Digital Commons Network^™

Identification Of A Translatable Animal Model For Dry Eye Disease Using Comparative Analysis Of Tear Proteins Across Species, Mayelín Pérez-Perdomo, Ana González-López, Laura Ortega-Llamas, David Alba-Molina, Mario Blanco-Blanco, María Del Mar Granados, Adrián Guerrero-Moreno, Stephen Carl Pflugfelder, Christoph Ullmer, Sascha Fauser, Yolanda Jiménez-Gómez, Miguel González-Andrades

Faculty, Staff and Students Publications

Purpose: This study aimed to assess the similarity of tear proteins between experimental animals and humans to identify the most translational animal model for dry eye disease (DED).

Methods: Eleven species were selected for a structural and physicochemical comparison of healthy human tear fluid proteins involved in DED. Amino acid sequences were compared using BLAST. Protein primary structure, isoelectric point (pI) and grand average of hydropathicity (GRAVY) were determined using ExPASy and compared with humans.

Results: Among non-primate mammals, the cat (69.7 %) and pig (68.7 %) showed the highest protein sequence similarity to humans. The ruminants and cat showed …

Corrigendum To “Glands Of Moll: History, Current Knowledge And Their Role In Ocular Surface Homeostasis And Disease” [Progr Retin Eye Res 106 (2025) 101362], Michael Stopfer, Ingrid Zahn, Katharina Jüngert, Gerhard Aumüller, Frans L Moll, Martin Schicht, Helen P Makarenkova, Cintia S De Paiva, Friedrich P Paulsen

Faculty, Staff and Students Publications

No abstract provided.

Dessicating Stress Triggers And Exacerbates Experimental Ocular Graft-Versus-Host-Disease, Uta Gehlsen, Martina Maass, Daniela Stary, Svenja Wagener-Ryczek, Gwen Musial, Manolis Pasparakis, Cintia S De Paiva, Michael E Stern, Philipp Steven

Faculty, Staff and Students Publications

Introduction: Chronic ocular graft-versus-host disease (oGVHD) is one of the most common complications after allogeneic hematopoietic stem cell transplantation (aHSCT). Recent studies indicate that desiccating stress by air-conditioning in transplantation wards increases the incidence of oGVHD. To test the hypothesis that experimental desiccating stress is a risk factor for oGVHD a mouse model of oGVHD was subjected to experimental desiccating stress.

Materials/methods: A previously established chemo-induced minor-mismatch mouse model of oGVHD was used. One group was challenged with desiccating stress for 18 days and compared to non-desiccated GVHD animals. Clinical phenotyping was performed weekly and ocular tissue and regional lymph …

Genomic Reporting Practices Across 5 Molecular Disciplines: A Study From The College Of American Pathologists, Larissa V Furtado, Annette S Kim, Ann M Moyer, Joel T Moncur, Rena R Xian, Angshumoy Roy, Avni B Santani, Yassmine Akkari, Karl V Voelkerding, Rhona J Souers, Jaimie Halley, Glenn E Palomaki

Faculty, Staff and Students Publications

Context.—: Genomic reports are primarily organized in a narrative and unstructured format with variations in content and format. Regulatory requirements and professional guidelines for genetic test reporting exist but provide little guidance for effective communication of information.

Objective.—: To assess clinical genomic reporting practices across 5 disciplines within molecular diagnostics, including germline, somatic solid tumors, somatic hematologic malignancies, pharmacogenomics, and prenatal cell-free DNA screening.

Design.—: Reporting practices were assessed by using a structured review of clinical genomic reports from multiple laboratories in 5 molecular disciplines spanning different practice settings. Report content was reviewed by the presence/absence of from 27 to …

Anemia In Inflammatory Bowel Disease: Practice Patterns And Clinical Outcomes In A Large National Veterans Cohort, Jared A Sninsky, Carolyn Brooks, Shubhada Sansgiry, Richa Shukla, Stalin Subramanian, Jason K Hou

Faculty, Staff and Students Publications

Background: Anemia is a common complication of inflammatory bowel disease (IBD), impacting patient quality of life and clinical outcomes. This study examines anemia management practices and clinical outcomes in a national cohort of veterans with IBD.

