Medical Specialties Commons^™

Snakes And Ladders: A Potential Therapy Of Hepatocyte Growth Factor And Pigment Epithelium-Derived Factor In Pulmonary Hypertension, Joseph M Zambelas, Harry Karmouty-Quintana

Faculty, Staff and Student Publications

No abstract provided.

Inhibition Of Autophagy In Microglia And Macrophages Exacerbates Innate Immune Responses And Worsens Brain Injury Outcomes, Nivedita Hegdekar, Chinmoy Sarkar, Sabrina Bustos, Rodney M Ritzel, Marie Hanscom, Prarthana Ravishankar, Deepika Philkana, Junfang Wu, David J Loane, Marta M Lipinski

Faculty, Staff and Student Publications

Excessive and prolonged neuroinflammation following traumatic brain injury (TBI) contributes to long-term tissue damage and poor functional outcomes. However, the mechanisms contributing to exacerbated inflammatory responses after brain injury remain poorly understood. Our previous work showed that macroautophagy/autophagy flux is inhibited in neurons following TBI in mice and contributes to neuronal cell death. In the present study, we demonstrate that autophagy is also inhibited in activated microglia and infiltrating macrophages, and that this potentiates injury-induced neuroinflammatory responses. Macrophage/microglia-specific knockout of the essential autophagy gene Becn1 led to overall increase in neuroinflammation after TBI. In particular, we observed excessive activation of …

Neoadjuvant Immunotherapy For Advanced, Resectable Non-Small Cell Lung Cancer: A Systematic Review And Meta-Analysis, Yajing Wu, Vivek Verma, Carl M Gay, Yujia Chen, Fei Liang, Qiang Lin, Jianing Wang, Wei Zhang, Zhouguang Hui, Min Zhao, Jun Wang, Joe Y Chang

Faculty, Staff and Student Publications

Background: Neoadjuvant immunotherapy (nIT) is a rapidly emerging paradigm for advanced resectable non-small cell lung cancer (NSCLC). The objectives of this PRISMA/MOOSE/PICOD-guided systematic review and meta-analysis were (1) to assess the safety and efficacy of nIT, (2) to compare the safety and efficacy of neoadjuvant chemoimmunotherapy (nCIT) versus chemotherapy alone (nCT), and (3) to explore predictors of pathologic response with nIT and their association with outcomes.

Methods: Eligibility was resectable stage I-III NSCLC and the receipt of programmed death-1/programmed cell death ligand-1 (PD-L1)/cytotoxic T-lymphocyte-associated antigen-4 inhibitors before resection; other forms and modalities of neoadjuvant and/or adjuvant therapies were allowed. For …

Stroke-Induced Respiratory Dysfunction Is Associated With Cognitive Decline, Anthony Patrizz, Ahmad El Hamamy, Michael Maniskas, Yashasvee Munshi, Louise Atadja, Hilda Ahnstedt, Matthew Howe, Fan Bu, Daniel K Mulkey, Louise D Mccullough, Jun Li

Faculty, Staff and Student Publications

BACKGROUND: Respiratory dysfunction is a common complication of stroke, with an incidence of over 60%. Despite the high prevalence of stroke-induced respiratory dysfunction, how disordered breathing influences recovery and cognitive outcomes after ischemic stroke is unknown. We hypothesized that stroke induces chronic respiratory dysfunction, breathing instability, and apnea in mice, which would contribute to higher mortality and greater poststroke cognitive deficits.

METHODS: Mice were subjected to a 60-minute transient middle cerebral artery occlusion or permanent distal middle cerebral artery occlusion. Whole body plethysmography was performed on C57BL/6 young (2-3 months) and aged (20 months) male and female mice. Animals were …

Screening Hydrogels For Antifibrotic Properties By Implanting Cellularly Barcoded Alginates In Mice And A Non-Human Primate, Sudip Mukherjee, Boram Kim, Lauren Y Cheng, Michael David Doerfert, Jiaming Li, Andrea Hernandez, Lily Liang, Maria I Jarvis, Peter D Rios, Sofia Ghani, Ira Joshi, Douglas Isa, Trisha Ray, Tanguy Terlier, Cody Fell, Ping Song, Roberto N Miranda, Jose Oberholzer, David Yu Zhang, Omid Veiseh

