Digital Commons Network^™

Food Assistance Use Among Food Bank Clients Affected By Type 2 Diabetes, Eliza Short, Jayati Sharma, Debbe I Thompson, Douglas Taren, Rhonda Gonzalez, Melanie Hingle

Children’s Nutrition Research Center Staff Publications

Objective: To understand the perspectives of food bank clients affected by type 2 diabetes (T2DM).

Design: Semi-structured in-depth interviews conducted with food bank clients.

Setting: Arizona regional food bank.

Participants: Twenty English- and Spanish-speaking food bank clients with T2DM or living with a person with T2DM, aged 45-83 years, majority female, Hispanic, and food insecure.

Phenomenon of interest: Food bank use and preferences, and how these related to T2DM management.

Analysis: A hybrid thematic analysis combining inductive and deductive reasoning.

Results: Three organizing themes emerged from the analysis. First, food assistance was influenced by food preferences and the ability to …

Global Variation In Studies Of Articular Cartilage Procedures Of The Knee: A Systematic Review, R. Garrett Steinmetz, J. Jared Guth, Matthew J Matava, Matthew V Smith, Robert H Brophy

Open Access Publications

OBJECTIVE: The objective of this study was to determine whether there are significant differences in terms of indications, techniques, patient variables, and objective and subjective outcome scores as a function of the geographic locale of published studies of knee articular cartilage surgery.

METHODS: An electronic database search was performed of clinical studies evaluating knee articular cartilage procedures from 2000 to 2021. Studies were separated into global regions (Europe, Asia, North America, and South America) based on the study country. All cartilage-based treatments in each region were recorded. Patient age and sex, mechanism of injury, cartilage lesion size and location, follow-up …

Pgc1Α/Β Expression Predicts Therapeutic Response To Oxidative Phosphorylation Inhibition In Ovarian Cancer, Carmen Ghilardi, Catarina Moreira-Barbosa, Laura Brunelli, Paola Ostano, Nicolò Panini, Monica Lupi, Alessia Anastasia, Fabio Fiordaliso, Monica Salio, Laura Formenti, Massimo Russo, Edoardo Arrigoni, Ferdinando Chiaradonna, Giovanna Chiorino, Giulio Draetta, Joseph R Marszalek, Christopher P Vellano, Roberta Pastorelli, Mariarosa Bani, Alessandra Decio, Raffaella Giavazzi

Faculty, Staff and Student Publications

Ovarian cancer is the deadliest gynecologic cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control ovarian cancer progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC1α and PGC1β. In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of PGC1α and PGC1β (PGC1α/β) fostered a unique transcriptional signature, leading to increased mitochondrial abundance, enhanced tricarboxylic acid cycling, and elevated cellular respiration that ultimately conferred vulnerability to OXPHOS inhibition. Treatment with the respiratory chain complex I inhibitor IACS-010759 caused mitochondrial swelling …

Intestinal Deletion Of 3-Hydroxy-3-Methylglutaryl-Coenzyme A Reductase Promotes Expansion Of The Resident Stem Cell Compartment, Alexandria M Doerfler, Jun Han, Kelsey E Jarrett, Li Tang, Antrix Jain, Alexander Saltzman, Marco De Giorgi, Marcel Chuecos, Ayrea E Hurley, Ang Li, Pauline Morand, Claudia Ayala, David R Goodlett, Anna Malovannaya, James F Martin, Thomas Q De Aguiar Vallim, Noah Shroyer, William R Lagor

Faculty, Staff and Students Publications

BACKGROUND: The intestine occupies the critical interface between cholesterol absorption and excretion. Surprisingly little is known about the role of de novo cholesterol synthesis in this organ, and its relationship to whole body cholesterol homeostasis. Here, we investigate the physiological importance of this pathway through genetic deletion of the rate-limiting enzyme.

METHODS: Mice lacking 3-hydroxy-3-methylglutaryl-coenzyme A reductase (Hmgcr) in intestinal villus and crypt epithelial cells were generated using a Villin-Cre transgene. Plasma lipids, intestinal morphology, mevalonate pathway metabolites, and gene expression were analyzed.