Methods: A retrospective cohort study of 89 687 veterans with IBD from 2000 to 2017 was conducted using Veterans Health Administration data. We assessed anemia screening, iron store assessments, and iron therapy. Primary outcomes included anemia resolution within 12 months. Secondary outcomes included IBD-related hospitalizations, steroid use, and surgery within five years. Multivariate logistic regression models assessed associations between patient characteristics and clinical outcomes. …

Cytokine Release Syndrome And Neurotoxicity Following Cd19 Car-T In B-Cell Lymphoma, Roni Shouval, Christopher Strouse, Soyoung Kim, Temitope Oloyede, Sairah Ahmed, Farrukh T Awan, Danny Luan, Veronika Bachanova, Talha Badar, Merav Bar, Pere Barba, Amer M Beitinjaneh, Amanda Cashen, Bhagirathbhai Dholaria, Mahmoud Elsawy, Siddhartha Ganguly, Praveen Ramakrishnan Geethakumari, Uri Greenbaum, Hamza Hashmi, Laquisa C Hill, Michael D Jain, Tania Jain, Partow Kebriaei, Adam S Kittai, Frederick L Locke, Premal D Lulla, Elena Mead, Joseph P Mcguirk, Alberto Mussetti, Taiga Nishihori, Amanda L Olson, Martina Pennisi, Miguel-Angel Perales, Peter A Riedell, Wael Saber, Abu-Sayeef Mirza, Margarida Magalhaes-Silverman, Elizabeth J Shpall, Mohamed Sorror, Kitsada Wudhikarn, Cameron J Turtle, Amy Moskop, Marcelo C Pasquini

Faculty, Staff and Students Publications

Chimeric antigen receptor T cell (CAR-T) therapy is an effective treatment for relapsed-refractory large B-cell lymphoma (LBCL). However, toxicities, particularly cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), remain significant concerns. Analyze temporal trends, risk factors, and associations between these toxicities and their severity. In this registry study by the Center for International Blood and Marrow Transplant Research, we studied CRS and ICANS in 1916 LBCL patients treated with commercial CAR-T therapies (axicabtagene ciloleucel 74.9%, tisagenlecleucel 25.1%) between 2018 and 2020. Outcomes include development of CRS/ICANS, timing and severity according to ASTC grading, overall survival (OS). Risk …

Complete Genomic Characterization Of Global Pathogens Respiratory Syntical Virus And Human Norovirus Using Probe Based Capture Enrichment, Sravya V Bhamidipati, Anil Surathu, Hsu Chao, Daniel P Agustinho, Qin Xiang, Kavya Kottapalli, Abirami Santhanam, Zeineen Momin, Kimberly Walker, Vipin K Menon, George Weissenberger, Nathanael Emerick, Faria Mahjabeen, Qingchang Meng, Jianhong Hu, Richard Sucgang, David Henke, Fritz J Sedlazeck, Ziad M Khan, Ginger A Metcalf, Vasanthi Avadhanula, Pedro A Piedra, Sasirekha Ramani, Robert L Atmar, Mary K Estes, Joseph F Petrosino, Richard A Gibbs, Donna M Muzny, Sara Cregeen Javornik, Harsha Doddapaneni

Faculty, Staff and Students Publications

Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections in children worldwide, while human noroviruses (HuNoV) are a leading cause of epidemic and sporadic acute gastroenteritis. Generating full-length genome sequences for these viruses is crucial for understanding viral diversity and tracking emerging variants. However, obtaining high-quality sequencing data is often challenging due to viral strain variability, quality, and low titers. Here, we present a set of comprehensive oligonucleotide probe sets designed from 1,570 RSV and 1,376 HuNoV isolate sequences in GenBank. Using these probe sets and a capture enrichment sequencing workflow, 85 RSV positive nasal swab …

Microbial Biosensor For Sensing And Treatment Of Intestinal Inflammation, Duolong Zhu, Jeffrey Galley, Jason Pizzini, Elena Musteata, Martin V Douglas, Walter J Chazin, Eric P Skaar, Jeffrey J Tabor, Robert A Britton

Faculty, Staff and Students Publications

Synthetic biology has enabled the development of biosensors to detect intestinal inflammation, yet few target the clinically validated biomarker of intestinal inflammation calprotectin with both diagnostic and therapeutic capabilities. Here, an optimized calprotectin biosensor is presented that leverages a zinc uptake regulator (Zur) controlled promoter coupled with a memory circuit to detect and record intestinal inflammation in vivo. The level of biosensor activation strongly correlates with calprotectin levels in the colon of two independent mouse models of colitis. Coupling of the biosensor with the production of the anti-inflammatory cytokine IL10 allowed for the resolution of chemically induced colitis, demonstrating the …