Faculty, Staff and Student Publications

Screening implantable biomaterials for antifibrotic properties is constrained by the need for in vivo testing. Here we show that the throughput of in vivo screening can be increased by cellularly barcoding a chemically modified combinatorial library of hydrogel formulations. The method involves the implantation of a mixture of alginate formulations, each barcoded with human umbilical vein endothelial cells from different donors, and the association of the identity and performance of each formulation by genotyping single nucleotide polymorphisms of the cells via next-generation sequencing. We used the method to screen 20 alginate formulations in a single mouse and 100 alginate formulations …

Free Ferrous Ions Sustain Activity Of Mammalian Stearoyl-Coa Desaturase-1, Jiemin Shen, Gang Wu, Brad S Pierce, Ah-Lim Tsai, Ming Zhou

Faculty, Staff and Student Publications

Mammalian stearoyl-CoA desaturase-1 (SCD1) introduces a double-bond to a saturated long-chain fatty acid in a reaction catalyzed by a diiron center. The diiron center is well-coordinated by conserved histidine residues and is thought to remain with the enzyme. However, we find here that SCD1 progressively loses its activity during catalysis and becomes fully inactive after about nine turnovers. Further studies show that the inactivation of SCD1 is due to the loss of an iron (Fe) ion in the diiron center and that the addition of free ferrous ions (Fe

Cisplatin Decreases Voluntary Wheel-Running Activity But Does Not Impair Food-Motivated Behavior In Mice, Kiersten S Scott, Brandon Chelette, Chinenye Chidomere, A Phillip West, Robert Dantzer

Faculty, Staff and Student Publications

Cisplatin is a chemotherapeutic agent that is still commonly used to treat solid tumors. However, it has several toxic side effects due in large part to the mitochondrial damage that it induces. As this mitochondrial damage is likely to result in a decrease in the amount of metabolic energy that is available for behavioral activities, it is not surprising that fatigue develops in cancer patients treated with cisplatin. The present preclinical study was initiated to determine whether the detrimental effects of cisplatin were more pronounced on physical effort requiring a lot of energy versus effort that not only requires less …

Exploring The Role Of Vitamin D And The Gut Microbiome: A Cross-Sectional Study Of Individuals With Irritable Bowel Syndrome And Healthy Controls, Sarah W Matthews, Anna Plantinga, Robert Burr, Kevin C Cain, Tor Savidge, Kendra Kamp, Margaret M Heitkemper

Faculty, Staff and Students Publications

Irritable bowel syndrome (IBS) is a common disorder of gut-brain interaction with multifaceted pathophysiology. Prior studies have demonstrated higher rates of vitamin D deficiency in individuals with IBS compared to healthy controls (HC), as well as associations of vitamin D concentration with IBS symptoms. A systematic review of 10 mouse and 14 human studies reported a positive association between vitamin D (serum levels and supplementation) and beta diversity of gut microbiome in a variety of conditions. The present retrospective case-control study aimed to compare vitamin D (25(OH)D) plasma concentrations and gut microbiome composition in adult women with IBS (n=99) and …

Identification Of Unique Α4 Chain Structure And Conserved Antiangiogenic Activity Of Α3nc1 Type Iv Collagen In Zebrafish, Valerie S Lebleu, Jianli Dai, Susan Tsutakawa, Brian A Macdonald, Joseph L Alge, Malin Sund, Liang Xie, Hikaru Sugimoto, John Tainer, Leonard I Zon, Raghu Kalluri

Faculty, Staff and Student Publications

BACKGROUND: Type IV collagen is an abundant component of basement membranes in all multicellular species and is essential for the extracellular scaffold supporting tissue architecture and function. Lower organisms typically have two type IV collagen genes, encoding α1 and α2 chains, in contrast with the six genes in humans, encoding α1-α6 chains. The α chains assemble into trimeric protomers, the building blocks of the type IV collagen network. The detailed evolutionary conservation of type IV collagen network remains to be studied.