RESULTS: Mice with intestine-specific loss of Hmgcr were markedly smaller at birth, but gain …

Identification Of An Optimal Dose Of Intravenous Ketamine For Late-Life Treatment-Resistant Depression: A Bayesian Adaptive Randomization Trial, Marijn Lijffijt, Nicholas Murphy, Sidra Iqbal, Charles E Green, Tabish Iqbal, Lee C Chang, Colin N Haile, Lorna C Hirsch, Nithya Ramakrishnan, Dylan A Fall, Alan C Swann, Rayan K Al Jurdi, Sanjay J Mathew

Faculty, Staff and Students Publications

Evidence supporting specific therapies for late-life treatment-resistant depression (LL-TRD) is necessary. This study used Bayesian adaptive randomization to determine the optimal dose for the probability of treatment response (≥50% improvement from baseline on the Montgomery-Åsberg Depression Rating Scale) 7 days after a 40 min intravenous (IV) infusion of ketamine 0.1 mg/kg (KET 0.1), 0.25 mg/kg (KET 0.25), or 0.5 mg/kg (KET 0.5), compared to midazolam 0.03 mg/kg (MID) as an active placebo. The goal of this study was to identify the best dose to carry forward into a larger clinical trial. Response durability at day 28, safety and tolerability, and …

Parent-Of-Origin Effects Propagate Through Networks To Shape Metabolic Traits, Juan F Macias-Velasco, Celine L St Pierre, Jessica P Wayhart, Li Yin, Larry Spears, Mario A Miranda, Caryn Carson, Katsuhiko Funai, James M Cheverud, Clay F Semenkovich, Heather A Lawson

2020-Current year OA Pubs

Parent-of-origin effects are unexpectedly common in complex traits, including metabolic and neurological traits. Parent-of-origin effects can be modified by the environment, but the architecture of these gene-by-environmental effects on phenotypes remains to be unraveled. Previously, quantitative trait loci (QTL) showing context-specific parent-of-origin effects on metabolic traits were mapped in the F

Development And Management Of Depression During And After Pregnancy, Alexa Bouts, Maria Patnella, Jourdan Ujlaki, Emily Wells, Hannah Lamb, Michelle Musser

Pharmacy and Wellness Review

Depression during pregnancy is common, whether it is a new onset of the disease or emerging symptoms of the already existent disease. Due to patient and prescriber concerns with antidepressant use during pregnancy, approximately three-quarters of those diagnosed with depression remain untreated. Furthermore, up to half of pregnant women with depression remain undiagnosed due to lack of recognition. As a result, both mother and fetus are at risk for negative health outcomes including substance abuse, functional impairment, increased risk of postnatal depression and poor pregnancy outcomes. Benefits must be balanced against the risks when considering pharmacologic treatment options to manage …

Adherence Enables Neisseria Gonorrhoeae To Overcome Zinc Limitation Imposed By Nutritional Immunity Proteins, Jocelyn C Ray, Asya Smirnov, Stavros A Maurakis, Simone A Harrison, Eugene Ke, Walter J Chazin, Cynthia Nau Cornelissen, Alison K Criss

Open Access Publications

Neisseria gonorrhoeae (Gc) must overcome the limitation of metals such as zinc to colonize mucosal surfaces in its obligate human host. While the zinc-binding nutritional immunity proteins calprotectin (S100A8/A9) and psoriasin (S100A7) are abundant in human cervicovaginal lavage fluid, Gc possesses TonB-dependent transporters TdfH and TdfJ that bind and extract zinc from the human version of these proteins, respectively. Here we investigated the contribution of zinc acquisition to Gc infection of epithelial cells of the female genital tract. We found that TdfH and TdfJ were dispensable for survival of strain FA1090 Gc that was associated with Ect1 human immortalized epithelial …

Functional Replacement Of Myostatin With Gdf-11 In The Germline Of Mice., Se-Jin Lee, Adam Lehar, Renata Rydzik, Daniel W Youngstrom, Shalender Bhasin, Yewei Liu, Emily L Germain-Lee

