Medical Specialties Commons^™

Hermansky-Pudlak Syndrome-2 Alters Mitochondrial Homeostasis In The Alveolar Epithelium Of The Lung, Karina Cuevas-Mora, Willy Roque, Hoora Shaghaghi, Bernadette R Gochuico, Ivan O Rosas, Ross Summer, Freddy Romero

Faculty, Staff and Students Publications

BACKGROUND: Mitochondrial dysfunction has emerged as an important player in the pathogenesis of idiopathic pulmonary fibrosis (IPF), a common cause of idiopathic interstitial lung disease in adults. Hermansky-Pudlak syndrome (HPS) is a rare autosomal recessive disorder that causes a similar type of pulmonary fibrosis in younger adults, although the role of mitochondrial dysfunction in this condition is not understood.

METHODS: We performed a detailed characterization of mitochondrial structure and function in lung tissues and alveolar epithelial cells deficient in the adaptor protein complex 3 beta 1 (Ap3b1) subunit, the gene responsible for causing subtype 2 of HPS (HPS-2).

RESULTS: We …

Cryo-Electron Tomography Of Candida Glabrata Plasma Membrane Proteins, Cristina Jiménez-Ortigosa, Jennifer Jiang, Muyuan Chen, Xuyuan Kuang, Kelley R Healey, Paul Castellano, Nikpreet Boparai, Steven J Ludtke, David S Perlin, Wei Dai

Faculty, Staff and Students Publications

Fungal plasma membrane proteins have long been recognized as targets for the development of antifungal agents. Despite recent progress in experimental approaches and computational structural predictions, our knowledge of the structural dynamics and spatial distribution of these membrane proteins in the context of their native lipid environment remains limited. By applying cryo-electron tomography (cryoET) and subtomogram analysis, we aim to characterize the structural characteristics and spatial distribution of membrane proteins present in Candida glabrata plasma membranes. This study has resulted in the identification of the membrane-embedded structure of the fungal H+-ATPase, Pma1. Tomograms of the plasma membrane revealed that Pma1 …

Long-Term Dynamics Of The Kidney Disease Epidemic Among Hiv-Infected Individuals, Heather Gudaz, Henry A. Ogu, Elissa J. Schwartz

Spora: A Journal of Biomathematics

One of many risks facing HIV+ individuals is the development of kidney dysfunction and end stage kidney disease (ESKD). A differential equation-based mathematical model was developed to assess the impact of antiretroviral therapy on the progression to kidney disease and on reducing mortality due to kidney failure. Analytical and numerical predictions of long-term HIV+ ESKD prevalence show that therapy can lead to either extremely low levels of disease prevalence or increased prevalence, depending on drug efficacy levels and mechanisms of action. Maintenance of HIV+ ESKD prevalence below one individual is possible with sufficient efficacy (e.g., 99%) against the progression from …

Efficacy And Safety Of The Mrna-1273 Sars-Cov-2 Vaccine, Lindsey R Baden, Hana M El Sahly, Brandon Essink, Karen Kotloff, Sharon Frey, Rick Novak, David Diemert, Stephen A Spector, Nadine Rouphael, C Buddy Creech, John Mcgettigan, Shishir Khetan, Nathan Segall, Joel Solis, Adam Brosz, Carlos Fierro, Howard Schwartz, Kathleen Neuzil, Larry Corey, Peter Gilbert, Holly Janes, Dean Follmann, Mary Marovich, John Mascola, Laura Polakowski, Julie Ledgerwood, Barney S Graham, Hamilton Bennett, Rolando Pajon, Conor Knightly, Brett Leav, Weiping Deng, Honghong Zhou, Shu Han, Melanie Ivarsson, Jacqueline Miller, Tal Zaks, Cove Study Group

Faculty, Staff and Students Publications

BACKGROUND: Vaccines are needed to prevent coronavirus disease 2019 (Covid-19) and to protect persons who are at high risk for complications. The mRNA-1273 vaccine is a lipid nanoparticle-encapsulated mRNA-based vaccine that encodes the prefusion stabilized full-length spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes Covid-19.

