Unlike at DNA ends, MRN does not use its endonucleolytic activity to cleave the 5'-terminated strand flanking the gap or the ssDNA. EXO1 and DNA2-WRN/BLM specifically resect the 5' end of the gap independent of MRN-CtIP. This resection process alters …

Selection Of Therapeutically Effective T-Cell Receptors From The Diverse Tumor-Bearing Repertoire, Leonie Rosenberger, Naresha Saligrama, Et Al.

2020-Current year OA Pubs

BACKGROUND: The development of T-cell receptor (TCR)-based T-cell therapies is hampered by the difficulties in identifying therapeutically effective tumor-specific TCRs from the natural repertoire of a patient's cancer-specific T cells.

METHODS: Here, we mimic experimentally near-patient conditions to analyze the T-cell repertoire in euthymic tumor-bearing mice responding to the H-2K

RESULTS: We found that mp68-specific TCRs isolated from either tumor-infiltrating T cells or spleens of mice immunized with mp68-expressing cancer cells are diverse and not inherently therapeutic when introduced into peripheral T cells and used for adoptive therapy of established tumors. While measuring short-term T-cell responses in vitro was unreliable …

The Association Of Discrimination, Inflammation, And Coping Style On Self-Rated Health Among South Asian Individuals In The Masala Study, Raji Pillai, Sahiti Myneni, Constance M Johnson, Nilay S Shah, Alka M Kanaya, Jennifer E S Beauchamp

Faculty, Staff and Student Publications

Objectives: South Asian individuals (SAs) may have heightened levels of inflammatory markers, such as C reactive protein (CRP), Tumor Necrosis Factor-α (TNF-α), leptin, and resistin, and decreased levels of anti-inflammatory adiponectin, contributing to higher cardiovascular disease (CVD) incidence. Social determinants of health, like discrimination, are also associated with risks for CVD in SAs. This study examined the associations between discrimination and inflammation and whether coping styles moderated the association between discrimination and self-rated health (SRH) among SAs in the United States.

Design: Secondary analysis of data obtained from 1164 SAs (mean age = 57 years, SD = 9.4, 48% women) …

Deciphering The Longitudinal Trajectories Of Glioblastoma Ecosystems By Integrative Single-Cell Genomics., Avishay Spitzer, Kevin C Johnson, Masashi Nomura, Luciano Garofano, Djamel Nehar-Belaid, Noam Galili Darnell, Alissa C Greenwald, Lillian Bussema, Young Taek Oh, Frederick S Varn, Fulvio D'Angelo, Simon Gritsch, Kevin J Anderson, Simona Migliozzi, L Nicolas Gonzalez Castro, Tamrin Chowdhury, Nicolas Robine, Catherine Reeves, Jong Bae Park, Anuja Lipsa, Frank Hertel, Anna Golebiewska, Simone P Niclou, Labeeba Nusrat, Sorcha Kellet, Sunit Das, Hyo-Eun Moon, Sun Ha Paek, Franck Bielle, Alice Laurenge, Anna Luisa Di Stefano, Bertrand Mathon, Alberto Picca, Marc Sanson, Shota Tanaka, Nobuhito Saito, David M Ashley, Stephen T Keir, Keith L Ligon, Jason T Huse, W K Alfred Yung, Anna Lasorella, Antonio Iavarone, Roel G W Verhaak, Itay Tirosh, Mario L Suvà

Faculty Research 2025

The evolution of isocitrate dehydrogenase (IDH)-wildtype glioblastoma (GBM) after standard-of-care therapy remains poorly understood. Here we analyzed matched primary and recurrent GBMs from 59 patients using single-nucleus RNA sequencing and bulk DNA sequencing, assessing the longitudinal evolution of the GBM ecosystem across layers of cellular and molecular heterogeneity. The most consistent change was a lower malignant cell fraction at recurrence and a reciprocal increase in glial and neuronal cell types in the tumor microenvironment (TME). The predominant malignant cell state differed between most matched pairs, but no states were exclusive or highly enriched in either time point, nor was there …