Faculty Research 2022

BACKGROUND: Myostatin (MSTN) is a transforming growth factor-ß superfamily member that acts as a major regulator of skeletal muscle mass. GDF-11, which is highly related to MSTN, plays multiple roles during embryonic development, including regulating development of the axial skeleton, kidneys, nervous system, and pancreas. As MSTN and GDF-11 share a high degree of amino acid sequence identity, behave virtually identically in cell culture assays, and utilize similar regulatory and signaling components, a critical question is whether their distinct biological functions result from inherent differences in their abilities to interact with specific regulatory and signaling components or whether their distinct …

The Targeted Smac Mimetic Sw Iv-134 Augments Platinum-Based Chemotherapy In Pre-Clinical Models Of Ovarian Cancer, Pratibha S Binder, Yassar M Hashim, James Cripe, Tommy Buchanan, Abigail Zamorano, Suwanna Vangveravong, David G Mutch, William G Hawkins, Matthew A Powell, Dirk Spitzer

2020-Current year OA Pubs

BACKGROUND: Ovarian cancer is initially responsive to frontline chemotherapy. Unfortunately, it often recurs and becomes resistant to available therapies and the survival rate for advanced and recurrent ovarian cancer is unacceptably low. We thus hypothesized that it would be possible to achieve more durable treatment responses by combining cisplatin chemotherapy with SW IV-134, a cancer-targeted peptide mimetic and inducer of cell death. SW IV-134 is a recently developed small molecule conjugate linking a sigma-2 ligand with a peptide analog (mimetic) of the intrinsic death pathway activator SMAC (second-mitochondria activator of caspases). The sigma-2 receptor is overexpressed in ovarian cancer and …

Prenatal Low-Protein Diet Affects Mitochondrial Structure And Function In The Skeletal Muscle Of Adult Female Offspring, Vipin A Vidyadharan, Ancizar Betancourt, Craig Smith, Chandrasekhar Yallampalli, Chellakkan S Blesson

Faculty, Staff and Students Publications

Gestational low-protein (LP) diet leads to glucose intolerance and insulin resistance in adult offspring. We had earlier demonstrated that LP programming affects glucose disposal in females. Mitochondrial health is crucial for normal glucose metabolism in skeletal muscle. In this study, we sought to analyze mitochondrial structure, function, and associated genes in skeletal muscles to explore the molecular mechanism of insulin resistance LP-programmed female offspring. On day four of pregnancy, rats were assigned to a control diet containing 20% protein or an isocaloric 6% protein-containing diet. Standard laboratory diet was given to the dams after delivery until the end of weaning …

Ezh2 And Endometrial Cancer Development: Insights From A Mouse Model, Xin Fang, Nan Ni, Xiaofang Wang, Yanan Tian, Ivan Ivanov, Monique Rijnkels, Kayla J Bayless, John P Lydon, Qinglei Li

Faculty, Staff and Students Publications

Enhancer of zeste homolog 2 (EZH2), a core component of polycomb repressive complex 2, plays an important role in cancer development. As both oncogenic and tumor suppressive functions of EZH2 have been documented in the literature, the objective of this study is to determine the impact of Ezh2 deletion on the development and progression of endometrial cancer induced by inactivation of phosphatase and tensin homolog (PTEN), a tumor suppressor gene frequently dysregulated in endometrial cancer patients. To this end, we created mice harboring uterine deletion of both Ezh2 and Pten using Cre recombinase driven by the progesterone receptor …

