Digital Commons Network^™

Retention Of Lysosomal Acid Sphingomyelinase Protects From Niemann-Pick Disease., Cameron A Beard, Kyra N Hermanson, Justin M Snider, Aki Hara, Brandon K Dahl, Janet J Allopenna, Marilyn T Marron, Benjamin Newcomb, Benjamin E. Low, Michael V. Wiles, Russell W Jenkins, Lina M Obeid, Yusuf A Hannun, Ashley J Snider

Faculty Research 2025

Niemann-Pick Disease (NPD) types A and B are lysosomal storage disorders resulting from dysfunction or loss of acid sphingomyelinase (aSMase), which hydrolyzes sphingomyelin (SM) to ceramide and phosphocholine. Patients with NPD-A develop severe neurologic and visceral pathology and rarely live beyond the age of 3 years, while patients with NPD-B typically live to adolescence/early adulthood without neurologic involvement. There are currently no therapies for NPD-A. SMPD1, the gene that encodes aSMase, gives rise to two distinct enzymes - lysosomal sphingomyelinase (L-SMase) and secretory sphingomyelinase (S-SMase), with the latter being associated with inflammation and chemokine amplification. This study sought to define …

Single-Cell Transcriptomics Of The Myeloid Milieu Reveals An Angiogenic Niche In Triple-Negative Breast Cancer., Yechan Choi, Minkyu Shim, Suhn Hyung Kim, Duk Ki Kim, Juhee Jeong, Jinyoung Byeon, Giyong Jang, Ji-Yeon Kim, Paul Robson, Charles Lee, Han-Byoel Lee, Keehoon Jung

Faculty Research 2025

Intratumoral myeloid cells are highly heterogeneous in terms of development and function and are pivotal for forming and regulating the tumor microenvironment. However, the myeloid milieu in triple-negative breast cancer (TNBC) remains poorly understood. Here, to elucidate this myeloid milieu, we integrated in-house and public single-cell RNA sequencing data. We detected diverse neutrophil and mononuclear-phagocyte subtypes and delineated their developmental trajectories and functions. Of particular interest were the VEGFA

Context-Dependent Contribution Of Peptidyl Arginine Deiminase 4 (Pad4) To Neutrophil Extracellular Trap Formation And Liver Injury In Acute And Chronic Hepatotoxicant Challenge, Gina E Capece, Amish K Patel, Daniel Hu, Tayana Roychowdhury, Bianca Hazel, Jessica Kothapalli, Noah A Mac, Frederik Denorme, Robert A Campbell, Lauren G Poole

2020-Current year OA Pubs

Neutrophils play a complex role in the pathogenesis of chronic liver disease and have been linked to both liver damage and injury resolution. Recent reports propose that neutrophils drive liver injury and fibrosis through the formation of neutrophil extracellular traps (NETs). This study tests the hypothesis that the enzyme peptidyl arginine deiminase-4 (PAD4) drives NET formation and liver fibrosis in experimental chronic liver injury. Wild-type (PAD4+/+) and PAD4-deficient (PAD4-/-) mice were chronically challenged twice weekly with carbon tetrachloride (CCl4, 1 ml/kg, i.p) or vehicle (corn oil) for 6 weeks, and samples were collected 24 h after the final challenge. In …

A Glial Circadian Gene Expression Atlas Reveals Cell-Type And Disease-Specific Reprogramming In Response To Amyloid Pathology Or Aging, Patrick W. Sheehan, Stuart B Fass, Darshan Sapkota, Sylvia Kang, Henry C Hollis, Jennifer H Lawrence, Sohui Park, Ashish Sharma, Dorothy P Schafer, Ron C Anafi, Joseph D Dougherty, John D Fryer, Erik S Musiek

2020-Current year OA Pubs

While circadian rhythm disruption may promote neurodegenerative disease, the impact of aging and neurodegenerative pathology on circadian gene expression patterns in different brain cell types remains unknown. Here we used a translating ribosome affinity purification to identify the circadian translatomes of astrocytes, microglia and bulk tissue in healthy mouse cortex and in the settings of amyloid-β plaque pathology or aging. We show that glial circadian translatomes are highly cell-type-specific and exhibit profound, context-dependent reprogramming in response to amyloid pathology or aging. Transcripts involved in glial reactivity, immunometabolism and proteostasis, as well as nearly half of all Alzheimer's disease risk genes, …