Complete Sequencing Of Ape Genomes., Dongahn Yoo, Arang Rhie, Prajna Hebbar, Francesca Antonacci, Glennis A Logsdon, Steven J Solar, Dmitry Antipov, Brandon D Pickett, Yana Safonova, Francesco Montinaro, Yanting Luo, Joanna Malukiewicz, Jessica M Storer, Jiadong Lin, Abigail N Sequeira, Riley J Mangan, Glenn Hickey, Graciela Monfort Anez, Parithi Balachandran, Anton Bankevich, Christine R Beck, Arjun Biddanda, Matthew Borchers, Gerard G Bouffard, Emry Brannan, Shelise Y Brooks, Lucia Carbone, Laura Carrel, Agnes P Chan, Juyun Crawford, Mark Diekhans, Eric Engelbrecht, Cedric Feschotte, Giulio Formenti, Gage H Garcia, Luciana De Gennaro, David Gilbert, Richard E Green, Andrea Guarracino, Ishaan Gupta, Diana Haddad, Junmin Han, Robert S Harris, Gabrielle A Hartley, William T Harvey, Michael Hiller, Kendra Hoekzema, Marlys L Houck, Hyeonsoo Jeong, Kaivan Kamali, Manolis Kellis, Bryce Kille, Chul Lee, Youngho Lee, William Lees, Alexandra P Lewis, Qiuhui Li, Mark Loftus, Yong Hwee Eddie Loh, Hailey Loucks, Jian Ma, Yafei Mao, Juan F I Martinez, Patrick Masterson, Rajiv C Mccoy, Barbara Mcgrath, Sean Mckinney, Britta S Meyer, Karen H Miga, Saswat K Mohanty, Katherine M Munson, Karol Pal, Matt Pennell, Pavel A Pevzner, David Porubsky, Tamara Potapova, Francisca R Ringeling, Joana L Rocha, Oliver A Ryder, Samuel Sacco, Swati Saha, Takayo Sasaki, Michael C Schatz, Nicholas J Schork, Cole Shanks, Linnéa Smeds, Dongmin R Son, Cynthia Steiner, Alexander P Sweeten, Michael G Tassia, Françoise Thibaud-Nissen, Edmundo Torres-González, Mihir Trivedi, Wenjie Wei, Julie Wertz, Muyu Yang, Panpan Zhang, Shilong Zhang, Yang Zhang, Zhenmiao Zhang, Sarah A Zhao, Yixin Zhu, Erich D Jarvis, Jennifer L Gerton, Iker Rivas-González, Benedict Paten, Zachary A Szpiech, Christian D Huber, Tobias L Lenz, Miriam K Konkel, Soojin V Yi, Stefan Canzar, Corey T Watson, Peter H Sudmant, Erin Molloy, Erik Garrison, Craig B Lowe, Mario Ventura, Rachel J O'Neill, Sergey Koren, Kateryna D Makova, Adam M Phillippy, Evan E Eichler

Faculty Research 2025

The most dynamic and repetitive regions of great ape genomes have traditionally been excluded from comparative studies. Consequently, our understanding of the evolution of our species is incomplete. Here we present haplotype-resolved reference genomes and comparative analyses of six ape species: chimpanzee, bonobo, gorilla, Bornean orangutan, Sumatran orangutan and siamang. We achieve chromosome-level contiguity with substantial sequence accuracy (< 1 error in 2.7 megabases) and completely sequence 215 gapless chromosomes telomere-to-telomere. We resolve challenging regions, such as the major histocompatibility complex and immunoglobulin loci, to provide in-depth evolutionary insights. Comparative analyses enabled investigations of the evolution and diversity of regions previously uncharacterized or incompletely studied without bias from mapping to the human reference genome. Such regions include newly minted gene families in lineage-specific segmental duplications, centromeric DNA, acrocentric chromosomes and subterminal heterochromatin. This resource serves as a comprehensive baseline for future evolutionary studies of humans and our closest living ape relatives.

Clonal Dynamics And Somatic Evolution Of Haematopoiesis In Mouse., Chiraag D Kapadia, Nicholas Williams, Kevin J Dawson, Caroline Watson, Matthew J Yousefzadeh, Duy Le, Kudzai Nyamondo, Sreeya Kodavali, Alex Cagan, Sarah Waldvogel, Xiaoyan Zhang, Josephine De La Fuente, Daniel Leongamornlert, Emily Mitchell, Marcus A Florez, Krzysztof Sosnowski, Rogelio Aguilar, Alejandra Martell, Anna Guzman, David E Harrison, Laura J Niedernhofer, Katherine Y King, Peter J Campbell, Jamie Blundell, Margaret A Goodell, Jyoti Nangalia