METHODS: This phase 3 randomized, observer-blinded, placebo-controlled trial was conducted at 99 centers across the United States. Persons at high risk for SARS-CoV-2 infection or its complications were randomly assigned in a 1:1 ratio to receive two intramuscular injections of mRNA-1273 (100 μg) or placebo 28 days apart. …

Macrophage And Adipocyte Interaction As A Source Of Inflammation In Kidney Disease, Cristina Martos-Rus, Goni Katz-Greenberg, Zhao Lin, Eurico Serrano, Diana Whitaker Menezes, Marina Domingo-Vidal, Megan Roche, Kavitha Ramaswamy, D. Craig Hooper, Bonita Falkner, Maria P Martinez Cantarin

Kimmel Cancer Center Faculty Papers

In obesity, adipose tissue derived inflammation is associated with unfavorable metabolic consequences. Uremic inflammation is prevalent and contributes to detrimental outcomes. However, the contribution of adipose tissue inflammation in uremia has not been characterized. We studied the contribution of adipose tissue to uremic inflammation in-vitro, in-vivo and in human samples. Exposure to uremic serum resulted in activation of inflammatory pathways including NFκB and HIF1, upregulation of inflammatory cytokines/chemokines and catabolism with lipolysis, and lactate production. Also, co-culture of adipocytes with macrophages primed by uremic serum resulted in higher inflammatory cytokine expression than adipocytes exposed only to uremic serum. Adipose tissue …

Lkb1 And Ampk Instruct Cone Nuclear Position To Modify Visual Function, Courtney A Burger, Nicholas E Albrecht, Danye Jiang, Justine H Liang, Ross A Poché, Melanie A Samuel

Faculty, Staff and Students Publications

Cone photoreceptors detect light and are responsible for color vision. These cells display a distinct polarized morphology where nuclei are precisely aligned in the apical retina. However, little is known about the mechanisms involved in cone nuclear positioning or the impact of this organization on retina function. We show that the serine/threonine kinase LKB1 and one of its substrates, AMPK, regulate cone nuclear positioning. In the absence of either molecule, cone nuclei are misplaced along the axon, resulting in altered nuclear lamination. LKB1 is required specifically in cones to mediate this process, and disruptions in nuclear alignment result in reduced …

Immune Checkpoint Inhibitor Therapy In Hiv-Associated Merkel Cell Carcinoma: A Case Series Of 3 Patients., Song Y Park, Candice Church, Nora A Alexander, Michi M Shinohara, Kelly G Paulson, Karl D Lewis, Nancy S Lee, Paul Nghiem

Articles, Abstracts, and Reports

No abstract provided.

Adherence To The Kidney Disease: Improving Global Outcomes Ckd Guideline In Nephrology Practice Across Countries, Bénédicte Stengel, Daniel Muenz, Charlotte Tu, Elodie Speyer, Natalia Alencar De Pinho, Christian Combe, Kunihiro Yamagata, Helmut Reichel, Danilo Fliser, Ziad A Massy, Antonio A Lopes, Michel Jadoul, Wolfgang C Winkelmayer, Ronald L Pisoni, Bruce M Robinson, Roberto Pecoits-Filho

Faculty, Staff and Students Publications

INTRODUCTION: The uptake of the Kidney Disease: Improving Global Outcomes (KDIGO) 2012 chronic kidney disease (CKD) Guideline is not fully described in real-world nephrology practice across the world.

METHODS: We used baseline data from the CKD Outcomes and Practice Patterns Study (2013-2017), a 4-country cohort of patients with estimated glomerular filtration rate/min per 1.73 m

RESULTS: The mean age ranged from 65 years in Brazil to 72 years in Germany. Albuminuria (mostly proteinuria) was measured routinely in 36% to 43% of patients in Brazil, Germany, and the United States. Blood pressure control (≤140/90 mm Hg) ranged from 49% in France …

Calcium Ions Trigger The Exposure Of Phosphatidylserine On The Surface Of Necrotic Cells, Yoshitaka Furuta, Omar Pena-Ramos, Zao Li, Lucia Chiao, Zheng Zhou

Faculty, Staff and Students Publications

Intracellular Ca2+ level is under strict regulation through calcium channels and storage pools including the endoplasmic reticulum (ER). Mutations in certain ion channel subunits, which cause mis-regulated Ca2+ influx, induce the excitotoxic necrosis of neurons. In the nematode Caenorhabditis elegans, dominant mutations in the DEG/ENaC sodium channel subunit MEC-4 induce six mechanosensory (touch) neurons to undergo excitotoxic necrosis. These necrotic neurons are subsequently engulfed and digested by neighboring hypodermal cells. We previously reported that necrotic touch neurons actively expose phosphatidylserine (PS), an "eat-me" signal, to attract engulfing cells. However, the upstream signal that triggers PS externalization remained elusive. Here we …

