Digital Commons Network^™

Transcriptional Differences In Identical Twins With Different Reproductive Capacities: A Case Report, Katherine Campbell, Alexandra Dullea, Christian Ramsoomair, Kyle Schuppe, Armin Ghomeshi, Kajal Khodamoradi, Himanshu Arora, Carolina Jorgez, Ranjith Ramasamy

Faculty, Staff and Students Publications

Disorders of sperm production can be classified quantitatively as oligospermia (low sperm count) or azoospermia (no sperm during ejaculation). Numerous genes have been implicated in spermatogenesis. We describe a case of two identical twins who presented with different reproductive capabilities. One brother was infertile due to azoospermia, and the other, although oligospermic, previously naturally fathered a child. They were found to have differential gene expression based on RNA sequencing analysis. In the man with azoospermia, we found elevated E2F1 and HOXB9 gene expressions when compared with his brother, suggesting that the increased RNA expression of these genes could influence sperm …

Synapse-Specific Changes In Arc And Bdnf In Rat Hippocampus Following Chronic Temporal Lobe Epilepsy, Daniel L Egbenya, Suleman Hussain, Yi-Chen Lai, Anne E Anderson, Svend Davanger

Faculty, Staff and Students Publications

Expression of immediate early genes (IEGs) in the brain is important for synaptic plasticity, and probably also in neurodegenerative conditions. To understand the cellular mechanisms of the underlying neuropathophysiological processes in epilepsy, we need to pinpoint changes in concentration of synaptic plasticity-related proteins at subsynaptic levels. In this study, we examined changes in synaptic expression of Activity-regulated cytoskeleton-associated (Arc) and Brai Derived Neurotrophic Factor (BDNF) in a rat model of kainate-induced temporal lobe epilepsy (TLE). Western blotting showed reduced concentrations of Arc and increased concentrations of BDNF in hippocampal synaptosomes in chronic TLE rats. Then, using quantitative electron microscopy, we …

Protein Phosphatase 1 Γ Modulates Steady-State Bad Phosphorylation And Murine Platelet Survival, Masahiro Yanagisawa, Hyojeong Han, Subhashree Pradhan, Tanvir Khatlani, Deepika Subramanyam, K Vinod Vijayan

Faculty, Staff and Students Publications

No abstract provided.

Preterm Birth Alters The Feeding-Induced Activation Of Akt Signaling In The Muscle Of Neonatal Piglets, Agus Suryawan, Marko Rudar, Jane K Naberhuis, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

BACKGROUND: Postnatal lean mass accretion is commonly reduced in preterm infants. This study investigated mechanisms involved in the blunted feeding-induced activation of Akt in the skeletal muscle of preterm pigs that contributes to lower protein synthesis rates.

METHODS: On day 3 following cesarean section, preterm and term piglets were fasted or fed an enteral meal. Activation of Akt signaling pathways in skeletal muscle was determined.

RESULTS: Akt1 and Akt2, but not Akt3, phosphorylation were lower in the skeletal muscle of preterm than in term pigs (P < 0.05). Activation of Akt-positive regulators, PDK1 and mTORC2, but not FAK, were lower in preterm than in term (P < 0.05). The formation of Akt complexes with GAPDH and Hsp90 and the abundance of Ubl4A were lower in preterm than in term (P < 0.05). The abundance of Akt inhibitors, PHLPP and SHIP2, but not PTEN and IP6K1, were higher in preterm than in term pigs (P < 0.05). PP2A activation was inhibited by feeding in term but not in preterm pigs (P < 0.05).

