Digital Commons Network^™

Transcribed Ultraconserved Regions Are Associated With Clinicopathological Features In Breast Cancer, Erika Pereira Zambalde, Douglas Adamoski, Daniela Fiori Gradia, Iris Rabinovich, Ana Carolina Rodrigues, Cristina Ivan, Enilze M S F Ribeiro, George Adrian Calin, Jaqueline Carvalho De Oliveira

Faculty, Staff and Student Publications

Ultraconserved regions (UCRs) are 481 genome segments, with length longer than 200 bp, that are 100% conserved among humans, mice, and rats. The majority of UCRs are transcriptionally active (T-UCRs) as many of them produce non-coding RNAs. In a previous study, we evaluated the expression level of T-UCRs in breast cancer (BC) patients and found that 63% of transcripts correlated with some clinical and/or molecular parameter of BC. In this study, we delved into the expression levels of 12 T-UCRs and correlated them with clinicopathological parameters, immunohistochemical markers, and overall survival in two breast cancer cohorts: TCGA and Brazilian patients. …

The Earth Biogenome Project 2020: Starting The Clock., Harris A Lewin, Stephen Richards, Erez Lieberman Aiden, Miguel L Allende, John M Archibald, Miklós Bálint, Katharine B Barker, Bridget Baumgartner, Katherine Belov, Giorgio Bertorelle, Mark L Blaxter, Jing Cai, Nicolette D Caperello, Keith Carlson, Juan Carlos Castilla-Rubio, Shu-Miaw Chaw, Lei Chen, Anna K Childers, Jonathan A Coddington, Dalia A Conde, Montserrat Corominas, Keith A. Crandall, Andrew J Crawford, Federica Dipalma, Richard Durbin, Thankgod E Ebenezer, Scott V Edwards, Olivier Fedrigo, Paul Flicek, Giulio Formenti, Richard A Gibbs, M Thomas P Gilbert, Melissa M. Goldstein, Jennifer Marshall Graves, Henry T Greely, Igor V Grigoriev, Kevin J Hackett, Neil Hall, David Haussler, Kristofer M Helgen, Carolyn J Hogg, Sachiko Isobe, Kjetill Sigurd Jakobsen, Axel Janke, Erich D Jarvis, Warren E Johnson, Steven J M Jones, Elinor K Karlsson, Paul J Kersey, Jin-Hyoung Kim, W John Kress, Shigehiro Kuraku, Mara K N Lawniczak, James H Leebens-Mack, Xueyan Li, Kerstin Lindblad-Toh, Xin Liu, Jose V Lopez, Tomas Marques-Bonet, Sophie Mazard, Jonna A K Mazet, Camila J Mazzoni, Eugene W Myers, Rachel J O'Neill, Sadye Paez, Hyun Park, Gene E Robinson, Cristina Roquet, Oliver A Ryder, Jamal S M Sabir, H Bradley Shaffer, Timothy M Shank, Jacob S Sherkow, Pamela S Soltis, Boping Tang, Leho Tedersoo, Marcela Uliano-Silva, Kun Wang, Xiaofeng Wei, Regina Wetzer, Julia L Wilson, Xun Xu, Huanming Yang, Anne D Yoder, Guojie Zhang

Health Policy and Management Faculty Publications

No abstract provided.

Steroid-Sensitive Nephrotic Syndrome Candidate Gene Clvs1 Regulates Podocyte Oxidative Stress And Endocytosis, Brandon M. Lane, Andrew F. Malone, Et Al.

2020-Current year OA Pubs

We performed next-generation sequencing in patients with familial steroid-sensitive nephrotic syndrome (SSNS) and identified a homozygous segregating variant (p.H310Y) in the gene encoding clavesin-1 (CLVS1) in a consanguineous family with 3 affected individuals. Knockdown of the clavesin gene in zebrafish (clvs2) produced edema phenotypes due to disruption of podocyte structure and loss of glomerular filtration barrier integrity that could be rescued by WT CLVS1 but not the p.H310Y variant. Analysis of cultured human podocytes with CRISPR/Cas9-mediated CLVS1 knockout or homozygous H310Y knockin revealed deficits in clathrin-mediated endocytosis and increased susceptibility to apoptosis that could be rescued with corticosteroid treatment, mimicking …

