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Nutrient Supplementation During The Prenatal Period In Substance-Using Mothers: A Narrative Review Of The Effects On Offspring Development., Catherine Serwatka, Adrianne K. Griebel-Thompson, Rina D. Eiden, Kai Ling Kong

Manuscripts, Articles, Book Chapters and Other Papers

Substance use during pregnancy increases the risk for poor developmental outcomes of the offspring, and for substance-dependent mothers, abstaining from substance use during pregnancy is often difficult. Given the addictive nature of many substances, strategies that may mitigate the harmful effects of prenatal substance exposure are important. Prenatal nutrient supplementation is an emerging intervention that may improve developmental outcomes among substance-exposed offspring. We provide a narrative review of the literature on micronutrient and fatty acid supplementation during pregnancies exposed to substance use in relation to offspring developmental outcomes. We first discuss animal models exposed to ethanol during pregnancy with supplementation …

Microrna-145 And Microrna-486 Are Potential Serum Biomarkers For Vascular Calcification, Sara Fernández-Villabrille, Beatriz Martín-Carro, Julia Martín-Vírgala, Cristina Alonso-Montes, Carmen Palomo-Antequera, Raúl García-Castro, Susana López-Ongil, Adriana S Dusso, José Luis Fernández-Martín, Manuel Naves-Díaz, Jorge B Cannata-Andía, Natalia Carrillo-López, Sara Panizo

2020-Current year OA Pubs

INTRODUCTION: MicroRNAs (miRs) regulate vascular calcification (VC), and their quantification may contribute to suspicion of the presence of VC.

METHODS: The study was performed in four phases. Phase 1: miRs sequencing of rat calcified and non-calcified aortas. Phase 2: miRs with the highest rate of change, plus miR-145 [the most abundant miR in vascular smooth muscle cells (VSMCs)], were validated in aortas and serum from rats with and without VC. Phase 3: the selected miRs were analyzed in epigastric arteries from kidney donors and recipients, and serum samples from general population. Phase 4: VSMCs were exposed to different phosphorus concentrations, …

Atoh1 Drives The Heterogeneity Of The Pontine Nuclei Neurons And Promotes Their Differentiation, Sih-Rong Wu, Jessica C Butts, Matthew S Caudill, Jean-Pierre Revelli, Ryan S Dhindsa, Mark A Durham, Huda Y Zoghbi

Faculty, Staff and Students Publications

Pontine nuclei (PN) neurons mediate the communication between the cerebral cortex andthe cerebellum to refine skilled motor functions. Prior studies showed that PN neurons fall into two subtypes based on their anatomic location and region-specific connectivity, but the extent of their heterogeneity and its molecular drivers remain unknown. Atoh1 encodes a transcription factor that is expressed in the PN precursors. We previously showed that partial loss of Atoh1 function in mice results in delayed PN development and impaired motor learning. In this study, we performed single-cell RNA sequencing to elucidate the cell state–specific functions of Atoh1 during PN development and …

Cortex-Wide Neural Dynamics Predict Behavioral States And Provide A Neural Basis For Resting-State Dynamic Functional Connectivity, Somayeh Shahsavarani, David N Thibodeaux, Weihao Xu, Sharon H Kim, Fatema Lodgher, Chinwendu Nwokeabia, Morgan Cambareri, Alexis J Yagielski, Hanzhi T Zhao, Daniel A Handwerker, Javier Gonzalez-Castillo, Peter A Bandettini, Elizabeth M C Hillman

Faculty, Staff and Student Publications

Although resting-state functional magnetic resonance imaging (fMRI) studies have observed dynamically changing brain-wide networks of correlated activity, fMRI's dependence on hemodynamic signals makes results challenging to interpret. Meanwhile, emerging techniques for real-time recording of large populations of neurons have revealed compelling fluctuations in neuronal activity across the brain that are obscured by traditional trial averaging. To reconcile these observations, we use wide-field optical mapping to simultaneously record pan-cortical neuronal and hemodynamic activity in awake, spontaneously behaving mice. Some components of observed neuronal activity clearly represent sensory and motor function. However, particularly during quiet rest, strongly fluctuating patterns of activity across …

