Digital Commons Network^™

An Annotated Biobank Of Triple-Negative Breast Cancer Patient-Derived Xenografts Features Treatment-Naïve And Longitudinal Samples During Neoadjuvant Chemotherapy, Amanda L Rinkenbaugh, Yuan Qi, Shirong Cai, Jiansu Shao, Faiza Baameur Hancock, Sabrina L Jeter-Jones, Xiaomei Zhang, Emily Powell, Lei Huo, Rosanna Lau, Chunxiao Fu, Rebekah Gould, Petra Den Hollander, Elizabeth E Ravenberg, Jason B White, Gaiane M Rauch, Banu Arun, Clinton Yam, Alastair M Thompson, Gloria V Echeverria, Stacy L Moulder, W Fraser Symmans, Jeffrey T Chang, Helen Piwnica-Worms

Faculty, Staff and Student Publications

Triple-negative breast cancer (TNBC) that fails to respond to neoadjuvant chemotherapy (NACT) can be lethal. Developing effective strategies to eradicate chemoresistant disease requires experimental models that recapitulate the heterogeneity characteristic of TNBC. To that end, we established a biobank of 92 orthotopic patient-derived xenograft (PDX) models of TNBC from the tumors of 75 patients enrolled in the ARTEMIS clinical trial (NCT02276443), including 12 longitudinal sets generated from serial patient biopsies collected throughout NACT treatment and from metastatic disease. Models were established from both chemosensitive and chemoresistant tumors, and nearly 30% of the PDX models were capable of metastasizing …

Integrative Proteogenomics And Forward Genetics Reveal A Novel Mitotic Vulnerability In Triple-Negative Breast Cancer, Nicholas J Neill, Shankha Satpathy, Karsten Krug, Jitendra K Meena, Nivetha Ramesh Babu, Cheyenne Calderon, Desmon Reed, Marcus J Weber, Lacey E Dobrolecki, Alaina Lewis, Christina Sallas, Meenakshi Anurag, Kimberly R Holloway, Chen Huang, Suhas Vasaikar, Maria F Cardenas, Beom-Jun Kim, Doug W Chan, Shayan C Avanessian, Siddhartha Tyagi, Mayra Orellana, Sufeng Mao, Heyuan Li, Fade Gong, Sarah J Kurley, Kristen L Meerbrey, Calla M Olson, Amritha Nair, Tingting Sun, Hsiang-Ching Chung, Elizabeth A Bowling, Jarey H Wang, Pengju Zhang, Peng Xiao, Duxiao Yang, Fabio Stossi, Mei-Yin C Polley, Alexander B Saltzman, Filip Mundt, D R Mani, Michael A Gillette, Susan G Hilsenbeck, George Miles, Carolina Gutierrez, C Kent Osborne, Charles Y Lin, Nathanael S Gray, Jinpeng Sun, David A Wheeler, Charles M Perou, Anna Malovannaya, Michael T Lewis, Bing Zhang, Matthew J Ellis, Steven A Carr, Thomas F Westbrook

Faculty, Staff and Students Publications

Triple-negative breast cancer (TNBC) is an aggressive subtype of breast cancer with few effective targeted therapies. Taxanes and other microtubule-targeting agents (MTAs) are frontline chemotherapies for TNBC; however, the molecular pathways that cause TNBC taxane sensitivity are largely unknown, preventing selection of taxane-responsive patients and development of more selective therapeutic strategies. In this study, we identified tumor-selective vulnerabilities in TNBC harboring inactivation of the tumor suppressor PTPN12 by integrating proteogenomic characterization and synthetic lethality screening. We discovered that PTPN12 inactivation drives mitotic defects through aberrant hyperactivation of the ubiquitin ligase complex APCFZR1, a critical regulator of the cell cycle. Consistent …

Developing Optogenetic Approaches To Study Ca2+ Signaling Processes, Tatsuki Nonomura, Xiaoxuan Liu, Megan Chiu, Zhi Tan, Tien-Hung Lan, Yubin Zhou

Faculty, Staff and Students Publications

Calcium ions (Ca2+) are essential second messengers intimately implicated in a variety of biological processes, ranging from short-term events such as muscle contraction to long-term effects like gene expression. Dysregulated Ca2+ signaling can disrupt cellular function and contribute to the development of various human diseases, including developmental, neurological, immunoinflammatory, metabolic, and cardiovascular disorders. To study the mechanisms and biological consequences of Ca2+ signaling, optogenetic approaches have proven invaluable, as they offer exceptional spatiotemporal resolution compared to traditional methods. Recent progress in non-opsin-based optogenetics, particularly those engineered from Ca2+ release–activated Ca2+ (CRAC) channels, has substantially advanced our understanding of Ca2+ signaling …