Disruption Of Mecp2-Tcf20 Complex Underlies Distinct Neurodevelopmental Disorders, Jian Zhou, Hamdan Hamdan, Hari Krishna Yalamanchili, Kaifang Pang, Amy E Pohodich, Joanna Lopez, Yingyao Shao, Juan A Oses-Prieto, Lifang Li, Wonho Kim, Mark A Durham, Sameer S Bajikar, Donna J Palmer, Philip Ng, Michelle L Thompson, E Martina Bebin, Amelie J Müller, Alma Kuechler, Antje Kampmeier, Tobias B Haack, Alma L Burlingame, Zhandong Liu, Matthew N Rasband, Huda Y Zoghbi

Duncan NRI Faculty and Staff Publications

MeCP2 is associated with Rett syndrome (RTT), MECP2 duplication syndrome, and a number of conditions with isolated features of these diseases, including autism, intellectual disability, and motor dysfunction. MeCP2 is known to broadly bind methylated DNA, but the precise molecular mechanism driving disease pathogenesis remains to be determined. Using proximity-dependent biotinylation (BioID), we identified a transcription factor 20 (TCF20) complex that interacts with MeCP2 at the chromatin interface. Importantly, RTT-causing mutations in MECP2 disrupt this interaction. TCF20 and MeCP2 are highly coexpressed in neurons and coregulate the expression of key neuronal genes. Reducing Tcf20 partially rescued the behavioral deficits caused …

Characterization Of The Copd Alveolar Niche Using Single-Cell Rna Sequencing, Maor Sauler, John E Mcdonough, Taylor S Adams, Neeharika Kothapalli, Thomas Barnthaler, Rhiannon B Werder, Jonas C Schupp, Jessica Nouws, Matthew J Robertson, Cristian Coarfa, Tao Yang, Maurizio Chioccioli, Norihito Omote, Carlos Cosme, Sergio Poli, Ehab A Ayaub, Sarah G Chu, Klaus H Jensen, Jose L Gomez, Clemente J Britto, Micha Sam B Raredon, Laura E Niklason, Andrew A Wilson, Pascal N Timshel, Naftali Kaminski, Ivan O Rosas

Faculty, Staff and Students Publications

Chronic obstructive pulmonary disease (COPD) is a leading cause of death worldwide, however our understanding of cell specific mechanisms underlying COPD pathobiology remains incomplete. Here, we analyze single-cell RNA sequencing profiles of explanted lung tissue from subjects with advanced COPD or control lungs, and we validate findings using single-cell RNA sequencing of lungs from mice exposed to 10 months of cigarette smoke, RNA sequencing of isolated human alveolar epithelial cells, functional in vitro models, and in situ hybridization and immunostaining of human lung tissue samples. We identify a subpopulation of alveolar epithelial type II cells with transcriptional evidence for aberrant …

Langerhans Cells And Cdc1s Play Redundant Roles In Mrna-Lnp Induced Protective Anti-Influenza And Anti-Sars-Cov-2 Immune Responses, Sonia Ndeupen, Aurélie Bouteau, Christopher Herbst, Zhen Qin, Sonya Jacobsen, Nicholas E Powers, Zachary Hutchins, Drishya Kurup, Leila Zabihi Diba, Megan Watson, Holly Ramage, Botond Z. Igyártó

Department of Microbiology and Immunology Faculty Papers

Nucleoside modified mRNA combined with Acuitas Therapeutics' lipid nanoparticles (LNPs) has been shown to support robust humoral immune responses in many preclinical animal vaccine studies and later in humans with the SARS-CoV-2 vaccination. We recently showed that this platform is highly inflammatory due to the LNPs' ionizable lipid component. The inflammatory property is key to support the development of potent humoral immune responses. However, the mechanism by which this platform drives T follicular helper (Tfh) cells and humoral immune responses remains unknown. Here we show that lack of Langerhans cells or cDC1s neither significantly affected the induction of PR8 HA …

Neutralizing Interleukin-6 In Tumor-Bearing Mice Does Not Abrogate Behavioral Fatigue Induced By Lewis Lung Carcinoma, Kiersten Scott, Thien Trong Phan, A Phillip West, Cullen M Taniguchi, Robert Dantzer