Fly Cell Atlas: A Single-Nucleus Transcriptomic Atlas Of The Adult Fruit Fly, Hongjie Li, Jasper Janssens, Maxime De Waegeneer, Sai Saroja Kolluru, Kristofer Davie, Vincent Gardeux, Wouter Saelens, Fabrice P A David, Maria Brbić, Katina Spanier, Jure Leskovec, Colleen N Mclaughlin, Qijing Xie, Robert C Jones, Katja Brueckner, Jiwon Shim, Sudhir Gopal Tattikota, Frank Schnorrer, Katja Rust, Todd G Nystul, Zita Carvalho-Santos, Carlos Ribeiro, Soumitra Pal, Sharvani Mahadevaraju, Teresa M Przytycka, Aaron M Allen, Stephen F Goodwin, Cameron W Berry, Margaret T Fuller, Helen White-Cooper, Erika L Matunis, Stephen Dinardo, Anthony Galenza, Lucy Erin O'Brien, Julian A T Dow, Fca Consortium, Heinrich Jasper, Brian Oliver, Norbert Perrimon, Bart Deplancke, Stephen R Quake, Liqun Luo, Stein Aerts, Devika Agarwal, Yasir Ahmed-Braimah, Michelle Arbeitman, Majd M Ariss, Jordan Augsburger, Kumar Ayush, Catherine C Baker, Torsten Banisch, Katja Birker, Rolf Bodmer, Benjamin Bolival, Susanna E Brantley, Julie A Brill, Nora C Brown, Norene A Buehner, Xiaoyu Tracy Cai, Rita Cardoso-Figueiredo, Fernando Casares, Amy Chang, Thomas R Clandinin, Sheela Crasta, Claude Desplan, Angela M Detweiler, Darshan B Dhakan, Erika Donà, Stefanie Engert, Swann Floc'hlay, Nancy George, Amanda J González-Segarra, Andrew K Groves, Samantha Gumbin, Yanmeng Guo, Devon E Harris, Yael Heifetz, Stephen L Holtz, Felix Horns, Bruno Hudry, Ruei-Jiun Hung, Yuh Nung Jan, Jacob S Jaszczak, Gregory S X E Jefferis, Jim Karkanias, Timothy L Karr, Nadja Sandra Katheder, James Kezos, Anna A Kim, Seung K Kim, Lutz Kockel, Nikolaos Konstantinides, Thomas B Kornberg, Henry M Krause, Andrew Thomas Labott, Meghan Laturney, Ruth Lehmann, Sarah Leinwand, Jiefu Li, Joshua Shing Shun Li, Kai Li, Ke Li, Liying Li, Tun Li, Maria Litovchenko, Han-Hsuan Liu, Yifang Liu, Tzu-Chiao Lu, Jonathan Manning, Anjeli Mase, Mikaela Matera-Vatnick, Neuza Reis Matias, Caitlin E Mcdonough-Goldstein, Aaron Mcgeever, Alex D Mclachlan, Paola Moreno-Roman, Norma Neff, Megan Neville, Sang Ngo, Tanja Nielsen, Caitlin E O'Brien, David Osumi-Sutherland, Mehmet Neset Özel, Irene Papatheodorou, Maja Petkovic, Clare Pilgrim, Angela Oliveira Pisco, Carolina Reisenman, Erin Nicole Sanders, Gilberto Dos Santos, Kristin Scott, Aparna Sherlekar, Philip Shiu, David Sims, Rene V Sit, Maija Slaidina, Harold E Smith, Gabriella Sterne, Yu-Han Su, Daniel Sutton, Marco Tamayo, Michelle Tan, Ibrahim Tastekin, Christoph Treiber, David Vacek, Georg Vogler, Scott Waddell, Wanpeng Wang, Rachel I Wilson, Mariana F Wolfner, Yiu-Cheung E Wong, Anthony Xie, Jun Xu, Shinya Yamamoto, Jia Yan, Zepeng Yao, Kazuki Yoda, Ruijun Zhu, Robert P Zinzen

Duncan NRI Faculty and Staff Publications

For more than 100 years, the fruit fly Drosophila melanogaster has been one of the most studied model organisms. Here, we present a single-cell atlas of the adult fly, Tabula Drosophilae, that includes 580,000 nuclei from 15 individually dissected sexed tissues as well as the entire head and body, annotated to >250 distinct cell types. We provide an in-depth analysis of cell type-related gene signatures and transcription factor markers, as well as sexual dimorphism, across the whole animal. Analysis of common cell types between tissues, such as blood and muscle cells, reveals rare cell types and tissue-specific subtypes. This …

