Digital Commons Network^™

Arginine Depletion Attenuates Renal Cystogenesis In Tuberous Sclerosis Complex Model, Athar Amleh, Hadass Pri Chen, Lana Watad, Ifat Abramovich, Bella Agranovich, Eyal Gottlieb, Iddo Z Ben-Dov, Morris Nechama, Oded Volovelsky

Faculty, Staff and Student Publications

Cystic kidney disease is a leading cause of morbidity in patients with tuberous sclerosis complex (TSC). We characterize the misregulated metabolic pathways using cell lines, a TSC mouse model, and human kidney sections. Our study reveals a substantial perturbation in the arginine biosynthesis pathway in TSC models with overexpression of argininosuccinate synthetase 1 (ASS1). The rise in ASS1 expression is dependent on the mechanistic target of rapamycin complex 1 (mTORC1) activity. Arginine depletion prevents mTORC1 hyperactivation and cell cycle progression and averts cystogenic signaling overexpression of c-Myc and P65. Accordingly, an arginine-depleted diet substantially reduces the TSC cystic load in …

A Novel Specific Aptamer Targets Cerebrovascular Endothelial Cells After Ischemic Stroke, Heng Hu, Silin Wu, Tae Jin Lee, Aaron M Gusdon, Yuxin Liu, Huimahn A Choi, Xuefang Sophie Ren

Faculty, Staff and Student Publications

Cell specific-targeted therapy (CSTT) for acute ischemic stroke remains underdeveloped. Cerebrovascular endothelial cells (CECs) are key components of the blood-brain barrier and are the first brain cells affected by ischemic stroke. After stroke, CEC injury causes insufficient energy supply to neurons and leads to cytotoxic and vasogenic brain edema. Aptamers are short single-stranded RNA or DNA molecules that can bind to specific ligands for cell specific delivery. The expression of vascular cell adhesion molecule-1 (VCAM-1) is increased on CECs after stroke. Herein, we report that an RNA-based VCAM-1-aptamer can specifically target CECs in stroke brains following transient middle cerebral artery …

Prolylcarboxypeptidase Alleviates Hypertensive Cardiac Remodeling By Regulating Myocardial Tissue Angiotensin Ii, Binh Y Nguyen, Fangchao Zhou, Pablo Binder, Wei Liu, Susanne S Hille, Xiaojing Luo, Min Zi, Hongyuan Zhang, Antony Adamson, Fozia Z Ahmed, Sam Butterworth, Elizabeth J Cartwright, Oliver J Müller, Kaomei Guan, Elizabeth M Fitzgerald, Xin Wang

Faculty, Staff and Student Publications

Background Prolonged activation of angiotensin II is the main mediator that contributes to the development of heart diseases, so converting angiotensin II into angiotensin 1-7 has emerged as a new strategy to attenuate detrimental effects of angiotensin II. Prolylcarboxypeptidase is a lysosomal pro-X carboxypeptidase that is able to cleave angiotensin II at a preferential acidic pH optimum. However, insufficient attention has been given to the cardioprotective functions of prolylcarboxylpeptidase. Methods and Results We established a CRISPR/CRISPR-associated protein 9-mediated global prolylcarboxylpeptidase-knockout and adeno-associated virus serotype 9-mediated cardiac prolylcarboxylpeptidase overexpression mouse models, which were challenged with the angiotensin II infusion (2 mg/kg …

Striatal Dopamine Synthesis And Cognitive Flexibility Differ Between Hormonal Contraceptive Users And Nonusers, Caitlin M Taylor, Daniella J Furman, Anne S Berry, Robert L White, William J Jagust, Mark D'Esposito, Emily G Jacobs

2020-Current year OA Pubs

In rodents and nonhuman primates, sex hormones are powerful modulators of dopamine (DA) neurotransmission. Yet less is known about hormonal regulation of the DA system in the human brain. Using positron emission tomography (PET), we address this gap by comparing hormonal contraceptive users and nonusers across multiple aspects of DA function: DA synthesis capacity via the PET radioligand 6-[18F]fluoro-m-tyrosine ([18F]FMT), baseline D2/3 receptor binding potential using [11C]raclopride, and DA release using methylphenidate-paired [11C]raclopride. Participants consisted of 36 healthy women (n = 15 hormonal contraceptive users; n = 21 naturally cycling/non users of hormonal contraception), and men (n = 20) as …

