Pediatrics Commons^™

The Economic Case For Hospital Discharge Services For People Experiencing Homelessness In England: An In-Depth Analysis With Different Service Configurations Providing Specialist Care, Joshua X Samuels, Jonathan J-M Calede, Robert M Hunt

Faculty, Staff and Student Publications

Dipodomyine heteromyids (kangaroo rats and mice) are a diverse group of arid-adapted ricochetal rodents of North America. Here, a new genus and species of a large dipodomyine is reported from early Miocene-aged deposits of the John Day Formation in Oregon that represents the earliest record of the subfamily. The taxon is known from a single specimen consisting of a nearly complete skull, dentary, partial pes, and caudal vertebra. The specimen is characterized by a mosaic of ancestral and highly derived cranial features of heteromyids. Specifically, the dental morphology and some cranial characteristics are similar to early heteromyids, but other aspects …

Spatial Analysis Of Nanoparticle Distribution In Human Breast Xenografts Reveals Nanoparticles Targeted To Cancer Cells Localized With Tumor-Associated Stromal Cells, Sean Healy, Elizabeth T Henderson, Suqi Ke, Jacqueline Kelly, Brian W Simons, Chen Hu, Robert Ivkov, Preethi Korangath

Faculty, Staff and Students Publications

The biological influence of physicochemical parameters of “targeted” nanoparticles on their delivery to cancer tumors remains poorly understood. A comparative analysis of nanoparticle distributions in tumors following systemic delivery across several models can provide valuable insights.

Methods: Bionized nanoferrite nanoparticles (iron oxide core coated with starch), either conjugated with a targeted anti-HER2 antibody (BH), or unconjugated (BP), were intravenously injected into athymic nude or NOD-scid gamma (NSG) female mice bearing one of five human breast cancer tumor xenografts growing in a mammary fat pad. Tumors were harvested 24 hours after nanoparticle injection, fixed, mounted, and stained. We performed detailed histopathology …

Forniceal Deep Brain Stimulation In A Mouse Model Of Rett Syndrome Increases Neurogenesis And Hippocampal Memory Beyond The Treatment Period, Qi Wang, Bin Tang, Shuang Hao, Zhenyu Wu, Tingting Yang, Jianrong Tang

Faculty, Staff and Students Publications

BACKGROUND: Rett syndrome (RTT), caused by mutations in the X-linked gene encoding methyl-CpG binding protein 2 (MeCP2), severely impairs learning and memory. We previously showed that forniceal deep brain stimulation (DBS) stimulates hippocampal neurogenesis with concomitant improvements in hippocampal-dependent learning and memory in a mouse model of RTT.

OBJECTIVES: To determine the duration of DBS benefits; characterize DBS effects on hippocampal neurogenesis; and determine whether DBS influences MECP2 genotype and survival of newborn dentate granular cells (DGCs) in RTT mice.

METHODS: Chronic DBS was delivered through an electrode implanted in the fimbria-fornix. We tested separate cohorts of mice in contextual …

Vaccine-Linked Chemotherapy Improves Cardiac Structure And Function In A Mouse Model Of Chronic Chagas Disease, Kathryn M Jones, Elise N Mangin, Corey L Reynolds, Liliana E Villanueva, Julio Vladimir Cruz, Leroy Versteeg, Brian Keegan, April Kendricks, Jeroen Pollet, Fabian Gusovsky, Maria Elena Bottazzi, Peter J Hotez

Faculty, Staff and Students Publications

INTRODUCTION: Chagas disease, caused by chronic infection with the protozoan parasite Trypanosoma cruzi, affects 6-7 million people worldwide. The major clinical manifestation of Chagas disease is chronic Chagasic cardiomyopathy (CCC), which encompasses a spectrum of symptoms including arrhythmias, hypertrophy, dilated cardiomyopathy, heart failure, and sudden death. Current treatment is limited to two antiparasitic drugs, benznidazole (BNZ) and nifurtimox, but both have limited efficacy to halt the progression of CCC. We developed a vaccine-linked chemotherapy strategy using our vaccine consisting of recombinant Tc24-C4 protein and a TLR-4 agonist adjuvant in a stable squalene emulsion, in combination with low dose benznidazole treatment. …