CONCLUSIONS: Our results suggest that preterm birth impairs regulatory components involved in Akt activation, …

A 3d-Printable, Low-Cost Obturator For Less Invasive Gynecologic Brachytherapy, Sanika Rane, Alexander Hanania, Elisa Arango, Krithika Kumar, Lauren Payne, Susannah Dittmar, Gaurav Gomber, Vincent Ugarte, Michelle Ludwig

Faculty, Staff and Students Publications

The purpose of this report is to design, develop, and evaluate a cost-effective applicator for interstitial brachytherapy (ISBT) to minimize patient morbidity and facilitate access to curative radiation treatment for gynecologic cancers, especially in low-resource settings. A computer-aided design and prototype were developed of a proposed applicator that incorporates 44 slotted channels to gently guide needles, with or without a tandem, through the vaginal canal, effectively eliminating the need for transcutaneous needle insertions typically employed during ISBT of advanced gynecologic cancer and thus reducing the risk of vaginal laceration and bladder or rectal injury. The tested prototype was developed using …

Clinical Spectrum And Genetic Causes Of Mitochondrial Hepatopathy Phenotype In Children, James E Squires, Alexander G Miethke, C Alexander Valencia, Kieran Hawthorne, Lisa Henn, Johan L K Van Hove, Robert H Squires, Kevin Bove, Simon Horslen, Rohit Kohli, Jean P Molleston, Rene Romero, Estella M Alonso, Jorge A Bezerra, Stephen L Guthery, Evelyn Hsu, Saul J Karpen, Kathleen M Loomes, Vicky L Ng, Philip Rosenthal, Krupa Mysore, Kasper S Wang, Marisa W Friederich, John C Magee, Ronald J Sokol, Childhood Liver Disease Research Network (Children)

Faculty, Staff and Students Publications

BACKGROUND: Alterations in both mitochondrial DNA (mtDNA) and nuclear DNA genes affect mitochondria function, causing a range of liver-based conditions termed mitochondrial hepatopathies (MH), which are subcategorized as mtDNA depletion, RNA translation, mtDNA deletion, and enzymatic disorders. We aim to enhance the understanding of pathogenesis and natural history of MH.

METHODS: We analyzed data from patients with MH phenotypes to identify genetic causes, characterize the spectrum of clinical presentation, and determine outcomes.

RESULTS: Three enrollment phenotypes, that is, acute liver failure (ALF, n = 37), chronic liver disease (Chronic, n = 40), and post-liver transplant (n = 9), were analyzed. …

Forging New Therapeutic Targets: Efforts Of Tumor Derived Exosomes To Prepare The Pre-Metastatic Niche For Cancer Cell Dissemination And Dormancy, Ranvir Bhatia, Joanna Chang, Jessian L Munoz, Nykia D Walker

Faculty, Staff and Students Publications

Tumor-derived exosomes play a multifaceted role in preparing the pre-metastatic niche, promoting cancer dissemination, and regulating cancer cell dormancy. A brief review of three types of cells implicated in metastasis and an overview of other types of extracellular vesicles related to metastasis are described. A central focus of this review is on how exosomes influence cancer progression throughout metastatic disease. Exosomes are crucial mediators of intercellular communication by transferring their cargo to recipient cells, modulating their behavior, and promoting tumor pro-gression. First, their functional role in cancer cell dissemination in the peripheral blood by facilitating the establishment of a pro-angiogenic …

The Role Of Limch1 Alternative Splicing In Skeletal Muscle Function, Matthew S Penna, Rong-Chi Hu, George G Rodney, Thomas A Cooper

Faculty, Staff and Students Publications

Postnatal skeletal muscle development is a highly dynamic period associated with widespread alternative splicing changes required to adapt tissues to adult function. These splicing events have significant implications because the reversion of adult mRNA isoforms to fetal isoforms is observed in forms of muscular dystrophy. LIMCH1 is a stress fiber–associated protein that is alternatively spliced to generate uLIMCH1, a ubiquitously expressed isoform, and mLIMCH1, a skeletal muscle–specific isoform containing six additional exons simultaneously included after birth in the mouse. CRISPR/Cas9 was used to delete the six alternatively spliced exons of LIMCH1 in mice, thereby forcing the constitutive expression of the …

The Voltage-Gated Sodium Channel In Drosophila, Para, Localizes To Dendrites As Well As Axons In Mechanosensitive Chordotonal Neurons, Thomas A Ravenscroft, Ashleigh Jacobs, Mingxue Gu, Daniel F Eberl, Hugo J Bellen