Faculty Research 2025

Haematopoietic stem cells maintain blood production throughout life1 . Although extensively characterized using the laboratory mouse, little is known about clonal selection and population dynamics of the haematopoietic stem cell pool during murine ageing. We isolated stem cells and progenitors from young and old mice, identifying 221,890 somatic mutations genome-wide in 1,845 single-cell-derived colonies. Mouse stem cells and progenitors accrue approximately 45 somatic mutations per year, a rate only approximately threefold greater than human progenitors despite the vastly different organismal sizes and lifespans. Phylogenetic patterns show that stem and multipotent progenitor cell pools are established during embryogenesis, after which they …

Systematic Ocular Phenotyping Of Knockout Mouse Lines Identifies Genes Associated With Age-Related Corneal Dystrophies., Andrew Briere, Peter Vo, Benjamin Yang, David Adams, Takanori Amano, Oana Amarie, Zorana Berberovic, Lynette Bower, Steve D M Brown, Samantha Burrill, Soo Young Cho, Sharon Clementson-Mobbs, Abigail D'Souza, Mohammad Eskandarian, Ann M Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Yann Hérault, Martin Hrabe De Angelis, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Hamid Meziane, Ki-Hoan Nam, Hyuna Noh, Lauryl M J Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jason Salazar, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Michelle Stewart, Karen L. Svenson, Masaru Tamura, Heather Tolentino, Sara Wells, Wolfgang Wurst, Atsushi Yoshiki, Louise Lanoue, K C Kent Lloyd, Brian C Leonard, Michel J Roux, Colin Mckerlie, Ala Moshiri

Faculty Research 2025

PURPOSE: This study investigates genes contributing to late-adult corneal dystrophies (LACDs) in aged mice, with potential implications for late-onset corneal dystrophies (CDs) in humans.

METHODS: The International Mouse Phenotyping Consortium (IMPC) database, containing data from 8901 knockout mouse lines, was filtered to include late-adult mice (49+ weeks) with significant (P < 0.0001) CD phenotypes. Candidate genes were mapped to human orthologs using the Mouse Genome Informatics group, with expression analyzed via PLAE and a literature review for prior CD associations. Comparative analyses of LACD genes from IMPC and established human CD genes from IC3D included protein interactions (STRING), biological processes (PANTHER), and molecular pathways (KEGG).

RESULTS: Analysis identified 14 genes linked to late-adult abnormal corneal phenotypes. Of these, 2 genes were previously associated with CDs in humans, while 12 were novel. Seven of the 14 genes (50%) were expressed in the human cornea based on single-cell transcriptomics. Protein-protein interactions via STRING showed several significant interactions …

Challenges And Opportunities For Conceiving Genetically Diverse Sickle Cell Mice., Rafiou Agoro, Gary Churchill

Faculty Research 2025

A milestone in sickle cell disease (SCD) therapeutics was achieved in December 2023 with the FDA-approved gene therapy for patients aged 12 years and older. However, these therapies may only suit a fraction of patients because of cost or health risks. A better understanding of SCD outcome heterogeneity is needed to propose patient-specific pharmacological interventions. To achieve this, humanized and genetically diverse mouse models are essential for associating candidate genotypes with specific hematological traits, organ function, and disease resilience. Here, we discuss the challenges and opportunities in developing genetically diverse sickle cell mice (GDS mice). These models are expected to …

An Intranasal Subunit Vaccine Induces Protective Systemic And Mucosal Antibody Immunity Against Respiratory Viruses In Mouse Models., Aina Karen Anthi, Anette Kolderup, Eline Benno Vaage, Malin Bern, Sopisa Benjakul, Elias Tjärnhage, Fulgencio Ruso-Julve, Kjell-Rune Jensen, Heidrun Elisabeth Lode, Marina Vaysburd, Jeannette Nilsen, Marie Leangen Herigstad, Siri Aastedatter Sakya, Lisa Tietze, Diego Pilati, Mari Nyquist-Andersen, Mirjam Dürkoop, Torleif Tollefsrud Gjølberg, Linghang Peng, Stian Foss, Morten C Moe, Benjamin E. Low, Michael V. Wiles, David Nemazee, Frode L Jahnsen, John Torgils Vaage, Kenneth A Howard, Inger Sandlie, Leo C James, Gunnveig Grødeland, Fridtjof Lund-Johansen, Jan Terje Andersen