Degenerating Intervertebral Discs In The Streptozotocin-High-Fat Diet Model Of Type 2 Diabetes Show Extensive Inflammation, Christian E Gonzalez, Rachana S Vaidya, Sade W Clayton, Simon Y Tang

2020-Current year OA Pubs

The chronic inflammation observed during type 2 diabetes (T2D) is associated with spinal pathologies, including intervertebral disc (IVD) degeneration and chronic spine pain. Despite confounding factors, such as obesity, studies show that, after adjusting for age, body mass index and genetics (e.g. twins), patients with T2D experience disproportionate severity of IVD degeneration and/or back pain than individuals without T2D. We hypothesized that chronic T2D fosters a proinflammatory microenvironment within the IVD that promotes degeneration and disrupts homeostasis. To test this, we evaluated two common mouse models of T2D - leptin-receptor deficient (db/db) mice and mice with a chronic high-fat diet …

Maternal Separation Disrupts Noradrenergic Control Of Adult Coping Behaviors, Chayla R Vazquez, Léa J Becker, Chao-Cheng Kuo, Solana A Cariello, Ayah N Hamdan, Ream Al-Hasani, Susan E Maloney, Jordan G Mccall

2020-Current year OA Pubs

Early life stress (ELS) profoundly impacts the brain and correlates with negative affective behaviors in adulthood. The locus coeruleus (LC), a stress-responsive brainstem nucleus that supplies most of the brain with norepinephrine (NE), is known to modulate negative affect. Using repeated maternal separation stress (MSS), we investigated the impact of ELS on the LC and stress-related behaviors in adulthood. We performed ex vivo cell-attached electrophysiology across the lifespan to reveal that MSS significantly increased LC firing during early development and adulthood but not in pre-adolescence and adolescence. We next examined potential changes in the expression of genes linked to LC …

Arousal As A Universal Embedding For Spatiotemporal Brain Dynamics, Ryan V Raut, Zachary P Rosenthal, Xiaodan Wang, Hanyang Miao, Zhanqi Zhang, Jin-Moo Lee, Marcus E Raichle, Adam Q Bauer, Steven L Brunton, Bingni W Brunton, J Nathan Kutz

2020-Current year OA Pubs

Neural activity in awake organisms shows widespread, spatiotemporally diverse correlations with behavioural and physiological measurements

Upregulation Of Adenosine A2a Receptor In Astrocytes Is Sufficient To Trigger Hippocampal Multicellular Dysfunctions And Memory Deficits, Agathe Launay, Miranda E Orr, Et Al.

2020-Current year OA Pubs

Adenosine is an ubiquitous neuromodulator that ensures cerebral homeostasis. It exerts numerous functions through the activation of G-protein-coupled adenosine receptors (ARs), in particular A

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 …

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 …

Opposing Roles Of Microglial And Macrophagic C3ar1 Signaling In Stress-Induced Synaptic And Behavioral Changes, Ashutosh Tripathi, Alona Bartosh, Dania Jose, Jocelyn Mata, Usama Hussein, Fernanda Laezza, Zhongming Zhao, Anilkumar Pillai

Faculty, Staff and Student Publications

The social deficits following chronic stress conditions are linked to synaptic dysfunction in the brain. Complement system plays a critical role in synapse regulation. Although complement has been implicated in chronic stress-induced behavior deficits the cellular substrates and mechanisms underlying complement-mediated behavior changes under chronic stress conditions are not known. In the present study, we investigated the role of complement component 3a receptor (C3ar1) in microglia and monocytes/macrophages (Mo/MΦ) in chronic unpredictable stress (CUS)-induced synapse loss and behavior deficits in mice. We found that deletion of microglial C3ar1 attenuated stress-induced social behavior deficits and changes in neuroinflammatory as well as …

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 …

Pkr-Driven Isr Signaling Controls Synaptic Translation And Structural Plasticity In An Age-Dependent Manner, Nicolás W Martínez, Felipe Gómez, Ariel Tapia-Godoy, Juan Francisco Roa, Fernanda Moreso-Contreras, Yuwei Liu, Claudia Jara, Cheril Tapia-Rojas, Iván Alfaro, Mauro Costa-Mattioli, Soledad Matus