RESULTS: We report on the molecular evolution of type IV collagen genes. The zebrafish α4 non-collagenous (NC1) domain, in …

A Serological Assay To Detect And Differentiate Rodent Exposure To Soft Tick And Hard Tick Relapsing Fever Infections In The United States, Christina M Parise, Ying Bai, Kevin S Brandt, Shelby L Ford, Sarah Maes, Adam J Replogle, Alexander R Kneubehl, Job E Lopez, Rebecca J Eisen, Andrias Hojgaard

Faculty, Staff and Students Publications

Human cases of relapsing fever (RF) in North America are caused primarily by Borrelia hermsii and Borrelia turicatae, which are spread by argasid (soft) ticks, and by Borrelia miyamotoi, which is transmitted by ixodid (hard) ticks. In some regions of the United States, the ranges of the hard and soft tick RF species are known to overlap; in many areas, recorded ranges of RF spirochetes overlap with Lyme disease (LD) group Borrelia spirochetes. Identification of RF clusters or cases detected in unusual geographic localities might prompt public health agencies to investigate environmental exposures, enabling prevention of additional cases through locally …

Genome-Wide Association Analyses Define Pathogenic Signaling Pathways And Prioritize Drug Targets For Iga Nephropathy, Krzysztof Kiryluk, Elena Sanchez-Rodriguez, Xu-Jie Zhou, Francesca Zanoni, Lili Liu, Nikol Mladkova, Atlas Khan, Maddalena Marasa, Jun Y Zhang, Olivia Balderes, Simone Sanna-Cherchi, Andrew S Bomback, Pietro A Canetta, Gerald B Appel, Jai Radhakrishnan, Hernan Trimarchi, Ben Sprangers, Daniel C Cattran, Heather Reich, York Pei, Pietro Ravani, Kresimir Galesic, Dita Maixnerova, Vladimir Tesar, Benedicte Stengel, Marie Metzger, Guillaume Canaud, Nicolas Maillard, Francois Berthoux, Laureline Berthelot, Evangeline Pillebout, Renato Monteiro, Raoul Nelson, Robert J Wyatt, William Smoyer, John Mahan, Al-Akash Samhar, Guillermo Hidalgo, Alejandro Quiroga, Patricia Weng, Raji Sreedharan, David Selewski, Keefe Davis, Mahmoud Kallash, Tetyana L Vasylyeva, Michelle Rheault, Aftab Chishti, Daniel Ranch, Scott E Wenderfer, Dmitry Samsonov, Donna J Claes, Oleh Akchurin, Dimitrios Goumenos, Maria Stangou, Judit Nagy, Tibor Kovacs, Enrico Fiaccadori, Antonio Amoroso, Cristina Barlassina, Daniele Cusi, Lucia Del Vecchio, Giovanni Giorgio Battaglia, Monica Bodria, Emanuela Boer, Luisa Bono, Giuliano Boscutti, Gianluca Caridi, Francesca Lugani, Gianmarco Ghiggeri, Rosanna Coppo, Licia Peruzzi, Vittoria Esposito, Ciro Esposito, Sandro Feriozzi, Rosaria Polci, Giovanni Frasca, Marco Galliani, Maurizio Garozzo, Adele Mitrotti, Loreto Gesualdo, Simona Granata, Gianluigi Zaza, Francesco Londrino, Riccardo Magistroni, Isabella Pisani, Andrea Magnano, Carmelita Marcantoni, Piergiorgio Messa, Renzo Mignani, Antonello Pani, Claudio Ponticelli, Dario Roccatello, Maurizio Salvadori, Erica Salvi, Domenico Santoro, Guido Gembillo, Silvana Savoldi, Donatella Spotti, Pasquale Zamboli, Claudia Izzi, Federico Alberici, Elisa Delbarba, Michał Florczak, Natalia Krata, Krzysztof Mucha, Leszek Pączek, Stanisław Niemczyk, Barbara Moszczuk, Malgorzata Pańczyk-Tomaszewska, Malgorzata Mizerska-Wasiak, Agnieszka Perkowska-Ptasińska, Teresa Bączkowska, Magdalena Durlik, Krzysztof Pawlaczyk, Przemyslaw Sikora, Marcin Zaniew, Dorota Kaminska, Magdalena Krajewska, Izabella Kuzmiuk-Glembin, Zbigniew Heleniak, Barbara Bullo-Piontecka, Tomasz Liberek, Alicja Dębska-Slizien, Tomasz Hryszko, Anna Materna-Kiryluk, Monika Miklaszewska, Maria Szczepańska, Katarzyna Dyga, Edyta Machura, Katarzyna Siniewicz-Luzeńczyk, Monika Pawlak-Bratkowska, Marcin Tkaczyk, Dariusz Runowski, Norbert Kwella, Dorota Drożdż, Ireneusz Habura, Florian Kronenberg, Larisa Prikhodina, David Van Heel, Bertrand Fontaine, Chris Cotsapas, Cisca Wijmenga, Andre Franke, Vito Annese, Peter K Gregersen, Sreeja Parameswaran, Matthew Weirauch, Leah Kottyan, John B Harley, Hitoshi Suzuki, Ichiei Narita, Shin Goto, Hajeong Lee, Dong Ki Kim, Yon Su Kim, Jin-Ho Park, Belong Cho, Murim Choi, Ans Van Wijk, Ana Huerta, Elisabet Ars, Jose Ballarin, Sigrid Lundberg, Bruno Vogt, Laila-Yasmin Mani, Yasar Caliskan, Jonathan Barratt, Thilini Abeygunaratne, Philip A Kalra, Daniel P Gale, Ulf Panzer, Thomas Rauen, Jürgen Floege, Pascal Schlosser, Arif B Ekici, Kai-Uwe Eckardt, Nan Chen, Jingyuan Xie, Richard P Lifton, Ruth J F Loos, Eimear E Kenny, Iuliana Ionita-Laza, Anna Köttgen, Bruce A Julian, Jan Novak, Francesco Scolari, Hong Zhang, Ali G Gharavi