Faculty Research 2025

Although vaccines are usually given intramuscularly, the intranasal delivery route may lead to better mucosal protection and limit the spread of respiratory virus while easing administration and improving vaccine acceptance. The challenge, however, is to achieve delivery across the selective epithelial cell barrier. Here we report on a subunit vaccine platform, in which the antigen is genetically fused to albumin to facilitate FcRn-mediated transport across the mucosal barrier in the presence of adjuvant. Intranasal delivery in conventional and transgenic mouse models induces both systemic and mucosal antigen-specific antibody responses that protect against challenge with SARS-CoV-2 or influenza A. When benchmarked …

Evaluating The Feasibility Of Gene Replacement Strategies To Treat Mtrfr Deficiency., Samia L Pratt, Mariana Zarate-Mendez, Lidiia Koludarova, Sonja Jansson, Mikko Airavaara, Irena Hlushchuk, David Coleman, Caleb Heffner, Rita Horvath, Brendan J Battersby, Robert W. Burgess

Faculty Research 2025

Mitochondrial translation release factor in rescue (MTRFR) catalyzes a termination step in protein synthesis, facilitating release of the nascent chain from mitoribosomes. Pathogenic variants in MTRFR cause MTRFR deficiency and are loss-of-function variants. Here, we tested gene replacement as a possible therapeutic strategy. A truncating mutation (K155*) was generated in mice; however, homozygotes die embryonically whereas mice heterozygous for this K155* allele are normal. We also generated transgenic strains expressing either wild-type human MTRFR or a partially functional MTRFR. Despite dose-dependent phenotypes from overexpression in vitro, neither transgene caused adverse effects in vivo. In K155* homozygous mice, the wild-type MTRFR …

Fentanyl Test Strip Use And Overdose Risk Reduction Behaviors Among People Who Use Drugs, Rachel A Vickers-Smith, Kitty H Gelberg, Janet E Childerhose, Denise C Babineau, Redonna Chandler, James L David, Lauren D'Costa, Megan Dzurec, Barry Eggleston, Amanda Fallin-Bennett, Laura C Fanucchi, Soledad Fernandez, Jace Gilbert, Louisa Gilbert, Megan E Hall, Brooke E Hiltz, Michael W Konstan, Kathryn E Lancaster, Beth Linas, Katherine R Marks, Nichole Michaels, Jennifer Miles, Fernando Montero, Haley J Ramsey Harden, Carter Roeber, Mary R Russo, Rachel Taylor, Melissa A Theis

Epidemiology and Environmental Health Faculty Publications

IMPORTANCE: Illegal fentanyl is driving overdose mortality, and fentanyl test strips (FTS) can be used to test drugs for fentanyl at the point of consumption. Evidence on whether FTS use is associated with overdose risk reduction behaviors is encouraging, but largely limited to smaller, single-site studies.

OBJECTIVE: To determine whether self-reported baseline FTS use among people who use drugs (PWUD) was associated with overdose risk reduction behaviors and nonfatal overdose over a 28-day follow-up.

DESIGN, SETTING, AND PARTICIPANTS: Multisite, observational cohort study of PWUD conducted from May to December 2023 as an ancillary study of the HEALing Communities Study, which …

Glim Consensus Approach To Diagnosis Of Malnutrition: A 5-Year Update., Gordon L Jensen, Tommy Cederholm, M Isabel T D Correia, M Cristina Gonzalez, Ryoji Fukushima, Veeradej Pisprasert, Renee Blaauw, Diana Cardenas Braz, Fernando Carrasco, Alfonso J Cruz Jentoft, Cristina Cuerda, David C Evans, Vanessa Fuchs-Tarlovsky, Leah Gramlich, Han Ping Shi, Jeanette M Hasse, Michael Hiesmayr, Naoki Hiki, Harriët Jager-Wittenaar, Shukri Jahit, Anayanet Jáquez, Heather Keller, Stanislaw Klek, Ainsley Malone, Kris M Mogensen, Naoharu Mori, Manpreet Mundi, Maurizio Muscaritoli, Doris Ng, Ibolya Nyulasi, Matthias Pirlich, Stephane Schneider, Marian De Van Der Schueren, Soranit Siltharm, Pierre Singer, Alison Steiber, Kelly A Tappenden, Jianchun Yu, André Van Gossum, Jaw-Yuan Wang, Marion F Winkler, Charlene Compher, Rocco Barazzoni

Ambulatory and Primary Care Articles

BACKGROUND: The Global Leadership Initiative on Malnutrition (GLIM) introduced an approach for malnutrition diagnosis in 2019 that comprised screening followed by assessment of three phenotypic criteria (weight loss, low body mass index [BMI], and low muscle mass) and two etiologic criteria (reduced food intake/assimilation and inflammation/disease burden). This planned update reconsiders the GLIM framework based on published knowledge and experience over the past 5 years.

