Digital Commons Network^™

Phosphoglycerate Mutase Regulates Treg Differentiation Through Control Of Serine Synthesis And One-Carbon Metabolism, Wesley H Godfrey, Judy J Lee, Shruthi Shanmukha, Kaho Cho, Xiaojing Deng, Chandra Shekar R Ambati, Vasanta Putluri, Abu Hena Mostafa Kamal, Paul M Kim, Nagireddy Putluri, Michael D Kornberg

Faculty, Staff and Students Publications

The differentiation and suppressive functions of regulatory CD4 T cells (Tregs) are supported by a broad array of metabolic changes, providing potential therapeutic targets for immune modulation. In this study, we focused on the regulatory role of glycolytic enzymes in Tregs and identified phosphoglycerate mutase (PGAM) as being differentially overexpressed in Tregs and associated with a highly suppressive phenotype. Pharmacologic or genetic inhibition of PGAM reduced Treg differentiation and suppressive function while reciprocally inducing markers of a pro-inflammatory, T helper 17 (Th17)-like state. The regulatory role of PGAM was dependent on the contribution of 3-phosphoglycerate (3 PG), the PGAM substrate, …

Melanoma Antigens In Pediatric Medulloblastoma Contribute To Tumor Heterogeneity And Species-Specificity Of Group 3 Tumors, Rebecca R J Collins, Rebecca R Florke Gee, Sima Tozandehjani, Tara Bayat, Maria Camila Hoyos Sanchez, Juan Sebastian Solano Gutierrez, Barbara Breznik, Anna K Lee, Samuel T Peters, Jon P Connelly, Shondra M Pruett-Miller, Martine F Roussel, Dinesh Rakheja, Heather S Tillman, Patrick Ryan Potts, Klementina Fon Tacer

Faculty, Staff and Student Publications

Medulloblastoma (MB) is the most malignant childhood brain cancer. Group 3 MB (G3 MB) subtype accounts for about 25% of MB and is associated with the worst outcomes. Herein, we report that more than half of G3 MB tumors express melanoma antigens (MAGEs), which are potential prognostic and therapeutic markers. MAGEs are cancer-testis antigens, aberrantly expressed in several adult cancers, and associated with poorer prognosis and therapy resistance; however, their role in pediatric cancers is mostly unknown. This study aimed to determine whether MAGEs are activated and important in pediatric MB. We obtained formalin-fixed paraffin-embedded tumor samples of 34 patients, …

Dietary Lipids Induce Ppard And Bcl6 To Repress Macrophage Il-23 Induction After Intestinal Injury And Lps Exposure, Ashleigh M Gil, Daniel F Zegarra-Ruiz, Wan-Jung Wu, Kendra Norwood, Adrien Assie, Buck S Samuel, Angela M Major, Gretchen E Diehl, Andrea A Hill Mcalester

Faculty, Staff and Students Publications

Unresolved tissue damage is a common feature of Inflammatory Bowel Disease (IBD) that facilitates disease progression. Here, we showed that high animal fat diets (HFD), an environmental risk factor associated with IBD pathogenesis, suppress intestinal macrophage production of critical tissue repair responses after damage. This includes reduced IL-23 production, which drives downstream production of IL-22, which is needed for barrier repair. Indicating that dietary lipids interfere with responses to microbial molecules needed to induce barrier protective functions, we found oleic acid could directly suppress macrophage Il23a induction after lipopolysaccharide (LPS) treatment. Deleting the lipid transporter CD36 on macrophages restored the …

Single-Cell Transcriptomics Of Ventral Forebrain Progenitors Identifies Evf2 Enhancer Lncrna-Enhancer Gene Guidance Through Direct Rna Binding And Rnp Recruitment Domains, Edward Li, Abhijit Chakraborty, Sara J Kohtz, Ivelisse Cajigas, Laura Hinojosa-Gonzalez, Fion Shiau, Ryan Bertossi, Robert J Vassar, Jack A Kessler, Ferhat Ay, Brian S Clark, Jhumku D Kohtz