Faculty, Staff and Students Publications

IgA nephropathy (IgAN) is a progressive form of kidney disease defined by glomerular deposition of IgA. Here we performed a genome-wide association study of 10,146 kidney-biopsy-diagnosed IgAN cases and 28,751 controls across 17 international cohorts. We defined 30 genome-wide significant risk loci explaining 11% of disease risk. A total of 16 loci were new, including TNFSF4/TNFSF18, REL, CD28, PF4V1, LY86, LYN, ANXA3, TNFSF8/TNFSF15, REEP3, ZMIZ1, OVOL1/RELA, ETS1, IGH, IRF8, TNFRSF13B and FCAR. The risk loci were enriched in gene orthologs causing abnormal IgA levels when genetically manipulated in mice. We also observed a positive genetic correlation between IgAN and serum …

Pdcl2 Is Essential For Sperm Acrosome Formation And Male Fertility In Mice, Yoshitaka Fujihara, Kiyonori Kobayashi, Ferheen Abbasi, Tsutomu Endo, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: Each year, infertility affects 15% of couples worldwide, with 50% of cases attributed to men. Globozoospermia is an uncommon cause of male factor infertility, characterized by defects in sperm acrosome formation, leading to round-headed spermatozoa.

OBJECTIVE: We generated Pdcl2 knockout mice to investigate the essential roles of PDCL2 in mammalian reproduction.

MATERIALS AND METHODS: We used reverse transcription-polymerase chain reaction to demonstrate that PDCL2 was expressed exclusively in the male reproductive tract in mice and humans. We created Pdcl2 knockout mice using the CRISPR-Cas9 system and analyzed their fertility. Pdcl2 null spermatozoa underwent further evaluation using computer-assisted sperm analysis, …

Generation Of Humanized Ldhc Knock-In Mice As A Tool To Assess Human Ldhc-Targeting Contraceptive Drugs, Rie Iida-Norita, Haruhiko Miyata, Yuki Kaneda, Chihiro Emori, Taichi Noda, Tatsuya Nakagawa, Martin M Matzuk, Masahito Ikawa

Faculty, Staff and Students Publications

Background: Lactate dehydrogenase C (LDHC) is specifically expressed in male germ cells and plays critical roles in glycolysis. Glycolysis is required to supply energy for sperm motility. Previous studies showed that Ldhc knock-out mice exhibit impaired sperm motility.