Therapeutic Radiation Drives Leptomeningeal Dissemination Of Medulloblastoma Through An Innate Immune Process, Carolina Nör, Kaitlin Kharas, Alex Rasnitsyn, Maria C Vladoiu, Nam Woo Cho, Jacob S Young, Felipe Nör, Ncedile Mankahla, Joonas Haapasalo, Kristiina Nordfors, Sara Rapic, Patryk Skowron, Raúl A Suárez, Alexander T Bahcheli, Oliver Ocsenas, Xin Chen, Shahrzad Bahrampour, Ali Momin, Lakshmikirupa Sundaresan, Winnie Ong, Liam D Hendrikse, Namal Abeysundara, Kyle Juraschka, Michelle Ly, Jonelle G Pallota, Tajana Douglas, Ning Huang, Hao Wang, Esta Mak, Lei Qin, Jessica Liu, Lily Shen, Betty Luu, Alex Manno, Sachin A Kumar, Laura K Donovan, Vernon Fong, Cory Richman, Craig Daniels, Livia Garzia, Jeremy N Rich, Cynthia Hawkins, Xiaochong Wu, Ralph Dacosta, Jüri Reimand, Xi Huang, Vijay Ramaswamy, David R Raleigh, Michael D Taylor

Faculty, Staff and Students Publications

Leptomeningeal metastases are the most important source of morbidity and mortality for medulloblastoma patients. Radiation of the entire brain is highly effective in the treatment and/or prevention of medulloblastoma leptomeningeal metastases. Infants treated on clinical trials with focal tumor radiation recur metastatically, whereas infants treated with only chemotherapy relapse locally. In murine medulloblastoma model systems, provision of a single dose of radiation to the tumor drives leptomeningeal dissemination. An inflammatory response after radiation-induced tumor cell death recruits a variety of immune cells. Inflammation opens the local blood-brain barrier, allowing intravasation of medulloblastoma cells. Experimental induction of inflammation with lipopolysaccharide drives …

Characterization Of Androctonus Mauritanicus Venom And In Vitro Screening Of Sars-Cov-2 Entry Inhibitors Candidates, Reda Chahir, Jacob Galan, Hicham Hboub, Ahmed Salim Lahlou, Salma Chakir, Hinde Aassila, Reda Ben Mrid, Najat Bouchmaa, Reto Stöcklin, Rachid El Fatimy, Naoual Oukkache

Human Genetics Publications

Animal venom, known for its complex biochemical composition, presents a valuable source of therapeutic molecules, particularly for antiviral applications. Despite this potential, the industrial use of venom remains limited, with fewer than a dozen venom-derived compounds reaching commercial markets. This study underscores the significance of exploring venom’s natural diversity as a reservoir for novel bioactive compounds that could drive innovative drug development. We investigated the venom of the Moroccan black scorpion Androctonus mauritanicus (Am), applying solid-phase extraction (SPE) and high-performance reversed-phase liquid chromatography (RP-HPLC) to fractionate the venom into 80 distinct samples. These fractions were subjected to detailed analysis …

The Genomes Of Nematode-Trapping Fungi Provide Insights Into The Origin And Diversification Of Fungal Carnivorism, Yani Fan, Minghao Du, Weiwei Zhang, Wei Deng, Ence Yang, Shunxian Wang, Luwen Yan, Liao Zhang, Seogchan Kang, Jacob L Steenwyk, Zhiqiang An, Xingzhong Liu, Meichun Xiang

The Brown Foundation: Institute of Molecular Medicine

Nematode-trapping fungi (NTF), most of which belong to a monophyletic lineage in Ascomycota, cannibalize nematodes and other microscopic animals, raising questions regarding the types and mechanisms of genomic changes that enabled carnivorism and adaptation to the carbon-rich and nitrogen-poor environment created by the Permian-Triassic extinction event. To address these questions, we conducted comparative genomic analyses of 21 NTF and 21 non-NTF. Carnivorism-associated changes include expanded genes for nematode capture, infection, and consumption (e.g., adhesive proteins, CAP superfamily, eukaryotic aspartyl proteases, and serine-type peptidases). Although the link between secondary metabolite (SM) production and carnivorism remains unclear, we found that the number …

A Tour Of Leukemia Progress In 2025, Viewed Through The Md Anderson Leukemia Research Lens, Hagop M Kantarjian, Gautam Borthakur, Naval Daver, Courtney Dinardo, Guillermo Garcia-Manero, Ghayas Issa, Elias Jabbour, Nitin Jain, Tapan Kadia, Sanam Loghavi, Farhad Ravandi, Guilin Tang, Mary Alma Welch, William Wierda