METHODS: A working group (n = 43 members) conducted a literature search spanning 2019-2024 using the keywords "Global Leadership Initiative on Malnutrition or GLIM." Prior GLIM guidance activities for using the criteria on muscle mass …

Bi-Allelic Uggt1 Variants Cause A Congenital Disorder Of Glycosylation, Zain Dardas, Laura Harrold, Daniel G Calame, Claire G Salter, Takashi Kikuma, Kevin P Guay, Bobby G Ng, Kanae Sano, Ahmad K Saad, Haowei Du, Riccardo Sangermano, Sohil G Patankar, Shalini N Jhangiani, Semra Gürsoy, Mohamed S Abdel-Hamid, Mahmoud K H Ahmed, Reza Maroofian, Rauan Kaiyrzhanov, Kamran Salayev, Wendy D Jones, Ana Pérez Caballero, Lucy Mcgavin, Michael Spiller, Miranda Durkie, Nick Wood, Lauren O'Grady, Paula Goldenberg, Ann M Neumeyer, Amber Begtrup, Sherif F Abdel-Ghafar, Maha S Zaki, Hilde Van Esch, Jennifer E Posey, Olivia K Wenger, Ethan M Scott, Kinga M Bujakowska, Richard A Gibbs, Davut Pehlivan, Dana Marafi, Joseph S Leslie, Nishanka Ubeyratna, Jacob Day, Martina Owens, Jessica Settle, Soher Balkhy, Abdullah Tamim, Lama Alabdi, Fowzan S Alkuraya, Yoichi Takeda, Hudson H Freeze, Daniel N Hebert, James R Lupski, Andrew H Crosby, Emma L Baple

Faculty, Staff and Students Publications

Congenital disorders of glycosylation (CDGs) comprise a large heterogeneous group of metabolic conditions caused by defects in glycoprotein and glycolipid glycan assembly and remodeling, a fundamental molecular process with wide-ranging biological roles. Herein, we describe bi-allelic UGGT1 variants in fifteen individuals from ten unrelated families of various ethnic backgrounds as a cause of a distinctive CDG of variable severity. The cardinal clinical features of UGGT1-CDG involve developmental delay, intellectual disability, seizures, characteristic facial features, and microcephaly in the majority (9/11 affected individuals for whom measurements were available). The more severely affected individuals display congenital heart malformations, variable skeletal abnormalities including …

Metastatic Medulloblastoma Remodels The Local Leptomeningeal Microenvironment To Promote Further Metastatic Colonization And Growth, Namal Abeysundara, Alexandra Rasnitsyn, Vernon Fong, Alexander Bahcheli, Randy Van Ommeren, Kyle Juraschka, Maria Vladoiu, Winnie Ong, Bryn Livingston, Pasqualino De Antonellis, Michelle Ly, Borja López Holgado, Olga Sirbu, Shahrzad Bahrampour, Hyun-Kee Min, Jerry Fan, Carolina Nor, Abhirami Visvanathan, Jiao Zhang, Hao Wang, Lei Qin, Ning Huang, Jonelle Pallotta, Tajana Douglas, Esta Mak, Haipeng Su, Karen Ng, Kevin Yang Zhang, Craig Daniels, Calixto-Hope G Lucas, Charles G Eberhart, Hailong Liu, Tao Jiang, Faiyaz Notta, Vijay Ramaswamy, Jüri Reimand, Marco Gallo, Jeremy N Rich, Xiaochong Wu, Xi Huang, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the major source of morbidity and mortality for patients with medulloblastoma. The biology of the leptomeningeal metastases and the local tumour microenvironment are poorly characterized. Here we show that metastasis-associated meningeal fibroblasts (MB-MAFs) are transcriptionally distinct and signal extensively to tumour cells and the tumour microenvironment. Metastatic cells secrete platelet-derived growth factor (PDGF) ligands into the local microenvironment to chemotactically recruit meningeal fibroblasts. Meningeal fibroblasts are reprogrammed to become MB-MAFs, expressing distinct transcriptomes and secretomes, including bone morphogenetic proteins. Active bone morphogenetic protein signalling and co-implantation of tumour cells with MB-MAFs enhances the colonization of the leptomeninges …