Objectives: We established human LDHC knock-in (hLDHC KI) mice and examined whether hLDHC KI mice can be used to assess LDHC-targeting drugs.

Material and methods: HLDHC was knocked-in to the mouse Ldhc (mLdhc) allele using the CRISPR/Cas9 system. Mating tests, sperm motility examinations with a computer-assisted sperm analysis (CASA) system, and in vitro fertilization (IVF) were performed. Furthermore, the effect of an …

Testis-Specific Serine Kinase 3 Is Required For Sperm Morphogenesis And Male Fertility, Kaori Nozawa, Thomas X Garcia, Katarzyna Kent, Mei Leng, Antrix Jain, Anna Malovannaya, Fei Yuan, Zhifeng Yu, Masahito Ikawa, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: The importance of phosphorylation in sperm during spermatogenesis has not been pursued extensively. Testis-specific serine kinase 3 (Tssk3) is a conserved gene, but TSSK3 kinase functions and phosphorylation substrates of TSSK3 are not known.

OBJECTIVE: The goals of our studies were to understand the mechanism of action of TSSK3.

MATERIALS AND METHODS: We analyzed the localization of TSSK3 in sperm, used CRISPR/Cas9 to generate Tssk3 knockout (KO) mice in which nearly all of the Tssk3 open reading frame was deleted (ensuring it is a null mutation), analyzed the fertility of Tssk3 KO mice by breeding mice for 4 months, …

Advancing Asms With Lc-Ms/Ms For The Discovery Of Novel Pdcl2 Ligands From Dna-Encoded Chemical Library Selections, Qiuji Ye, Hassane Belabed, Yong Wang, Zhifeng Yu, Murugesan Palaniappan, Jian-Yuan Li, Stacey A Kalovidouris, Kevin R Mackenzie, Mingxing Teng, Damian W Young, Yoshitaka Fujihara, Martin M Matzuk

Faculty, Staff and Students Publications

BACKGROUND: A safe, effective, and reversible nonhormonal male contraceptive drug is greatly needed for male contraception as well as for circumventing the side effects of female hormonal contraceptives. Phosducin-like 2 (PDCL2) is a testis-specific phosphoprotein in mice and humans. We recently found that male PDCL2 knockout mice are sterile due to globozoospermia caused by impaired sperm head formation, indicating that PDCL2 is a potential target for male contraception. Herein, our study for the first time developed a biophysical assay for PDCL2 allowing us to screen a series of small molecules, to study structure-activity relationships, and to discover two PDCL2 binders …

Fkbp5 Inhibitors Modulate Alcohol Drinking And Trauma-Related Behaviors In A Model Of Comorbid Post-Traumatic Stress And Alcohol Use Disorder, Bryan Cruz, Valentina Vozella, Benjamin A Carper, Joy C Xu, Dean Kirson, Shawn Hirsch, Tracy Nolen, Lauren Bradley, Katie Fain, Meg Crawford, Thomas R Kosten, Eric P Zorrilla, Marisa Roberto

Faculty, Staff and Students Publications

Post-traumatic stress disorder (PTSD) leads to enhanced alcohol drinking and development of alcohol use disorder (AUD). Identifying shared neural mechanisms might help discover new therapies for PTSD/AUD. Here, we employed a rat model of comorbid PTSD/AUD to evaluate compounds that inhibit FK506-binding protein 51 (FKBP5), a co-chaperone modulator of glucocorticoid receptors implicated in stress-related disorders. Male and female rats received a familiar avoidance-based shock stress followed by voluntary alcohol drinking. We then assessed trauma-related behaviors through sleep bout cycles, hyperarousal, fear overgeneralization, and irritability. To evaluate the role of stress and alcohol history on the sensitivity to FKBP5 inhibitors, in …