Scutellaria Baicalensis Enhances 5-Fluorouracil-Based Chemotherapy Via Inhibition Of Proliferative Signaling Pathways, Haizhou Liu, Hui Liu, Zhiyi Zhou, Jessica Chung, Guojing Zhang, Jin Chang, Robert A Parise, Edward Chu, John C Schmitz

Abington Jefferson Health Papers

Fluoropyridine-based chemotherapy remains the most widely used treatment for colorectal cancer (CRC). In this study, we investigated the mechanism by which the natural product Scutellaria baicalensis (Huang Qin; HQ) and one of its main components baicalin enhanced 5-fluorouracil (5-FU) antitumor activity against CRC. Cell proliferation assays, cell cycle analysis, reverse-phase protein array (RPPA) analysis, immunoblot analysis, and qRT-PCR were performed to investigate the mechanism(s) of action of HQ and its active components on growth of CRC cells. HQ exhibited in vitro antiproliferative activity against drug resistant human CRC cells, against human and mouse CRC cells with different genetic backgrounds and …

Sox7 Deficiency Causes Ventricular Septal Defects Through Its Effects On Endocardial-To-Mesenchymal Transition And The Expression Of Wnt4 And Bmp2, Andrés Hernández-García, Katherine E Pendleton, Sangbae Kim, Yumei Li, Bum J Kim, Hitisha P Zaveri, Valerie K Jordan, Aliska M Berry, M Cecilia Ljungberg, Rui Chen, Rainer B Lanz, Daryl A Scott

Faculty, Staff and Students Publications

SOX7 is a transcription factor-encoding gene located in a region on chromosome 8p23.1 that is recurrently deleted in individuals with ventricular septal defects (VSDs). We have previously shown that Sox7-/- embryos die of heart failure around E11.5. Here, we demonstrate that these embryos have hypocellular endocardial cushions with severely reduced numbers of mesenchymal cells. Ablation of Sox7 in the endocardium also resulted in hypocellular endocardial cushions, and we observed VSDs in rare E15.5 Sox7flox/-;Tie2-Cre and Sox7flox/flox;Tie2-Cre embryos that survived to E15.5. In atrioventricular explant studies, we showed that SOX7 deficiency leads to a severe reduction in endocardial-to-mesenchymal transition (EndMT). RNA-seq …

Use Of Novel Structural Features To Identify Urinary Biomarkers During Acute Kidney Injury That Predict Progression To Chronic Kidney Disease, Jennifer R Charlton, Teng Li, Teresa Wu, Kimberly Deronde, Yanzhe Xu, Edwin J Baldelomar, Kevin M Bennett

2020-Current year OA Pubs

BACKGROUND: A significant barrier to biomarker development in the field of acute kidney injury (AKI) is the use of kidney function to identify candidates. Progress in imaging technology makes it possible to detect early structural changes prior to a decline in kidney function. Early identification of those who will advance to chronic kidney disease (CKD) would allow for the initiation of interventions to halt progression. The goal of this study was to use a structural phenotype defined by magnetic resonance imaging and histology to advance biomarker discovery during the transition from AKI to CKD.

METHODS: Urine was collected and analyzed …

Evidence-Based Guide To Using Artificial Introns For Tissue-Specific Knockout In Mice, Elena Mcbeath, Keigi Fujiwara, Marie-Claude Hofmann

Faculty, Staff and Student Publications

Up until recently, methods for generating floxed mice either conventionally or by CRISPR (Clustered Regularly Interspaced Short Palindromic Repeats)-Cas9 (CRISPR-associated protein 9) editing have been technically challenging, expensive and error-prone, or time-consuming. To circumvent these issues, several labs have started successfully using a small artificial intron to conditionally knockout (KO) a gene of interest in mice. However, many other labs are having difficulty getting the technique to work. The key problem appears to be either a failure in achieving correct splicing after the introduction of the artificial intron into the gene or, just as crucial, insufficient functional KO of the …