2020-Current year OA Pubs

During mouse embryonic brain development, the Evf2 ultraconserved enhancer (UCE) lncRNA guides the Dlx5/6UCE to ~129 sites across chr6. However, previous work identified only 4 transcriptionally regulated targets associated with Evf2-Dlx5/6UCE-gene guidance, raising questions about the significance of Evf2-regulated Dlx5/6UCE-gene interactions. Here, single-cell transcriptomics reveal far greater alignment between Evf2-Dlx5/6UCE-gene guidance and transcriptional regulation than previously reported. Evf2 divides chr6 into short-range ( < 10 Mb distant), activated genes, and long/super-long-range (10-129 Mb distant), repressed genes, identifying seizure regulating genes in the embryonic subventricular zone that predict adult phenotypes. Evf2-regulated Dlx5/6UCE-gene distances and directions (closer to or further from gene targets) can be decoupled from gene target transcriptional effects. Evf2 regulates Evf2-ribonucleoprotein (RNP) binding in a combinatorial manner to key regulatory sites, including chr6 Evf2-Dlx5/6UCE-gene guided sites, Evf1/2 RNA-directly bound sites (RBSs), and inter-chromosomal HiC looping interactions. RBSs divide chromosomes into multi-megabase domains enriched for Evf2-regulated RNP recruitment, transcription factor motifs, and HiC looping interactions. Together with Evf2-controlled homeobox motif recognition at Evf2-RNP recruitment sites and transcription factor motif enrichment in RBSs with DNA identity, this work supports direct roles for Evf2 in enhancer-gene guidance and transcriptional regulation, with the potential for both site-specific and chromosomal domain specific RNP recruitment.

Rna Sequencing Reveals Inflammatory And Metabolic Changes In The Lung And Brain After Carbon Black And Naphthalene Whole Body Inhalation Exposure In A Rodent Model Of Military Burn Pit Exposures, Allison M. Haaning, Brian J. Sandri, Henry L. Wyneken, William T. Goldsmith, Joshua P. Nixon, Timothy R. Nurkiewicz, Chris H. Wendt, Paul Barach, Janeen H. Trembley, Tammy A. Butterick

College of Population Health Faculty Papers

Military personnel deployed to Iraq and Afghanistan were exposed to emissions from open-air burn pits, where plastics, metals, and medical waste were incinerated. These exposures have been linked to deployment-related respiratory diseases (DRRD) and may also impact neurological health via the lung-brain axis. To investigate molecular mechanisms, adult male rats were exposed to filtered air, naphthalene (a representative volatile organic compound), or a combination of naphthalene and carbon black (surrogate for particulate matter; CBN) via whole-body inhalation (six hours/day, three consecutive days). Lung, brain, and plasma samples were collected 24 h after the final exposure. Pro-inflammatory biomarkers were assessed using …

Specialization Of Sesquiterpene Lactone Metabolites In Liriodendron Plant Defense, Shiwei Chen, Sarah Al Kinani, Oli Horyn, Colin Galliano, Era Srivastava, David C Rowley, Kathryn M Ramsey, Divita Mathur, Matthew J Bertin

Faculty, Staff and Students Publications

Tulip trees (Liriodendron tulipifera and Liriodendron chinense), members of the Magnolia family, are known for their distinctive morphology and ecological significance, but their chemical diversity remains understudied. In this study, we report the identification and characterization of an array of sesquiterpene lactones (SQLs) produced by L. tulipifera. Through comprehensive chemical analysis, including high-resolution mass spectrometry and nuclear magnetic resonance spectroscopy, we identified a series of STLs with distinct bioactivity profiles. Notably, one of these compounds exhibited antibacterial activity but was only present in L. tulipifera, being absent in L. chinense. Additionally, some STLs demonstrated significant …

Human Ipsc-Based Breast Cancer Model Identifies S100p-Dependent Cancer Stemness Induced By Brca1 Mutation, Jingxin Liu, Cai Zhao, Jiahao Chen, Pengguihang Zeng, Qingjian Li, Ranran Dai, Xingqiang Lai, Wenqian Song, Jianing Chen, Xixi Zhu, Xinyi Liu, Jun Sun, Jia Wang, Peihang Fang, Tengfei Wang, Wenjie Chen, Diana Guallar, Nan Cao, Jianli Zhao, Shicheng Su, Andy Peng Xiang, Yi Arial Zeng, Jie Li, Junchao Cai, Dung-Fang Lee, Jinxin Bei, Yongliang Huo, Hai Hu, Shengbao Suo, Dong-Feng Huang, Jin Bai, Junjun Ding