Targeting Aav Vectors To The Central Nervous System By Engineering Capsid-Receptor Interactions That Enable Crossing Of The Blood-Brain Barrier, Qin Huang, Albert T Chen, Ken Y Chan, Hikari Sorensen, Andrew J Barry, Bahar Azari, Qingxia Zheng, Thomas Beddow, Binhui Zhao, Isabelle G Tobey, Cynthia Moncada-Reid, Fatma-Elzahraa Eid, Christopher J Walkey, M Cecilia Ljungberg, William R Lagor, Jason D Heaney, Yujia A Chan, Benjamin E Deverman

Faculty, Staff and Students Publications

Viruses have evolved the ability to bind and enter cells through interactions with a wide variety of cell macromolecules. We engineered peptide-modified adeno-associated virus (AAV) capsids that transduce the brain through the introduction of de novo interactions with 2 proteins expressed on the mouse blood-brain barrier (BBB), LY6A or LY6C1. The in vivo tropisms of these capsids are predictable as they are dependent on the cell- and strain-specific expression of their target protein. This approach generated hundreds of capsids with dramatically enhanced central nervous system (CNS) tropisms within a single round of screening in vitro and secondary validation in vivo …

Remote Neuronal Activity Drives Glioma Progression Through Sema4f, Emmet Huang-Hobbs, Yi-Ting Cheng, Yeunjung Ko, Estefania Luna-Figueroa, Brittney Lozzi, Kathryn R Taylor, Malcolm Mcdonald, Peihao He, Hsiao-Chi Chen, Yuhui Yang, Ehson Maleki, Zhung-Fu Lee, Sanjana Murali, Michael R Williamson, Dongjoo Choi, Rachel Curry, James Bayley, Junsung Woo, Ali Jalali, Michelle Monje, Jeffrey L Noebels, Akdes Serin Harmanci, Ganesh Rao, Benjamin Deneen

Faculty, Staff and Students Publications

The tumor microenvironment (TME) plays an essential role in malignancy and neurons have emerged as a key component of the TME that promotes tumorigenesis across a host of cancers1,2. Recent studies on glioblastoma (GBM) highlight bi-directional signaling between tumors and neurons that propagates a vicious cycle of proliferation, synaptic integration, and brain hyperactivity3-8; however, the identity of neuronal subtypes and tumor subpopulations driving this phenomenon are incompletely understood. Here we show that callosal projection neurons located in the hemisphere contralateral to primary GBM tumors promote progression and widespread infiltration. Using this platform …

Nanoparticle Contrast-Enhanced Mri For Visualization Of Retroplacental Clear Space Disruption In A Mouse Model Of Placental Accreta Spectrum (Pas), Andrew A Badachhape, Prajwal Bhandari, Laxman Devkota, Mayank Srivastava, Eric A Tanifum, Verghese George, Karin A Fox, Chandrasekhar Yallampalli, Ananth V Annapragada, Ketan B Ghaghada

Faculty, Staff and Students Publications

Introduction:

Prior preclinical studies established the utility of liposomal nanoparticle blood-pool contrast agents in visualizing the retroplacental clear space (RPCS), a marker of normal placentation, while sparing fetuses from exposure because the agent does not cross the placental barrier. In this work, we characterized RPCS disruption in a mouse model of placenta accreta spectrum (PAS) using these agents.

Methods:

Contrast-enhanced MRI (CE-MRI) and computed tomography (CE-CT) using liposomal nanoparticles bearing gadolinium (liposomal-Gd) and iodine were performed in pregnant Gab3^−/− and wild type (WT) mice at day 16 of gestation. CE-MRI was performed on a 1T scanner using a 2D …

Prematurity Blunts Protein Synthesis In Skeletal Muscle Independently Of Body Weight In Neonatal Pigs, Marko Rudar, Jane K Naberhuis, Agus Suryawan, Hanh V Nguyen, Marta L Fiorotto, Teresa A Davis

Faculty, Staff and Students Publications

Background

Postnatal growth failure in premature infants is associated with reduced lean mass accretion. Prematurity impairs the feeding-induced stimulation of translation initiation and protein synthesis in the skeletal muscle of neonatal pigs. The objective was to determine whether body weight independently contributes to the blunted postprandial protein synthesis.