Identification Of A Humanized Mouse Model For Functional Testing Of Immune-Mediated Biomaterial Foreign Body Response., Joshua C Doloff, Minglin Ma, Atieh Sadraei, Hok Hei Tam, Shady Farah, Jennifer Hollister-Lock, Arturo J Vegas, Omid Veiseh, Victor M Quiroz, Amanda Rakoski, Stephanie Aresta-Dasilva, Andrew R Bader, Marissa Griffin, Gordon C Weir, Michael A Brehm, Leonard D. Shultz, Robert Langer, Dale L Greiner, Daniel G Anderson

Faculty Research 2023

Biomedical devices comprise a major component of modern medicine, however immune-mediated fibrosis and rejection can limit their function over time. Here, we describe a humanized mouse model that recapitulates fibrosis following biomaterial implantation. Cellular and cytokine responses to multiple biomaterials were evaluated across different implant sites. Human innate immune macrophages were verified as essential to biomaterial rejection in this model and were capable of cross-talk with mouse fibroblasts for collagen matrix deposition. Cytokine and cytokine receptor array analysis confirmed core signaling in the fibrotic cascade. Foreign body giant cell formation, often unobserved in mice, was also prominent. Last, high-resolution microscopy …

Dietary Sources Of Linoleic Acid (La) Differ By Race/Ethnicity In Adults Participating In The National Health And Nutrition Examination Survey (Nhanes) Between 2017-2018, Shabnam R Momin, Mackenzie K Senn, Ani Manichaikul, Chaojie Yang, Rasika Mathias, Mimi Phan, Stephen S Rich, Susan Sergeant, Michael Seeds, Lindsay Reynolds, Floyd H Chilton, Alexis C Wood

Faculty, Staff and Students Publications

Linoleic acid (LA) is a primary n-6 polyunsaturated fatty acid (PUFA), which is of interest to nutritional professionals as it has been associated with health outcomes. However, as some LA-rich foods offer protection against chronic diseases such as CVD (e.g., fatty fish), while others increase risk (e.g., red meat), the individual foods contributing to LA intake may be an important factor to consider. Therefore, this analysis sought to examine whether there are racial/ethnic differences in the proportion of overall LA intake accounted for by individual food groups, via a cross-sectional analysis of 3815 adults participating in the National Health …

Induction Of Astrocytic Slc22a3 Regulates Sensory Processing Through Histone Serotonylation, Debosmita Sardar, Yi-Ting Cheng, Junsung Woo, Dong-Joo Choi, Zhung-Fu Lee, Wookbong Kwon, Hsiao-Chi Chen, Brittney Lozzi, Alexis Cervantes, Kavitha Rajendran, Teng-Wei Huang, Antrix Jain, Benjamin R Arenkiel, Ian Maze, Benjamin Deneen

Faculty, Staff and Students Publications

Neuronal activity drives alterations in gene expression within neurons, yet how it directs transcriptional and epigenomic changes in neighboring astrocytes in functioning circuits is unknown. We found that neuronal activity induces widespread transcriptional upregulation and downregulation in astrocytes, highlighted by the identification of a neuromodulator transporter Slc22a3 as an activity-inducible astrocyte gene regulating sensory processing in the olfactory bulb. Loss of astrocytic Slc22a3 reduced serotonin (5HT) levels in astrocytes, leading to alterations in histone serotonylation. Inhibition of histone serotonylation in astrocytes reduced expression of GABA biosynthetic genes and GABA release, culminating in olfactory deficits. Our study revealed that neuronal activity …