Analysis Of Variable Major Protein Antigenic Variation In The Relapsing Fever Spirochete, Borrelia Miyamotoi, In Response To Polyclonal Antibody Selection Pressure, Robert D Gilmore, Brittany A Armstrong, Kevin S Brandt, Taylor J Van Gundy, Andrias Hojgaard, Job E Lopez, Alexander R Kneubehl

Faculty, Staff and Students Publications

Borrelia miyamotoi is a tick-transmitted spirochete that is genetically grouped with relapsing fever Borrelia and possesses multiple archived pseudogenes that encode variable major proteins (Vmps). Vmps are divided into two groups based on molecular size; variable large proteins (Vlps) and variable small proteins (Vsps). Relapsing fever Borrelia undergo Vmp gene conversion at a single expression locus to generate new serotypes by antigenic switching which is the basis for immune evasion that causes relapsing fever in patients. This study focused on B. miyamotoi vmp expression when spirochetes were subjected to antibody killing selection pressure. We incubated a low passage parent …

Evaluation Of Murine Host Sex As A Biological Variable In Transplanted Human Intestinal Organoid Development, Eoin P Mcneill, Vikas S Gupta, David J Sequeira, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

Background: Human intestinal organoids (HIOs), when transplanted into immunocompromised mice (tHIOs), demonstrate significant growth and maturation. While both male and female mice are reported to be viable hosts for these experiments, a direct comparison of sex-related differences in tHIO structure and development has not been performed.

Aims: We sought to identify host sex-related differences in tHIO engraftment, morphology, and epithelial and mesenchymal development.

Methods: HIOs were generated in vitro and transplanted beneath the kidney capsule of NSG male and female mice. tHIOs were harvested at 8-9 weeks. Anthropometric measurements were captured. tHIOs were divided in half and histology or RT-qPCR …

Investigation Of Murine Host Sex As A Biological Variable In Epithelial Barrier Function And Muscle Contractility In Human Intestinal Organoids, Brooke T Beanland, Eoin P Mcneill, David J Sequeira, Hasen Xue, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

Intestinal failure (IF) occurs when intestinal surface area or function is not sufficient to support digestion and nutrient absorption. Human intestinal organoid (HIO)-derived tissue-engineered intestine is a potential cure for IF. Research to date has demonstrated successful HIO transplantation (tHIO) into mice with significant in vivo maturation. An area lacking in the literature is exploration of murine host sex as a biological variable (SABV) in tHIO function. In this study, we investigate murine host SABV in tHIO epithelial barrier function and muscle contractility. HIOs were generated in vitro and transplanted into nonobese diabetic, severe combined immunodeficiency gamma chain deficient male …

Sex Difference Leads To Differential Gene Expression Patterns And Therapeutic Efficacy In Mucopolysaccharidosis Iva Murine Model Receiving Aav8 Gene Therapy, Matthew Matthew Piechnik, Paige C. Amendum, Kazuki Sawamoto, Molly Stapleton, Shaukat Khan, Nidhi Fnu, Victor Álvarez, Angelica Maria Herreño Pachon, Olivier Danos, Joseph T. Bruder, Subha Karumuthil-Melethil, Shunji Tomatsu

Student Papers, Posters & Projects

Adeno-associated virus (AAV) vector-based therapies can effectively correct some disease pathology in murine models with mucopolysaccharidoses. However, immunogenicity can limit therapeutic effect as immune responses target capsid proteins, transduced cells, and gene therapy products, ultimately resulting in loss of enzyme activity. Inherent differences in male versus female immune response can significantly impact AAV gene transfer. We aim to investigate sex differences in the immune response to AAV gene therapies in mice with mucopolysaccharidosis IVA (MPS IVA). MPS IVA mice, treated with different AAV vectors expressing human N-acetylgalactosamine 6-sulfate sulfatase (GALNS), demonstrated a more robust antibody response in female mice resulting …