Faculty, Staff and Student Publications

Tumor growth is associated with metabolic reprogramming of various organs including the liver. This metabolic reprogramming is responsible for the development of behavioral fatigue represented by decreased voluntary wheel running in a murine model of lung cancer. To determine whether interleukin (IL-)6 induced by the tumor is responsible for the metabolic reprogramming, mice injected with Lewis lung carcinoma cells in the flank were treated with an anti-mouse IL-6 monoclonal neutralizing antibody using a 2 × 2 factorial design (+/- tumor and +/- anti-IL-6 antibody). Endpoints were represented by behavioral, metabolic and immune phenotypes. Despite its ability to abrogate the increase …

Neuronal Population Activity Dynamics Reveal A Low-Dimensional Signature Of Operant Learning In Aplysia, Renan M Costa, Douglas A Baxter, John H Byrne

Faculty, Staff and Student Publications

Learning engages a high-dimensional neuronal population space spanning multiple brain regions. However, it remains unknown whether it is possible to identify a low-dimensional signature associated with operant conditioning, a ubiquitous form of learning in which animals learn from the consequences of behavior. Using single-neuron resolution voltage imaging, here we identify two low-dimensional motor modules in the neuronal population underlying Aplysia feeding. Our findings point to a temporal shift in module recruitment as the primary signature of operant learning. Our findings can help guide characterization of learning signatures in systems in which only a smaller fraction of the relevant neuronal population …

“Why Should The Fish Feel Safe? I Don’T Feel Safe!”: An Audit Of Pet Ownership Within An Nhs Service For Adults With Severe Mental Illness, With Lessons For Service Improvement, Abigail Alfrey, Steve Church, Niki Christodoulou, Emma Harding

People and Animals: The International Journal of Research and Practice

Background—Several studies have identified that pets can promote mental health, wellness, and recovery. However, little is known about the impact of pet ownership upon those with a severe mental illness (SMI), or whether mental health services are offering sufficient support that is specific to the needs of pet-owning service users. Aims—To identify the proportion of pet owners among an urban, U.K.-based community psychosis service; and to elicit service users’ views on pet ownership, to better understand and support this population’s particular needs. Method—The proportion of pet owners among this sample (n = 212) was compared with U.K. population data …

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries., Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty Research 2022

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

Common Genetic Variants Contribute To Risk Of Transposition Of The Great Arteries, Doris Škorić-Milosavljević, Rafik Tadros, Fernanda M Bosada, Federico Tessadori, Jan Hendrik Van Weerd, Odilia I Woudstra, Fleur V Y Tjong, Najim Lahrouchi, Fanny Bajolle, Heather J Cordell, A J Agopian, Gillian M Blue, Daniela Q C M Barge-Schaapveld, Marc Gewillig, Christoph Preuss, Elisabeth M Lodder, Phil Barnett, Aho Ilgun, Leander Beekman, Karel Van Duijvenboden, Regina Bokenkamp, Martina Müller-Nurasyid, Hubert W Vliegen, Thelma C Konings, Joost P Van Melle, Arie P J Van Dijk, Roland R J Van Kimmenade, Jolien W Roos-Hesselink, Gertjan T Sieswerda, Folkert Meijboom, Hashim Abdul-Khaliq, Felix Berger, Sven Dittrich, Marc-Phillip Hitz, Julia Moosmann, Frank-Thomas Riede, Stephan Schubert, Pilar Galan, Mark Lathrop, Hans M Munter, Ammar Al-Chalabi, Christopher E Shaw, Pamela J Shaw, Karen E Morrison, Jan H Veldink, Leonard H Van Den Berg, Sylvia Evans, Marcelo A Nobrega, Ivy Aneas, Milena Radivojkov-Blagojević, Thomas Meitinger, Erwin Oechslin, Tapas Mondal, Lynn Bergin, John F Smythe, Luis Altamirano-Diaz, Jane Lougheed, Berto J Bouma, Marie-A Chaix, Jennie Kline, Anne S Bassett, Gregor Andelfinger, Roel L F Van Der Palen, Patrice Bouvagnet, Sally-Ann B Clur, Jeroen Breckpot, Wilhelmina S Kerstjens-Frederikse, David S Winlaw, Ulrike M M Bauer, Seema Mital, Elizabeth Goldmuntz, Bernard Keavney, Damien Bonnet, Barbara J Mulder, Michael W T Tanck, Jeroen Bakkers, Vincent M Christoffels, Cornelis J Boogerd, Alex V Postma, Connie R Bezzina

Faculty, Staff and Student Publications

RATIONALE: Dextro-transposition of the great arteries (D-TGA) is a severe congenital heart defect which affects approximately 1 in 4,000 live births. While there are several reports of D-TGA patients with rare variants in individual genes, the majority of D-TGA cases remain genetically elusive. Familial recurrence patterns and the observation that most cases with D-TGA are sporadic suggest a polygenic inheritance for the disorder, yet this remains unexplored.