Faculty, Staff and Student Publications

Breast cancer is the most common malignancy in females and remains the leading cause of cancer-related deaths for women worldwide. The cellular and molecular basis of breast tumorigenesis is not completely understood partly due to the lack of human research models which simulate the development of breast cancer. Here, we developed a method for generating functional mammary-like cells (MCs) from human-induced pluripotent stem cells (iPSCs). The iPSC-MCs closely resemble human primary MCs at cellular, transcriptional, and functional levels. Using this method, a breast cancer model was generated using patient-derived iPSCs harboring germline

Choline-An Essential Nutrient With Health Benefits And A Signaling Molecule, Brianne C. Burns, Jitendra D. Belani, Hailey N. Wittorf, Eugen Brailoiu, G. Cristina Brailoiu

College of Pharmacy Faculty Papers

Choline has been recognized as an essential nutrient involved in various physiological functions critical to human health. Adequate daily intake of choline has been established by the US National Academy of Medicine in 1998, considering choline requirements for different ages, sex differences and physiological states (e.g., pregnancy). By serving as a precursor for acetylcholine and phospholipids, choline is important for cholinergic transmission and the structural integrity of cell membranes. In addition, choline is involved in lipid and cholesterol transport and serves as a methyl donor after oxidation to betaine. Extracellular choline is transported across the cell membrane via various transport …

Gene Therapy Ameliorates Neuromuscular Pathology In Cln3 Disease, Ewa A Ziółkowska, Albina Jablonka-Shariff, Letitia L Williams, Matthew J Jansen, Sophie H Wang, Elizabeth M Eultgen, Matthew D Wood, Daniel A Hunter, Jaiprakash Sharma, Marco Sardiello, Robyn Reese, Alan Pestronk, Mark S Sands, Alison K Snyder-Warwick, Jonathan D Cooper

2020-Current year OA Pubs

CLN3 disease is a neuronopathic lysosomal storage disorder that severely impacts the central nervous system (CNS) while also inducing notable peripheral neuromuscular symptoms. Although considerable attention has been directed towards the neurodegenerative consequences within the CNS, the involvement of peripheral tissues, including skeletal muscles and their innervation, has been largely neglected. We hypothesized that, CLN3 deficiency could directly influence peripheral nerves and investigated the neuromuscular system in Cln3

Sepsis Restructures The Mitochondrial Calcium Uniporter Complex In The Lymphoid Tissues Of Mice And Humans, Xianghong Zhang, Jianguo Lin, Baobo Zou, Jack R Killinger, Andrew C Sayce, Thiagarajan Meyyappan, Zeyu Xiong, Melanie J Scott, Janet S Lee, Matthew R Rosengart

2020-Current year OA Pubs

Survivors of sepsis suffer from an elevated risk of premature death that is not explained by a higher burden of chronic diseases prior to the infection. Nearly 1 out of 4 survivors have persistent elevations of inflammation biomarkers, such as interleukin (IL) 6. These observations suggest that sepsis imparts durable changes to organismal biology. Eukaryotic life depends upon ATP and calcium (Ca

Macrophage-T Cell Interactions Promote Slamf1 Expression For Enhanced Tb Defense, G V R Krishna Prasad, Steven J Grigsby, Gideon A Erkenswick, Cynthia Portal-Celhay, Ekansh Mittal, Guozhe Yang, Samuel M Fallon, Fengyixin Chen, Thais Klevorn, Neharika Jain, Yuanyuan Li, Makedonka Mitreva, Amanda J Martinot, Joel D Ernst, Jennifer A Philips

2020-Current year OA Pubs

CD4+ T cells are crucial for protective immunity to intracellular pathogens. In addition to secreting cytokines, CD4+ T cells promote control of Mycobacterium tuberculosis infection through cognate interactions with macrophages, but the mechanism has been unclear. Here, we show that SLAMF1/CD150 is highly and uniquely induced in macrophages by antigen-specific interactions with CD4+ T cells. In macrophages, SLAMF1 enhances the generation of reactive oxygen species and restricts Mtb replication. Mtb-infection of mice promotes SLAMF1 expression specifically on infected macrophages, not uninfected bystanders. SLAMF1 expression depends on adaptive immunity and also autophagy. Moreover, Slamf1