A Hydrogen-Sulfide Derivative Of Mesalamine Reduces The Severity Of Intestinal And Lung Injury In Necrotizing Enterocolitis Through Endothelial Nitric Oxide Synthase, Brian D Hosfield, Chelsea E Hunter, Hongge Li, Natalie A Drucker, Anthony R Pecoraro, Krishna Manohar, W Christopher Shelley, Troy A Markel

Faculty, Staff and Student Publications

Necrotizing enterocolitis (NEC) remains a devastating disease that affects preterm infants. Hydrogen sulfide (H2S) donors have been shown to reduce the severity of NEC, but the optimal compound has yet to be identified. We hypothesized that oral H2S-Mesalamine (ATB-429) would improve outcomes in experimental NEC, and its benefits would be dependent on endothelial nitric oxide synthase (eNOS) pathways. NEC was induced in 5-day-old wild-type (WT) and eNOS knockout (eNOSKO) pups by formula feeding and stress. Four groups were studied in both WT and eNOSKO mice: 1) breastfed controls, 2) NEC, 3) NEC + 50 mg/kg mesalamine, and …

An Enzymatically Cleavable Tripeptide Linker For Maximizing The Therapeutic Index Of Antibody-Drug Conjugates, Summer Y Y Ha, Yasuaki Anami, Chisato M Yamazaki, Wei Xiong, Candice M Haase, Scott D Olson, Jangsoon Lee, Naoto T Ueno, Ningyan Zhang, Zhiqiang An, Kyoji Tsuchikama

Faculty, Staff and Student Publications

Valine-citrulline is a protease-cleavable linker commonly used in many drug delivery systems, including antibody-drug conjugates (ADC) for cancer therapy. However, its suboptimal in vivo stability can cause various adverse effects such as neutropenia and hepatotoxicity, leading to dose delays or treatment discontinuation. Here, we report that glutamic acid-glycine-citrulline (EGCit) linkers have the potential to solve this clinical issue without compromising the ability of traceless drug release and ADC therapeutic efficacy. We demonstrate that our EGCit ADC resists neutrophil protease-mediated degradation and spares differentiating human neutrophils. Notably, our anti-HER2 ADC shows almost no sign of blood and liver toxicity in healthy …

A Phospholipid Mimetic Targeting Lrh-1 Ameliorates Colitis, Suzanne G Mays, Emma H D'Agostino, Autumn R Flynn, Xiangsheng Huang, Guohui Wang, Xu Liu, Elizabeth J Millings, C Denise Okafor, Anamika Patel, Michael L Cato, Jeffery L Cornelison, Diana Melchers, René Houtman, David D Moore, John W Calvert, Nathan T Jui, Eric A Ortlund

Faculty, Staff and Students Publications

Phospholipids are ligands for nuclear hormone receptors (NRs) that regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions is a robust strategy to improve agonists of liver receptor homolog-1 (LRH-1), a therapeutic target for colitis. Conventional LRH-1 modulators only partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. We show that the phospholipid-mimicking groups interact with the targeted residues in crystal structures and improve binding affinity, LRH-1 transcriptional activity, …

Gene-Based Therapeutics For Rare Genetic Neurodevelopmental Psychiatric Disorders, Beverly L Davidson, Guangping Gao, Elizabeth Berry-Kravis, Allison M Bradbury, Carsten Bönnemann, Joseph D Buxbaum, Gavin R Corcoran, Steven J Gray, Heather Gray-Edwards, Robin J Kleiman, Adam J Shaywitz, Dan Wang, Huda Y Zoghbi, Terence R Flotte, Sitra Tauscher-Wisniewski, Cynthia J Tifft, Mustafa Sahin

Duncan NRI Faculty and Staff Publications

We are in an emerging era of gene-based therapeutics with significant promise for rare genetic disorders. The potential is particularly significant for genetic central nervous system disorders that have begun to achieve Food and Drug Administration approval for select patient populations. This review summarizes the discussions and presentations of the National Institute of Mental Health-sponsored workshop "Gene-Based Therapeutics for Rare Genetic Neurodevelopmental Psychiatric Disorders," which was held in January 2021. Here, we distill the points raised regarding various precision medicine approaches related to neurodevelopmental and psychiatric disorders that may be amenable to gene-based therapies.