OBJECTIVE: We sought to study the role of common single nucleotide polymorphisms (SNPs) in risk for D-TGA.

METHODS AND RESULTS: We conducted a genome-wide association study in an international set of 1,237 patients …

Loss Of Irf2bpl Impairs Neuronal Maintenance Through Excess Wnt Signaling, Paul C Marcogliese, Debdeep Dutta, Shrestha Sinha Ray, Nghi D P Dang, Zhongyuan Zuo, Yuchun Wang, Di Lu, Fatima Fazal, Thomas A Ravenscroft, Hyunglok Chung, Oguz Kanca, Jijun Wan, Emilie D Douine, Undiagnosed Diseases Network, Loren D M Pena, Shinya Yamamoto, Stanley F Nelson, Matthew Might, Kathrin C Meyer, Nan Cher Yeo, Hugo J Bellen

Duncan NRI Faculty and Staff Publications

De novo truncations in Interferon Regulatory Factor 2 Binding Protein Like (IRF2BPL) lead to severe childhood-onset neurodegenerative disorders. To determine how loss of IRF2BPL causes neural dysfunction, we examined its function in Drosophila and zebrafish. Overexpression of either IRF2BPL or Pits, the Drosophila ortholog, represses Wnt transcription in flies. In contrast, neuronal depletion of Pits leads to increased wingless (wg) levels in the brain and is associated with axonal loss, whereas inhibition of Wg signaling is neuroprotective. Moreover, increased neuronal expression of wg in flies is sufficient to cause age-dependent axonal loss, similar to reduction …

Using Cryo-Et To Distinguish Platelets During Pre-Acute Myeloid Leukemia From Steady State Hematopoiesis, Yuewei Wang, Tong Huo, Yu-Jung Tseng, Lan Dang, Zhili Yu, Wenjuan Yu, Zachary Foulks, Rebecca L Murdaugh, Steven J Ludtke, Daisuke Nakada, Zhao Wang

Faculty, Staff and Students Publications

Early diagnosis of acute myeloid leukemia (AML) in the pre-leukemic stage remains a clinical challenge, as pre-leukemic patients show no symptoms, lacking any known morphological or numerical abnormalities in blood cells. Here, we demonstrate that platelets with structurally abnormal mitochondria emerge at the pre-leukemic phase of AML, preceding detectable changes in blood cell counts or detection of leukemic blasts in blood. We visualized frozen-hydrated platelets from mice at different time points during AML development in situ using electron cryo-tomography (cryo-ET) and identified intracellular organelles through an unbiased semi-automatic process followed by quantitative measurement. A large proportion of platelets exhibited changes …

Clinical Utility Of Anti-Mullerian Hormone In Pediatrics, Roopa Kanakatti Shankar, Tazim Dowlut-Mcelroy, Andrew Dauber, Veronica Gomez-Lobo

Pediatrics Faculty Publications

CONTEXT: Anti-Mullerian hormone (AMH) was originally described in the context of sexual differentiation in the male fetus but has gained prominence now as a marker of ovarian reserve and fertility in females. In this mini-review, we offer an updated synopsis on AMH and its clinical utility in pediatric patients.

DESIGN AND RESULTS: A systematic search was undertaken for studies related to the physiology of AMH, normative data, and clinical role in pediatrics. In males, AMH, secreted by Sertoli cells, is found at high levels prenatally and throughout childhood and declines with progression through puberty to overlap with levels in females. …

B Cell Receptor Isotypes Differentially Associate With Cell Signaling, Kinetics, And Outcome In Chronic Lymphocytic Leukemia, Andrea N Mazzarello, Eva Gentner-Göbel, Marcus Dühren-Von Minden, Tatyana N Tarasenko, Antonella Nicolò, Gerardo Ferrer, Stefano Vergani, Yun Liu, Davide Bagnara, Kanti R Rai, Jan A Burger, Peter J Mcguire, Palash C Maity, Hassan Jumaa, Nicholas Chiorazzi

