Digital Commons Network^™

Multimodal Spatial-Omics Reveal Co-Evolution Of Alveolar Progenitors And Proinflammatory Niches In Progression Of Lung Precursor Lesions, Fuduan Peng, Ansam Sinjab, Yibo Dai, Warapen Treekitkarnmongkol, Sujuan Yang, Lorena I Gomez Bolanos, Tieling Zhou, Minyue Chen, Alejandra G Serrano, Avantika Krishna, Nastaran Karimi, Manvi Sharma, Akshay Basi, Guangsheng Pei, Jianlong Liao, Yunhe Liu, Jiping Feng, Zahraa Rahal, Yang Liu, Jiahui Jiang, Kai Yu, Tala Noun, Yuejiang Liu, Khaja Khan, Kyung Serk Cho, Jichao Chen, Luisa M Solis, Sarah Mazzilli, Steven Dubinett, Tina Cascone, Avrum E Spira, Stephen Swisher, Naoe Jimbo, Takuo Hayashi, Satsuki Kishikawa, Kazuya Takamochi, Tomoo Itoh, Takashi Yao, Kenji Suzuki, Neda Kalhor, Ignacio I Wistuba, Mingyao Li, Seyed Javad Moghaddam, Junya Fujimoto, Jared Burks, Jeffrey Myers, Kadir Akdemir, Linghua Wang, Humam Kadara

Faculty, Staff and Student Publications

The co-evolution of different cell subsets in the progression of precursor lesions to lung adenocarcinoma (LUAD) is incompletely understood. We generated spatial transcriptomic maps of 56 human precursor lesions and LUADs from 25 patients and of an independent cohort of 36 lesions from 19 patients, analyzing a total of 486,519 spots and 5.4 million cells. We identify region-specific programs that distinguish precursors from LUADs. Spatially resolved clonal architectures reveal patient-specific heterogeneity in evolution of precursors to LUADs. We find epithelial alveolar progenitors expressing tumor-associated meta-programs and residing in niches enriched with proinflammatory subsets including IL1B high macrophages. Epithelial-proinflammatory niches are …

Tracking Focal Adhesion Turnover: A Novel Reporter For Fa-Phagy Flux, Kuizhi Qu, Mengjun Dai, Ying Jiang, Sophie Liu, John P Hagan, Louise D Mccullough, Zhen Xu, Yan-Ning Rui

Faculty, Staff and Student Publications

Focal adhesions (FAs) are critical multi-protein complexes regulating cell adhesion, migration, and survival, and their dysregulation contributes to cancer metastasis and vascular diseases. Despite extensive research on FA formation, little is known about FA turnover, particularly its regulation by autophagy. This study introduces a novel tandem fluorescence reporter capable of tracking the entire FA-phagy flux, from autophagosome formation to lysosomal degradation. The reporter, based on a red–green fluorescence system with a lysosome-specific cleavage site, integrates seamlessly into endogenous focal adhesion complexes, demonstrating sensitivity and specificity to autophagy stimuli. Validated in multiple cell lines, the tool revealed dynamic FA-phagy responses to …

Bi-Allelic Variants In Neuronal Adhesion Molecule Astrotactin 1 Gene Astn1 Cause Diverse Neurodevelopmental Disorders, Jesse M Levine, Daniel G Calame, Riccardo Sangermano, Haowei Du, Ahmed Saad, Jasmin Lisfeld, Tatjana Bierhals, Jonas Denecke, Eyyup Uctepe, Merve Yoldas Celik, Ahmet Yesilyurt, Hilal Yildiz Er, Elif Yilmaz Gulec, Aziza Mushiba, Naif Almontashiri, Pawel Gawlinski, Wojciech Wiszniewski, Ender Karaca, Lama Alabdi, Davut Pehlivan, Dana Marafi, Maha S Zaki, Fowzan S Alkuraya, Joseph G Gleeson, Shalini N Jhangiani, Richard A Gibbs, Jennifer E Posey, Kinga M Bujakowska, James R Lupski