Prevalence Of Gastric Intestinal Metaplasia In A Multiethnic Us Veterans Population, Theresa H Nguyen, Mimi C Tan, Yan Liu, Massimo Rugge, Aaron P Thrift, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND & AIMS: There is a need to identify individuals with gastric intestinal metaplasia, a precursor to gastric cancer, so they can be offered screening and surveillance. We examined the prevalence of gastric intestinal metaplasia, detected by upper endoscopy biopsy analysis, in different race and ethnic subgroups. We also investigated the extent to which Helicobacter pylori infection, with or without acute and chronic gastritis, accounts for observed associations between race or ethnicity and risk of gastric intestinal metaplasia.

METHODS: We used data from a cross-sectional study of consecutively recruited patients at the Michael E. DeBakey Veterans Affairs Medical Center in …

Prevalence Of Barrett’S Esophagus And Performance Of Societal Screening Guidelines In An Unreferred Primary Care Population Of Us Veterans, Theresa H Nguyen, Aaron P Thrift, Massimo Rugge, Hashem B El-Serag

Faculty, Staff and Students Publications

BACKGROUND AND AIMS: Less than 10% of patients diagnosed with esophageal adenocarcinoma have a pre-existing Barrett's esophagus (BE) diagnosis, possibly because of suboptimal performance of guidelines. We examined the prevalence of BE in a previously unscreened primary care population and the potential yield of practice BE screening guidelines.

METHODS: This was a retrospective analysis of a prospective cross-sectional study of consecutively recruited unreferred patients from primary care clinics who underwent study upper endoscopy. We examined the performance of BE screening guidelines of the European Society of Gastrointestinal Endoscopy (ESGE), British Society of Gastroenterology (BSG), American Society for Gastrointestinal Endoscopy (ASGE), …

Links Between Thrombosis And Inflammation In Traumatic Brain Injury, W Brad Hubbard, Jing-Fei Dong, Miguel A Cruz, Rolando E Rumbaut

Faculty, Staff and Students Publications

Traumatic brain injury (TBI) continues to be a major healthcare problem and there is much to be explored regarding the secondary pathobiology to identify early predictive markers and new therapeutic targets. While documented changes in thrombosis and inflammation in major trauma have been well described, growing evidence suggests that isolated TBI also results in systemic alterations in these mechanisms. Here, we review recent experimental and clinical findings that demonstrate how blood-brain barrier dysfunction, systemic immune response, inflammation, platelet activation, and thrombosis contribute significantly to the pathogenesis of TBI. Despite advances in the links between thrombosis and inflammation, there is a …

Relation Of Magnetic Resonance Imaging Based Arterial Signal Enhancement To Markers Of Peripheral Artery Disease, Olga A Gimnich, Jonathan Holbrook, Tatiana Belousova, Christina M Short, Addison A Taylor, Vijay Nambi, Joel D Morrisett, Christie M Ballantyne, Jean Bismuth, Dipan J Shah, Gerd Brunner

Faculty, Staff and Students Publications

Peripheral artery disease (PAD) is associated with impaired lower extremity function. We hypothesized that contrast-enhanced magnetic resonance imaging (CE-MRI) based arterial signal enhancement (SE) measures are associated with markers of PAD. A total of 66 participants were enrolled, 10 were excluded due to incomplete data, resulting in 56 participants for the final analyses (36 PAD, 20 matched controls). MR imaging was performed postreactive hyperemia using bilateral thigh blood-pressure cuffs. First pass-perfusion images were acquired at the mid-calf region with a high-resolution saturation recovery gradient echo pulse sequence, and arterial SE was measured for the lower extremity arteries. As expected, peak …

Education Of Infectious Diseases Fellows During The Covid-19 Pandemic Crisis: Challenges And Opportunities, Lisa M Chirch, Wendy S Armstrong, Gayle P Balba, Prathit A Kulkarni, Constance A Benson, Victoria Konold, Vera P Luther, Obinna N Nnedu, Sarah Perloff, Raymund R Razonable, Wendy Stead, George R Thompson, Michael T Melia