Faculty, Staff and Student Publications

In chronic lymphocytic leukemia (CLL), the B cell receptor (BCR) plays a critical role in disease development and progression, as indicated by the therapeutic efficacy of drugs blocking BCR signaling. However, the mechanism(s) underlying BCR responsiveness are not completely defined. Selective engagement of membrane IgM or IgD on CLL cells, each coexpressed by more than 90% of cases, leads to distinct signaling events. Since both IgM and IgD carry the same antigen-binding domains, the divergent actions of the receptors are attributed to differences in immunoglobulin (Ig) structure or the outcome of signal transduction. We showed that IgM, not IgD, level …

Rspo2 And Rankl Signal Through Lgr4 To Regulate Osteoclastic Premetastatic Niche Formation And Bone Metastasis, Zhiying Yue, Xin Niu, Zengjin Yuan, Qin Qin, Wenhao Jiang, Liang He, Jingduo Gao, Yi Ding, Yanxi Liu, Ziwei Xu, Zhenxi Li, Zhengfeng Yang, Rong Li, Xiwen Xue, Yankun Gao, Fei Yue, Xiang H-F Zhang, Guohong Hu, Yi Wang, Yi Li, Geng Chen, Stefan Siwko, Alison Gartland, Ning Wang, Jianru Xiao, Mingyao Liu, Jian Luo

Faculty, Staff and Students Publications

Therapeutics targeting osteoclasts are commonly used treatments for bone metastasis; however, whether and how osteoclasts regulate premetastatic niche and bone tropism are largely unknown. In this study, we report that osteoclast precursors (OPs) can function as a premetastatic niche component that facilitates breast cancer (BCa) bone metastasis at early stages. At the molecular level, unbiased GPCR ligand/agonist screening in BCa cells suggested that R-spondin 2 (RSPO2) and RANKL, through interaction with their receptor LGR4, promoted osteoclastic premetastatic niche formation and enhanced BCa bone metastasis. This was achieved by RSPO2/RANKL-LGR4 signal modulating the WNT inhibitor DKK1 through Gαq and β-catenin signaling. …

Murine Roseolovirus Does Not Accelerate Amyloid-Β Pathology And Human Roseoloviruses Are Not Over-Represented In Alzheimer Disease Brains, Tarin M Bigley, Monica Xiong, Muhammad Ali, Yun Chen, Chao Wang, Javier Remolina Serrano, Abdallah Eteleeb, Oscar Harari, Liping Yang, Swapneel J Patel, Carlos Cruchaga, Wayne M Yokoyama, David M Holtzman

2020-Current year OA Pubs

BACKGROUND: The role of viral infection in Alzheimer Disease (AD) pathogenesis is an area of great interest in recent years. Several studies have suggested an association between the human roseoloviruses, HHV-6 and HHV-7, and AD. Amyloid-β (Aβ) plaques are a hallmark neuropathological finding of AD and were recently proposed to have an antimicrobial function in response to infection. Identifying a causative and mechanistic role of human roseoloviruses in AD has been confounded by limitations in performing in vivo studies. Recent -omics based approaches have demonstrated conflicting associations between human roseoloviruses and AD. Murine roseolovirus (MRV) is a natural murine pathogen …

Automated Sleep State Classification Of Wide-Field Calcium Imaging Data Via Multiplex Visibility Graphs And Deep Learning, Xiaohui Zhang, Eric C. Landsness, Wei Chen, Hanyang Miao, Michelle Tang, Lindsey M. Brier, Joseph P. Culver, Jin-Moo Lee, Mark A. Anastasio

2020-Current year OA Pubs

BACKGROUND: Wide-field calcium imaging (WFCI) allows for monitoring of cortex-wide neural dynamics in mice. When applied to the study of sleep, WFCI data are manually scored into the sleep states of wakefulness, non-REM (NREM) and REM by use of adjunct EEG and EMG recordings. However, this process is time-consuming and often suffers from low inter- and intra-rater reliability and invasiveness. Therefore, an automated sleep state classification method that operates on WFCI data alone is needed.