Constitutive Il-7 Signaling Promotes Car-Nk Cell Survival In The Solid Tumor Microenvironment But Impairs Tumor Control, Matthew Dysthe, Ishwar Navin, Dayenne Van Leeuwen, Josue Pineda, Corrine Baumgartner, Cliona M Rooney, Robin Parihar

Faculty, Staff and Students Publications

Background: Adoptive transfer of chimeric antigen receptor (CAR)-expressing natural killer (NK) cells has demonstrated success against hematological malignancies. Efficacy against solid tumors has been limited by poor NK cell survival and function in the suppressive tumor microenvironment (TME). To enhance efficacy against solid tumors, stimulatory cytokines have been incorporated into CAR-NK cell therapeutic approaches. However, current cytokine strategies have limitations, including systemic toxicities, exogenous dependencies, and unwanted TME bystander effects. Here, we aimed to overcome these limitations by modifying CAR-NK cells to express a constitutively active interleukin (IL)-7 receptor, termed C7R, capable of providing intrinsic CAR-NK cell activation that does …

The Histone H3 Lysine 36 Demethylase Kdm2a/Fbxl11 Controls Polycomb-Mediated Gene Repression And Germ Cell Development In Male Mice, Michael T Bocker, Grigorios Fanourgakis, Kristie Wetzel, Pavel A Komarov, Hélène Royo, Alexia Rohmer, Sunwoo Chun, Ching-Yeu Liang, Hubertus Kohler, Taiping Chen, Xiaohong Mao, Mark A Labow, Reginald A Valdez, Michael B Stadler, Dirk G De Rooij, Paola Capodieci, John Tallarico, Antoine H F M Peters, Thomas B Nicholson

Faculty, Staff and Student Publications

KDM2A/FBXL11 is a Jumonji-domain containing lysine demethylase catalyzing the removal of mono- and di-methyl modifications of histone H3 lysine 36 (H3K36me1/2). While Kdm2a is required for mouse embryogenesis, its role in adult physiology has been largely unexplored. Using conditional deletion approaches, we demonstrate that Kdm2a deficiency leads to testicular atrophy and male infertility. Although spermatogonial stem cells remain unaffected, proliferating and differentiating spermatogonia exhibit delayed cell cycle progression and apoptosis. RNA-sequencing of purified spermatogonia and spermatocytes reveals Kdm2a-dependent repression of over 750 genes during spermatogonial differentiation. Chromatin immunoprecipitation followed by sequencing (ChIP-seq) demonstrates increased H3K36me2 levels at CpG-rich gene promoters …

Templating Of Monomeric Alpha-Synuclein Results In Inflammation And Snpc Dopamine Neuron Death In A Genetic Mouse Model Of Induced Synucleinopathy, Matthew D. Byrne, Peyman Petramfar, Jae-Kyung Lee, Richard J. Smeyne

Department of Neuroscience Faculty Papers

While the etiology of most cases of Parkinson's disease (PD) are idiopathic, it has been estimated that 5-10% of PD arise from known genetic mutations. The first mutations described that leads to the development of an autosomal dominant form of PD are in the SNCA gene that codes for the protein alpha-synuclein (α-syn). α-syn is an abundant presynaptic protein that is natively disordered and whose function is still unclear. In PD, α-syn misfolds into multimeric b-pleated sheets that aggregate in neurons (Lewy Bodies/neurites) and spread throughout the neuraxis in a pattern that aligns with disease progression. Here, using IHC, HC, …

Role Of Progesterone Action In Inguinal Hernia Formation Via Skeletal Muscle Fibrosis And Atrophy, Tianming You, Mehrdad Zandigohar, Tanvi Potluri, Natalie Piehl, John S Coon V, Elizabeth Baker, Maya Kafali, Yang Dai, Jonah J Stulberg, David J Escobar, Richard L Lieber, Hong Zhao, Serdar E Bulun

Faculty, Staff and Student Publications

More than 1 in 4 men will undergo surgery for inguinal hernia, which is commonly associated with fibrotic degeneration of the lower abdominal muscle (LAM) in the groin region. Utilizing a male mouse model expressing the human aromatase gene (Aromhum), previous studies showed that locally produced estradiol acting via estrogen receptor α in LAM fibroblasts leads to fibrosis, myofiber atrophy, and hernia development. Here, we found that upregulation of progesterone receptor (PGR) in a LAM fibroblast population mediates this estrogenic effect. A PGR-selective progesterone antagonist in Aromhum mice decreased LAM fibrosis and atrophy, preventing hernia formation and stopping progression of …