Aging Fly Cell Atlas Identifies Exhaustive Aging Features At Cellular Resolution, Tzu-Chiao Lu, Maria Brbić, Ye-Jin Park, Tyler Jackson, Jiaye Chen, Sai Saroja Kolluru, Yanyan Qi, Nadja Sandra Katheder, Xiaoyu Tracy Cai, Seungjae Lee, Yen-Chung Chen, Niccole Auld, Chung-Yi Liang, Sophia H Ding, Doug Welsch, Samuel D'Souza, Angela Oliveira Pisco, Robert C Jones, Jure Leskovec, Eric C Lai, Hugo J Bellen, Liqun Luo, Heinrich Jasper, Stephen R Quake, Hongjie Li

Duncan NRI Faculty and Staff Publications

Aging is characterized by a decline in tissue function, but the underlying changes at cellular resolution across the organism remain unclear. Here, we present the Aging Fly Cell Atlas, a single-nucleus transcriptomic map of the whole aging Drosophila. We characterize 163 distinct cell types and perform an in-depth analysis of changes in tissue cell composition, gene expression, and cell identities. We further develop aging clock models to predict the fly age and show that ribosomal gene expression is a conserved predictive factor for age. Combining all aging features, we find unique cell type-specific aging patterns. This atlas provides a …

Targeting Energy Intake And Circadian Biology To Engage Mechanisms Of Aging In Older Adults With Obesity: Calorie Restriction And Time-Restricted Eating, Satchidananda Panda, Geraldine Maier, Dennis T Villareal

Faculty, Staff and Students Publications

With the rise in obesity across age groups, it has been a hindrance to engaging in physical activity and mobility in older adults. Daily calorie restriction (CR) up to 25% has been the cornerstone of obesity management even though the safety in older adults remains incompletely understood. Although some adults can follow CR with clinically significant weight loss and improved health metrics, CR faces 2 obstacles-many fail to adopt CR and even among those who can adopt it short term, long-term compliance can be difficult. Furthermore, there is a continuing debate about the net benefits of CR-induced weight loss in …

Strict Conservation Yet Non-Essential Nature Of Plasmid Gene Bba40 In The Lyme Disease Spirochete Borrelia Burgdorferi, Irene N Kasumba, Kit Tilly, Tao Lin, Steven J Norris, Patricia A Rosa

Faculty, Staff and Student Publications

The highly segmented genome of Borrelia burgdorferi, the tick-borne bacterium that causes Lyme disease, is composed of a linear chromosome and more than 20 co-existing endogenous plasmids. Many plasmid-borne genes are unique to B. burgdorferi and some have been shown to provide essential functions at discrete points of the infectious cycle between a tick vector and rodent host. In this study, we investigated the role of

Extracellular Rna Sensing Mediates Inflammation And Organ Injury In A Murine Model Of Polytrauma, Andrew O Suen, Fengqian Chen, Sheng Wang, Ziyi Li, Jing Zhu, Yang Yang, Olivia Conn, Kerri Lopez, Ping Cui, Laurence Wechsler, Alan Cross, Gary Fiskum, Rosemary Kozar, Peter Hu, Catriona Miller, Lin Zou, Brittney Williams, Wei Chao

Faculty, Staff and Student Publications

Severe traumatic injury leads to marked systemic inflammation and multiorgan injury. Endogenous drivers such as extracellular nucleic acid may play a role in mediating innate immune response and the downstream pathogenesis. Here, we explored the role of plasma extracellular RNA (exRNA) and its sensing mechanism in inflammation and organ injury in a murine model of polytrauma. We found that severe polytrauma—bone fracture, muscle crush injury, and bowel ischemia—induced a marked increase in plasma exRNA, systemic inflammation, and multiorgan injury in mice. Plasma RNA profiling with RNA sequencing in mice and humans revealed a dominant presence of miRNAs and marked differential …

The Insulin Receptor Regulates The Persistence Of Mechanical Nociceptive Sensitization In Flies And Mice, Yan Wang, Roger Lopez-Bellido, Xiaojiao Huo, Annemieke Kavelaars, Michael J Galko