Inhibition Of The Gsk3Β/Nav16 Complex Suppresses Early-Stage Alzheimer’S Hyperexcitability, Timothy John Baumgartner, Manuel Silva-Pérez, Zahra Haghighijoo, Nolan Michael Dvorak, Aditya Kumar Singh, Nana Aboadwe Goode, Jully Singh, Berenice Gutierrez Grebenkova, Mate Marosi, Jessica Di Re, Leandra Koff, Wissarut Wijitrmektong, Manu Bala, Hanyue Liao, Marijn Lijffijt, Adam Thomas Szafran, Michael James Bolt, Michael A Mancini, Gregory D Cuny, Diana Shu-Lian Chow, Agenor Limon, Jeannie Chin, Fernanda Laezza

Faculty, Staff and Students Publications

Introduction: Network hyperexcitability (NH) is observed in patients with early-stage Alzheimer's disease (AD), emerging decades before cognitive decline. A key molecular determinant of NH is voltage-gated Na+ channel 1.6 (Nav1.6), which mediates action potential firing in CA1 hippocampal neurons. Ameliorating NH through inhibition of the glycogen-synthase kinase 3β (GSK3β/Nav1.6 complex may provide immediate benefits to cognition and memory and slow AD progression.

Methods: Hight-throughput virtual screening and multiple in vitro biological assays were utilized to identify compound 1063. Patch-clamp electrophysiology and electroencephalogram recordings were utilized to functionally assess 1063 in models of AD neuropathology.

Results: Building on previous studies identifying …

Decoding Metastatic Microenvironments Through Single-Cell Omics Reveals New Insights Into Niche Dynamics And Tumor Evolution, Fengshuo Liu, Xiang H-F Zhang

Faculty, Staff and Students Publications

Metastasis is the predominant cause of cancer mortality, primarily driven by complex tumor-host interactions within specialized metastatic niches. Recent advances in single-cell technologies have provided unprecedented insights into metastatic niche formation, evolution and function, including how primary tumors precondition distant organs for metastases and how disseminated tumor cells dynamically interact with host cells to modulate their environments. Integrated single-cell studies across multiple cancer types have also revealed divergent and convergent metastatic adaptation strategies. These findings collectively highlight metastasis as a dynamic, cooperative process shaped by intricate tumor-host interactions, and provide a foundation for novel therapeutic strategies targeting components of the …

Association Of Statin Use On Survival Outcomes Of Patients With Early-Stage Her2-Positive Breast Cancer In The Aphinity Trial, Christian Maurer, Elisa Agostinetto, Lieveke Ameye, Matteo Lambertini, Samuel Martel, Noam Ponde, Mariana Brandão, Francesca Poggio, Arlindo Ferreira, Rachel Schiff, Carmine De Angelis, Richard D Gelber, Susan Dent, Christoph Thomssen, Martine Piccart, Evandro De Azambuja

Faculty, Staff and Students Publications

Purpose: There is evidence that statins might improve the outcome of patients with breast cancer. The role of statins in patients with early HER2-positive breast cancer is unknown. Therefore, we explored the association between statin use and survival outcomes in early HER2-positive breast cancer patients in the phase III APHINITY trial (adjuvant pertuzumab/trastuzumab).

Methods: All patients (intent-to-treat population, n = 4804) were included (6.2 years median follow-up database). The primary objective was to investigate the association of statin use on invasive disease-free survival (IDFS), distant relapse-free interval (DRFI), and overall survival (OS). Patients who received statins at baseline, or started …

Comprehensive Genome Analysis And Variant Detection At Scale Using Dragen, Sairam Behera, Severine Catreux, Massimiliano Rossi, Sean Truong, Zhuoyi Huang, Michael Ruehle, Arun Visvanath, Gavin Parnaby, Cooper Roddey, Vitor Onuchic, Andrea Finocchio, Daniel L Cameron, Adam English, Shyamal Mehtalia, James Han, Rami Mehio, Fritz J Sedlazeck

Faculty, Staff and Students Publications

Research and medical genomics require comprehensive, scalable methods for the discovery of novel disease targets, evolutionary drivers and genetic markers with clinical significance. This necessitates a framework to identify all types of variants independent of their size or location. Here we present DRAGEN, which uses multigenome mapping with pangenome references, hardware acceleration and machine learning-based variant detection to provide insights into individual genomes, with ~30 min of computation time from raw reads to variant detection. DRAGEN outperforms current state-of-the-art methods in speed and accuracy across all variant types (single-nucleotide variations, insertions or deletions, short tandem repeats, structural variations and copy …