An Alternative Neural Basis Underlying Leptin Resistance, Hongli Li, Cunjin Su, Yuanzhong Xu, Mette Q Ludwig, Jon Davis, Qingchun Tong

Faculty, Staff and Student Publications

Overconsumption of a palatable Western diet, a condition linked to central leptin resistance, contributes extensively to the current obesity epidemic. In this context, intensive efforts have focused on detailing the molecular mechanisms underlying leptin resistance. Here, we demonstrate that chronic inhibition of hypothalamic arcuate GABAergic neurons (ArcGABA) effectively reduced diet-induced obesity (DIO). Interestingly, palatable food exposure increased the activity level of ArcGABA neurons, which do not express the leptin receptor (non-LepR neurons; nonresponsive to leptin). Chronic activation of ArcGABA non-LepR neurons led to massive obesity, which was associated with normal leptin-induced pSTAT3 signaling but phenotypic leptin resistance; i.e., high leptin …

Chondrocyte-Specific Knockout Of Piezo1 And Piezo2 Protects Against Post-Traumatic Osteoarthritis Structural Damage And Pain In Mice, Erica V Ely, Kristin L Lenz, Sophie G Paradi, Seth Ack, Abraham Behrmann, Sarah Dunivan, Lauryn Braxton, Wolfgang Liedtke, Yong Chen, Kelsey H Collins, Farshid Guilak

2020-Current year OA Pubs

BACKGROUND: Osteoarthritis (OA) is a debilitating joint disease characterized by cartilage degeneration, synovial inflammation, and bone remodeling, with limited therapeutic options targeting the underlying pathophysiology. Mechanosensitive ion channels Piezo1 and Piezo2 play crucial roles in chondrocyte responses to mechanical stress, mediating mechanotransduction pathways that influence chondrocyte survival, matrix production, and inflammatory signaling, but their distinct contributions to OA pathogenesis remain unclear.

METHODS: Using inducible, chondrocyte-specific Aggrecan-Cre (Acan) mice, we investigated Piezo1, Piezo2, and combined Piezo1/2 conditional knockouts (cKOs) using the destabilization of the medial meniscus (DMM) model of post-traumatic OA in male and female mice. Pain and behavioral assessments were …

Direct Histone Proteoform Profiling Of The Unannotated, Endangered Coral Acropora Cervicornis, Cassandra N Fuller, Sabrina Mansoor, Kevin Jeanne Dit Fouque, Lilian Valadares Tose, Javier Rodriguez-Casariego, Mariangela Kosmopoulou, Detlev Suckau, Francisca N De Luna Vitorino, Benjamin A Garcia, Jose M Eirin-Lopez, Francisco Fernandez-Lima

2020-Current year OA Pubs

Epigenetic modifications directly regulate the patterns of gene expression by altering DNA accessibility and chromatin structure. A knowledge gap is presented by the need to directly measure these modifications, especially for unannotated organisms with unknown primary histone sequences. In the present work, we developed and applied a novel workflow for identifying and annotating histone proteoforms directly from mass spectrometry-based measurements for the endangered Caribbean coral Acropora cervicornis. Combining high-accuracy de novo top-down and bottom-up analysis based on tandem liquid chromatography, trapped ion mobility spectrometry, non-ergodic electron-based fragmentation, and high-resolution mass spectrometry, near complete primary sequence (up to 99%) and over …

Mouse Metastable Epialleles Are Extremely Rare, Chathura J Gunasekara, Uditha Maduranga, Taylor Zhang, Jonathan N Wells, Maria S Baker, Eleonora Laritsky, Yumei Li, Cristian Coarfa, Yi Zhu, Robert A Waterland

Faculty, Staff and Students Publications

Metastable epialleles (MEs) are genomic loci at which epigenetic marks are established stochastically during early embryonic development and maintained during subsequent differentiation and throughout life, leading to stable epigenetic and phenotypic variation among genetically identical individuals. Although MEs were first described in mice over 20 years ago, the extent of epigenetic metastability in the mouse genome remains unknown. We present the first unbiased genome-wide screen for MEs in mice. Using deep whole-genome bisulfite sequencing across tissues derived from the three embryonic germ layers in isogenic C57BL/6J mice, we identified only 29 MEs, precisely localizing them and documenting their rarity. Consistent …

Cdc1s Promote Atherosclerosis Via Local Immunity And Are Targetable For Therapy, Miguel Galán, Suin Jo, Tian-Tian Liu, Kenneth M. Murphy, Et Al.