Faculty, Staff and Student Publications

Early phase diabetes is often accompanied by pain sensitization. In Drosophila, the insulin receptor (InR) regulates the persistence of injury-induced thermal nociceptive sensitization. Whether Drosophila InR also regulates the persistence of mechanical nociceptive sensitization remains unclear. Mice with a sensory neuron deletion of the insulin receptor (Insr) show normal nociceptive baselines; however, it is uncertain whether deletion of Insr in nociceptive sensory neurons leads to persistent nociceptive hypersensitivity. In this study, we used fly and mouse nociceptive sensitization models to address these questions. In flies, InR mutants and larvae with sensory neuron-specific expression of RNAi transgenes targeting InR exhibited persistent …

Cutting Edge: Il-21 And Tissue-Specific Signals Instruct Tbet+Cd11c+ B Cell Development Following Viral Infection, Wenzhi Song, Gina M Sanchez, Daniel P Mayer, Holly N Blackburn, Irene Chernova, Richard A Flavell, Jason S Weinstein, Joe Craft

Faculty, Staff and Student Publications

Tbet+CD11c+ B cells, also known as age-associated B cells (ABCs), are pivotal contributors to humoral immunity following infection and in autoimmunity, yet their in vivo generation is incompletely understood. We used a mouse model of systemic acute lymphocytic choriomeningitis virus infection to examine the developmental requirements of ABCs that emerged in the spleen and liver. IL-21 signaling through STAT3 was indispensable for ABC development. In contrast, IFN-γ signaling through STAT1 was required for B cell activation and proliferation. Mice that underwent splenectomy or were deficient in lymphotoxin α generated hepatic ABCs despite the lack of secondary lymphoid organ contributions, suggesting …

Gonadotropin-Dependent Precocious Puberty: Single-Center Experience From Western India, Aditya Phadte, Vijaya Sarathi, Sweta Budyal, Anurag Lila, Saba Samad Memon, Manjiri Karlekar, Virendra Patil, Nalini Shah, Tushar Bandgar

Faculty, Staff and Student Publications

Objective: To describe the characteristics of gonadotropin-dependent precocious puberty (GDPP) in Indian children.

Methods: Clinical profiles of GDPP (n=78, 61 females) and premature thelarche (n=12) from a single center in Western India were retrospectively studied.

Results: Pubertal onset was earlier in boys than girls (29 vs 75 months, respec-tively; P=0.008). The basal luteinizing hormone (LH) was ≥0.3 mIU/mL, except 18% of GDPP girls. At 60 minutes after GnRHa-stimulation, all patients (except one girl) had LH ≥5 mIU/mL. The GnRHa-stimulated LH/FSH ratio was ≥0.34 at 60 minutes in girls with GDPP unlike premature thelarche. Only one girl had an allergic reaction …

Stroke Survivors' Telemedicine Experiences During The Covid-19 Pandemic: A Phenomenological Investigation, Irene N Kasumba, Kit Tilly, Tao Lin, Steven J Norris, Patricia A Rosa

Faculty, Staff and Student Publications

The highly segmented genome of Borrelia burgdorferi, the tick-borne bacterium that causes Lyme disease, is composed of a linear chromosome and more than 20 co-existing endogenous plasmids. Many plasmid-borne genes are unique to B. burgdorferi and some have been shown to provide essential functions at discrete points of the infectious cycle between a tick vector and rodent host. In this study, we investigated the role of bba40, a highly conserved and differentially expressed gene on a ubiquitous linear plasmid of B. burgdorferi. In a prior genome-wide analysis, inactivation of bba40 by transposon insertion was linked with a …

Hematopoietic Progenitor Kinase 1 Inhibits The Development And Progression Of Pancreatic Intraepithelial Neoplasia, Hua Wang, Rohan Moniruzzaman, Lei Li, Baoan Ji, Yi Liu, Xiangsheng Zuo, Reza Abbasgholizadeh, Jun Zhao, Guangchao Liu, Ruiqi Wang, Hongli Tang, Ryan Sun, Xiaoping Su, Tse-Hua Tan, Anirban Maitra, Huamin Wang