Baseline Cognition And Demographic, Lifestyle, And Cardiovascular Risk Factors In Us Pointer, Kathryn V Papp, Sarah Tomaszewski Farias, Marjorie Howard, Amber Thro, Tiia Ngandu, Brad Caudle, Bonnie C Sachs, Michelle Chan, Kristin R Krueger, Elizabeth R T Hartman, Athene Lee, Michele K York, Marie T Austin, Kathryn E Demos, Thomas M Holland, Xiaoyan Leng, Rema Raman, Heather M Snyder, Maria C Carrillo, Rachel A Whitmer, Mark A Espeland, Laura D Baker

Faculty, Staff and Students Publications

Introduction: Validation of the primary cognitive composite and baseline cognitive characteristics are presented for the US-Study-to-Protect-Brain-Health-Through-Lifestyle-Intervention-to-Reduce-Risk (US POINTER).

Methods: US POINTER is a multicenter, randomized clinical trial of two lifestyle interventions testing cognitive benefit in older adults without significant cognitive impairment but at-risk for decline due to well-established factors. Cognition is measured using a global cognitive composite (US POINTER modified Neuropsychological Test Battery-PmNTB).

Results: The PmNTB is a valid cognitive composite, exhibiting good psychometric properties and tracking with other established outcomes. Among the 2111 enrolled participants (mean age = 68.2 years, 69% women, 31% from race and ethnic minoritized groups), …

Dynamic Microbiome Responses To Structurally Diverse Anthocyanin-Rich Foods In A Western Diet Context, Mohammed F. Almatani, Giovanni Rompato, Eliza C. Stewart, Marcus Hayden, Jeremy Case, Samuel Rice, Korry J. Hintze, Abby D. Benninghoff

Animal, Dairy, and Veterinary Science Student Research

Background/Objectives: Anthocyanin (ACN)-rich foods are known to influence the gut microbiota composition, but the temporal dynamics and structural specificity of these effects remain poorly understood. This study investigated how distinct ACN-rich fruit supplements impact the gut microbiome over time in the context of a Western-style diet. We hypothesized that ACN-induced microbial shifts would occur rapidly, differ by ACN source, and require continued intake to persist. Methods: C57BL/6J mice were fed the total Western diet (TWD) supplemented with freeze-dried powders from bilberry (BB), tart cherry (TC), chokeberry (CB), elderberry (EB), black currant (BC), or black raspberry (BRB) for 0, 1, 3, …

Improving Health In Overweight Equines, Mikayla Joy, Karl Hoopes

All Current Publications

The primary treatments for overweight horses include diet modifications and incorporating exercise routines, with the most effective solution being a combination of both. There are special considerations and treatments for horses with equine metabolic syndrome (EMS), which is prevalent in obese equines. This fact sheet provides information on determining body condition, managing nutrition, and incorporating exercise to improve a horse's health.

Thriving Hives: Making Products With Honey - Skincare And Food Recipes, Brynn Meredith, Teresa Hunsaker, Andree' Walker Bravo

All Current Publications

While keeping bees is beneficial for many reasons, one of the most notable benefits is producing honey and wax, which have many practical uses. This fact sheet provides information on honey's properties and how to make creamed honey to control crystallization. It also provides instructions on how to make skincare and various food products using honey.

Basic Rabbit Selection And Breeding Considerations, Joseph Okoh, Jessie Hadfield

All Current Publications

This fact sheet is designed to assist rabbit producers in understanding breed selection for a profitable enterprise. It can also serve as a training tool for new producers, aiding them in breed selection and breeding practices.

Integrative Analysis Reveals The Prognostic Effects Of Epigenetic Regulators In Bladder Cancer, Venugopalareddy Mekala, Yupei Lin, Xiang Wang, Naail Chowdhury, Jianrong Li, Chao Cheng

Faculty, Staff and Students Publications

Background: Epigenetic regulatory genes (epiRG) are pivotal in the epigenetic regulation of the human genome, primarily through DNA and histone modifications. These genes are frequently mutated in human cancers, particularly bladder cancer (BC). However, the functional impact of epiRG mutations on patient outcomes remains poorly understood.