Methods

Preterm and term pigs that were either fasted or fed were stratified into quartiles according to birth weight to yield preterm and term groups of similar body weight; first and second quartiles of preterm pigs and third and fourth quartiles of term pigs were compared (preterm-fasted, n = 23; preterm-fed, n …

Ywhae Loss Of Function Causes A Rare Neurodevelopmental Disease With Brain Abnormalities In Human And Mouse, Anne-Sophie Denommé-Pichon, Stephan C Collins, Ange-Line Bruel, Anna Mikhaleva, Christel Wagner, Valerie E Vancollie, Quentin Thomas, Martin Chevarin, Mathys Weber, Carlos E Prada, Alexis Overs, María Palomares-Bralo, Fernando Santos-Simarro, Marta Pacio-Míguez, Tiffany Busa, Eric Legius, Carlos A Bacino, Jill A Rosenfeld, Gwenaël Le Guyader, Matthieu Egloff, Xavier Le Guillou, Maria Antonietta Mencarelli, Alessandra Renieri, Salvatore Grosso, Jonathan Levy, Blandine Dozières, Isabelle Desguerre, Antonio Vitobello, Yannis Duffourd, Christopher J Lelliott, Christel Thauvin-Robinet, Christophe Philippe, Laurence Faivre, Binnaz Yalcin

Faculty, Staff and Students Publications

Purpose: Miller-Dieker syndrome is caused by a multiple gene deletion, including PAFAH1B1 and YWHAE. Although deletion of PAFAH1B1 causes lissencephaly unambiguously, deletion of YWHAE alone has not clearly been linked to a human disorder.

Methods: Cases with YWHAE variants were collected through international data sharing networks. To address the specific impact of YWHAE loss of function, we phenotyped a mouse knockout of Ywhae.

Results: We report a series of 10 individuals with heterozygous loss-of-function YWHAE variants (3 single-nucleotide variants and 7 deletions < 1 Mb encompassing YWHAE but not PAFAH1B1), including 8 new cases and 2 follow-ups, added with 5 cases (copy number variants) from literature review. Although, until now, only 1 intragenic deletion has been described in YWHAE, we report 4 new variants specifically in YWHAE (3 splice variants and 1 intragenic deletion). The most frequent manifestations are developmental delay, delayed speech, seizures, and brain malformations, including corpus callosum hypoplasia, delayed myelination, and ventricular dilatation. Individuals with variants affecting YWHAE alone have milder features than those with larger deletions. Neuroanatomical studies in Ywhae-/- mice revealed brain structural defects, including thin cerebral cortex, corpus callosum dysgenesis, and hydrocephalus paralleling those seen in humans.

Conclusion: This study further demonstrates that YWHAE loss-of-function variants cause a neurodevelopmental disease with brain abnormalities.

Ceramide Compensation By Ceramide Synthases Preserves Retinal Function And Structure In A Retinal Dystrophy Mouse Model, Xinye Qian, Tanmay Srinivasan, Jessica He, Jiaxiong Lu, Yan Jin, Haiwei Gu, Rui Chen

Faculty, Staff and Students Publications

Increasing evidence has supported the role of ceramide as a mediator of photoreceptor dysfunction or cell death in ceramide accumulation and deficiency contexts. TLCD3B, a non-canonical ceramide synthase, was previously identified in addition to the six canonical ceramide synthases (CerSs), and the Tlcd3b-/- mouse model exhibited both retinal dysfunction and degeneration. As previous canonical CerS-deficient mouse models failed to display retinal degeneration, the mechanisms of how TLCD3B interacts with CerSs have not been investigated. Additionally, as the ceramide profile of each CerS is distinct, it is unclear whether the overall level or the homeostasis of different ceramide species plays a …

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 …

Immune Cells Localize To Sites Of Corneal Erosions In C57bl/6 Mice., Phuong M. Le, Sonali Pal-Ghosh, A. Menko, Mary Ann Stepp