Faculty, Staff and Students Publications

The fruit fly Drosophila melanogaster has provided important insights into how sensory information is transduced by transient receptor potential (TRP) channels in the peripheral nervous system (PNS). However, TRP channels alone have not been able to completely model mechanosensitive transduction in mechanoreceptive chordotonal neurons (CNs). Here, we show that, in addition to TRP channels, the sole voltage-gated sodium channel (NaV) in Drosophila, Para, is localized to the dendrites of CNs. Para is localized to the distal tip of the dendrites in all CNs, from embryos to adults, and is colocalized with the mechanosensitive TRP channels No mechanoreceptor potential C …

The Clinical And Molecular Spectrum Of The Kdm6b-Related Neurodevelopmental Disorder, Dmitrijs Rots, Taryn E Jakub, Crystal Keung, Adam Jackson, Siddharth Banka, Rolph Pfundt, Bert B A De Vries, Richard H Van Jaarsveld, Saskia M J Hopman, Ellen Van Binsbergen, Irene Valenzuela, Maja Hempel, Tatjana Bierhals, Fanny Kortüm, Francois Lecoquierre, Alice Goldenberg, Jens Michael Hertz, Charlotte Brasch Andersen, Maria Kibæk, Eloise J Prijoles, Roger E Stevenson, David B Everman, Wesley G Patterson, Linyan Meng, Charul Gijavanekar, Karl De Dios, Shenela Lakhani, Tess Levy, Matias Wagner, Dagmar Wieczorek, Paul J Benke, María Soledad Lopez Garcia, Renee Perrier, Sergio B Sousa, Pedro M Almeida, Maria José Simões, Bertrand Isidor, Wallid Deb, Andrew A Schmanski, Omar Abdul-Rahman, Christophe Philippe, Ange-Line Bruel, Laurence Faivre, Antonio Vitobello, Christel Thauvin, Jeroen J Smits, Livia Garavelli, Stefano G Caraffi, Francesca Peluso, Laura Davis-Keppen, Dylan Platt, Erin Royer, Lisette Leeuwen, Margje Sinnema, Alexander P A Stegmann, Constance T R M Stumpel, George E Tiller, Daniëlle G M Bosch, Stephanus T Potgieter, Shelagh Joss, Miranda Splitt, Simon Holden, Matina Prapa, Nicola Foulds, Sofia Douzgou, Kaija Puura, Regina Waltes, Andreas G Chiocchetti, Christine M Freitag, F Kyle Satterstrom, Silvia De Rubeis, Joseph Buxbaum, Bruce D Gelb, Aleksic Branko, Itaru Kushima, Jennifer Howe, Stephen W Scherer, Alessia Arado, Chiara Baldo, Olivier Patat, Demeer Bénédicte, Diego Lopergolo, Filippo M Santorelli, Tobias B Haack, Andreas Dufke, Miriam Bertrand, Ruth J Falb, Angelika Rieß, Peter Krieg, Stephanie Spranger, Maria Francesca Bedeschi, Maria Iascone, Sarah Josephi-Taylor, Tony Roscioli, Michael F Buckley, Jan Liebelt, Aditi I Dagli, Emmelien Aten, Anna C E Hurst, Alesha Hicks, Mohnish Suri, Ermal Aliu, Sunil Naik, Richard Sidlow, Juliette Coursimault, Gaël Nicolas, Hanna Küpper, Florence Petit, Veyan Ibrahim, Deniz Top, Francesca Di Cara, Raymond J Louie, Elliot Stolerman, Han G Brunner, Lisenka E L M Vissers, Jamie M Kramer, Tjitske Kleefstra

Faculty, Staff and Students Publications

De novo variants are a leading cause of neurodevelopmental disorders (NDDs), but because every monogenic NDD is different and usually extremely rare, it remains a major challenge to understand the complete phenotype and genotype spectrum of any morbid gene. According to OMIM, heterozygous variants in KDM6B cause "neurodevelopmental disorder with coarse facies and mild distal skeletal abnormalities." Here, by examining the molecular and clinical spectrum of 85 reported individuals with mostly de novo (likely) pathogenic KDM6B variants, we demonstrate that this description is inaccurate and potentially misleading. Cognitive deficits are seen consistently in all individuals, but the overall phenotype is …