Faculty, Staff and Student Publications

Advances in the prognostication, monitoring, and treatment of both the acute and chronic leukemias have led to drastically improved outcomes over the past 2 decades. With the advent of targeted therapies, including antibodies such as blinatumomab and inotuzumab and small molecule inhibitors, such as the BCR::ABL1 tyrosine kinase inhibitors, Bruton tyrosine kinase inhibitors, and venetoclax, the treatment landscape of leukemia has drastically changed, improving survival outcomes while relying less on overall chemotherapy intensity in many leukemia types. This progress has allowed the categorization of more leukemia types as favorable (i.e., chronic lymphocytic leukemia, younger acute lymphoblastic leukemia [patients younger than …

Brain-Wide Patterns Of Crf Receptor 1 Expression In The Transgenic Crfr1-Cre-2a-Tdtom Rat, Douglas S Engelke, Lierni Ugartemendia, Jonathan Tao, Shivakumar Rajamanikam, Fabricio H Do Monte, Nicholas J Justice

Faculty, Staff and Student Publications

The ability to manipulate neurons that express corticotropin-releasing factor (CRF) or its receptors has led to many new discoveries about how CRF signaling modulates stress-related behaviors in mice. However, similar advances in rats have been limited by the lack of reporter lines targeting CRF receptors, restricting access to behavioral paradigms that are more suitable for, or specific to, rats. Here, we provide an extensive neuroanatomical characterization of a recently generated CRFR1-Cre rat. We show that Cre and tdTomato are expressed in a pattern that closely aligns with previously reported CRFR1 expression patterns, as determined by in situ hybridization in rats …

Sars-Cov-2 Mrna Vaccines Sensitize Tumours To Immune Checkpoint Blockade, Adam J Grippin, Christiano Marconi, Sage Copling, Nan Li, Chen Braun, Cole Woody, Elliana Young, Priti Gupta, Min Wang, Annette Wu, Seong Dong Jeong, Dhruvkumar Soni, Frances Weidert, Chao Xie, Eden Goldenberg, Andrew Kim, Chong Zhao, Anna Devries, Paul Castillo, Rishabh Lohray, Michael K Rooney, Benjamin R Schrank, Yifan Wang, Yifan Ma, Enoch Chang, Ramez Kouzy, Kyle Dyson, Jordan Jafarnia, Nina Nariman, Gregory Gladish, Jacob New, Ada Argueta, Diana Amaya, Nagheme Thomas, Andria Doty, Joe Chen, Nikhil Copling, Gabriel Alatrash, Julie Simon, Alicia Bea Davies, William Dennis, Richard Liang, Jeff Lewis, Xiong Wei, Waree Rinsurongkawong, Ara A Vaporciyan, Andrew Johns, D3code Team, Jack Lee, Ji-Hyun Lee, Ryan Sun, Padmanee Sharma, Hai Tran, Jianjun Zhang, Don L Gibbons, Jennifer Wargo, Betty Y S Kim, John V Heymach, Hector R Mendez-Gomez, Wen Jiang, Elias J Sayour, Steven H Lin

Faculty, Staff and Student Publications

Immune checkpoint inhibitors (ICIs) extend survival in many patients with cancer but are ineffective in patients without pre-existing immunity1–9. Although personalized mRNA cancer vaccines sensitize tumours to ICIs by directing immune attacks against preselected antigens, personalized vaccines are limited by complex and time-intensive manufacturing processes10–14. Here we show that mRNA vaccines targeting SARS-CoV-2 also sensitize tumours to ICIs. In preclinical models, SARS-CoV-2 mRNA vaccines led to a substantial increase in type I interferon, enabling innate immune cells to prime CD8+ T cells that target tumour-associated antigens. Concomitant ICI treatment is required for …

Rank-Based Learning: A Novel High-Throughput Algorithm Resilient To Missing Data And Effective For Datasets With Small Sample Size, Lulu Song, Hamid Khoshfekr Rudsari, Johannes F Fahrmann, Jody Vykoukal, Sam Hanash, James P Long, Kim-Anh Do, Ehsan Irajizad

Faculty, Staff and Student Publications

High-throughput omics data present challenges for binary classification due to platform variability, batch effects, missing values, and high dimensionality. This study presents a novel Rank-Based Learning (RBL) method that leverages relative feature rankings to improve robustness and generalizability. We evaluated RBL against established methods like Logistic Regression (LR) and Random Forest (RF) using simulated data and two real-world plasma proteomics datasets: early-stage small cell lung cancer (SCLC) and duodenopancreatic neuroendocrine tumors (dpNET) in patients with Multiple Endocrine Neoplasia type 1 (MEN1). In simulation experiments, RBL outperformed LR under conditions involving batch effects, missing data, and varying numbers of true differential …

Protein Kinase Giα Oxidation Negatively Regulates Antibody Production By B Cells, Hyun-Ju Cho, Rebecca L Charles, Oleksandra Prysyazhna, Sapna Arjun, Asvi A Francois, Kevin M Mcbride, Philip Eaton

Faculty, Staff and Student Publications

Endogenous oxidants induce a C42-dependent interprotein disulfide between the subunits of protein kinase G (PKG) Iα in cardiovascular tissues to control blood pressure and ventricular relaxation during diastole. PKGIα is expressed in other cell types, including those of the immune system, where the redox state of this kinase is likely to regulate other important physiological processes. The role of PKGIα oxidation in antibody production by B cells, which produce oxidants such as hydrogen peroxide during differentiation, was examined by comparing the immune response of oxidation-resistant C42S PKGIα knock-in (KI) mice to their wild type (WT) littermates.