Regulation Of Pgc1Α Downstream Of The Insulin Signaling Pathway Plays A Role In The Hepatic Proteotoxicity Of Mutant Α1-Antitrypsin Deficiency Variant Z, David A Rudnick, Jiansheng Huang, Tunda Hidvegi, Andrew S Chu, Pamela Hale, Admire Munanairi, Dennis J Dietzen, Paul F Cliften, Eric Tycksen, Andrew J Lutkewitte, Brian N Finck, Stephen C Pak, Gary A Silverman, David H Perlmutter

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Insulin signaling is known to regulate essential proteostasis mechanisms.

METHODS: The analyses here examined effects of insulin signaling in the PiZ mouse model of α1-antitrypsin deficiency in which hepatocellular accumulation and proteotoxicity of the misfolded α1-antitrypsin Z variant (ATZ) causes liver fibrosis and cancer.

RESULTS: We first studied the effects of breeding PiZ mice to liver-insulin-receptor knockout (LIRKO) mice (with hepatocyte-specific insulin-receptor gene disruption). The results showed decreased hepatic ATZ accumulation and liver fibrosis in PiZ x LIRKO vs PiZ mice, with reversal of those effects when we bred PiZ x LIRKO mice onto a FOXO1-deficient background. …

Lmod2-Related Dilated Cardiomyopathy Presenting In Late Infancy, Erica Lay, Mahshid S Azamian, Susan W Denfield, William Dreyer, Joseph A Spinner, Debra Kearney, Lilei Zhang, Kim C Worley, Weimin Bi, Seema R Lalani

Faculty, Staff and Students Publications

Leiomodin-2 (LMOD2) is an important regulator of the thin filament length, known to promote elongation of actin through polymerization at pointed ends. Mice with Lmod2 deficiency die around 3 weeks of age due to severe dilated cardiomyopathy (DCM), resulting from decreased heart contractility due to shorter thin filaments. To date, there have been three infants from two families reported with biallelic variants in LMOD2, presenting with perinatal onset DCM. Here, we describe a third family with a child harboring a previously described homozygous frameshift variant, c.1243_1244delCT (p.L415Vfs*108) with DCM, presenting later in infancy at 9 months of age. Family history …

Whole Exome Sequencing Identifies Potential Candidate Genes For Spina Bifida Derived From Mouse Models, Chunyan Wang, Steve Seltzsam, Bixia Zheng, Chen-Han Wilfred Wu, Camille Nicolas-Frank, Kirollos Yousef, Kit Sing Au, Nina Mann, Dalia Pantel, Sophia Schneider, Luca Schierbaum, Thomas M Kitzler, Dervla M Connaughton, Youying Mao, Rufeng Dai, Makiko Nakayama, Jameela A Kari, Sherif El Desoky, Mohammed Shalaby, Loai A Eid, Hazem S Awad, Velibor Tasic, Shrikant M Mane, Richard P Lifton, Michelle A Baum, Shirlee Shril, Carlos R Estrada, Friedhelm Hildebrandt

Faculty, Staff and Student Publications

Spina bifida (SB) is the second most common nonlethal congenital malformation. The existence of monogenic SB mouse models and human monogenic syndromes with SB features indicate that human SB may be caused by monogenic genes. We hypothesized that whole exome sequencing (WES) allows identification of potential candidate genes by (i) generating a list of 136 candidate genes for SB, and (ii) by unbiased exome-wide analysis. We generated a list of 136 potential candidate genes from three categories and evaluated WES data of 50 unrelated SB cases for likely deleterious variants in 136 potential candidate genes, and for potential SB candidate …