Methods: In this study, we developed gene signatures for the most frequent genomic aberrations of epiRG using The Cancer Genome Atlas Bladder Carcinoma (TCGA-BLCA) dataset and validated these signatures with independent tumor expression profiles for prognostic relevance. Furthermore, we evaluated the role of these signature scores in the immune system within the tumor microenvironment …

Crispr-Cas9 Mediated Proteinase 3 Autoantigen Deletion As A Treatment Strategy For Anti-Neutrophil Cytoplasmic Autoantibody-Associated Vasculitis, Uwe Jerke, Claudia Eulenberg-Gustavus, Dimitrios Laurin Wagner, Adrian Schreiber, Ralph Kettritz

Faculty, Staff and Students Publications

Introduction: Proteinase 3 (PR3) is a major autoantigen in patients with anti-neutrophil cytoplasmic autoantibody (ANCA)-associated vasculitis (AAV). Here, we performed a proof-of-principle study using ex vivo CRISPR-Cas9 guided gene editing to eliminate the PR3 autoantigen as an alternative to suppressing the autoimmune response to PR3.

Methods: A ribonucleoprotein (RNP) complex of Cas9 protein and a PR3-specific single guide-RNA was transfected into human CD34+ hematopoietic stem and progenitor cells (HSPC) by electroporation. Effects on PR3 protein abundance, neutrophil differentiation, and ANCA-dependent and -independent neutrophil responses were assessed.

Results: Gene editing introduced a frame shift in exon 2 of PRTN3. Consequently, PR3 …

Functional Assays In Drosophila Facilitate Classification Of Variants Of Uncertain Significance Associated With Rare Diseases, Jung-Wan Mok, Shelley B Gibson, Haley A Dostalik, Shinya Yamamoto

Faculty, Staff and Students Publications

Individuals living with rare diseases often undergo a frustrating and expensive diagnostic odyssey. Clinical geneticists who analyze exome or genome sequencing data from rare disease patients often encounter a list of variants of uncertain significance (VUS) in known disease-causing genes or rare variants in genes of uncertain significance (GUS) that are difficult to interpret, even with the integration of the latest bioinformatic tools. In this Perspective, we review how studies using the fruit fly Drosophila melanogaster have facilitated rare disease diagnosis by uncovering the clinical relevance of GUS and classifying rare variants into specific allelic categories (loss-of-function or gain-of-function, Muller's …

The Brussels International Declaration On Lipoprotein(A) Testing And Management, Florian Kronenberg, Nicola Bedlington, Zanfina Ademi, Marius Geantă, Tobias Silberzahn, Marc Rijken, Aedan Kaal, Mariko Harada-Shiba, Zhenyue Chen, George Thanassoulis, Bogi Eliasen, Jean-Luc Eiselé, Albert Wiegman, Christie M Ballantyne, Emma Broome, Michele Calabrò, Pablo Corral, Annelies Dol, Leslie J Donato, Elsie Evans, Sayaka Funabashi, Ioanna Gouni-Berthold, Iñaki Gutierrez Ibarluzea, Neil Johnson, Joanna Lane, Samia Mora, Børge G Nordestgaard, Ivan Pećin, Renate Kaal-Poppelaars, Michel R Langlois, Kausik K Ray, Arthur Rodenbach, Raul D Santos, Erik S G Stroes, Hayato Tada, Michal Vrablík, Michelle Winokur, Masayuki Yoshida, Stephen J Nicholls, Magdalena Daccord

Faculty, Staff and Students Publications

There is striking evidence that a high lipoprotein(a) [Lp(a)] concentration is a strong, independent, and causal cardiovascular risk factor. However, Lp(a) testing rates are very low (1 %-2 %) despite the fact that 1 in 5 individuals have elevated Lp(a) concentrations. The Brussels International Declaration on Lp(a) Testing and Management was co-created by the Lp(a) International Task Force and global leaders at the Lp(a) Global Summit, held in Brussels, Belgium, on March 24-25, 2025. The event, organized by FH Europe Foundation, brought together scientific experts, people with the lived experience of elevated Lp(a) and policy makers from the European Institutions …

Development And Diversity Of Astrocytes, Michael R Williamson, Sanjana Murali, Benjamin Deneen

Faculty, Staff and Students Publications

Proper development of the central nervous system (CNS) depends on astrocytes, which are the most abundant glial cells in the CNS. Here, we provide an overview of astrocyte ontogeny and morphogenesis, highlighting mechanisms that regulate astrocyte development. In addition, we describe the roles of astrocytes in regulating the development of other CNS cell types, with emphasis on neural circuits and vascular networks. We also discuss evidence for astrocyte diversity and its implications for CNS development. Finally, we pose open questions related to astrocyte development and its intersection with astrocyte diversity.