Immunization with the 4 …

Acute Kidney Injury Is Associated With Elevated Urinary Endotrophin, Amanda J Clark, Brenda Mendoza Flores, Marie Christelle Saade, Kyle Q Vu, Isaac J Pence, Ningyan Zhang, Zhiqiang An, Dawei Bu, Philipp E Scherer, Samir M Parikh

Faculty, Staff and Student Publications

Acute kidney injury (AKI) is prevalent among hospitalized patients. Novel biomarkers are needed to diagnose AKI and target therapies. Endotrophin (ETP) is a molecule released during collagen type VI formation that may promote injury and fibrosis. Although serum ETP elevation has been associated with adverse outcomes in AKI, urinary ETP has not been assessed in AKI, nor has ETP been evaluated in a pediatric population. Urine samples were collected from a tertiary children's hospital. Medical records were reviewed, and patients who met criteria were sorted into three categories:

Misfolded Amyloid-Beta Conformational Variants (Strains) As Drivers Of Alzheimer's Disease Neuropathology, Salvatore Saieva, Rodrigo Morales

Faculty, Staff and Student Publications

No abstract provided.

Perfluoroalkyl Substance Pollutants Disrupt Microglia Function And Trigger Transcriptional And Epigenomic Changes, Yating Cheng, Jian-Rong Li, Hangjin Yu, Shuang Li, Boranai Tychhon, Chao Cheng, Yi-Lan Weng

Faculty, Staff and Students Publications

Per- and polyfluoroalkyl substances (PFAS), commonly referred to as "forever chemicals", are widely utilized in various industries and consumer products worldwide. Their exposure has been associated with numerous diseases and malignancies, including neurodevelopmental and neurodegenerative disorders. However, the molecular mechanisms underlying PFAS-induced adverse effects on the central nervous system (CNS) remain poorly understood. In this study, we investigated the transcriptomic and epigenetic changes in microglia exposed to perfluorooctane sulfonate (PFOS), a prevalent PFAS compound. Our findings demonstrate that 24-hour PFOS exposure (25 and 50 µM) disrupts the microglial transcriptome and compromises their homeostatic state, marked by increased inflammation and impaired …

Targeting Steroid Receptor Coactivators For The Treatment Of Benign Female Reproductive Disorders, Yuri Park, Jaeyeong Jeong, Eunsu Kim, Nuri Sung, Sang Jun Han

Faculty, Staff and Students Publications

Steroid receptor coactivators (SRCs) are master regulators of nuclear receptor signaling and play essential roles in female reproductive physiology. By integrating steroid hormone signaling with growth factors and metabolic pathways, SRC-1, SRC-2, and SRC-3 coordinate key processes such as decidualization, placental development, and ovarian function. Dysregulation of SRCs is strongly linked to the progression of benign gynecologic disorders, including polycystic ovary syndrome (PCOS), endometriosis, and uterine fibroids, largely through enhancing hormonal hypersensitivity and disrupting nuclear receptor-mediated cellular pathways. Emerging evidence further implicates specific SRC isoforms in disease pathogenesis, underscoring their potential as biomarkers and therapeutic targets. To inhibit SRC activity, …

Alterations In Cardiovascular Parameters In 5xfad Murine Model, Andrea G Marshall, Dominique Stephens, Kit Neikirk, Sepiso K Masenga, Bryanna Shao, Amber Crabtree, Zer Vue, Heather K Beasley, Edgar Garza-Lopez, Estevão Scudese, Benjamin I Rodriguez, Han Le, Steven Damo, George E Taffet, Okwute M Ochayi, Ronald Mcmillan, Jeremiah M Afolabi, Vernat Exil, Ashton Oliver, Vineeta Sharma, Pamela Martin, Amadou Gaye, Chanel Harris, Briar Tomeau, Lacara Bell, Markis Hamilton, Taneisha Gillyard, Railyn Webster, Marcus Jackson, Prem Prakash, Shanilah Frierson, Chandravanu Dash, Margaret Mungai, Annet Kirabo, Jennifer A Gaddy, Nelson Wandira, Antentor Hinton, Anilkumar K Reddy