Pediatric Swine Model Of Methicillin-Resistant Staphylococcus Aureus Sepsis-Induced Coagulopathy, Disseminated Microvascular Thrombosis, And Organ Injuries, Trung C Nguyen, Juan C Marini, Bobby Guillory, Christian Valladolid-Brown, Marina Martinez-Vargas, Deepika Subramanyam, Daniel Cohen, Sonya C Cirlos, Fong Lam, Barbara Stoll, Inka C Didelija, Caitlin Vonderohe, Renan Orellana, Arun Saini, Subhashree Pradhan, Dalia Bashir, Moreshwar S Desai, Saul Flores, Manpreet Virk, Hossein Tcharmtchi, Amir Navaei, Sheldon Kaplan, Linda Lamberth, Kristina G Hulten, Brooks P Scull, Carl E Allen, Ayse Akcan-Arikan, K Vinod Vijayan, Miguel A Cruz

Faculty, Staff and Students Publications

Sepsis-induced coagulopathy leading to disseminated microvascular thrombosis is associated with high mortality and has no existing therapy. Despite the high prevalence of Gram-positive bacterial sepsis, especially methicillin-resistant

HYPOTHESIS: Our objective is to develop a pediatric sepsis-induced coagulopathy swine model that last 70 hours.

METHODS AND MODELS: Ten 3 weeks old piglets, implanted with telemetry devices for continuous hemodynamic monitoring, were IV injected with MRSA (

RESULTS: Compared with the saline treated piglets (control), the septic piglets within 24 hours had significantly lower neurologic and respiratory scores. Over time, PT, d-dimer, and fibrinogen increased, while platelet counts and activities of factors …

Magnesium Increases Numbers Of Foxp3+ Treg Cells And Reduces Arthritis Severity And Joint Damage In An Il-10-Dependent Manner Mediated By The Intestinal Microbiome, Teresina Laragione, Carolyn Harris, Nasim Azizgolshani, Christine Beeton, Gerold Bongers, Percio S Gulko

Faculty, Staff and Students Publications

BACKGROUND: Rheumatoid arthritis (RA) is a common autoimmune disease with emerging environmental and microbiome risk factors. The western diet is typically deficient in magnesium (Mg), and there is some evidence suggesting that Mg may have anti-inflammatory properties. But the actual role of Mg supplementation in arthritis or in T cell subsets has not been explored.

METHODS: We investigated the role of a high Mg diet in two different mouse models of RA induced with the KRN serum, and collagen-induced arthritis. We also characterized the phenotypes of splenocytes, gene expression, and an extensive intestinal microbiome analyses including fecal material transplantation (FMT). …

Three-Dimensional Microct Imaging Of Mouse Heart Development From Early Post-Implantation To Late Fetal Stages, Nanbing Li-Villarreal, Tara L Rasmussen, Audrey E Christiansen, Mary E Dickinson, Chih-Wei Hsu

Faculty, Staff and Students Publications

Comprehensive detailed characterization of new mouse models can be challenging due to the individual focus involved in developing these models. Often models are engineered to test a specific hypothesis in a limited number of tissues, stages, and/or other contexts. Whether or not the model produces the desired phenotypes, phenotyping beyond the desired context can be extremely work intensive and these studies are often not undertaken. However, the general information resulting from broader phenotyping can be invaluable to the wider scientific community. The International Mouse Phenotyping Consortium (IMPC) and its subsidiaries, like the Knockout Mouse Project (KOMP), has made great strides …

Mouse Models Of Spontaneous Atrial Fibrillation, Joshua A Keefe, Mohit M Hulsurkar, Svetlana Reilly, Xander H T Wehrens

Faculty, Staff and Students Publications

Atrial fibrillation (AF) is the most common arrhythmia in adults, with a prevalence increasing with age. Current clinical management of AF is focused on tertiary prevention (i.e., treating the symptoms and sequelae) rather than addressing the underlying molecular pathophysiology. Robust animal models of AF, particularly those that do not require supraphysiologic stimuli to induce AF (i.e., showing spontaneous AF), enable studies that can uncover the underlying mechanisms of AF. Several mouse models of AF have been described to exhibit spontaneous AF, but pathophysiologic drivers of AF differ among models. Here, we describe relevant AF mechanisms and provide an overview of …