Effect Of Tai Chi Practice On The Adaptation To Sensory And Motor Perturbations While Standing In Older Adults, Arion Dey, Huiyeong Chang, Laila Shaaban, Armaan Suga, Genavieve Braden, Andres Bustamante, Jisang Park, Shenhua Zhang, Yang Hu, Manuel E. Hernandez

Faculty Research, Scholarly, and Creative Activity

Tai Chi provides an age-appropriate exercise to decrease fall risks in older adults. However, the exact mechanism underlying the benefits of Tai Chi practice remains an open question. Thus, this study examined how aging and Tai Chi practice impact adaptation to sensory and motor perturbations while standing. We hypothesized that older Tai Chi practitioners would exhibit a decreased reliance on visual processes as sensory and motor perturbations increased, relative to naive healthy older adults. Using rambling and trembling decompositions of the center of pressure (COP) and frequency-domain features, we examined changes in low (0–0.3 Hz), medium (0.3–1 Hz), and high …

Performance Comparison Of Quantum And Classical Machine Learning Models For Chronic Kidney Disease Prediction, Parama Sridevi, Paramita Basak Upama, Masud Rabbani, Sheikh Iqbal Ahamed

Computer Science Faculty Research and Publications

In this study, we develop and compare quantum and classical machine learning-based chronic kidney disease prediction models. We used the "Chronic_Kidney_Disease Data Set" of the UCI Machine Learning Repository. We performed data preprocessing and applied feature engineering techniques to select the best features. We developed two quantum machine learning-based models and two classical machine learning-based models. We used a hybrid classical-quantum environment for building quantum machine learning models. Finally, we compared the performances of all four models. We found that the Quantum Support Vector Machine performs best among the quantum models. The model’s accuracy was 95% with a k-fold cross-validation …

Figo Position Statement: Gamete Donations, Laurie Henry, Aris Antsaklis, Dov Feldberg, Jaideep Malhotra, Suchitra Pandit, Carlos Salazar, Alex Vidaeff, Rafal Zadykowicz, M Louise Hull, Nikhil Purandare

Faculty, Staff and Students Publications

Gamete donation has become a crucial part of Assisted Reproductive Technologies (ARTs), providing hope to individuals, including those who may have no other option for parenthood. This process comes with a wide range of ethical, medical, and legal challenges that need to be carefully addressed to protect the well-being and rights of all parties involved: donors, recipients, and offspring. Navigating these complexities requires strict ethical standards, robust regulatory frameworks, and international collaboration. By standardizing these, the field of gamete donation can continue to develop while ensuring that all parties are well informed and safeguarded. This paper explores the ethical concerns …

Deficits In Mitochondrial Dynamics And Iron Balance Result In Templated Insertions, Jordan Fox, Yang Yu, Yang Yu, Pilendra Thakre, Chloe Fox, Qian Li, Yunxia Wang, Adam Hughes, Xin Wang, Kaifu Chen, Grzegorz Ira

Faculty, Staff and Students Publications

Mitochondrial membrane dynamics control the shape, number, and distribution of mitochondria and regulate energy production and cell health. In a screen for yeast mutants with increased levels of templated insertions (~10-1000 bp) in the nuclear genome, we identified mitochondrial fusion deficient mutants (mgm1Δ, ugo1Δ, fzo1Δ). We found that fusion mutants activate the iron regulon, have decreased iron-sulfur clusters (ISCs), and increased DNA damage, suggesting a role of iron homeostasis in preventing insertions. Consistently, a secondary screen found mutants affecting iron-sulfur cluster production (yfh1Δ, grx5Δ), vacuolar iron storage (ccc1Δ) or general iron homeostasis (aft1Δ) to exhibit high insertion levels. Treatment with …

Defining Lipedema’S Molecular Hallmarks By Multi-Omics Approach For Disease Prediction In Women, Leon G Straub, Jan-Bernd Funcke, Nolwenn Joffin, Chanmin Joung, Sara Al-Ghadban, Shangang Zhao, Qingzhang Zhu, Ilja L Kruglikov, Yi Zhu, Paul R Langlais, Ruth Gordillo, Karen L Herbst, Philipp E Scherer