Faculty, Staff and Students Publications

Alzheimer's Disease (AD) is a global health issue, affecting over 6 million people in the United States, with that number expected to increase as the population ages. As a neurodegenerative disorder that affects memory and cognitive functions, it is well established that AD is associated with cardiovascular risk factors beyond only cerebral decline. In this study, we measured hemodynamic parameters related to cardiovascular and cerebrovascular function in 5xFAD mice with AD and their littermates. Specifically, we measured cardiovascular pulse wave velocity parameters, a marker of arterial stiffness and cardiovascular risk, and cerebrovascular pulse wave velocity, a novel technique to measure …

Gregor: Accelerating Genomics For Rare Diseases, Moez Dawood, Ben Heavner, Marsha M Wheeler, Rachel A Ungar, Jonathan Lotempio, Laurens Wiel, Seth Berger, Jonathan A Bernstein, Jessica X Chong, Emmanuèle C Délot, Evan E Eichler, James R Lupski, Ali Shojaie, Michael E Talkowski, Alex H Wagner, Chia-Lin Wei, Christopher Wellington, Matthew T Wheeler, Gregor Partner Members, Claudia M B Carvalho, Richard A Gibbs, Casey A Gifford, Susanne May, Danny E Miller, Heidi L Rehm, Kaitlin E Samocha, Fritz J Sedlazeck, Eric Vilain, Anne O'Donnell-Luria, Jennifer E Posey, Lisa H Chadwick, Michael J Bamshad, Stephen B Montgomery, Genomics Research To Elucidate The Genetics Of Rare Diseases (Gregor) Consortium

Faculty, Staff and Students Publications

Rare diseases are collectively common, affecting approximately 1 in 20 individuals worldwide. In recent years, rapid progress has been made in rare disease diagnostics due to advances in next-generation sequencing, development of new computational and functional genomics approaches to prioritize genes and variants and increased global sharing of clinical and genetic data. However, more than half of individuals suspected to have a rare disease lack a genetic diagnosis. The Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) Consortium was initiated to study thousands of challenging rare disease cases and families and apply, standardize and evaluate emerging genomics technologies …

Optic Nerve Injury Impairs Intrinsic Mechanisms Underlying Electrical Activity In A Resilient Retinal Ganglion Cell, Thomas E Zapadka, Nicholas M Tran, Jonathan B Demb

Faculty, Staff and Students Publications

Retinal ganglion cells (RGCs) are the sole output neurons of the retina and convey visual information to the brain via their axons in the optic nerve. Following injury to the optic nerve, RGCs axons degenerate and many cells die. For example, a model of axon injury, the optic nerve crush (ONC), kills ~80% of RGCs after two weeks. Surviving cells are biased towards ‘resilient’ types, including several with sustained firing to light stimulation. RGC survival may depend on activity, and there is limited understanding of how or why activity changes following optic nerve injury. Here we quantified the electrophysiological properties …

Neurodevelopmental Abnormalities Underlying Behavioral Deficits In A Model Of Pediatric Obstructive Sleep Apnea, Arvind Chandrakantan, Michael R Williamson, Vaishnav Krishnan, Mahyar J Hedayatpour, Adam C Adler, Nandani Adyapak, Chris S Ward, Russell Ray, David Durgan, Farrah Kheradmand, Benjamin Deneen

Faculty, Staff and Students Publications

Rationale: Pediatric Obstructive Sleep Apnea (POSA) is a relatively common childhood sleep disorder whose neurodevelopmental phenotype includes deficits in learning and memory, olfaction, and fine motor abilities.

Objectives: To date, there has not been a validated preclinical model of POSA, hampering efforts in understanding how nocturnal episodes of intermittent hypoxia disrupt neurodevelopmental trajectories. The objective of this study was to create a faithful sculpting of the human condition in a preclinical murine model.

Methods: We used clinical data from children with POSA to develop and validate a mouse model of POSA that faithfully recapitulates several behavioral deficits seen in the …

Targeting The Hippo Pathway For Cardiac Regeneration, Rich Gang Li, Fansen Meng, James F Martin

Faculty, Staff and Students Publications

Ischemic heart disease, which affects more than 200 million people worldwide, is caused by reduced blood flow to the heart and leads to widespread cardiomyocyte death. Due to the limited regenerative potential of cardiomyocytes, the lost tissue is replaced by a fibrotic scar, resulting in reduced cardiac function and progression to heart failure. Current therapeutic interventions aim to improve blood flow but cannot address the inability of cardiomyocytes to renew after injury. However, multiple studies have shown that modulating the Hippo signaling pathway to activate Yes-associated protein (YAP), a transcription coactivator, in adult murine and porcine cardiomyocytes induces robust cardiomyocyte …

Reprogrammed Glucose Metabolism In Vascular Smooth Muscle Cells And Its Implications For Vascular Diseases, Qian Ma, Yongfeng Cai, Qiuhua Yang, Wendy Zhang, Suowen Xu, Yuqing Huo