Faculty, Staff and Students Publications

The integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2α), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with …

Apol2 Stabilizes Ku80 To Confer Nhej-Mediated Radioresistance In Gastric Cancer, Dan Zu, Qimei Bao, Hanyi He, Yuke Zhong, Mingcong Deng, Yangchan Hu, Chunkai Zhang, Chen Liang, Yixing Huang, Haidong Liu, Xiao Li, Yanhua He, Guoyan Luo, Weixin Wu, Fenghui Guan, Shengfeng Xu, Min Liu, Albino Bacolla, Ji Jing, Yian Du, John A Tainer, Yin Shi, Zu Ye, Xiangdong Cheng

Faculty, Staff and Student Publications

Radiotherapy is one of the most important adjuvant treatment methods for gastric cancer (GC). However, radioresistance remains a major clinical obstacle. In this study, APOL2 is identified as a key player in promoting non-homologous end joining (NHEJ)-mediated double-strand break (DSB) repair and enhancing radioresistance in GC. Bioinformatics and clinical data revealed that high APOL2 expression is correlated with poor prognosis in GC patients. Functional experiments showed that APOL2 overexpression enhances genomic stability by accelerating DSB repair via the NHEJ pathway, while APOL2 knockout impairs repair capacity. Mechanistically, APOL2 binds to and stabilizes Ku80 by enhancing USP7-mediated deubiquitylation, thereby increasing Ku80 …

Sensory-Selective Peripheral And Neuraxial Nerve Blockade With 2',6'-Pipecoloxylidide, Claire A Ostertag-Hill, Shuanglong Chen, Tianrui Xue, Rachelle Shao, Matthew Torre, Bin Feng, Zahra Vahedi, Longtu Chen, Steven J Staffa, Yueqin Zheng, Daniel S Kohane

Duncan NRI Faculty and Staff Publications

Background: Safe sensory-selective local anesthetics would be a major advance in the management of acute and chronic pain. This articles describes the sensory-selective local anesthetic properties and the toxicity profile of a known metabolite of amino-amide local anesthetics, 2',6'-pipecoloxylidide (PPX).

Methods: PPX was synthesized and made into its hydrochloride salt. PPX or ropivacaine (ROP) were injected at the sciatic nerve or intrathecally in rats, who then underwent modified hotplate (sensory) testing and weight-bearing (motor) testing. Rats injected with PPX or ROP were assessed for clinical toxicity endpoints. Conduction blockade was studied with single-unit recordings in mice. Biocompatibility was assessed histologically. …

Pathogenic Xpo1 Variants Cause A Dominant Neurodevelopmental Disorder, Amber S E Van Oirsouw, Pavla Nedbalova, Miroslava Hancarova, Jan Prchal, Darina Prchalova, Marketa Vlckova, Sarka Bendova, Kristin G Monaghan, Lisa M Dyer, Yanmin Chen, Deanna Alexis Carere, Emma A M Te Bogt, Heather Fisher, Angela E Scheuerle, Stephanie Riley, Mahim Jain, Weiyi Mu, Joann N Bodurtha, Albertien M Van Eerde, Marijn F Stokman, Nicola Longo, Meena Balasubramanian, Michael Spiller, Gregory Costain, Charlotte Von Der Lippe, Kristian Tveten, Marianne Jortveit, Øystein L Holla, Bertrand Isidor, Benjamin Cogné, Kevin E Glinton, Blake Vuocolo, Roberta Ann Sierra, Brad Angle, Kelly Bontempo, Klaas Koop, Rachel Rabin, John Pappas, David A Staffenberg, Pascal Joset, Peter Miny, Isabel Filges, Abdulrazak Alali, Kara Vitalone, Jill A Rosenfeld, Weimin Bi, Samuel Bradbrook, Renee Perrier, Subhadra Ramanathan, June-Anne Gold, María Palomares Bralo, María Ángeles Gómez-Cano, Ann Haskins Olney, Shelly Nielsen, Alban Ziegler, Dominique Bonneau, Clément Prouteau, Ange-Line Bruel, Charlotte Caille-Benigni, Laëtitia Lambert, Andrea C Yu, Nathaniel H Robin, Dana Goodloe, Jan Fischer, Joseph Porrmann, Yvonne D Hennig, Rami Abou Jamra, Isabella Herman, Ivy R Johnson, Lucas Hérissant, Guillaume Jouret, Koen L I Van Gassen, Ellen Van Binsbergen, Bert Van Der Zwaag, Alwin Kamermans, Renske Oegema, Zdenek Sedlacek, Michaela Fenckova, Richard H Van Jaarsveld