Faculty, Staff and Students Publications

One of the many challenges that has befallen the Infectious Diseases and Graduate Medical Education communities during the coronavirus disease 2019 (COVID-19) pandemic is the maintenance of continued effective education and training of the future leaders of our field. With the remarkable speed and innovation that has characterized the responses to this pandemic, educators everywhere have adapted existing robust and safe learning environments to meet the needs of our learners. This paper will review distinct aspects of education and training of the Infectious Diseases fellows we believe the COVID-19 pandemic has impacted most, including mentoring, didactics, and wellness. We anticipate …

Parenteral Lipid Emulsions Induce Unique Ileal Fatty Acid And Metabolomic Profiles But Do Not Increase The Risk Of Necrotizing Enterocolitis In Preterm Pigs, William Yakah, Pratibha Singh, Joanne Brown, Barbara Stoll, Doug Burrin, Muralidhar H Premkumar, Hasan H Otu, Xuesong Gu, Simon T Dillon, Towia A Libermann, Steven D Freedman, Camilia R Martin

Children’s Nutrition Research Center Staff Publications

Necrotizing enterocolitis (NEC) is a manifestation of maladaptive intestinal responses in preterm infants centrally medicated by unattenuated inflammation. Early in the postnatal period, preterm infants develop a deficit in arachidonic and docosahexaenoic acid, both potent regulators of inflammation. We hypothesized that the fatty acid composition of parenteral lipid emulsions uniquely induces blood and intestinal fatty acid profiles which, in turn, modifies the risk of NEC development. Forty-two preterm pigs were randomized to receive one of three lipid emulsions containing 100% soybean oil (SO), 15% fish oil (MO15), or 100% fish oil (FO100) with enteral feedings over an 8-day protocol. Blood …

Fructan-Sensitive Children With Irritable Bowel Syndrome Have Distinct Gut Microbiome Signatures, Bruno P Chumpitazi, Kristi L Hoffman, Daniel P Smith, Ann R Mcmeans, Salma Musaad, James Versalovic, Joseph F Petrosino, Robert J Shulman

Children’s Nutrition Research Center Staff Publications

Background: Dietary fructans may worsen gastrointestinal symptoms in children with irritable bowel syndrome (IBS).

Aim: To determine whether gut microbiome composition and function are associated with childhood IBS fructan-induced symptoms.

Methods: Faecal samples were collected from 38 children aged 7-17 years with paediatric Rome III IBS, who previously completied a double-blind, randomised, placebo-controlled crossover (fructan vs maltodextrin) trial. Fructan sensitivity was defined as an increase of ≥30% in abdominal pain frequency during the fructan diet. Gut microbial composition was determined via 16Sv4 rDNA sequencing. LEfSe evaluated taxonomic composition differences. Tax4Fun2 predicted microbial fructan metabolic pathways.

Results: At baseline, 17 fructan-sensitive …

Overview Of Breath Testing In Clinical Practice In North America, Buford L Nichols, Robert D Baker, Susan S Baker

Children’s Nutrition Research Center Staff Publications

Human breath is an easily, noninvasively obtained substance. It offers insight into metabolism and is used to diagnose disaccharide malabsorption, infection, small bowel bacterial over growth, and transit times. Herein, we discuss the readily available clinical breath tests, how they function, how they are administered and interpreted and some pitfalls in their use.

Rationale And Design Of The Baylor Infant Twin Study-A Study Assessing Obesity-Related Risk Factors From Infancy, Shabnam R Momin, Mackenzie K Senn, Scott Buckley, Neil R M Buist, Manisha Gandhi, Amy B Hair, Sheryl O Hughes, Kelly R Hodges, William C Lange, Maria A Papaioannou, Mimi Phan, Robert A Waterland, Alexis C Wood

Children’s Nutrition Research Center Staff Publications

Background: Early childhood (0-3 years) is a critical period for obesity prevention, when tendencies in eating behaviors and physical activity are established. Yet, little is understood about how the environment shapes children's genetic predisposition for these behaviors during this time. The Baylor Infant Twin Study (BITS) is a two phase study, initiated to study obesity risk factors from infancy. Data collection has been completed for Phase 1 in which three sub-studies pilot central measures for Phase 2. A novel infant temperament assessment, based on observations made by trained researchers was piloted in Behavior Observation Pilot Protocol (BOPP) study, a new …

The Gut Microbiome Contributes To Blood-Brain Barrier Disruption In Spontaneously Hypertensive Stroke Prone Rats, James W Nelson, Sharon C Phillips, Bhanu P Ganesh, Joseph F Petrosino, David J Durgan, Robert M Bryan