Faculty, Staff and Students Publications

Vascular smooth muscle cells (VSMCs) play a pivotal role in maintaining vascular homeostasis and are critical contributors to the pathogenesis of various vascular diseases, including atherosclerosis, calcification, aneurysms, and pulmonary hypertension. Emerging evidence highlights the significance of glucose metabolism in regulating VSMC phenotypic transitions during these pathologies. This review provides a comprehensive overview of the major glucose metabolic pathways in VSMCs, glycolysis, the pentose phosphate pathway (PPP), and the hexosamine biosynthetic pathway (HBP), and their roles in disease development. We summarize the molecular mechanisms linking glucose metabolic reprogramming to VSMC dysfunction, focusing on key regulatory enzymes and signaling pathways. Additionally, …

Endothelial Adenosine Receptor 2a Loss Alleviates Diabetic Vascular Calcification By Blocking Creb1-Snai1-Driven Endmt, Yaqi Zhou, Dingwei Zhao, Qian Ma, Jiean Xu, Yongfeng Cai, Qiuhua Yang, Qingen Da, Kian Sheridan, Chunxiang Zhang, Clint L Miller, Rajeev Malhotra, Suowen Xu, Mei Hong, Yuqing Huo

Faculty, Staff and Students Publications

Vascular calcification (VC), a common complication associated with diabetes mellitus (DM), substantially increases the risk of cardiovascular diseases and is associated with elevated mortality in individuals with DM. Endothelial-to-mesenchymal transition (EndMT) imparts phenotypic plasticity to vascular endothelial cells (VECs), granting them the potential for osteogenic differentiation, which is a crucial mechanism in regulating VC. Notably, adenosine-ADORA2A-mediated endothelial dysfunction plays a pivotal regulatory role in cardiovascular diseases. However, the specific role of endothelial ADORA2A in diabetic VC remains to be elucidated. In this study, we found that ADORA2A was upregulated in the endothelium of diabetic mice and cultured human aortic endothelial …

Inhibition Of Bmper Mitigates Pulmonary Hypertension By Modulating Lrp1-Yap Interaction In Smooth Muscle Cells, Hua Mao, Claire M Li, Bing Sun, Christopher S Ward, Alan R Waich-Cohen, Ivan O Rosas, Howard J Huang, Harry Karmouty-Quintana, Liang Xie, Lavannya M Pandit, Xinchun Pi

Faculty, Staff and Students Publications

Background: BMPER (bone morphogenetic protein-binding endothelial regulator) is a secreted protein that is highly expressed in endothelial cells. It regulates the BMP (bone morphogenetic protein) pathway during vascular development and adulthood. Mutations in the BMP pathway are recognized as risk factors for pulmonary arterial hypertension group 1 pulmonary hypertension (PH). However, the roles of BMPER in pulmonary arterial hypertension remain unknown.

Methods: We assessed BMPER expression in Group 1 pulmonary arterial hypertension patient samples and examined its role in vascular remodeling using in vivo and in vitro approaches.

Results: BMPER level was elevated in pulmonary arterial hypertension lungs and significantly …

Beyond Seizures As An Outcome Measure: A Global Severity Scoring System For Cdkl5 Deficiency Disorder, Peter Jacoby, Eric D Marsh, Scott Demarest, Jacinta M Saldaris, Helen Leonard, Heather E Olson, Joni N Saby, Elia Pestana-Knight, Rajsekar Rajaraman, Dana Price, Judith Weisenberg, Bernhard Suter, Jenny Downs, Tim A Benke

Faculty, Staff and Students Publications

Background: CDKL5 deficiency disorder (CDD) is a rare developmental and epileptic encephalopathy (DEE) associated with multiple impairments and comorbidities. Outcome measures for disease-modifying clinical trials for DEEs should measurably capture a spectrum of caregiver priorities and be externally validated.

Methods: The International CDKL5 Clinical Research Network was the data source for this observational study. A Structural Equation Model was constructed with latent, exogenous variables related to observed clinical features to calculate a global severity score from the following assessments: the CDKL5 Clinical Severity Assessment-Clinician and -Caregiver, Communication and Symbolic Behavior Scales Developmental Profile Infant Toddler Checklist and the Sleep Disturbance …

Selective Agonism Of Liver And Gut Fxr Prevents Cholestasis And Intestinal Atrophy In Parenterally Fed Neonatal Pigs, Yanjun Jiang, Zhengfeng Fang, Gregory Guthrie, Barbara Stoll, Shaji Chacko, Sen Lin, Bolette Hartmann, Jens J Holst, Harry Dawson, Jose J Pastor, Ignacio R Ipharraguerre, Douglas G Burrin