Faculty, Staff and Student Publications

Ras plays an essential role in the development of acinar-to-ductal metaplasia (ADM) and pancreatic ductal adenocarcinoma (PDAC). However, mutant Kras is an inefficient driver for PDAC development. The mechanisms of the switching from low Ras activity to high Ras activity that are required for development and progression of pancreatic intraepithelial neoplasias (PanINs) are unclear. In this study, we found that hematopoietic progenitor kinase 1 (HPK1) was upregulated during pancreatic injury and ADM. HPK1 interacted with the SH3 domain and phosphorylated Ras GTPase-activating protein (RasGAP) and upregulated RasGAP activity. Using transgenic mouse models of HPK1 or M46, a kinase-dead mutant of …

Microbiome Alterations Driven By Trypanosoma Cruzi Infection In Two Disjunctive Murine Models, Sergio Castañeda, Marina Muñoz, Peter J Hotez, Maria Elena Bottazzi, Alberto E Paniz-Mondolfi, Kathryn M Jones, Rojelio Mejia, Cristina Poveda, Juan David Ramírez

Faculty, Staff and Students Publications

Alterations caused by Trypanosoma cruzi in the composition of gut microbiome may play a vital role in the host-parasite interactions that shapes physiology and immune responses against infection. Thus, a better understanding of this parasite-host-microbiome interaction may yield relevant information in the comprehension of the pathophysiology of the disease and the development of new prophylactic and therapeutic alternatives. Therefore, we implemented a murine model with two mice strains (BALB/c and C57BL/6) to evaluate the impact of Trypanosoma cruzi (Tulahuen strain) infection on the gut microbiome utilizing cytokine profiling and shotgun metagenomics. Higher parasite burdens were observed in cardiac and intestinal …

Complement C3ar Depletion Reverses Hif-1Α-Induced Metabolic Impairment And Enhances Microglial Response To Aβ Pathology, Manasee Gedam, Michele M Comerota, Nicholas E Propson, Tao Chen, Feng Jin, Meng C Wang, Hui Zheng

Faculty, Staff and Students Publications

Microglia are the major cell type expressing complement C3a receptor (C3aR) in the brain. Using a knockin mouse line in which a Td-tomato reporter is incorporated into the endogenous C3ar1 locus, we identified 2 major subpopulations of microglia with differential C3aR expression. Expressing the Td-tomato reporter on the APPNL-G-F-knockin (APP-KI) background revealed a significant shift of microglia to a high-C3aR-expressing subpopulation and they were enriched around amyloid β (Aβ) plaques. Transcriptomic analysis of C3aR-positive microglia documented dysfunctional metabolic signatures, including upregulation of hypoxia-inducible factor 1 (HIF-1) signaling and abnormal lipid metabolism in APP-KI mice compared with wild-type controls. Using primary …

Gene Therapy Ameliorates Spontaneous Seizures Associated With Cortical Neuron Loss In A Cln2r207x Mouse Model, Keigo Takahashi, Elizabeth M. Eultgen, Sophie H. Wang, Nicholas R. Rensing, Hemanth R. Nelvagal, Joshua T. Dearborn, Olivier Danos, Nicholas Buss, Mark S. Sands, Michael Wong, Jonathan D. Cooper

2020-Current year OA Pubs

Although a disease-modifying therapy for classic late infantile neuronal ceroid lipofuscinosis (CLN2 disease) exists, poor understanding of cellular pathophysiology has hampered the development of more effective and persistent therapies. Here, we investigated the nature and progression of neurological and underlying neuropathological changes in Cln2R207X mice, which carry one of the most common pathogenic mutations in human patients but are yet to be fully characterized. Long-term electroencephalography recordings revealed progressive epileptiform abnormalities, including spontaneous seizures, providing a robust, quantifiable, and clinically relevant phenotype. These seizures were accompanied by the loss of multiple cortical neuron populations, including those stained for interneuron markers. …

Poly(Adp-Ribose) Polymerase 9 Mediates Early Protection Against Mycobacterium Tuberculosis Infection By Regulating Type I Ifn Production, Shyamala Thirunavukkarasu, Mushtaq Ahmed, Bruce A. Rosa, Mark Boothby, Sung Hoon Cho, Javier Rangel-Moreno, Stanley K. Mbandi, Valérie Schreiber, Ananya Gupta, Joaquin Zuniga, Makedonka Mitreva, Deepak Kaushal, Thomas J. Scriba, Shabaana A. Khader