Comprehensive Ecg Reference Intervals In C57bl/6n Substrains Provide A Generalizable Guide For Cardiac Electrophysiology Studies In Mice, Manuela A Oestereicher, Janine M Wotton, Shinya Ayabe, Ghina Bou About, Tsz Kwan Cheng, Jae-Hoon Choi, Dave Clary, Emily M Dew, Lahcen Elfertak, Alain Guimond, Hamed Haseli Mashhadi, Jason D Heaney, Lois Kelsey, Piia Keskivali-Bond, Federico Lopez Gomez, Susan Marschall, Michael Mcfarland, Hamid Meziane, Violeta Munoz Fuentes, Ki-Hoan Nam, Zuzana Nichtová, Dale Pimm, Lynette Bower, Jan Prochazka, Jan Rozman, Luis Santos, Michelle Stewart, Nobuhiko Tanaka, Christopher S Ward, Amelia M E Willett, Robert Wilson, Robert E Braun, Mary E Dickinson, Ann M Flenniken, Yann Herault, K C Kent Lloyd, Ann-Marie Mallon, Colin Mckerlie, Stephen A Murray, Lauryl M J Nutter, Radislav Sedlacek, Je Kyung Seong, Tania Sorg, Masaru Tamura, Sara Wells, Elida Schneltzer, Helmut Fuchs, Valerie Gailus-Durner, Martin Hrabe De Angelis, Jacqueline K White, Nadine Spielmann

Faculty, Staff and Students Publications

Reference ranges provide a powerful tool for diagnostic decision-making in clinical medicine and are enormously valuable for understanding normality in pre-clinical scientific research that uses in vivo models. As yet, there are no published reference ranges for electrocardiography (ECG) in the laboratory mouse. The first mouse-specific reference ranges for the assessment of electrical conduction are reported herein generated from an ECG dataset of unprecedented scale. International Mouse Phenotyping Consortium data from over 26,000 conscious or anesthetized C57BL/6N wildtype control mice were stratified by sex and age to develop robust ECG reference ranges. Interesting findings include that heart rate and key …

A Short-Term Method To Evaluate Anti-Leishmania Drugs By Inhibition Of Stage Differentiation In Leishmania Mexicana Using Flow Cytometry, Christian Florian Teh-Poot, Victor Manuel Dzul-Huchim, Jonathan M Mercado, Liliana Estefanía Villanueva-Lizama, Maria Elena Bottazzi, Kathryn M Jones, Francis T F Tsai, Julio Vladimir Cruz-Chan

Faculty, Staff and Students Publications

Leishmaniasis is a vector-borne neglected tropical disease caused by the Leishmania spp. Parasite. The disease is transmitted to humans and animals by the bite of infected female sandflies during the ingestion of bloodmeal. Because current drug treatments induce toxicity and parasite resistance, there is an urgent need to evaluate new drugs. Most therapeutics target the differentiation of promastigotes to amastigotes, which is necessary to maintain Leishmania infection. However, in vitro assays are laborious, time-consuming, and depend on the experience of the technician. In this study, we aimed to establish a short-term method to assess the differentiation status of Leishmania mexicana …

Long Non-Coding Rnas: Definitions, Functions, Challenges And Recommendations, John S Mattick, Paulo P Amaral, Piero Carninci, Susan Carpenter, Howard Y Chang, Ling-Ling Chen, Runsheng Chen, Caroline Dean, Marcel E Dinger, Katherine A Fitzgerald, Thomas R Gingeras, Mitchell Guttman, Tetsuro Hirose, Maite Huarte, Rory Johnson, Chandrasekhar Kanduri, Philipp Kapranov, Jeanne B Lawrence, Jeannie T Lee, Joshua T Mendell, Timothy R Mercer, Kathryn J Moore, Shinichi Nakagawa, John L Rinn, David L Spector, Igor Ulitsky, Yue Wan, Jeremy E Wilusz, Mian Wu