2020-Current year OA Pubs

BACKGROUND: Atherosclerosis is characterized by immune cell accumulation in the arterial wall and adaptive CD4

METHODS: We tested atherosclerosis in

RESULTS: Expansion of DCs in

CONCLUSIONS: Using state-of-the-art strategies, our results establish that cDC1s have a proatherogenic role in atherosclerosis by boosting CD4

Discovery Of N-(6-Methoxypyridin-3-Yl)Quinoline-2-Amine Derivatives For Imaging Aggregated Α-Synuclein In Parkinson's Disease With Positron Emission Tomography, Haiyang Zhao, Tianyu Huang, Dhruva D Dhavale, Jennifer Y O'Shea, Jiwei Gu, Xuyi Yue, Ying-Hwey Nai, Hao Jiang, Paul T Kotzbauer, Joel S Perlmutter, Zhude Tu, Et Al.

2020-Current year OA Pubs

The fibrillary aggregation of α-synuclein is a hallmark of Parkinson's disease (PD) and a potential target for diagnostics and therapeutics. Although substantial effort has been devoted to the development of positron emission tomography (PET) probes for detecting α-synuclein aggregates, no clinically suitable tracer has been reported. The design and synthesis of 43 new

Electrophysiological Characterization Of Sex-Dependent Hypnosis By An Endogenous Neuroactive Steroid Epipregnanolone, Tamara Timic Stamenic, Ian Coulter, Douglas F Covey, Slobodan M Todorovic

2020-Current year OA Pubs

Neuroactive steroids (NAS) have long been recognized for their hypnotic and anesthetic properties in both clinical and preclinical settings. While sex differences in NAS sensitivity are acknowledged, the underlying mechanisms remain poorly understood. Here, we examined sex-specific responses to an endogenous NAS epipregnanolone (EpiP) in wild-type mice using behavioral assessment of hypnosis (loss of righting reflex, LORR) and in vivo electrophysiological recordings. Specifically, local field potentials (LFPs) were recorded from the central medial thalamus (CMT) and electroencephalogram (EEG) signals were recorded from the barrel cortex. We found that EpiP-induced LORR exhibited clear sex differences, with females showing increased sensitivity. Spectral …

Sensing The Stiffness: Cellular Mechano-Sensing At The Implant Interface, Patricia S Pardo, Delia Danila, Raja Devesh Kumar Misra, Aladin M Boriek

Faculty, Staff and Students Publications

In this perspective, we highlight the relevance of the FA-Hippo signaling pathway and its regulation of the Yes-associated protein (YAP) and the transcriptional coactivator with a PDZ-binding domain (TAZ) as main players in the process of implants integration. The modulation and responses of YAP/TAZ triggered by substrate and ECM stiffness are of particular interest in the construction of materials used for medical implants. YAP/TAZ nuclear localization and activity respond to the substrate stiffness by several mechanisms that involve the canonical and non-canonical Hippo signaling and independently of the Hippo cascade. YAP/TAZ regulate the expression of genes involved in several mechanisms …

Efficacy Of A Novel Bcl-Xl Degrader, Dt2216, In Preclinical Models Of Jak2-Mutated Post-Mpn Aml, Zhe Wang, Anna Skwarska, Gowri Poigaialwar, Sovira Chaudhry, Alba Rodriguez-Meira, Pinpin Sui, Emmanuel Olivier, Yannan Jia, Varun Gupta, Warren Fiskus, Cassandra L Ramage, Guangrong Zheng, Alexandra Schurer, Kira Gritsman, Eirini P Papapetrou, Kapil Bhalla, Daohong Zhou, Adam J Mead, Raajit K Rampal, Jeffrey W Tyner, Hussein A Abbas, Naveen Pemmaraju, Qi Zhang Tatarata, Marina Konopleva