Children’s Nutrition Research Center Staff Publications

Lipedema is a chronic disease in females characterized by pathologic subcutaneous adipose tissue expansion and hitherto remains without druggable targets. In this observational study, we investigated the molecular hallmarks of lipedema using an unbiased multi-omics approach. We found adipokine dysregulation in lipedema patients participating in a cross-sectional clinical study (ClinicalTrial.gov, NCT02838277), pointing towards the adipocyte as a key player. Analyses of newly generated transcriptomic (SRA, PRJNA940039) and proteomic (ProteomeXchange, PXD058489) datasets of early- and late-stage lipedema samples revealed a local downregulation of factors involved in inflammation. Concomitantly, factors involved in cellular respiration, oxidative phosphorylation, as well as in mitochondrial …

Definition And Classification Of Dystonia, Alberto Albanese, Kailash P Bhatia, Victor S C Fung, Mark Hallett, Joseph Jankovic, Christine Klein, Joachim K Krauss, Anthony E Lang, Jonathan W Mink, Sanjay Pandey, Jan K Teller, Marina A J Tijssen, Marie Vidailhet, H A Jinnah

Faculty, Staff and Students Publications

Dystonia is a movement disorder with varied clinical features and diverse etiologies. Here we present a revision of the 2013 consensus definition and classification of dystonia in light of subsequent publications and experience with its application during the last decade. A panel of movement disorder specialists with expertise in dystonia reviewed the original document and proposed some revision. There was broad consensus to retain the definition of dystonia with only minor clarifications to the wording. Dystonia is defined as a movement disorder characterized by sustained or intermittent abnormal movements, postures, or both. Dystonic movements and postures are typically patterned and …

C-Terminal Frameshift Variants In Gpkow Are Associated With A Multisystemic X-Linked Disorder, Jung-Wan Mok, Laura Mackay, Maria Blazo, Elizabeth Mizerik, Jozef Gecz, Renee Carroll, Mathilde Nizon, Sophie Rondeau, Madeleine Joubert, Silvestre Cuinat, Wallid Deb, Fernanda Valle Sirias, Monika Weisz-Hubshman, Shamika Ketkar, Urszula Polak, Alyssa A Tran, Debra Kearney, Neil A Hanchard, Oguz Kanca, Michael F Wangler, Hugo J Bellen, Brendan H Lee, Shinya Yamamoto, Keren Machol

Duncan NRI Faculty and Staff Publications

Purpose: GPKOW, a gene on the X-chromosome, encodes a nuclear RNA-binding protein important in messenger RNA (mRNA) processing as a spliceosome subunit. This work aims to establish GPKOW as a disease-associated gene.

Methods: We describe 3 males from 2 unrelated families with hemizygous frameshift variants affecting the last exon of GPKOW p.(Arg441SerfsTer30) and p.(Ser444GlufsTer28). The effect of p.(Ser444GlufsTer28) on gene expression was evaluated in patient's fibroblasts. In vivo studies in Drosophila melanogaster targeting the sole GPKOW fly ortholog, CG10324 (Gpkow) were performed.

Results: Clinical presentations included intrauterine growth restriction, microcephaly/microencephaly, and eye, brain, skin, and skeletal abnormalities. Heterozygote females presented …

Enzyme-Independent Functions Of Hdac3 In The Adult Hear, Sichong Qian, Chen Zhang, Wenbo Li, Shiyang Song, Guanqiao Lin, Zixiu Cheng, Wenjun Zhou, Huiqi Yin, Yueli Wang, Haiyang Li, Ying H Shen, Zheng Sun

Center on Aging Staff Publications

The cardioprotective effects of histone deacetylase (HDAC) inhibitors (HDIs) are at odds with the deleterious effects of HDAC depletion. Here, we use HDAC3 as a prototype HDAC to address this contradiction. We show that adult-onset cardiac-specific depletion of HDAC3 in mice causes cardiac hypertrophy and contractile dysfunction on a high-fat diet (HFD), excluding developmental disruption as a major reason for the contradiction. Genetically abolishing HDAC3 enzymatic activity without affecting its protein level does not cause cardiac dysfunction on HFD. HDAC3 depletion causes robust downregulation of lipid oxidation/bioenergetic genes and upregulation of antioxidant/anti-apoptotic genes. In contrast, HDAC3 enzyme activity abolishment causes …