2020-Current year OA Pubs

The ADP ribosyltransferases (PARPs 1-17) regulate diverse cellular processes, including DNA damage repair. PARPs are classified on the basis of their ability to catalyze poly-ADP-ribosylation (PARylation) or mono-ADP-ribosylation (MARylation). Although PARP9 mRNA expression is significantly increased in progressive tuberculosis (TB) in humans, its participation in host immunity to TB is unknown. Here, we show that PARP9 mRNA encoding the MARylating PARP9 enzyme was upregulated during TB in humans and mice and provide evidence of a critical modulatory role for PARP9 in DNA damage, cyclic GMP-AMP synthase (cGAS) expression, and type I IFN production during TB. Thus, Parp9-deficient mice were susceptible …

Snx3 Is Important For Mammalian Neural Tube Closure Via Its Role In Canonical And Non-Canonical Wnt Signaling, Lei Dong, Mengchuan Xu, Yang Li, Wanting Xu, Chengwei Wu, Hanfei Zheng, Zhenyu Xiao, Guochen Sun, Lei Ding, Xiaobo Li, Wenming Li, Liying Zhou, Qin Xia

Faculty, Staff and Student Publications

Cancer cells consistently utilize the unfolded protein response (UPR) to encounter the abnormal endoplasmic reticulum (ER) stress induced by the accumulation of misfolded proteins. Extreme activation of the UPR could also provoke maladaptive cell death. Previous reports have shown that NRF2 antioxidant signaling is activated by UPR and serves as noncanonical pathway to defense and reduce excessive ROS levels during ER stress. However, the mechanisms of regulating NRF2 signaling upon ER stress in glioblastoma have not been fully elucidated. Here we identify that SMURF1 protects against ER stress and facilitates glioblastoma cell survival by rewiring KEAP1-NRF2 pathway. We show that …

Dynamic Contrast Enhanced (Dce) Mri Estimation Of Vascular Parameters Using Knowledge-Based Adaptive Models, Hassan Bagher-Ebadian, Stephen L. Brown, Mohammad M. Ghassemi, Tavarekere N. Nagaraja, Olivia G. Valadie, Prabhu C. Acharya, Glauber Cabral, George Divine, Robert A. Knight, Ian Y. Lee, Jun Xu, Benjamin Movsas, Indrin J. Chetty, James R. Ewing

Radiation Oncology Articles

We introduce and validate four adaptive models (AMs) to perform a physiologically based Nested-Model-Selection (NMS) estimation of such microvascular parameters as forward volumetric transfer constant, K(trans), plasma volume fraction, v(p), and extravascular, extracellular space, v(e), directly from Dynamic Contrast-Enhanced (DCE) MRI raw information without the need for an Arterial-Input Function (AIF). In sixty-six immune-compromised-RNU rats implanted with human U-251 cancer cells, DCE-MRI studies estimated pharmacokinetic (PK) parameters using a group-averaged radiological AIF and an extended Patlak-based NMS paradigm. One-hundred-ninety features extracted from raw DCE-MRI information were used to construct and validate (nested-cross-validation, NCV) four AMs for estimation of model-based regions …

Shank2 Identifies A Subset Of Glycinergic Neurons Involved In Altered Nociception In An Autism Model, Florian Olde Heuvel, Sanjay Jain, Et Al.

2020-Current year OA Pubs

BACKGROUND: Autism Spectrum Disorders (ASD) patients experience disturbed nociception in the form of either hyposensitivity to pain or allodynia. A substantial amount of processing of somatosensory and nociceptive stimulus takes place in the dorsal spinal cord. However, many of these circuits are not very well understood in the context of nociceptive processing in ASD.