Faculty, Staff and Students Publications

Purpose: XPO1 functions in key cellular processes, including nucleo-cytoplasmic export and mitosis. The gene is deleted in a subset of patients with the 2p15p16.1 microdeletion syndrome; however, no monogenic XPO1-related disorder has been described to date.

Methods: We collected clinical data of individuals with de novo XPO1 variants through online matchmaking. We used Drosophila to study XPO1 function in development and habituation learning.

Results: A total of 22 individuals met the criteria to be included in the main study cohort. Of these, half have putative loss-of-function variants, and half have coding variants (10 missense and 1 in-frame deletion variant). We …

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 …

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 …

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 …

Multiomic And Electrophysiologic Analyses Reveal That An Inherited Mrc2 Variant Causes Fibroblast Dysfunction And Increased Atrial Fibrillation Susceptibility, Kevin S Ho, Joshua A Keefe, Shuai Zhao, Mohit M Hulsurkar, Sung Yun Jung, Md Abul Hassan Samee, Xander H T Wehrens

Faculty, Staff and Students Publications

A recent study identified a rare variant in the mannose receptor C type 2 (MRC2) gene in individuals with familial reentrant supraventricular tachycardia, a Wolff-Parkinson-White (WPW) electrocardiogram pattern, and structurally normal hearts. WPW syndrome is associated with atrial fibrillation (AF), and MRC2 was recently proposed as a protective gene for AF. We determined whether the E990G-heterozygous (het) loss-of-function variant in Mrc2 increases AF susceptibility and identified aberrant cellular mechanisms resulting from Mrc2 deficiency in atrial cardiofibroblasts (ACFs) and atrial tissue in mice that may promote AF. Programmed electrical stimulation was performed to determine AF susceptibility in Mrc2 E990G-het …

Single-Nucleus Mrna-Sequencing Reveals Dynamics Of Lipogenic And Thermogenic Adipocyte Populations In Murine Brown Adipose Tissue In Response To Cold Exposure, Janina Behrens, Tongtong Wang, Christoph Kilian, Anna Worthmann, Mark A Herman, Joerg Heeren, Lorenz Adlung, Ludger Scheja

Faculty, Staff and Students Publications

Objective and methods: Brown adipose tissue (BAT) comprises a heterogeneous population of adipocytes and non-adipocyte cell types. To characterize these cellular subpopulations and their adaptation to cold, we performed single-nucleus mRNA-sequencing (snRNA-seq) on interscapular BAT from mice maintained at room temperature or exposed to acute (24h) or chronic (10 days) cold (6 °C). To investigate the role of the de novo lipogenesis (DNL)-regulating transcription factor carbohydrate response element-binding protein (ChREBP), we analyzed control and brown adipocyte-specific ChREBP knockout mice.

Results: We identified different cell populations, including seven brown adipocyte subtypes with distinct metabolic profiles. One of them highly expressed ChREBP …

Myeloid-Specific Camkk2 Deficiency Protects Against Diet-Induced Obesity And Insulin Resistance By Rewiring Metabolic Gene Expression And Enhancing Energy Expenditure, Andrea R Ortiz, Kevin Nay, Brittany A Stork, Adam M Dean, Sean M Hartig, Cristian Coarfa, Surafel Tegegne, Christopher Rm Asquith, Daniel E Frigo, Brian York, Anthony R Means, Mark A Febbraio, John W Scott

Faculty, Staff and Students Publications

Objective: Obesity is associated with chronic, low-grade inflammation in metabolic tissues such as liver, adipose tissue and skeletal muscle implicating insulin resistance and type 2 diabetes as inflammatory diseases. This inflammatory response involves the accumulation of pro-inflammatory macrophages in these metabolically relevant organs. The Ca2+-calmodulin-dependent protein kinase kinase-2 (CAMKK2) is a key regulator of cellular and systemic energy metabolism, and a coordinator of macrophage-mediated inflammatory responses. However, its role in obesity-associated metabolic dysfunction is not fully defined. The aim of this study was to determine the contribution of CAMKK2 to the regulation of inflammation and systemic metabolism during diet-induced obesity. …