Faculty, Staff and Student Publications

Acute myeloid leukemia (AML) that evolves from myeloproliferative neoplasm (MPN) is known as post-MPN AML. Current treatments do not significantly extend survival beyond 12 months. B-cell lymphoma-extra large (BCL-xL) has been found to be overexpressed in leucocytes from patients with MPN, making it a potential therapeutic target. We investigated the role of BCL-xL in post-MPN AML and tested the efficacy of DT2216, a platelet-sparing BCL-xL proteolysis-targeting chimera, in preclinical models of post-MPN AML. We found that BCL2L1, the gene encoding BCL-xL, is expressed at higher levels in patients with post-MPN AML than in those with de novo AML. Single-cell multiomics …

V2b Neurons Act Via Multiple Targets To Produce In Phase Inhibition During Locomotion, Mohini Sengupta, Alaina Bertram, Shuyu Iris Zhu, Geoffrey J Goodhill, Martha W Bagnall

2020-Current year OA Pubs

Spinal interneurons shape motor neuron activity. Gata3

Altered Patterning Of Neural Activity In A Neuropathology, Clarissa Hoffman, Jingheng Cheng, Rodrigo Morales, Daoyun Ji, Yuri Dabaghian

Faculty, Staff and Students Publications

The dynamics of neural circuits and their role in mediating cellular and organismal phenomena remain poorly understood, despite numerous efforts to dissect these processes through precise instantaneous measurements or longer-time averages and approximations. We use an alternative approach: we investigate these dynamics at the system's mesoscale by analyzing spike trains and waveforms. These extended activity patterns carry robust, tractable information, are highly responsive to physiological specifics, and enable detailed tracking of circuit behavior. In particular, this methodology allows for characterizing the functionality of tau-pathology-afflicted hippocampal circuits and identifying circuit-level abnormalities that are missed by through traditional analyses. In healthy mice, …

Spase: Spatially Resolved Pathology Scores Using Optimal Transport On Spatial Transcriptomics Data, Mohammad Nuwaisir Rahman, Mohammed Abid Abrar, Vikram Rakesh Shaw, James F Martin, M Saifur Rahman, Md Abul Hassan Samee

Faculty, Staff and Students Publications

Pathological events often impact tissue regions in a spatial variable manner, making it challenging to identify therapeutic targets. Spatial transcriptomics (ST) is a powerful technology to map spatially variable molecular mechanisms, yet suitable analytical methods have been lacking. We introduce SPaSE (Spatially-resolved Pathology ScorE), an optimal transport-based algorithm to compare ST data from diseased and control tissues. SPaSE computes a “pathology score” for each spot in the diseased sample, quantifying the pathological impact at that spot. In post-MI (myocardial infarction) mouse hearts, these scores delineated zones that matched independent expert annotations. Modeling pathology scores from gene expression revealed signatures predictive …

Epha4 Signaling Dysregulation Links Abnormal Locomotion And The Development Of Idiopathic Scoliosis, Lianlei Wang, Xinyu Yang, Sen Zhao, Pengfei Zheng, Wen Wen, Kexin Xu, Xi Cheng, Qing Li, Anas M Khanshour, Yoshinao Koike, Junjun Liu, Xin Fan, Nao Otomo, Zefu Chen, Yaqi Li, Lulu Li, Haibo Xie, Panpan Zhu, Xiaoxin Li, Yuchen Niu, Shengru Wang, Sen Liu, Suomao Yuan, Chikashi Terao, Ziquan Li, Shaoke Chen, Xiuli Zhao, Pengfei Liu, Jennifer E Posey, Zhihong Wu, Guixing Qiu, Disco Study Group (Deciphering Disorders Involving Scoliosis & Comorbidities), Shiro Ikegawa, James R Lupski, Jonathan J Rios, Carol A Wise, Jianguo T Zhang, Chengtian Zhao, Nan Wu

Faculty, Staff and Students Publications

Idiopathic scoliosis (IS) is the most common form of spinal deformity with unclear pathogenesis. In this study, we first reanalyzed the loci associated with IS, drawing upon previous studies. Subsequently, we mapped these loci to candidate genes using either location-based or function-based strategies. To further substantiate our findings, we verified the enrichment of variants within these candidate genes across several large IS cohorts encompassing Chinese, East Asian, and European populations. Consequently, we identified variants in the EPHA4 gene as compelling candidates for IS. To confirm their pathogenicity, we generated zebrafish mutants of epha4a. Remarkably, the zebrafish epha4a mutants exhibited …