Faculty, Staff and Students Publications

Genes specifying long non-coding RNAs (lncRNAs) occupy a large fraction of the genomes of complex organisms. The term 'lncRNAs' encompasses RNA polymerase I (Pol I), Pol II and Pol III transcribed RNAs, and RNAs from processed introns. The various functions of lncRNAs and their many isoforms and interleaved relationships with other genes make lncRNA classification and annotation difficult. Most lncRNAs evolve more rapidly than protein-coding sequences, are cell type specific and regulate many aspects of cell differentiation and development and other physiological processes. Many lncRNAs associate with chromatin-modifying complexes, are transcribed from enhancers and nucleate phase separation of nuclear condensates …

Characterization Of Folic Acid, 5-Methyltetrahydrofolate And Synthetic Folinic Acid In The High-Affinity Folate Transporters: Impact On Pregnancy And Development, Ana M Palacios, Rachel A Feiner, Robert M Cabrera

Faculty, Staff and Students Publications

Folates are B vitamins that are essential for several molecular, cellular, and biological processes, including nucleotide synthesis, methylation, and methionine cycling. The physiological impacts of these processes on health also extend to cell proliferation, folate deficiency anemia, and reduction of the risk of birth defects during pregnancy. The primary objective of this study was to characterize the binding affinities of different folate forms, folic acid (FA), 5-methyltetrahydrofolate (5MTHF), and folinic acid, to the folate receptors α and β, and to the bovine milk folate binding protein. These three dietary forms of folate are found in enriched grains (FA), various fruits …

Steroidal Or Non-Steroidal Mras: Should We Still Enable Raasi Use Through K Binders?, L Parker Gregg, Sankar D Navaneethan

Faculty, Staff and Students Publications

Renin-angiotensin-aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions …

Probiotics And Human Milk Differentially Influence The Gut Microbiome And Nec Incidence In Preterm Pigs, Valeria Melendez Hebib, Diana H Taft, Barbara Stoll, Jinxin Liu, Lee Call, Gregory Guthrie, Nick Jensen, Amy B Hair, David A Mills, Douglas G Burrin

Faculty, Staff and Students Publications

Necrotizing enterocolitis (NEC) is the leading cause of death caused by gastrointestinal disease in preterm infants. Major risk factors include prematurity, formula feeding, and gut microbial colonization. Microbes have been linked to NEC, yet there is no evidence of causal species, and select probiotics have been shown to reduce NEC incidence in infants. In this study, we evaluated the effect of the probiotic Bifidobacterium longum subsp. infantis (BL. infantis), alone and in combination with a human milk oligosaccharide (HMO)—sialylactose (3′SL)—on the microbiome, and the incidence of NEC in preterm piglets fed an infant formula diet. We studied 50 …

Gastrulation Morphogenesis In Synthetic Systems, Alyssa A Emig, Margot L K Williams

Faculty, Staff and Students Publications

Recent advances in pluripotent stem cell culture allow researchers to generate not only most embryonic cell types, but also morphologies of many embryonic structures, entirely in vitro. This recreation of embryonic form from naïve cells, known as synthetic morphogenesis, has important implications for both developmental biology and regenerative medicine. However, the capacity of stem cell-based models to recapitulate the morphogenetic cell behaviors that shape natural embryos remains unclear. In this review, we explore several examples of synthetic morphogenesis, with a focus on models of gastrulation and surrounding stages. By varying cell types, source species, and culture conditions, researchers have recreated …

Discovery Of Phosphorylated Lantibiotics With Proimmune Activity That Regulate The Oral Microbiome, Abdelahhad Barbour, Leif Smith, Morvarid Oveisi, Mckinley Williams, Ruo Chen Huang, Cara Marks, Noah Fine, Chunxiang Sun, Fereshteh Younesi, Sina Zargaran, Ravi Orugunty, Thomas D Horvath, Sigmund J Haidacher, Anthony M Haag, Amarpreet Sabharwal, Boris Hinz, Michael Glogauer

Faculty, Staff and Students Publications

Lantibiotics are ribosomally synthesized and posttranslationally modified peptides (RiPPs) that are produced by bacteria. Interest in this group of natural products is increasing rapidly as alternatives to conventional antibiotics. Some human microbiome–derived commensals produce lantibiotics to impair pathogens’ colonization and promote healthy microbiomes. Streptococcus salivarius is one of the first commensal microbes to colonize the human oral cavity and gastrointestinal tract, and its biosynthesis of RiPPs, called salivaricins, has been shown to inhibit the growth of oral pathogens. Herein, we report on a phosphorylated class of three related RiPPs, collectively referred to as salivaricin 10, that exhibit proimmune activity and …