Faculty, Staff and Students Publications

We aimed to investigate the relative efficacy of feeding different bile acids in preventing PNALD in neonatal pigs. Newborn pigs given total parenteral nutrition (TPN) combined with minimal enteral feeding of chenodeoxycholic acid (CDCA) or increasing doses of obeticholic acid (OCA) for 19 days. Enteral OCA (5 and 15 mg/kg), but not CDCA (30 mg/kg) reduced blood cholestasis markers compared to TPN controls and increased bile acids in the gallbladder and intestine. Major bile acids in the liver and distal intestine were CDCA, HCA, HDCA, and OCA, and their relative proportions were increased by the type of bile acid (CDCA …

Glycerol-3-Phosphate Activates Chrebp, Fgf21 Transcription And Lipogenesis In Citrin Deficiency, Vinod Tiwari, Byungchang Jin, Olivia Sun, Edwin D J Lopez Gonzalez, Min-Hsuan Chen, Xiwei Wu, Hardik Shah, Andrew Zhang, Mark A Herman, Cassandra N Spracklen, Russell P Goodman, Charles Brenner

Faculty, Staff and Students Publications

Citrin deficiency (CD) is caused by the inactivation of SLC25A13, a mitochondrial membrane protein required to move electrons from cytosolic NADH to the mitochondrial matrix in hepatocytes. People with CD do not like sweets. Here we show that SLC25A13 loss causes the accumulation of glycerol-3-phosphate (G3P), which activates the carbohydrate response element-binding protein (ChREBP) to transcribe FGF21, which acts in the brain to restrain intake of sweets and alcohol and to transcribe key genes driving lipogenesis. Mouse and human data suggest that G3P-ChREBP is a mechanistic component of the Randle Cycle that contributes to metabolic-dysfunction-associated steatotic liver disease and forms …

Mutations In The Key Autophagy Tethering Factor Epg5 Link Neurodevelopmental And Neurodegenerative Disorders Including Early-Onset Parkinsonism, Hormos Salimi Dafsari, Celine Deneubourg, Kritarth Singh, Reza Maroofian, Zita Suprenant, Ay Lin Kho, Neil J Ingham, Karen P Steel, Preethi Sheshadri, Franciska Baur, Lea Hentrich, Birgit Gerisch, Mina Zamani, Cesar Alves, Ata Siddiqui, Haidar S Dafsari, Mehri Salari, Anthony E Lang, Michael Harris, Alice Abdelaleem, Saeid Sadeghian, Reza Azizimalamiri, Hamid Galehdari, Gholamreza Shariati, Alireza Sedaghat, Jawaher Zeighami, Daniel Calame, Dana Marafi, Ruizhi Duan, Adrian Boehnke, Gary D Clark, Jill A Rosenfeld, Carrie A Mohila, Dora Steel, Saurabh Chopra, Suvasini Sharma, Nicolai Kohlschmidt, Steffi Patzer, Afshin Saffari, Darius Ebrahimi-Fakhari, Büşra Eser Çavdartepe, Irene J Chang, Erika Beckman, Renate Peters, Andrew Paul Fennell, Bernice Lo, Luisa Averdunk, Felix Distelmaier, Martina Baethmann, Frances Elmslie, Kairit Joost, Sheela Nampoothiri, Dhanya Yesodharan, Hanna Mandel, Amy Kimball, Antonie D Kline, Cyril Mignot, Boris Keren, Vincent Laugel, Katrin Õunap, Kalpana Devadathan, Frederique M C Van Berkestijn, Arpana Silwal, Saskia Koene, Sumit Verma, Mohammed Yousuf Karim, Chahynez Boubidi, Majid Aziz, Gehad Elghazali, Lauren Mattas, Mohammad Miryounesi, Farzad Hashemi-Gorji, Shahryar Alavi, Nayereh Nouri, Mehrdad Noruzinia, Saeideh Kavousi, Arveen Kamath, Sandeep Jayawant, Russell Saneto, Nourelhoda A Haridy, Pinar Ozkan Kart, Ali Cansu, Madeleine Joubert, Claire Beneteau, Kyra E Stuurman, Martina Wilke, Tahsin Stefan Barakat, Homa Tajsharghi, Annarita Scardamaglia, Sadeq Vallian, Semra Hız, Ali Shoeibi, Reza Boostani, Narges Hashemi, Meisam Babaei, Norah Saleh Alsaleh, Julie Porter, Tania Attié-Bitach, Pauline Marzin, Dorota Wicher, Jessica I Gold, Elisabeth Schuler, Amna Kashgari, Rakan F Alanazi, Wafaa Eyaid, Marc Engelen, Mirjam Langeveld, Burkhard Stüve, Yun Li, Gökhan Yigit, Bernd Wollnik, Mariana H G Monje, Dimitri Krainc, Niccolò E Mencacci, Somayeh Bakhtiari, Michael Kruer, Emanuela Argilli, Elliott Sherr, Yalda Jamshidi, Ehsan Ghayoor Karimiani, Yiu Wing Sunny Cheung, Ivan Karin, Giovanni Zifarelli, Peter Bauer, Wendy K Chung, James R Lupski, Manju A Kurian, Jörg Dötsch, Jürgen-Christoph Von Kleist-Retzow, Thomas Klopstock, Matias Wagner, Calvin Yip, Andreas Roos, Rita Carsetti, Carlo Dionisi-Vici, Mathias Gautel, Michael R Duchen, Adam Antebi, Henry Houlden, Manolis Fanto, Heinz Jungbluth