Chemical Modulation Of Gut Bacterial Metabolism Induces Colanic Acid And Extends The Lifespan Of Nematode And Mammalian Hosts, Guo Hu, Marzia Savini, Matthew Brandon Cooke, Xin Wei, Dinghuan Deng, Shihong M Gao, Ruyue Alps Xia, Youchen Guan, Alice X Wen, Xin Yu, Jin Wang, Chao Jiang, Christophe Herman, Jiefu Li, Meng C Wang

Faculty, Staff and Students Publications

Microbiota-derived metabolites have emerged as key regulators of longevity. The metabolic activity of the gut microbiota, influenced by dietary components and ingested chemical compounds, profoundly impacts host fitness. While the benefits of dietary prebiotics are well-known, chemically targeting the gut microbiota to enhance host fitness remains largely unexplored. Here, we report a novel chemical approach to induce a pro-longevity bacterial metabolite in the host gut. We discovered that wild-type Escherichia coli strains overproduce colanic acids (CAs) when exposed to a low dose of cephaloridine, leading to an increased life span in the host organism Caenorhabditis elegans. In the mouse gut, …

Coco-St Detects Global And Local Biological Structures In Spatial Transcriptomics Datasets, Muhammad Aminu, Bo Zhu, Natalie Vokes, Hong Chen, Lingzhi Hong, Jianrong Li, Junya Fujimoto, Mehdi Chaib, Yuqiu Yang, Bo Wang, Alissa Poteete, Monique B Nilsson, Xiuning Le, Tina Cascone, David Jaffray, Nicholas Navin, Tao Wang, Lauren A Byers, Don L Gibbons, John Heymach, Ken Chen, Chao Cheng, Jianjun Zhang, Jia Wu

Faculty, Staff and Students Publications

Spatial domain detection methods often focus on high-variance structures, such as tumour-adjacent regions with sharp gene expression changes, while missing low-variance structures with subtle gene expression shifts, like those between adjacent normal and early adenoma regions. Here, to address this, we introduce ‘compare and contrast spatial transcriptomics’ (CoCo-ST), a graph contrastive feature representation framework. By comparing a target sample with a background sample, CoCo-ST detects both high-variance, broadly shared structures and low-variance, tissue-specific features. It offers technical advantages, including multisample integration, batch-effect correction and scalability across technologies from spot-level Visium data to single-cell Xenium Prime 5K and subcellular Visium HD …

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 …

Basal Cell Of Origin Resolves Neuroendocrine-Tuft Lineage Plasticity In Cancer, Abbie S Ireland, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

Neuroendocrine and tuft cells are rare chemosensory epithelial lineages defined by the expression of ASCL1 and POU2F3 transcription factors, respectively. Neuroendocrine cancers, including small cell lung cancer (SCLC), frequently display tuft-like subsets, a feature linked to poor patient outcomes

Iron Supplementation Switches Mode Of Cell Death To Ferroptosis During Acetaminophen-Induced Liver Injury In Mice Rendering It Resistant To N-Acetylcysteine., Olamide B. Adelusi, Aparna Venkatraman, Jephte Y. Akakpo, Anup Ramachandran, Hartmut Jaeschke

Manuscripts, Articles, Book Chapters and Other Papers

Acetaminophen (APAP) overdose can cause liver injury and is the leading cause of acute liver failure in Western countries. Hepatocellular necrosis induced by APAP involves the formation of a reactive metabolite, triggering mitochondrial oxidant stress and peroxynitrite formation. Iron-catalyzed protein nitration is critical for mitochondrial dysfunction and cell death in the absence of lipid peroxidation (LPO). However, co-treatment of APAP and ferrous sulfate aggravated protein nitration and liver injury but also triggered extensive LPO (measured as malondialdehyde and hydroxy eicosatetraenoic acid (HETE) species). The objective of this study was to evaluate whether the aggravated injury under these conditions is caused …