Lateral Septum As A Melanocortin Downstream Site In Obesity Development, Yuanzhong Xu, Zhiying Jiang, Hongli Li, Jing Cai, Yanyan Jiang, Joshua Otiz-Guzman, Yong Xu, Benjamin R Arenkiel, Qingchun Tong

Faculty, Staff and Students Publications

The melanocortin pathway is well established to be critical for body-weight regulation in both rodents and humans. Despite extensive studies focusing on this pathway, the downstream brain sites that mediate its action are not clear. Here, we found that, among the known paraventricular hypothalamic (PVH) neuron groups, those expressing melanocortin receptors 4 (PVHMc4R) preferably project to the ventral part of the lateral septum (LSv), a brain region known to be involved in emotional behaviors. Photostimulation of PVHMc4R neuron terminals in the LSv reduces feeding and causes aversion, whereas deletion of Mc4Rs or disruption of glutamate release from LSv-projecting PVH neurons …

Tau Polarizes An Aging Transcriptional Signature To Excitatory Neurons And Glia, Timothy Wu, Jennifer M Deger, Hui Ye, Caiwei Guo, Justin Dhindsa, Brandon T Pekarek, Rami Al-Ouran, Zhandong Liu, Ismael Al-Ramahi, Juan Botas, Joshua M Shulman

Faculty, Staff and Students Publications

Aging is a major risk factor for Alzheimer’s disease (AD), and cell-type vulnerability underlies its characteristic clinical manifestations. We have performed longitudinal, single-cell RNA-sequencing in Drosophila with pan-neuronal expression of human tau, which forms AD neurofibrillary tangle pathology. Whereas tau- and aging-induced gene expression strongly overlap (93%), they differ in the affected cell types. In contrast to the broad impact of aging, tau-triggered changes are strongly polarized to excitatory neurons and glia. Further, tau can either activate or suppress innate immune gene expression signatures in a cell-type-specific manner. Integration of cellular abundance and gene expression pinpoints nuclear factor kappa B …

Connecting Circuits With Networks In Addiction Neuroscience: A Salience Network Perspective, Adriana K Cushnie, Wei Tang, Sarah R Heilbronner

Faculty, Staff and Students Publications

Human neuroimaging has demonstrated the existence of large-scale functional networks in the cerebral cortex consisting of topographically distant brain regions with functionally correlated activity. The salience network (SN), which is involved in detecting salient stimuli and mediating inter-network communication, is a crucial functional network that is disrupted in addiction. Individuals with addiction display dysfunctional structural and functional connectivity of the SN. Furthermore, while there is a growing body of evidence regarding the SN, addiction, and the relationship between the two, there are still many unknowns, and there are fundamental limitations to human neuroimaging studies. At the same time, advances in …

An Ocular Th1 Immune Response Promotes Corneal Nerve Damage Independently Of The Development Of Corneal Epitheliopathy, Alexia Vereertbrugghen, Manuela Pizzano, Florencia Sabbione, Irene Angelica Keitelman, Carolina Maiumi Shiromizu, Douglas Vera Aguilar, Federico Fuentes, Cintia S De Paiva, Mirta Giordano, Analía Trevani, Jeremías G Galletti

Faculty, Staff and Students Publications

Proper sight is not possible without a smooth, transparent cornea, which is highly exposed to environmental threats. The abundant corneal nerves are interspersed with epithelial cells in the anterior corneal surface and are instrumental to corneal integrity and immunoregulation. Conversely, corneal neuropathy is commonly observed in some immune-mediated corneal disorders but not in others, and its pathogenesis is poorly understood. Here we hypothesized that the type of adaptive immune response may influence the development of corneal neuropathy. To test this, we first immunized OT-II mice with different adjuvants that favor T helper (Th)1 or Th2 responses. Both Th1-skewed mice (measured …