Faculty, Staff and Students Publications

Objective: Autophagy is a fundamental biological pathway with vital roles in intracellular homeostasis. During autophagy, defective cargoes including mitochondria are targeted to lysosomes for clearance and recycling. Recessive truncating variants in the autophagy gene EPG5 have been associated with Vici syndrome, a severe early-onset neurodevelopmental disorder with extensive multisystem involvement. Here, we aimed to delineate the extended, age-dependent EPG5-related disease spectrum.

Methods: We investigated clinical, radiological, and molecular features from the largest cohort of EPG5-related patients identified to date, complemented by experimental investigation of cellular and animal models of EPG5 defects.

Results: Through worldwide collaboration, we identified 211 patients, 97 …

Targeting Adenosine 2a Receptor Signaling Suppresses Vascular Calcification By Restraining Smooth Muscle Osteogenic Differentiation, Yaqi Zhou, Dingwei Zhao, Qian Ma, Sujin Lee, Kangsan Roh, Yongfeng Cai, Jiean Xu, Qiuhua Yang, Qingen Da, Zhiping Liu, Kunfu Ouyang, Eric J Belin De Chantemele, Mei Hong, Clint L Miller, Rajeev Malhotra, Chunxiang Zhang, Suowen Xu, Yuqing Huo

Faculty, Staff and Students Publications

Vascular calcification (VC) is a major contributor to cardiovascular morbidity and mortality, particularly in patients with chronic kidney disease (CKD). Adenosine 2 A receptor (ADORA2A) is highly expressed in vascular cells and implicated in cardiovascular disease; however, its specific role in VC pathogenesis remains unclear. Here, we investigated the role of ADORA2A using in vitro (vascular smooth muscle cells; VSMCs), ex vivo (mouse aortic rings), and in vivo (5/6th nephrectomy with high phosphate and cholecalciferol) models of VC. The ADORA2A expression was significantly upregulated in calcified human and murine aortic tissues, as well as in VSMCs, under osteogenic conditions. Genetic …

The Efficacy Of Longevity Interventions In Caenorhabditis Elegans Is Determined By The Early Life Activity Of Rna Splicing Factors, Sneha Dutta, Maria Camila Perez Matos, Caroline Heintz, Ayse Sena Mutlu, Mary Piper, Meeta Mistry, Arpit Sharma, Christopher S Morrow, Hannah Smith, Porsha Howell, Rohan Sehgal, Anne Lanjuin, Meng C Wang, William B Mair

Faculty, Staff and Students Publications

Geroscience aims to target the aging process to extend healthspan. However, even isogenic individuals show heterogeneity in natural aging rate and responsiveness to pro-longevity interventions, limiting translational potential. Using RNAseq analysis of young, isogenic, subpopulations of Caenorhabditis elegans selected solely on the basis of the splicing pattern of an in vivo minigene reporter that is predictive of future life expectancy, we find a strong correlation in young animals between predicted life span and alternative splicing of mRNAs related to lipid metabolism. The activity of two RNA splicing factors, Reversed Polarity-1 (REPO-1) and Splicing Factor 1 (SFA-1), early in life is …

Bicontinuous Interconnected Porous Biomaterials For Tissue Engineering And Regeneration, Aihik Banerjee, Anjana Khanal, Prince D Okoro, Shankar P Kharal, Kevin Dalsania, Baishali Kanjilal, Shiril B Iragavarapu, Yiqing Chen, Janitha M Unagolla, Huinan H Liu, Joshua T Morgan, Robert P Hesketh, Arash Pezhouman, Reza Ardehali, Bahman Anvari, Martin F Haase, Iman Noshadi

Faculty, Staff and Students Publications

Biomaterials mimicking natural extracellular matrix are necessary to create an optimal microenvironment for cell adhesion, migration, proliferation, and differentiation. These scaffolds must possess bicontinuous interconnected porosity to ensure the effective exchange of oxygen, nutrients, and metabolic waste, which are crucial for developing functional tissues. Here, a novel bicontinuous interfacially jammed emulsion (BIJEL)-Integrated PORous Engineered System (BIPORES) is developed to confer bioinert synthetic polyethylene glycol diacrylate (PEGDA) with unique bicontinuous interconnected porosity and surface topography. This platform is fabricated through controlled phase separation and interfacial stabilization of two continuous phases by nanoparticles. Functional validation using human mesenchymal stem cells, and human …