A D2 To D1 Shift In Dopaminergic Inputs To Midbrain 5-Ht Neurons Causes Anorexia In Mice, Xing Cai, Hailan Liu, Bing Feng, Meng Yu, Yang He, Hesong Liu, Chen Liang, Yongjie Yang, Longlong Tu, Nan Zhang, Lina Wang, Na Yin, Junying Han, Zili Yan, Chunmei Wang, Pingwen Xu, Qi Wu, Qingchun Tong, Yanlin He, Yong Xu

Faculty, Staff and Students Publications

Midbrain dopamine (DA) and serotonin (5-HT) neurons regulate motivated behaviors, including feeding, but less is known about how these circuits may interact. In this study, we found that DA neurons in the mouse ventral tegmental area bidirectionally regulate the activity of 5-HT neurons in the dorsal raphe nucleus (DRN), with weaker stimulation causing DRD2-dependent inhibition and overeating, while stronger stimulation causing DRD1-dependent activation and anorexia. Furthermore, in the activity-based anorexia (ABA) paradigm, which is a mouse model mimicking some clinical features of human anorexia nervosa (AN), we observed a DRD2 to DRD1 shift of DA neurotransmission on 5-HT

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 …

The Autophagic Protein P62 Is A Target Of Reactive Aldehydes In Human And Murine Cholestatic Liver Disease, Colin T Shearn, Aimee L Anderson, Michael W Devereux, David J Orlicky, Cole Michel, Dennis R Petersen, Colin G Miller, Sanjiv Harpavat, Edward E Schmidt, Ronald J Sokol

Faculty, Staff and Students Publications

Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in …

Pathologic Inflammation In Malnutrition Is Driven By Proinflammatory Intestinal Microbiota, Large Intestine Barrier Dysfunction, And Translocation Of Bacterial Lipopolysaccharide, Grace T Patterson, Elvia Y Osorio, Alex Peniche, Sara M Dann, Erika Cordova, Geoffrey A Preidis, Ji Ho Suh, Ichiaki Ito, Omar A Saldarriaga, Michael Loeffelholz, Nadim J Ajami, Bruno L Travi, Peter C Melby

Faculty, Staff and Students Publications

Acute malnutrition, or wasting, is implicated in over half of all deaths in children under five and increases risk of infectious disease. Studies in humans and preclinical models have demonstrated that malnutrition is linked to an immature intestinal microbiota characterized by increased prevalence of Enterobacteriaceae. Observational studies in children with moderate acute malnutrition (MAM) have also observed heightened systemic inflammation and increased circulating bacterial lipopolysaccharides (LPS; endotoxin). However, the mechanisms that underpin the systemic inflammatory state and endotoxemia, and their pathophysiological consequences, remain uncertain. Understanding these pathophysiological mechanisms is necessary to design targeted treatments that will improve the unacceptable rate …

Paraventricular Vitamin D Receptors Are Required For Glucose Tolerance In Males But Not Females, Jessie Beck, Silvania Da Silva Teixeira, Keisha Harrison, Gabrielle Phillips, Yanlin He, Stephanie Sisley

Faculty, Staff and Students Publications

When delivered directly into the brain, vitamin D, can improve glucose levels in male mice. Additionally, the loss of the vitamin D receptor (VDR) in male mice's paraventricular hypothalamus (PVH) results in impaired glucose tolerance. Data in humans shows that low vitamin D levels are detrimental to glucose homeostasis, an effect that may be more prominent in men. However, it is unknown if vitamin D action in the brain is required for normal glucose regulation in female mice. This study shows that in both viral and genetic models, male mice with obesity and PVH VDR loss have impaired glucose tolerance …

Defining The Transcriptional Control Of Pediatric Aml Highlights Rara As A Superenhancer-Regulated Druggable Dependency, Monika W Perez, Oscar Sias-Garcia, Alfred Daramola, Helen Wei, Maci Terrell, Raushan Rashid, Woojun D Park, Kevin Duong, Terzah M Horton, Feng Li, Nikitha Cherayil, Jost Vrabic Koren, Vincent U Gant, Jacob J Junco, Choladda V Curry, Alexandra M Stevens, Charles Y Lin, Joanna S Yi