Enhanced Immunoprecipitation Techniques For The Identification Of Rna-Binding Protein Partners: Igf2bp1 Interactions In Mammary Epithelial Cells, Saja A Fakhraldeen, Scott M Berry, David J Beebe, Avtar Roopra, Celia M Bisbach, Vladimir S Spiegelman, Natalie M Niemi, Caroline M Alexander

2020-Current year OA Pubs

RNA-binding proteins (RBPs) regulate the expression of large cohorts of RNA species to produce programmatic changes in cellular phenotypes. To describe the function of RBPs within a cell, it is key to identify their mRNA-binding partners. This is often done by crosslinking nucleic acids to RBPs, followed by chemical release of the nucleic acid fragments for analysis. However, this methodology is lengthy, which involves complex processing with attendant sample losses, thus large amounts of starting materials and prone to artifacts. To evaluate potential alternative technologies, we tested "exclusion-based" purification of immunoprecipitates (IFAST or SLIDE) and report here that these methods …

Sars-Cov-2 Omicron Virus Causes Attenuated Disease In Mice And Hamsters, Peter J Halfmann, Shun Iida, Kiyoko Iwatsuki-Horimoto, Tadashi Maemura, Maki Kiso, Suzanne M Scheaffer, Tamarand L Darling, Astha Joshi, Baoling Ying, James Brett Case, Zhenlu Chong, Bradley Whitener, Zhenlu Chong, Larissa B Thackray, Adrianus C M Boon, Michael S Diamond, Et Al

Open Access Publications

The recent emergence of B.1.1.529, the Omicron variant

Metabolic Stress Induces Gd2+ Cancer Stem Cell-Like Phenotype In Triple-Negative Breast Cancer, Appalaraju Jaggupilli, Stanley Ly, Khoa Nguyen, Vivek Anand, Bin Yuan, Fouad El-Dana, Yuanqing Yan, Zoe Arvanitis, Danthasinghe Waduge Badrajee Piyarathna, Nagireddy Putluri, Helen Piwnica-Worms, Henry Charles Manning, Michael Andreeff, V Lokesh Battula

Faculty, Staff and Student Publications

Background: Metabolic stress resulting from nutrient deficiency is one of the hallmarks of a growing tumour. Here, we tested the hypothesis that metabolic stress induces breast cancer stem-like cell (BCSC) phenotype in triple-negative breast cancer (TNBC).

Methods: Flow cytometry for GD2 expression, mass spectrometry and Ingenuity Pathway Analysis for metabolomics, bioinformatics, in vitro tumorigenesis and in vivo models were used.

Results: Serum/glucose deprivation not only increased stress markers but also enhanced GD2+ BCSC phenotype and function in TNBC cells. Global metabolomics profiling identified upregulation of glutathione biosynthesis in GD2high cells, suggesting a role of glutamine in the BCSC phenotype. Cueing …

Chronic Estrus Disrupts Uterine Gland Development And Homeostasis, C Allison Stewart, M David Stewart, Ying Wang, Rachel D Mullen, Bonnie K Kircher, Rui Liang, Yu Liu, Richard R Behringer

Faculty, Staff and Student Publications

Female mice homozygous for an engineered Gnrhr E90K mutation have reduced gonadotropin-releasing hormone signaling, leading to infertility. Their ovaries have numerous antral follicles but no corpora lutea, indicating a block to ovulation. These mutants have high levels of circulating estradiol and low progesterone, indicating a state of persistent estrus. This mouse model provided a unique opportunity to examine the lack of cyclic levels of ovarian hormones on uterine gland biology. Although uterine gland development appeared similar to controls during prepubertal development, it was compromised during adolescence in the mutants. By age 20 weeks, uterine gland development was comparable to controls, …