Fgfr3-Induced Y158 Parp1 Phosphorylation Promotes Parp Inhibitor Resistance Via Brg1/Mre11-Mediated Dna Repair In Breast Cancer Models, Mei-Kuang Chen, Hirohito Yamaguchi, Yuan Gao, Weiya Xia, Jeffrey T Chang, Yu-Chun Hsiao, Tewodros W Shegute, Zong-Shin Lin, Chen-Shiou Wu, Yu-Han Wang, Jennifer K Litton, Qingqing Ding, Yongkun Wei, Yu-Yi Chu, Funda Meric-Bernstam, Helen Piwnica-Worms, Banu Arun, Jordi Rodon Ahnert, Jinsong Liu, Jun Yao, Wei-Chao Chang, Hung-Ling Wang, Coya Tapia, Constance T Albarracin, Khandan Keyomarsi, Shao-Chun Wang, Ying-Nai Wang, Gabriel N Hortobagyi, Chunru Lin, Liuqing Yang, Dihua Yu, Mien-Chie Hung

Faculty, Staff and Student Publications

Poly(ADP-ribose) polymerase (PARP) inhibitors (PARPis) are used to treat BRCA-mutated (BRCAm) cancer patients; however, resistance has been observed. Therefore, biomarkers to indicate PARPi resistance and combination therapy to overcome that are urgently needed. We identified a high prevalence of activated FGF receptor 3 (FGFR3) in BRCAm triple-negative breast cancer (TNBC) cells with intrinsic and acquired PARPi resistance. FGFR3 phosphorylated PARP1 at tyrosine 158 (Y158) to recruit BRG1 and prolong chromatin-loaded MRE11, thus promoting homologous recombination (HR) to enhance PARPi resistance. FGFR inhibition prolonged PARP trapping and synergized with PARPi in vitro and in vivo. High-level PARP1 Y158 phosphorylation (p-Y158) positively …

Sensory Neuron-Expressed Fgf13 Controls Nociceptive Signaling In Diabetic Neuropathy Models, Aditya K Singh, Matteo Bernabucci, Nolan M Dvorak, Zahra Haghighijoo, Jessica Di Re, Nana A Goode, Feni K Kadakia, Laura A Maile, Olumarotimi O Folorunso, Paul A Wadsworth, Cynthia M Tapia, Pingyuan Wang, Jigong Wang, Haiying Chen, Yu Xue, Jully Singh, Kali Hankerd, Isaac J Gamez, Makenna Kager, Vincent Truong, Patrick Walsh, Stephanie I Shiers, Nishka Kuttanna, Hanyue Liao, Margherita Marchi, Erika Salvi, Ilaria D'Amato, Daniela D'Amico, Parsa Arman, Catharina G Faber, Rayaz A Malik, Marina De Tommaso, Dan Ziegler, Krishna Rajarathnam, Thomas A Green, Peter M Grace, Matthew R Sapio, Michael J Iadarola, Gregory D Cuny, Diana S Chow, Giuseppe Lauria Pinter, Steve Davidson, Dustin P Green, Jun-Ho La, Jin Mo Chung, Jia Zhou, Theodore J Price, Elizabeth Salisbury, Subo Yuan, Fernanda Laezza

Faculty, Staff and Student Publications

Nociception involves complex signaling, yet intrinsic mechanisms bidirectionally regulating this process remain unexplored. Here, we show that the fibroblast growth factor 13 (FGF13)/Nav1.7 protein-protein interaction (PPI) complex bidirectionally modulates nociception, and that the FGF13/Nav1.7 ratio is upregulated in type 2 diabetic neuropathy (T2DN). PW164, an FGF13/Nav1.7 channel C-terminal tail domain (CTD) PPI interface inhibitor, which reduces complex assembly, selectively suppressed Na+ currents sensitized by capsaicin-induced activation of TRPV1 channels in human induced pluripotent stem cell-derived (hIPSC-derived) sensory neurons and inhibited mechanical and thermal hyperalgesia in mice. FGF13 silencing mimics PW164 activity in culture and in vivo. Conversely, ZL192, an FGF13 …