Spatial Single-Cell Sequencing Of Meiosis I Arrested Oocytes Indicates Acquisition Of Maternal Transcripts From The Soma, Kenneth A Trimmer, Peisen Zhao, Jacob Seemann, Shin-Yu Chen, Sudip Mondal, Adela Ben-Yakar, Swathi Arur

Faculty, Staff and Student Publications

Maternal RNAs are stored from minutes to decades in oocytes throughout meiosis I arrest in a transcriptionally quiescent state. Recent reports, however, propose a role for nascent transcription in arrested oocytes. Whether arrested oocytes launch nascent transcription in response to environmental or hormonal signals while maintaining the meiosis I arrest remains undetermined. We test this by integrating single-cell RNA sequencing, RNA velocity, and RNA fluorescence in situ hybridization on C. elegans meiosis I arrested oocytes. We identify transcripts that increase as the arrested meiosis I oocyte ages, but rule out extracellular signaling through ERK MAPK and nascent transcription as a …

Evaluation Of The Orally Bioavailable 4-Phenylbutyrate-Tethered Trichostatin A Analogue Ar42 In Models Of Spinal Muscular Atrophy, Casey J. Lumpkin, Ashlee W. Harris, Andrew J. Connell, Ryan W. Kirk, Joshua A. Whiting, Luciano Saieva, Livio Pellizzoni, Arthur H.M. Burghes, Matthew E.R. Butchbach

Department of Pediatrics Faculty Papers

Proximal spinal muscular atrophy (SMA) is a leading genetic cause for infant death in the world and results from the selective loss of motor neurons in the spinal cord. SMA is a consequence of low levels of SMN protein and small molecules that can increase SMN expression are of considerable interest as potential therapeutics. Previous studies have shown that both 4-phenylbutyrate (4PBA) and trichostatin A (TSA) increase SMN expression in dermal fibroblasts derived from SMA patients. AR42 is a 4PBA-tethered TSA derivative that is a very potent histone deacetylase inhibitor. SMA patient fibroblasts were treated with either AR42, AR19 (a …

Transcriptome- And Proteome-Wide Association Studies Nominate Determinants Of Kidney Function And Damage, Pascal Schlosser, Jingning Zhang, Hongbo Liu, Aditya L Surapaneni, Eugene P Rhee, Dan E Arking, Bing Yu, Eric Boerwinkle, Paul A Welling, Nilanjan Chatterjee, Katalin Susztak, Josef Coresh, Morgan E Grams

Faculty, Staff and Student Publications

BACKGROUND: The pathophysiological causes of kidney disease are not fully understood. Here we show that the integration of genome-wide genetic, transcriptomic, and proteomic association studies can nominate causal determinants of kidney function and damage.

RESULTS: Through transcriptome-wide association studies (TWAS) in kidney cortex, kidney tubule, liver, and whole blood and proteome-wide association studies (PWAS) in plasma, we assess for effects of 12,893 genes and 1342 proteins on kidney filtration (glomerular filtration rate (GFR) estimated by creatinine; GFR estimated by cystatin C; and blood urea nitrogen) and kidney damage (albuminuria). We find 1561 associations distributed among 260 genomic regions that are …

Detrimental Effects Of Pcsk9 Loss-Of-Function In The Pediatric Host Response To Sepsis Are Mediated Through Independent Influence On Angiopoietin-1., Mihir R. Atreya, Natalie Z. Cvijanovich, Julie C. Fitzgerald, Scott L. Weiss, Michael T. Bigham, Parag N. Jain, Adam J. Schwarz, Riad Lutfi, Jeffrey Nowak, Geoffrey L. Allen, Neal J. Thomas, Jocelyn R. Grunwell, Torrey Baines, Michael Quasney, Bereketeab Haileselassie, Matthew N. Alder, Patrick Lahni, Scarlett Ripberger, Adesuwa Ekunwe, Kyle R. Campbell, Keith R. Walley, Stephen W. Standage

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Sepsis is associated with significant mortality. Yet, there are no efficacious therapies beyond antibiotics. PCSK9 loss-of-function (LOF) and inhibition, through enhanced low-density lipoprotein receptor (LDLR) mediated endotoxin clearance, holds promise as a potential therapeutic approach among adults. In contrast, we have previously demonstrated higher mortality in the juvenile host. Given the potential pleiotropic effects of PCSK9 on the endothelium, beyond canonical effects on serum lipoproteins, both of which may influence sepsis outcomes, we sought to test the influence of PCSK9 LOF genotype on endothelial dysfunction.