Faculty, Staff and Students Publications

In recent years, it has become apparent that the gut microbiome can influence the functioning and pathological states of organs and systems throughout the body. In this study, we tested the hypothesis that the gut microbiome has a major role in the disruption of the blood-brain barrier (BBB) in the spontaneously hypertensive stroke prone rats (SHRSP), an animal model for hypertensive cerebral small vessel disease (CSVD). Loss of BBB is thought to be an early and initiating component to the full expression of CSVD in animal models and humans. To test this hypothesis, newly born SHRSP pups were placed with …

Regional N-Glycan And Lipid Analysis From Tissues Using Maldi-Mass Spectrometry Imaging, Alexandra E. Stanback, Lindsey R. Conroy, Lyndsay E. A. Young, Tara R. Hawkinson, Kia H. Markussen, Harrison A. Clarke, Derek B. Allison, Ramon C. Sun

Neuroscience Faculty Publications

N-glycans and lipids are structural metabolites that play important roles in cellular processes. Both show unique regional distribution in tissues; therefore, spatial analyses of these metabolites are crucial to our understanding of cellular physiology. Matrix-assisted laser desorption/ionization-mass spectrometry imaging (MALDI-MSI) is an innovative technique that enables in situ detection of analytes with spatial distribution. This workflow details a MALDI-MSI protocol for the spatial profiling of N-glycans and lipids from tissues following application of enzyme and MALDI matrix.

For complete details on the use and execution of this protocol, please refer to Drake et al. (2018) and Andres et al. (2020).

Mucosal Genomics Implicate Lymphocyte Activation And Lipid Metabolism In Refractory Environmental Enteric Dysfunction, Najeeha Talat Iqbal, Najeeb Rahman, Kamran Sadiq, Zubair Ahmad, Romana Idress, Junaid Iqbal, Sheraz Ahmed, Aneeta Hotwani, Fayyaz Umrani, Sana Syed, Syed Asad Ali

Department of Paediatrics and Child Health

Background & aims: Environmental enteric dysfunction (EED) limits the Sustainable Development Goals of improved childhood growth and survival. We applied mucosal genomics to advance our understanding of EED.
Methods: The Study of Environmental Enteropathy and Malnutrition (SEEM) followed 416 children from birth to 24 months in a rural district in Pakistan. Biomarkers were measured at 9 months and tested for association with growth at 24 months. The duodenal methylome and transcriptome was determined in 52 undernourished SEEM participants and 42 North American controls and celiac disease patients.
Results: After accounting for growth at study entry, circulating IGF-1 and ferritin predicted …

Macrophage-Engineered Vesicles For Therapeutic Delivery And Bidirectional Reprogramming Of Immune Cell Polarization, Khaga R. Neupane, J. Robert Mccorkle, Timothy J. Kopper, Jourdan E. Lakes, Surya P. Aryal, Masud Abdullah, Aaron A. Snell, John C. Gensel, Jill M. Kolesar, Christopher I. Richards

Spinal Cord and Brain Injury Research Center Faculty Publications

Macrophages, one of the most important phagocytic cells of the immune system, are highly plastic and are known to exhibit diverse roles under different pathological conditions. The ability to repolarize macrophages from pro-inflammatory (M1) to anti-inflammatory (M2) or vice versa offers a promising therapeutic approach for treating various diseases such as traumatic injury and cancer. Herein, it is demonstrated that macrophage-engineered vesicles (MEVs) generated by disruption of macrophage cellular membranes can be used as nanocarriers capable of reprogramming macrophages and microglia toward either pro- or anti-inflammatory phenotypes. MEVs can be produced at high yields and easily loaded with diagnostic molecules …

Broad Kinase Inhibition Mitigates Early Neuronal Dysfunction In Tauopathy, Shon A. Koren, Matthew J. Hamm, Ryan Cloyd, Sarah N. Fontaine, Emad Chishti, Chiara Lanzillotta, Jennifer Rodriguez-Rivera, Alexandria Ingram, Michelle Bell, Sara M. Galvis-Escobar, Nicholas Zulia, Fabio Di Domenico, Duc Duong, Nicholas T. Seyfried, David K. Powell, Moriel Vandsburger, Tal Frolinger, Anika M. S. Hartz, John Koren Iii, Jeffrey M. Axten, Nicholas J. Laping, Jose F. Abisambra