METHODS: We have used a Shank2

RESULTS: We determined that Shank2

LIMITATIONS: Our investigation is limited to male mice, in agreement with the higher representation of ASD in males; therefore, caution should be applied to extrapolate the findings to females. Furthermore, ASD is characterized by extensive …

Apoe4, Age, And Sex Regulate Respiratory Plasticity Elicited By Acute Intermittent Hypercapnic-Hypoxia, Jayakrishnan Nair, Joseph F. Welch, Alexandria B. Marciante, Tingting Hou, Qing Lu, Emily J. Fox, Gordon S. Mitchell

Department of Physical Therapy Faculty Papers

Rational

Acute intermittent hypoxia (AIH) shows promise for enhancing motor recovery in chronic spinal cord injuries and neurodegenerative diseases. However, human trials of AIH have reported significant variability in individual responses.

Objectives

Identify individual factors (eg, genetics, age, and sex) that determine response magnitude of healthy adults to an optimized AIH protocol, acute intermittent hypercapnic-hypoxia (AIHH).

Methods

In 17 healthy individuals (age = 27 ± 5 yr), associations between individual factors and changes in the magnitude of AIHH (15, 1-min O2 = 9.5%, CO2 = 5% episodes) induced changes in diaphragm motor-evoked potential (MEP) amplitude and inspiratory mouth occlusion pressures …

Antitumor Efficacy Of Dual Blockade With Encorafenib + Cetuximab In Combination With Chemotherapy In Human Brafv600e-Mutant Colorectal Cancer, Stefania Napolitano, Melanie Woods, Hey Min Lee, Vincenzo De Falco, Giulia Martini, Carminia Maria Della Corte, Erika Martinelli, Vincenzo Famiglietti, Davide Ciardiello, Amanda Anderson, Natalie Wall Fowlkes, Oscar Eduardo Villareal, Alexey Sorokin, Preeti Kanikarla, Olu Coker, Van Morris, Lucia Altucci, Josep Tabernero, Teresa Troiani, Fortunato Ciardiello, Scott Kopetz

Faculty, Staff and Student Publications

PURPOSE: Encorafenib + cetuximab (E+C) is an effective therapeutic option in chemorefractory BRAFV600E metastatic colorectal cancer (mCRC). However, there is a need to improve the efficacy of this molecular-targeted therapy and evaluate regimens suitable for untreated BRAFV600E in patients with mCRC.

EXPERIMENTAL DESIGN: We performed a series of in vivo studies using BRAFV600E mCRC tumor xenografts. Mice were randomized to receive 5-fluoruracil (5-FU), irinotecan, or oxaliplatin regimens (FOLFIRI or FOLFOX), (E+C) or the combination. Patients received long-term treatment until disease progression, with deescalation strategies used to mimic maintenance therapy. Transcriptomic changes after progression on cytotoxic chemotherapy or targeted therapy were …

Ngr1 Binding To Reovirus Reveals An Unusual Bivalent Interaction And A New Viral Attachment Protein, Danica M Sutherland, Michael Strebl, Melanie Koehler, Olivia L Welsh, Xinzhe Yu, Liya Hu, Rita Dos Santos Natividade, Jonathan J Knowlton, Gwen M Taylor, Rodolfo A Moreno, Patrick Wörz, Zachery R Lonergan, Pavithra Aravamudhan, Camila Guzman-Cardozo, Sukhleen Kour, Udai Bhan Pandey, David Alsteens, Zhao Wang, B V Venkataram Prasad, Thilo Stehle, Terence S Dermody

Faculty, Staff and Students Publications

Nogo-66 receptor 1 (NgR1) binds a variety of structurally dissimilar ligands in the adult central nervous system to inhibit axon extension. Disruption of ligand binding to NgR1 and subsequent signaling can improve neuron outgrowth, making NgR1 an important therapeutic target for diverse neurological conditions such as spinal crush injuries and Alzheimer's disease. Human NgR1 serves as a receptor for mammalian orthoreovirus (reovirus), but the mechanism of virus-receptor engagement is unknown. To elucidate how NgR1 mediates cell binding and entry of reovirus, we defined the affinity of interaction between virus and receptor, determined the structure of the virus-receptor complex, and identified …