NEW METHOD: A hybrid, two-step method is proposed. In the first step, spatial-temporal WFCI data is mapped to multiplex visibility graphs (MVGs). Subsequently, a two-dimensional …

Generation And Application Of Inducible Chimeric Rna, Yichen Luo, Liang Du, Zhimeng Yao, Fan Liu, Kai Li, Feifei Li, Jianlin Zhu, Robert P Coppes, Dianzheng Zhang, Yunlong Pan, Shegan Gao, Hao Zhang

PCOM Scholarly Works

Chimeric RNAs (chiRNAs) play many previously unrecognized roles in different diseases including cancer. They can not only be used as biomarkers for diagnosis and prognosis of various diseases but also serve as potential therapeutic targets. In order to better understand the roles of chiRNAs in pathogenesis, we inserted human sequences into mouse genome and established a knockin mouse model of the tamoxifen-inducible expression of ASTN2-PAPPA antisense chimeric RNA (A-PaschiRNA). Mice carrying the A-PaschiRNA knockin gene do not display any apparent abnormalities in growth, fertility, histological, hematopoietic, and biochemical indices. Using this model, we dissected the role of …

Novel Mouse Model Of Murine Cytomegalovirus-Induced Adaptive Nk Cells, Isaac J Jensen, Matthew D Martin, Sandeep K Tripathy, Vladimir P Badovinac

2020-Current year OA Pubs

NK cells are important mediators of viral control with the capacity to form adaptive immune features following infection. However, studies of infection-induced adaptive NK cells require adoptive cell transfer to lower the precursor frequency of "Ag-specific" NK cells, potentially limiting the diversity of the NK cell response. In seeking an unmanipulated model to probe the adaptive NK cells, we interrogated a wide range of Collaborative Cross (CC) inbred mice, inbred mouse strains that exhibit broad genetic diversity across strains. Our assessment identified and validated a putative "ideal" CC strain, CC006, which does not require manipulation to generate and maintain adaptive …

Metabolic Sensing In Agrp Neurons Integrates Homeostatic State With Dopamine Signalling In The Striatum, Alex Reichenbach, Alexxai V. Kravitz, Et Al

Open Access Publications

Agouti-related peptide (AgRP) neurons increase motivation for food, however, whether metabolic sensing of homeostatic state in AgRP neurons potentiates motivation by interacting with dopamine reward systems is unexplored. As a model of impaired metabolic-sensing, we used the AgRP-specific deletion of carnitine acetyltransferase (

The Antibody Response To Sars-Cov-2 Beta Underscores The Antigenic Distance To Other Variants, Chang Liu, Rita E Chen, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Alpha-B.1.1.7, Beta-B.1.351, Gamma-P.1, and Delta-B.1.617.2 variants of SARS-CoV-2 express multiple mutations in the spike protein (S). These may alter the antigenic structure of S, causing escape from natural or vaccine-induced immunity. Beta is particularly difficult to neutralize using serum induced by early pandemic SARS-CoV-2 strains and is most antigenically separated from Delta. To understand this, we generated 674 mAbs from Beta-infected individuals and performed a detailed structure-function analysis of the 27 most potent mAbs: one binding the spike N-terminal domain (NTD), the rest the receptor-binding domain (RBD). Two of these RBD-binding mAbs recognize a neutralizing epitope conserved between SARS-CoV-1 and …

Stride-Level Analysis Of Mouse Open Field Behavior Using Deep-Learning-Based Pose Estimation., Keith Sheppard, Justin Gardin, Gautam S Sabnis, Asaf Peer, Megan Darrell, Sean P Deats, Brian Q Geuther, Cathleen Lutz, Vivek Kumar

Faculty Research 2022

Gait and posture are often perturbed in many neurological, neuromuscular, and neuropsychiatric conditions. Rodents provide a tractable model for elucidating disease mechanisms and interventions. Here, we develop a neural-network-based assay that adopts the commonly used open field apparatus for mouse gait and posture analysis. We quantitate both with high precision across 62 strains of mice. We characterize four mutants with known gait deficits and demonstrate that multiple autism spectrum disorder (ASD) models show gait and posture deficits, implying this is a general feature of ASD. Mouse gait and posture measures are highly heritable and fall into three distinct classes. We …

Cxcl10 Chemokine Regulates Heterogeneity Of The Cd8+ T Cell Response And Viral Set Point During Chronic Infection, Aleksandra J Ozga, Melvyn T Chow, Mateus E Lopes, Rachel L Servis, Mauro Di Pilato, Philippe Dehio, Jeffrey Lian, Thorsten R Mempel, Andrew D Luster

Faculty, Staff and Student Publications

CD8+ T cells responding to chronic infection adapt an altered differentiation program that provides some restrain on pathogen replication yet limits immunopathology. This adaptation is imprinted in stem-like cells and propagated to their progeny. Understanding the molecular control of CD8+ T cell differentiation in chronic infection has important therapeutic implications. Here, we found that the chemokine receptor CXCR3 was highly expressed on viral-specific stem-like CD8+ T cells and that one of its ligands, CXCL10, regulated the persistence and heterogeneity of responding CD8+ T cells in spleens of mice chronically infected with lymphocytic choriomeningitis virus. CXCL10 was produced by inflammatory monocytes …

P300 Or Cbp Is Required For Insulin-Stimulated Glucose Uptake In Skeletal Muscle And Adipocytes, Vitor F. Martins, Gretchen A. Meyer, Et Al.