Sanders-Brown Center on Aging Faculty Publications

Tauopathies are a group of more than twenty known disorders that involve progressive neurodegeneration, cognitive decline and pathological tau accumulation. Current therapeutic strategies provide only limited, late-stage symptomatic treatment. This is partly due to lack of understanding of the molecular mechanisms linking tau and cellular dysfunction, especially during the early stages of disease progression. In this study, we treated early stage tau transgenic mice with a multi-target kinase inhibitor to identify novel substrates that contribute to cognitive impairment and exhibit therapeutic potential. Drug treatment significantly ameliorated brain atrophy and cognitive function as determined by behavioral testing and a sensitive imaging …

Differential Expression Of Αvβ3 And Αvβ6 Integrins In Prostate Cancer Progression, Fabio Quaglia, Shiv Ram Krishn, Yanqing Wang, David W Goodrich, Peter Mccue, Andrew Kossenkov, Amy C Mandigo, Karen Knudsen, Paul H Weinreb, Eva Corey, William Kevin Kelly, Lucia R Languino

Department of Cancer Biology Faculty Papers

Neuroendocrine prostate cancer (NEPrCa) arises de novo or after accumulation of genomic alterations in pre-existing adenocarcinoma tumors in response to androgen deprivation therapies. We have provided evidence that small extracellular vesicles released by PrCa cells and containing the αVβ3 integrin promote neuroendocrine differentiation of PrCa in vivo and in vitro. Here, we examined αVβ3 integrin expression in three murine models carrying a deletion of PTEN (SKO), PTEN and RB1 (DKO), or PTEN, RB1 and TRP53 (TKO) genes in the prostatic epithelium; of these three models, the DKO and TKO tumors develop NEPrCa with a gene signature comparable to those of …

Calcaneal Ultrasound And Its Relation To Dietary And Lifestyle Factors, Anthropometry, And Vitamin D Deficiency In Young Medical Students, Lena Jafri, Hafsa Majid, Sibtain Ahmed, Ghazala Naureen, Aysha Habib Khan

Department of Pathology and Laboratory Medicine

Background: Bone quality and peak bone mass are greatly affected by lifestyle factors. The objective of the study was to investigate the relationships between anthropometry, dietary and caloric intake, body composition measurements, physical activity, and vitamin D status with quantitative ultrasound-based bone parameters among medical students.
Methods: Both male and female medical college students were included in this study. A detailed questionnaire was administered, collecting clinical, dietary, physical activity information, physical examination details, including body mass index (BMI). Body composition (total body fat, total body water, muscle mass, mean visceral fat mass, basal metabolic rate, bone mass using a bioelectrical …

Spliceosome-Targeted Therapies Trigger An Antiviral Immune Response In Triple-Negative Breast Cancer, Elizabeth A Bowling, Jarey H Wang, Fade Gong, William Wu, Nicholas J Neill, Ik Sun Kim, Siddhartha Tyagi, Mayra Orellana, Sarah J Kurley, Rocio Dominguez-Vidaña, Hsiang-Ching Chung, Tiffany Y-T Hsu, Julien Dubrulle, Alexander B Saltzman, Heyuan Li, Jitendra K Meena, Gino M Canlas, Srinivas Chamakuri, Swarnima Singh, Lukas M Simon, Calla M Olson, Lacey E Dobrolecki, Michael T Lewis, Bing Zhang, Ido Golding, Jeffrey M Rosen, Damian W Young, Anna Malovannaya, Fabio Stossi, George Miles, Matthew J Ellis, Lihua Yu, Silvia Buonamici, Charles Y Lin, Kristen L Karlin, Xiang H-F Zhang, Thomas F Westbrook

Faculty, Staff and Students Publications

Many oncogenic insults deregulate RNA splicing, often leading to hypersensitivity of tumors to spliceosome-targeted therapies (STTs). However, the mechanisms by which STTs selectively kill cancers remain largely unknown. Herein, we discover that mis-spliced RNA itself is a molecular trigger for tumor killing through viral mimicry. In MYC-driven triple-negative breast cancer, STTs cause widespread cytoplasmic accumulation of mis-spliced mRNAs, many of which form double-stranded structures. Double-stranded RNA (dsRNA)-binding proteins recognize these endogenous dsRNAs, triggering antiviral signaling and extrinsic apoptosis. In immune-competent models of breast cancer, STTs cause tumor cell-intrinsic antiviral signaling, downstream adaptive immune signaling, and tumor cell death. Furthermore, RNA …