Clinical Opinion: The Diagnosis And Management Of Suspected Fetal Growth Restriction: An Evidence-Based Approach, Christoph C Lees, Roberto Romero, Tamara Stampalija, Andrea Dall'asta, Greggory A Devore, Federico Prefumo, Tiziana Frusca, Gerard H A Visser, John C Hobbins, Ahmet A Baschat, Caterina M Bilardo, Henry L Galan, Stuart Campbell, Dev Maulik, Francesc Figueras, Wesley Lee, Julia Unterscheider, Herbert Valensise, Fabricio Da Silva Costa, Laurent J Salomon, Liona C Poon, Enrico Ferrazzi, Giancarlo Mari, Giuseppe Rizzo, John C Kingdom, Torvid Kiserud, Kurt Hecher

Faculty, Staff and Students Publications

This study reviewed the literature about the diagnosis, antepartum surveillance, and time of delivery of fetuses suspected to be small for gestational age or growth restricted. Several guidelines have been issued by major professional organizations, including the International Society of Ultrasound in Obstetrics and Gynecology and the Society for Maternal-Fetal Medicine. The differences in recommendations, in particular about Doppler velocimetry of the ductus venosus and middle cerebral artery, have created confusion among clinicians, and this review has intended to clarify and highlight the available evidence that is pertinent to clinical management. A fetus who is small for gestational age is …

Acquired Hydrocephalus Is Associated With Neuroinflammation, Progenitor Loss, And Cellular Changes In The Subventricular Zone And Periventricular White Matter, Maria Garcia-Bonilla, Leandro Castaneyra-Ruiz, Sarah Zwick, Michael Talcott, Ayodamola Otun, Albert M Isaacs, Diego M Morales, David D Limbrick, James P Mcallister

2020-Current year OA Pubs

BACKGROUND: Hydrocephalus is a neurological disease with an incidence of 80-125 per 100,000 births in the United States. Neuropathology comprises ventriculomegaly, periventricular white matter (PVWM) alterations, inflammation, and gliosis. We hypothesized that hydrocephalus in a pig model is associated with subventricular and PVWM cellular alterations and neuroinflammation that could mimic the neuropathology described in hydrocephalic infants.

METHODS: Hydrocephalus was induced by intracisternal kaolin injections in 35-day old female pigs (n = 7 for tissue analysis, n = 10 for CSF analysis). Age-matched sham controls received saline injections (n = 6). After 19-40 days, MRI scanning was performed to measure the …

Spatiotemporal Dynamics Of Clonal Selection And Diversification In Normal Endometrial Epithelium., Manako Yamaguchi, Hirofumi Nakaoka, Kazuaki Suda, Kosuke Yoshihara, Tatsuya Ishiguro, Nozomi Yachida, Kyota Saito, Haruka Ueda, Kentaro Sugino, Yutaro Mori, Kaoru Yamawaki, Ryo Tamura, Sundaramoorthy Revathidevi, Teiichi Motoyama, Kazuki Tainaka, Roel G W Verhaak, Ituro Inoue, Takayuki Enomoto

Faculty Research 2022

It has become evident that somatic mutations in cancer-associated genes accumulate in the normal endometrium, but spatiotemporal understanding of the evolution and expansion of mutant clones is limited. To elucidate the timing and mechanism of the clonal expansion of somatic mutations in cancer-associated genes in the normal endometrium, we sequence 1311 endometrial glands from 37 women. By collecting endometrial glands from different parts of the endometrium, we show that multiple glands with the same somatic mutations occupy substantial areas of the endometrium. We demonstrate that "rhizome structures", in which the basal glands run horizontally along the muscular layer and multiple …

Spatial Transcriptomics Of Dorsal Root Ganglia Identifies Molecular Signatures Of Human Nociceptors, Diana Tavares-Ferreira, Stephanie Shiers, Pradipta R Ray, Andi Wangzhou, Vivekanand Jeevakumar, Ishwarya Sankaranarayanan, Anna M Cervantes, Jeffrey C Reese, Alexander Chamessian, Bryan A Copits, Patrick M Dougherty, Robert W Gereau, Michael D Burton, Gregory Dussor, Theodore J Price