2020-Current year OA Pubs

While current thinking posits that insulin signaling to glucose transporter 4 (GLUT4) exocytic translocation and glucose uptake in skeletal muscle and adipocytes is controlled by phosphorylation-based signaling, many proteins in this pathway are acetylated on lysine residues. However, the importance of acetylation and lysine acetyltransferases to insulin-stimulated glucose uptake is incompletely defined. Here, we demonstrate that combined loss of the acetyltransferases E1A binding protein p300 (p300) and cAMP response element binding protein binding protein (CBP) in mouse skeletal muscle caused a complete loss of insulin-stimulated glucose uptake. Similarly, brief (i.e., 1 hour) pharmacological inhibition of p300/CBP acetyltransferase activity recapitulated this …

Mapk4 Promotes Triple Negative Breast Cancer Growth And Reduces Tumor Sensitivity To Pi3k Blockade, Wei Wang, Dong Han, Qinbo Cai, Tao Shen, Bingning Dong, Michael T Lewis, Runsheng Wang, Yanling Meng, Wolong Zhou, Ping Yi, Chad J Creighton, David D Moore, Feng Yang

Faculty, Staff and Students Publications

About 15-20% of breast cancer (BCa) is triple-negative BCa (TNBC), a devastating disease with limited therapeutic options. Aberrations in the PI3K/PTEN signaling pathway are common in TNBC. However, the therapeutic impact of PI3K inhibitors in TNBC has been limited and the mechanism(s) underlying this lack of efficacy remain elusive. Here, we demonstrate that a large subset of TNBC expresses significant levels of MAPK4, and this expression is critical for driving AKT activation independent of PI3K and promoting TNBC cell and xenograft growth. The ability of MAPK4 to bypass PI3K for AKT activation potentially provides a direct mechanism regulating tumor sensitivity …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Emergence Of Clinical Clostridioides Difficile Isolates With Decreased Susceptibility To Vancomycin, Charles Darkoh, Kadiatou Keita, Chioma Odo, Micah Oyaro, Eric L Brown, Cesar A Arias, Blake M Hanson, Herbert L Dupont

Faculty, Staff and Student Publications

BACKGROUND: Clostridioides difficile infection (CDI) is a leading cause of hospital-associated antibiotic-related diarrhea and deaths worldwide. Vancomycin is one of the few antibiotics recommended for both nonsevere and severe CDI cases. We sought to determine whether vancomycin nonsusceptible C. difficile strains are circulating in the patient population.

METHODS: Stool samples from patients with CDI were collected from 438 and 98 patients at a large university hospital in Houston, Texas, and Nairobi, Kenya, respectively. The stools were examined for the presence of vancomycin and metronidazole nonsusceptible C. difficile using broth dilution culture, Etest (BioMérieux, France), polymerase chain reaction (PCR), whole-genome sequencing, …

Constitutively Active Sarm1 Variants That Induce Neuropathy Are Enriched In Als Patients, A Joseph Bloom, Xianrong Mao, Amy Strickland, Yo Sasaki, Jeffrey Milbrandt, Aaron Diantonio

2020-Current year OA Pubs

BACKGROUND: In response to injury, neurons activate a program of organized axon self-destruction initiated by the NAD

METHODS: To investigate whether naturally occurring human variants might disrupt SARM1 autoinhibition and potentially contribute to risk for neurodegenerative disease, we assayed the enzymatic activity of all 42 rare SARM1 alleles identified among 8507 amyotrophic lateral sclerosis (ALS) patients and 9671 controls. We then intrathecally injected mice with virus expressing SARM1 constructs to test the capacity of an ALS-associated constitutively active SARM1 variant to promote neurodegeneration in vivo.

RESULTS: Twelve out of 42 SARM1 missense variants or small in-frame deletions assayed exhibit constitutive …