A Pathogenic Ufsp2 Variant In An Autosomal Recessive Form Of Pediatric Neurodevelopmental Anomalies And Epilepsy, Min Ni, Bushra Afroze, Chao Xing, Chunxiao Pan, Yanqiu Shao, Ling Cai, Brandi L. Cantarel, Jimin Pei, Nick V. Grishin, Stacy Hewson

Department of Paediatrics and Child Health

Purpose: Neurodevelopmental disabilities are common and genetically heterogeneous. We identified a homozygous variant in the gene encoding UFM1-specific peptidase 2 (UFSP2), which participates in the UFMylation pathway of protein modification. UFSP2 variants are implicated in autosomal dominant skeletal dysplasias, but not neurodevelopmental disorders. Homozygosity for the variant occurred in eight children from four South Asian families with neurodevelopmental delay and epilepsy. We describe the clinical consequences of this variant and its effect on UFMylation.
Methods: Exome sequencing was used to detect potentially pathogenic variants and identify shared regions of homozygosity. Immunoblotting assessed protein expression and post-translational modifications in patient-derived fibroblasts. …

Excessive Intake Of Iodine And Low Prevalence Of Goiter In School Age Children Five Years After Implementation Of National Salt Iodization In Shebedino Woreda, Southern Ethiopia, Elilta Elias, Workneh Tsegaya, Barbara J. Stoecker, Tafere Gebreegziabher Belay

All Faculty Scholarship for the College of the Sciences

Background

Iodine is a trace element required for the synthesis of thyroid hormones. The multiple effects of iodine deficiency on human health are called iodine deficiency disorders (IDDs). IDDs have been common nutritional problems in Ethiopia. In 2012, Ethiopia launched a national salt iodization program to address IDDs. The objective of this study was to assess the effects of this program after 5 years by measuring urinary iodine concentration (UIC) and prevalence of goiter in school age children as well as household salt iodine concentration (SIC).

Methods

A school-based cross-sectional design was employed. After ethical approval, 408 children from eight …

[(Wr)8Wkβa]-Doxorubicin Conjugate: A Delivery System To Overcome Multi-Drug Resistance Against Doxorubicin, Khalid Zoghebi, Hamidreza Montazeri Aliabadi, Rakesh Kumar Tiwari, Keykavous Parang

Pharmacy Faculty Articles and Research

Doxorubicin (Dox) is an anthracycline chemotherapeutic agent used to treat breast, leukemia, and lymphoma malignancies. However, cardiotoxicity and inherent acquired resistance are major drawbacks, limiting its clinical application. We have previously shown that cyclic peptide [WR]₉ containing alternate tryptophan (W) and arginine (R) residues acts as an efficient molecular transporter. An amphiphilic cyclic peptide containing a lysine (K) residue and alternative W and R was conjugated through a free side chain amino group with Dox via a glutarate linker to afford [(WR)₈WKβA]-Dox conjugate. Antiproliferative assays were performed in different cancer cell lines using the conjugate and the …

Arginase 1 Insufficiency Precipitates Amyloid-Β Deposition And Hastens Behavioral Impairment In A Mouse Model Of Amyloidosis, Chao Ma, Jerry B. Hunt, Maj-Linda B. Selenica, Awa Sanneh, Leslie A. Sandusky-Beltran, Mallory Watler, Rana Daas, Andrii Kovalenko, Huimin Liang, Devon Placides, Chuanhai Cao, Xiaoyang Lin, Michael B. Orr, Bei Zhang, John C. Gensel, David J. Feola, Marcia N. Gordon, Dave Morgan, Paula C. Bickford, Daniel C. Lee

Sanders-Brown Center on Aging Faculty Publications

Alzheimer’s disease (AD) includes several hallmarks comprised of amyloid-β (Aβ) deposition, tau neuropathology, inflammation, and memory impairment. Brain metabolism becomes uncoupled due to aging and other AD risk factors, which ultimately lead to impaired protein clearance and aggregation. Increasing evidence indicates a role of arginine metabolism in AD, where arginases are key enzymes in neurons and glia capable of depleting arginine and producing ornithine and polyamines. However, currently, it remains unknown if the reduction of arginase 1 (Arg1) in myeloid cell impacts amyloidosis. Herein, we produced haploinsufficiency of Arg1 by the hemizygous deletion in myeloid cells using Arg1 …