Beclin-1-Dependent Autophagy, But Not Apoptosis, Is Critical For Stem-Cell-Mediated Endometrial Programming And The Establishment Of Pregnancy, Pooja Popli, Suni Tang, Sangappa B Chadchan, Chandni Talwar, Edmund B Rucker, Xiaoming Guan, Diana Monsivais, John P Lydon, Christina L Stallings, Kelle H Moley, Ramakrishna Kommagani

Faculty, Staff and Students Publications

The human endometrium shows a remarkable regenerative capacity that enables cyclical regeneration and remodeling throughout a woman's reproductive life. Although early postnatal uterine developmental cues direct this regeneration, the vital factors that govern early endometrial programming are largely unknown. We report that Beclin-1, an essential autophagy-associated protein, plays an integral role in uterine morphogenesis during the early postnatal period. We show that conditional depletion of Beclin-1 in the uterus triggers apoptosis and causes progressive loss of Lgr5+/Aldh1a1+ endometrial progenitor stem cells, with concomitant loss of Wnt signaling, which is crucial for stem cell renewal and epithelial gland development. Beclin-1 knockin …

The First Transcriptomic Atlas Of The Adult Lacrimal Gland Reveals Epithelial Complexity And Identifies Novel Progenitor Cells In Mice, Vanessa Delcroix, Olivier Mauduit, Hyun Soo Lee, Anastasiia Ivanova, Takeshi Umazume, Sarah M Knox, Cintia S De Paiva, Darlene A Dartt, Helen P Makarenkova

Faculty, Staff and Students Publications

The lacrimal gland (LG) secretes aqueous tears. Previous studies have provided insights into the cell lineage relationships during tissue morphogenesis. However, little is known about the cell types composing the adult LG and their progenitors. Using scRNAseq, we established the first comprehensive cell atlas of the adult mouse LG to investigate the cell hierarchy, its secretory repertoire, and the sex differences. Our analysis uncovered the complexity of the stromal landscape. Epithelium subclustering revealed myoepithelial cells, acinar subsets, and two novel acinar subpopulations: Tfrc^hi and Car6^hi cells. The ductal compartment contained Wfdc2+ multilayered ducts and an Ltf+ cluster formed …

Whole-Exome Sequencing Study Of Hypospadias, Zhongzhong Chen, Yunping Lei, Richard H Finnell, Yu Ding, Zhixi Su, Yaping Wang, Hua Xie, Fang Chen

Faculty, Staff and Students Publications

Hypospadias results from the impaired urethral development, which is influenced by androgens, but its genetic etiology is still unknown. Through whole exome sequencing analysis, we identified NR5A1, SRD5A2, and AR as mutational hotspots in the etiology of severe hypospadias, as these genes are related to androgen signaling. Additionally, rare damaging variants in cilia-related outer dynein arm heavy chain (ODNAH) genes (DNAH5, DNAH8, DNAH9, DNAH11, and DNAH17) (p = 8.5 × 10−47) were significantly enriched in hypospadias cases. The Dnah8 KO mice exhibited significantly decreased testosterone levels, which had an impact on …

Neutralizing Antibody Formation With Onabotulinumtoxina (Botox®) Treatment From Global Registration Studies Across Multiple Indications: A Meta-Analysis, Joseph Jankovic, Jean Carruthers, Markus Naumann, Patricia Ogilvie, Terry Boodhoo, Mayssa Attar, Swati Gupta, Ritu Singh, John Soliman, Irina Yushmanova, Mitchell F Brin, Jie Shen

Faculty, Staff and Students Publications

Though the formation of neutralizing antibodies (NAbs) during treatment with botulinum neurotoxin is rare, their presence may nonetheless affect the biological activity of botulinum toxin and negatively impact clinical response. The goal of this updated meta-analysis was to evaluate and characterize the rate of NAb formation using an expanded dataset composed of 33 prospective placebo-controlled and open-label clinical trials with nearly 30,000 longitudinal subject records prior to and following onabotulinumtoxinA treatment in 10 therapeutic and aesthetic indications. Total onabotulinumtoxinA doses per treatment ranged from 10 U to 600 U administered in ≤15 treatment cycles. The NAb formation at baseline and …