Faculty, Staff and Students Publications

Somatic mutations are rare in pediatric acute myeloid leukemia (pAML), indicating that alternate strategies are needed to identify targetable dependencies. We performed the first enhancer mapping of pAML in 22 patient samples. Generally, pAML samples were distinct from adult AML samples, and MLL (KMT2A)-rearranged samples were also distinct from non-KMT2A-rearranged samples. Focusing specifically on superenhancers (SEs), we identified SEs associated with many known leukemia regulators. The retinoic acid receptor alpha (RARA) gene was differentially regulated in our cohort, and a RARA-associated SE was detected in 64% of the study cohort across all cytogenetic and molecular subtypes tested. RARA SE+ pAML …

Hop2 Interacts With The Transcription Factor Cebpα And Suppresses Adipocyte Differentiation, Tonghui Lin, Yang Zhang, Tingting Zhang, Rita A Steckler, Xiangli Yang

Faculty, Staff and Student Publications

CCAAT enhancer binding protein (CEBP) transcription factors (TFs) are known to promote adipocyte differentiation; however, suppressors of CEBP TFs have not been reported thus far. Here, we find that homologous chromosome pairing protein 2 (Hop2) functions as an inhibitor for the TF CEBPα. We found that Hop2 mRNA is highly and specifically expressed in adipose tissue, and that ectopic Hop2 expression suppresses reporter activity induced by CEBP as revealed by DNA transfection. Recombinant and ectopically expressed Hop2 was shown to interact with CEBPα in pull-down and coimmunoprecipitation assays, and interaction between endogenous Hop2 and CEBPα was observed in the nuclei …

In Vivo Transplantation Of Human Intestinal Organoids Enhances Select Tight Junction Gene Expression, Mariaelena A Boyle, David J Sequeira, Eoin P Mcneill, Zachary K Criss, Noah F Shroyer, Allison L Speer

Faculty, Staff and Student Publications

BACKGROUND: Short bowel syndrome is a potentially fatal condition with inadequate management options. Tissue-engineered small intestine (TESI) is a promising solution, but confirmation of TESI function will be crucial before human application. We sought to define intestinal epithelial barrier function in human intestinal organoid (HIO)-derived TESI.

MATERIALS AND METHODS: HIOs were generated in vitro from human embryonic stem cells. After 1 mo, HIOs were collected for analysis or transplanted into the kidney capsule of immunocompromised mice. Transplanted HIOs (tHIOs) were harvested for analysis at 4 or 8 wk. Reverse transcription quantitative polymerase chain reaction and immunofluorescent staining were performed for …

Social And Leisure Activities Predict Transitions In Cognitive Functioning In Older Mexican Adults: A Latent Transition Analysis Of The Mexican Health And Aging Study, Heather Mary Brown, Stephen A Murray, Hope Northrup, Kit Sing Au, Lee A Niswander

Faculty, Staff and Student Publications

Disruptions in neural tube (NT) closure result in neural tube defects (NTDs). To understand the molecular processes required for mammalian NT closure, we investigated the role of Snx3, a sorting nexin gene. Snx3−/− mutant mouse embryos display a fully-penetrant cranial NTD. In vivo, we observed decreased canonical WNT target gene expression in the cranial neural epithelium of the Snx3−/− embryos and a defect in convergent extension of the neural epithelium. Snx3−/− cells show decreased WNT secretion, and live cell imaging reveals aberrant recycling of the WNT ligand-binding protein WLS and mis-trafficking to the lysosome for degradation. The importance …

Atrx Deletion In Neurons Leads To Sexually Dimorphic Dysregulation Of Mir-137 And Spatial Learning And Memory Deficits., Renee J. Tamming, Vanessa Dumeaux, Yan Jiang, Sarfraz Shafiq, Luana Langlois, Jacob Ellegood, Lily R. Qiu, Jason P. Lerch, Nathalie G. Bérubé