Computational Medicine Center Faculty Papers

Recurrent epithelial erosions develop in the cornea due to prior injury or genetic predisposition. Studies of recurrent erosions in animal models allow us to gain insight into how erosions form and are resolved. While slowing corneal epithelial cell migration and reducing their proliferation following treatment with mitomycin C reduce erosion formation in mice after sterile debridement injury, additional factors have been identified related to cytokine expression and immune cell activation. The relationship between recruitment of immune cells to the region of the cornea where erosions form and their potential roles in erosion formation and/or erosion repair remains unexplored in the …

Increased Glucose Availability Sensitizes Pancreatic Cancer To Chemotherapy, Ali Vaziri-Gohar, Jonathan J. Hue, Ata Abbas, Hallie J. Graor, Omid Hajihassani, Mehrdad Zarei, George Titomihelakis, John Feczko, Moeez Rathore, Sylwia Chelstowska, Alexander W. Loftus, Rui Wang, Mahsa Zarei, Maryam Goudarzi, Renliang Zhang, Belinda Willard, Li Zhang, Adam Kresak, Joseph E. Willis, Gi-Ming Wang, Curtis Tatsuoka, Joseph M. Salvino, Ilya Bederman, Henri Brunengraber, Costas A. Lyssiotis, Jonathan R. Brody, Jordan M. Winter

Student Papers, Posters & Projects

Pancreatic Ductal Adenocarcinoma (PDAC) is highly resistant to chemotherapy. Effective alternative therapies have yet to emerge, as chemotherapy remains the best available systemic treatment. However, the discovery of safe and available adjuncts to enhance chemotherapeutic efficacy can still improve survival outcomes. We show that a hyperglycemic state substantially enhances the efficacy of conventional single- and multi-agent chemotherapy regimens against PDAC. Molecular analyses of tumors exposed to high glucose levels reveal that the expression of GCLC (glutamate-cysteine ligase catalytic subunit), a key component of glutathione biosynthesis, is diminished, which in turn augments oxidative anti-tumor damage by chemotherapy. Inhibition of GCLC phenocopies …

Chronic Social Defeat Alters Brain Vascular-Associated Cell Gene Expression Patterns Leading To Vascular Dysfunction And Immune System Activation, Joshua D Samuels, Madison L Lotstein, Michael L Lehmann, Abdel G Elkahloun, Subhadra Banerjee, Miles Herkenham

Faculty, Staff and Student Publications

Brain vascular integrity is critical for brain health, and its disruption is implicated in many brain pathologies, including psychiatric disorders. Brain-vascular barriers are a complex cellular landscape composed of endothelial, glial, mural, and immune cells. Yet currently, little is known about these brain vascular-associated cells (BVACs) in health and disease. Previously, we demonstrated that 14 days of chronic social defeat (CSD), a mouse paradigm that produces anxiety and depressive-like behaviors, causes cerebrovascular damage in the form of scattered microbleeds. Here, we developed a technique to isolate barrier-related cells from the mouse brain and subjected the isolated cells to single-cell RNA …

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 …

Effect Of Ishophloroglucin A Isolated From Ishige Okamurae On In Vitro Osteoclastogenesis And Osteoblastogenesis, Su-Hyeon Cho, Hyun-Soo Kim, Hye-Yeon Jung, Jae-Il Park, You-Jee Jang, Juhee Ahn, Kil-Nam Kim

Faculty, Staff and Student Publications

The balance between bone-resorbing osteoclasts and bone-forming osteoblasts is essential for the bone remodeling process. This study aimed to investigate the effect of Ishophloroglucin A (IPA) isolated from Ishige okamurae on the function of osteoclasts and osteoblasts in vitro. First, we demonstrated the effect of IPA on osteoclastogenesis in receptor activator of nuclear factor κB ligand (RANKL)-induced RAW 264.7 cells. IPA inhibited the tartrate-resistant acid phosphatase (TRAP) activity and osteoclast differentiation in RANKL-induced RAW 264.7 cells. Moreover, it inhibited the RANKL-induced osteoclast-related factors, such as TRAP, matrix metalloproteinase-9 (MMP-9), and calcitonin receptor (CTR), and transcription factors, such as nuclear factor …

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 …