Faculty, Staff and Student Publications

Nociceptors are specialized sensory neurons that detect damaging or potentially damaging stimuli and are found in the dorsal root ganglia (DRG) and trigeminal ganglia. These neurons are critical for the generation of neuronal signals that ultimately create the perception of pain. Nociceptors are also primary targets for treating acute and chronic pain. Single-cell transcriptomics on mouse nociceptors has transformed our understanding of pain mechanisms. We sought to generate equivalent information for human nociceptors with the goal of identifying transcriptomic signatures of nociceptors, identifying species differences and potential drug targets. We used spatial transcriptomics to molecularly characterize transcriptomes of single DRG …

Selective Elimination Of Pluripotent Stem Cells By Pikfyve Specific Inhibitors., Arup R Chakraborty, Alex Vassilev, Sushil K Jaiswal, Constandina E O'Connell, John F Ahrens, Barbara S Mallon, Martin Pera, Melvin L Depamphilis

Faculty Research 2022

Inhibition of PIKfyve phosphoinositide kinase selectively kills autophagy-dependent cancer cells by disrupting lysosome homeostasis. Here, we show that PIKfyve inhibitors can also selectively eliminate pluripotent embryonal carcinoma cells (ECCs), embryonic stem cells, and induced pluripotent stem cells under conditions where differentiated cells remain viable. PIKfyve inhibitors prevented lysosome fission, induced autophagosome accumulation, and reduced cell proliferation in both pluripotent and differentiated cells, but they induced death only in pluripotent cells. The ability of PIKfyve inhibitors to distinguish between pluripotent and differentiated cells was confirmed with xenografts derived from ECCs. Pretreatment of ECCs with the PIKfyve specific inhibitor WX8 suppressed their …

Parasite Dynamics In Untreated Horses Through One Calendar Year, Ashley E. Steuer, Haley P. Anderson, Taylor Shepherd, Morgan Clark, Jessica A. Scare, Holli S. Gravatte, Martin K. Nielsen

Veterinary Science Faculty Publications

BACKGROUND: Horses are host to a plethora of parasites. Knowledge of the seasonality of parasite egg shedding and transmission is important for constructing parasite control programs. However, studies describing these patterns are sparse, and have largely been conducted only in the United Kingdom. This study evaluated strongylid egg shedding patterns and transmission dynamics of Strongylus vulgaris in naturally infected and untreated mares and foals through one calendar year in Kentucky, USA. The study also investigated the existence of a peri-parturient rise (PPR) in strongylid egg counts in foaling mares and collected information about Strongyloides westeri and Parascaris spp. in the …

Regulation Of The Double-Stranded Rna Response Through Adar1 Licenses Metaplastic Reprogramming In Gastric Epithelium, José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills

2020-Current year OA Pubs

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of …

Ddr1 Contributes To Kidney Inflammation And Fibrosis By Promoting The Phosphorylation Of Bcr And Stat3, Corina M. Borza, Gema Bolas, Fabian Bock, Xiuqi Zhang, Favour C Akabogu, Ming-Zhi Zhang, Mark De Caestecker, Min Yang, Haichun Yang, Ethan Lee, Leslie Gewin, Agnes B Fogo, W Hayes Mcdonald, Roy Zent, Ambra Pozzi

Open Access Publications

Discoidin domain receptor 1 (DDR1), a receptor tyrosine kinase activated by collagen, contributes to chronic kidney disease. However, its role in acute kidney injury and subsequent development of kidney fibrosis is not clear. Thus, we performed a model of severe ischemia/reperfusion-induced acute kidney injury that progressed to kidney fibrosis in WT and Ddr1-null mice. We showed that Ddr1-null mice had reduced acute tubular injury, inflammation, and tubulointerstitial fibrosis with overall decreased renal monocyte chemoattractant protein (MCP-1) levels and STAT3 activation. We identified breakpoint cluster region (BCR) protein as a phosphorylated target of DDR1 that controls MCP-1 production in renal proximal …

Regulation Of The Double-Stranded Rna Response Through Adar1 Licenses Metaplastic Reprogramming In Gastric Epithelium, José B Sáenz, Nancy Vargas, Charles J Cho, Jason C Mills