METHODS: Secondary analyses of a prospective observational cohort of pediatric septic shock. Genetic variants …

Dual Functions Of Tet1 In Germ Layer Lineage Bifurcation Distinguished By Genomic Context And Dependence On 5-Methylcytosine Oxidation, Bernard K Van Der Veer, Lehua Chen, Colin Custers, Paraskevi Athanasouli, Mariana Schroiff, Riet Cornelis, Jonathan Sai-Hong Chui, Richard H Finnell, Frederic Lluis, Kian Peng Koh

Faculty, Staff and Students Publications

Gastrulation begins when the epiblast forms the primitive streak or becomes definitive ectoderm. During this lineage bifurcation, the DNA dioxygenase TET1 has bipartite functions in transcriptional activation and repression, but the mechanisms remain unclear. By converting mouse embryonic stem cells (ESCs) into neuroprogenitors, we defined how Tet1-/- cells switch from neuroectoderm fate to form mesoderm and endoderm. We identified the Wnt repressor Tcf7l1 as a TET1 target that suppresses Wnt/β-catenin and Nodal signalling. ESCs expressing catalytic dead TET1 retain neural potential but activate Nodal and subsequently Wnt/β-catenin pathways to generate also mesoderm and endoderm. At CpG-poor distal enhancers, TET1 maintains …

Defining Diurnal Fluctuations In Mouse Choroid Plexus And Csf At High Molecular, Spatial, And Temporal Resolution, Ryann M Fame, Yong Zhang, Michael J Holtzman, Et Al.

2020-Current year OA Pubs

Transmission and secretion of signals via the choroid plexus (ChP) brain barrier can modulate brain states via regulation of cerebrospinal fluid (CSF) composition. Here, we developed a platform to analyze diurnal variations in male mouse ChP and CSF. Ribosome profiling of ChP epithelial cells revealed diurnal translatome differences in metabolic machinery, secreted proteins, and barrier components. Using ChP and CSF metabolomics and blood-CSF barrier analyses, we observed diurnal changes in metabolites and cellular junctions. We then focused on transthyretin (TTR), a diurnally regulated thyroid hormone chaperone secreted by the ChP. Diurnal variation in ChP TTR depended on Bmal1 clock gene …

Continuous Positive Airway Pressure Increases Csf Flow And Glymphatic Transport, Burhan Ozturk, Sunil Koundal, Ehab Al Bizri, Xinan Chen, Zachary Gursky, Feng Dai, Andrew Lim, Paul Heerdt, Jonathan Kipnis, Allen Tannenbaum, Hedok Lee, Helene Benveniste

2020-Current year OA Pubs

Respiration can positively influence cerebrospinal fluid (CSF) flow in the brain, yet its effects on central nervous system (CNS) fluid homeostasis, including waste clearance function via glymphatic and meningeal lymphatic systems, remain unclear. Here, we investigated the effect of supporting respiratory function via continuous positive airway pressure (CPAP) on glymphatic-lymphatic function in spontaneously breathing anesthetized rodents. To do this, we used a systems approach combining engineering, MRI, computational fluid dynamics analysis, and physiological testing. We first designed a nasal CPAP device for use in the rat and demonstrated that it functioned similarly to clinical devices, as evidenced by its ability …

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 …

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 …

Il-11 Induces Nlrp3 Inflammasome Activation In Monocytes And Inflammatory Cell Migration To The Central Nervous System, Maryamsadat Seyedsadr, Yan Wang, Manal Elzoheiry, Sowmya Shree Gopal, Soohwa Jang, Gayel Duran, Inna Chervoneva, Ezgi Kasimoglu, John A. Wrobel, Daniel Hwang, James Garifallou, Xin Zhang, Tabish H. Khan, Ulrike Lorenz, Maureen Su, Jenny P. Ting, Bieke Broux, A M Rostami, Dhanashri Miskin, Silva Markovic-Plese