Paediatrics Publications

ATRX gene mutations have been identified in syndromic and non-syndromic intellectual disabilities in humans. ATRX is known to maintain genomic stability in neuroprogenitor cells, but its function in differentiated neurons and memory processes remains largely unresolved. Here, we show that the deletion of neuronal Atrx in mice leads to distinct hippocampal structural defects, fewer presynaptic vesicles, and an enlarged postsynaptic area at CA1 apical dendrite-axon junctions. We identify male-specific impairments in long-term contextual memory and in synaptic gene expression, linked to altered miR-137 levels. We show that ATRX directly binds to the miR-137 locus and that the enrichment of the …

Effects Of A Postnatal Atrx Conditional Knockout In Neurons On Autism-Like Behaviours In Male And Female Mice., Nicole Martin-Kenny, Nathalie G Bérubé

Paediatrics Publications

BACKGROUND: Alpha-thalassemia/mental retardation, X-linked, or ATRX, is an autism susceptibility gene that encodes a chromatin remodeler. Mutations of ATRX result in the ATR-X intellectual disability syndrome and have been identified in autism spectrum disorder (ASD) patients. The mechanisms by which ATRX mutations lead to autism and autistic-like behaviours are not yet known. To address this question, we generated mice with postnatal Atrx inactivation in excitatory neurons of the forebrain and performed a battery of behavioural assays that assess autistic-like behaviours.

METHODS: Male and female mice with a postnatal conditional ablation of ATRX were generated using the Cre/lox system under the …

Insights Image For "Evidence Of Increased Hypoxia Signalling In Fetal Liver From Maternal Nutrient Restriction In Mice"., Bethany N Radford, Victor K M Han

Paediatrics Publications

No abstract provided.

Evidence Of Increased Hypoxia Signaling In Fetal Liver From Maternal Nutrient Restriction In Mice., Bethany N Radford, Victor K M Han

Paediatrics Publications

BACKGROUND: Intrauterine growth restriction (IUGR) is a pregnancy condition where fetal growth is reduced, and offspring from IUGR pregnancies are at increased risk for type II diabetes as adults. The liver is susceptible to fetal undernutrition experienced by IUGR infants and animal models of growth restriction. This study aimed to examine hepatic expression changes in a maternal nutrient restriction (MNR) mouse model of IUGR to understand fetal adaptations that influence adult metabolism.

METHODS: Liver samples of male offspring from MNR (70% of ad libitum starting at E6.5) or control pregnancies were obtained at E18.5 and differential expression was assessed by …

A High-Throughput Screen Indicates Gemcitabine And Jak Inhibitors May Be Useful For Treating Pediatric Aml, Christina D. Drenberg, Anang Shelat, Jinjun Dang, Anitria Cotton, Shelley J. Orwick, Mengyu Li, Jae Yoon Jeon, Qiang Fu, Daelynn R. Buelow, Marissa Pioso, Shuiying Hu, Hiroto Inaba, Raul C. Ribeiro, Jeffrey E. Rubnitz, Tanja A. Gruber, R. Kiplin Guy, Sharyn D. Baker

Pharmaceutical Sciences Faculty Publications

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates < 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

Ctcf Governs The Identity And Migration Of Mge-Derived Cortical Interneurons., Adrienne Elbert, Daniel Vogt, Ashley Watson, Michael Levy, Yan Jiang, Emilie Brûlé, Megan E Rowland, John Rubenstein, Nathalie G Bérubé

Paediatrics Publications

The CCCTC-binding factor (CTCF) is a central regulator of chromatin topology recently linked to neurodevelopmental disorders such as intellectual disability, autism, and schizophrenia. The aim of this study was to identify novel roles of CTCF in the developing mouse brain. We provide evidence that CTCF is required for the expression of the LIM homeodomain factor LHX6 involved in fate determination of cortical interneurons (CINs) that originate in the medial ganglionic eminence (MGE). Conditional