Faculty, Staff and Students Publications

Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of …

Selective Reduction Of Astrocyte Apoe3 And Apoe4 Strongly Reduces Aβ Accumulation And Plaque-Related Pathology In A Mouse Model Of Amyloidosis, Thomas E Mahan, Chao Wang, Xin Bao, Ankit Choudhury, Jason D Ulrich, David M Holtzman

2020-Current year OA Pubs

BACKGROUND: One of the key pathological hallmarks of Alzheimer disease (AD) is the accumulation of the amyloid-β (Aβ) peptide into amyloid plaques. The apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD and has been shown to influence the accumulation of Aβ in the brain in an isoform-dependent manner. ApoE can be produced by different cell types in the brain, with astrocytes being the largest producer of apoE, although reactive microglia also express high levels of apoE. While studies have shown that altering apoE levels in the brain can influence the development of Aβ plaque pathology, …

Constitutive Activation Of Canonical Wnt Signaling Disrupts Choroid Plexus Epithelial Fate, Arpan Parichha, Varun Suresh, Mallika Chatterjee, Aditya Kshirsagar, Lihi Ben-Reuven, Tsviya Olender, M Mark Taketo, Velena Radosevic, Mihaela Bobic-Rasonja, Sara Trnski, Michael J Holtzman, Nataša Jovanov-Milosevic, Orly Reiner, Shubha Tole

Open Access Publications

The choroid plexus secretes cerebrospinal fluid and is critical for the development and function of the brain. In the telencephalon, the choroid plexus epithelium arises from the Wnt- expressing cortical hem. Canonical Wnt signaling pathway molecules such as nuclear β-CATENIN are expressed in the mouse and human embryonic choroid plexus epithelium indicating that this pathway is active. Point mutations in human β-CATENIN are known to result in the constitutive activation of canonical Wnt signaling. In a mouse model that recapitulates this perturbation, we report a loss of choroid plexus epithelial identity and an apparent transformation of this tissue to a …

Host Tissue Proteomics Reveal Insights Into The Molecular Basis Of Schistosoma Haematobium-Induced Bladder Pathology., Derick N M Osakunor, Kenji Ishida, Olivia K Lamanna, Mario Rossi, Louis Dwomoh, Michael H. Hsieh

Urology Faculty Publications

Urogenital schistosomiasis remains a major public health concern worldwide. In response to egg deposition, the host bladder undergoes gross and molecular morphological changes relevant for disease manifestation. However, limited mechanistic studies to date imply that the molecular mechanisms underlying pathology are not well-defined. We leveraged a mouse model of urogenital schistosomiasis to perform for the first time, proteome profiling of the early molecular events that occur in the bladder after exposure to S. haematobium eggs, and to elucidate the protein pathways involved in urogenital schistosomiasis-induced pathology. Purified S. haematobium eggs or control vehicle were microinjected into the bladder walls of …

Safety And Efficacy Of Mass Drug Administration With A Single-Dose Triple-Drug Regimen Of Albendazole + Diethylcarbamazine + Ivermectin For Lymphatic Filariasis In Papua New Guinea: An Open-Label, Cluster-Randomised Trial, Livingstone Tavul, Kobie O'Brian, Gary J. Weil, Charles W. Goss, Et Al

Open Access Publications

BACKGROUND: Papua New Guinea (PNG) has a high burden of lymphatic filariasis (LF) caused by Wuchereria bancrofti, with an estimated 4.2 million people at risk of infection. A single co-administered dose of ivermectin, diethylcarbamazine and albendazole (IDA) has been shown to have superior efficacy in sustained clearance of microfilariae compared to diethylcarbamazine and albendazole (DA) in small clinical trials. A community-based cluster-randomised trial of DA versus IDA was conducted to compare the safety and efficacy of IDA and DA for LF in a moderately endemic, treatment-naive area in PNG.

METHODOLOGY: All consenting, eligible residents of 24 villages in Bogia district, …