Department of Neurology Faculty Papers

The objective of this study is to examine IL-11-induced mechanisms of inflammatory cell migration to the central nervous system (CNS). We report that IL-11 is produced at highest frequency by myeloid cells among the peripheral blood mononuclear cell (PBMC) subsets. Patients with relapsing-remitting multiple sclerosis (RRMS) have an increased frequency of IL-11+ monocytes, IL-11+ and IL-11R+ CD4+ lymphocytes, and IL-11R+ neutrophils in comparison to matched healthy controls. IL-11+ and granulocyte-macrophage colony-stimulating factor (GM-CSF)+ monocytes, CD4+ lymphocytes, and neutrophils accumulate in the cerebrospinal fluid (CSF). The effect of IL-11 in-vitro stimulation, examined using single-cell RNA sequencing, revealed the highest number of …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

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 …

Embryonic Vitamin D Deficiency Programs Hematopoietic Stem Cells To Induce Type 2 Diabetes, Jisu Oh, Amy E Riek, Kevin T Bauerle, Adriana Dusso, Kyle P Mcnerney, Ruteja A Barve, Isra Darwech, Jennifer E Sprague, Clare Moynihan, Rong M Zhang, Greta Kutz, Ting Wang, Xiaoyun Xing, Daofeng Li, Marguerite Mrad, Nicholas M Wigge, Esmeralda Castelblanco, Monika Bambouskova, Richard D Head, Mark S Sands, Carlos Bernal-Mizrachi, Et Al.

2020-Current year OA Pubs

Environmental factors may alter the fetal genome to cause metabolic diseases. It is unknown whether embryonic immune cell programming impacts the risk of type 2 diabetes in later life. We demonstrate that transplantation of fetal hematopoietic stem cells (HSCs) made vitamin D deficient in utero induce diabetes in vitamin D-sufficient mice. Vitamin D deficiency epigenetically suppresses Jarid2 expression and activates the Mef2/PGC1a pathway in HSCs, which persists in recipient bone marrow, resulting in adipose macrophage infiltration. These macrophages secrete miR106-5p, which promotes adipose insulin resistance by repressing PIK3 catalytic and regulatory subunits and down-regulating AKT signaling. Vitamin D-deficient monocytes from …

Examining Parent-Of-Origin Effects On Transcription And Rna Methylation In Mediating Aggressive Behavior In Honey Bees (Apis Mellifera), Sean T. Bresnahan, Ellen Lee, Lindsay Clark, Rong Ma, Michael P. Markey, Juliana Rangel, Christina M. Grozinger, Hongmei Li-Byarlay

Biochemistry and Molecular Biology Faculty Publications

Conflict between genes inherited from the mother (matrigenes) and the father (patrigenes) is predicted to arise during social interactions among offspring if these genes are not evenly distributed among offspring genotypes. This intragenomic conflict drives parent-specific transcription patterns in offspring resulting from parent-specific epigenetic modifications. Previous tests of the kinship theory of intragenomic conflict in honey bees (Apis mellifera) provided evidence in support of theoretical predictions for variation in worker reproduction, which is associated with extreme variation in morphology and behavior. However, more subtle behaviors – such as aggression – have not been extensively studied. Additionally, the canonical epigenetic mark …

Whole Genome Analysis For 163 Grnas In Cas9-Edited Mice Reveals Minimal Off-Target Activity., Kevin A Peterson, Sam Khalouei, Nour Hanafi, Joshua A Wood, Denise G Lanza, Lauri G Lintott, Brandon J Willis, John R Seavitt, Robert E Braun, Mary E Dickinson, Jacqueline K White, K C Kent Lloyd, Jason D Heaney, Stephen A Murray, Arun Ramani, Lauryl M J Nutter

Faculty Research 2023

Genome editing with CRISPR-associated (Cas) proteins holds exceptional promise for "correcting" variants causing genetic disease. To realize this promise, off-target genomic changes cannot occur during the editing process. Here, we use whole genome sequencing to compare the genomes of 50 Cas9-edited founder mice to 28 untreated control mice to assess the occurrence of S. pyogenes Cas9-induced off-target mutagenesis. Computational analysis of whole-genome sequencing data detects 26 unique sequence variants at 23 predicted off-target sites for 18/163 guides used. While computationally detected variants are identified in 30% (15/50) of Cas9 gene-edited founder animals, only 38% (10/26) of the variants in 8/15 …