Faculty, Staff and Students Publications

ASTN1 encodes astrotactin 1, a neuronal-glial ligand in the developing brain that promotes neuronal migration along radial glia in brain structures with laminar organization, such as the cerebral cortex, hippocampus, and cerebellum. In mouse models, disruption of Astn1 results in neuronal migration deficits, a mild reduction in cerebellar volume, and balance and coordination deficits. In humans, bi-allelic ASTN1 variants have been identified in nine individuals with neurodevelopmental disorders (NDDs) with or without brain malformations. ASTN1 additionally interacts with astrotactin 2 (ASTN2) to implement neuronal migration; ASTN2 deletions associate with NDDs with reduced penetrance. Here, we describe eighteen individuals with NDDs …

Targeting Pediatric Glioblastomas By Combining Olig2 Inhibitor Ct-179 With Fractionated Radiation In A Panel Of Patient-Derived Orthotopic Xenograft Mouse Models., Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank K Braun, Mari Kogiso, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Santosh Kesari, Steven Neuhauser, Timothy M Stearns, Jeffrey Chuang, Emily L Jocoy, Carol J Bult, Beverly Teicher, Malcolm A Smith, Xiao-Nan Li

Faculty Research 2026

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined …

Targeting Pediatric Glioblastomas By Combining Olig2 Inhibitor Ct-179 With Fractionated Radiation In A Panel Of Patient-Derived Orthotopic Xenograft Mouse Models., Holly Lindsay, Yuchen Du, Lin Qi, Huiyuan Zhang, Sibo Zhao, Frank K Braun, Mari Kogiso, Clifford Stephan, Gordon Alton, Gregory Stein, Graham Beaton, Santosh Kesari, Steven Neuhauser, Timothy M Stearns, Jeffrey Chuang, Emily L Jocoy, Carol J Bult, Beverly Teicher, Malcolm A Smith, Xiao-Nan Li

Faculty Research 2026

The poor clinical outcomes of pediatric high-grade glioma (pHGG) highlight the urgent need for new therapies. Oligodendrocyte lineage transcription factor 2 (OLIG2) is a pro-mitotic transcription factor highly expressed in glioma stem cells and may represent a novel therapeutic target. To evaluate the therapeutic efficacy of an OLIG2 inhibitor CT-179 in pHGG, we determined the OLIG2 mRNA expression in 10 patient-derived orthotopic xenograft (PDOX) models. In vitro activities of CT-179 were analyzed in monolayer and neurosphere cells (0–10 µM) with and without radiation (XRT) (0–8 Gy), brain penetration was evaluated in tumor-bearing PDOX mice, and in vivo efficacy was determined …

Multiparent Recombinant Inbred Lines Crossed To A Tester Provide Novel Insights Into Sources Of Cis And Trans Regulation Of Gene Expression, Fabio Marroni, Alison M Morse, Adalena V Nanni, Nadja Nolte, Patricka Williams-Simon, Luis G León-Novelo, Rita M Graze, Paul Schmidt, Elizabeth King, Lauren M Mcintyre

Faculty, Staff and Student Publications

To understand the relative importance of cis and trans effects on regulation, we crossed multi-parent recombinant-inbred lines (RILs) to a common tester and measured allele-specific gene expression in the offspring. Testing the difference of allelic imbalance between two RIL × Tester crosses is a test of cis or trans, depending on the RIL alleles compared. The study design also enables to separation of two sources of trans variation, genetic and environmental, detected via interactions with cis effects. We demonstrate the effectiveness of this approach in a long-read RNA-seq experiment in female abdominal tissue at two time points in Drosophila melanogaster. …

Ubiquitination Of Oncogenic Mutant P53 Via Attenuation Of Ribosome Biogenesis Machinery Effectively Inhibits Pancreatic Tumor Growth, Mudassier Ahmad, Sahir Sultan Alvi, Haider Ahsan, Carlos Perez, Andrew Massey, Vivek K Kashyap, Neeraj Chauhan, Emmanuel Anning, Manish K Tripathi, Dae J Kim, Nirakar Sahoo, Tamer Oraby, Murali M Yallapu, Mohammad Moshahid Khan, Manu M Sebastian, Subhash C Chauhan, Bilal B Hafeez

Faculty, Staff and Student Publications

Dysregulated ribosome biogenesis and p53 mutations are known to play oncogenic roles in various cancers, including pancreatic cancer. In this study, we demonstrated the therapeutic potential of BMH-21, a pharmacologic inhibitor of RNA polymerase I, against pancreatic cancer by uncovering a novel molecular mechanism involving RPA194-mediated ubiquitination of mutant p53 without affecting the ubiquitination of wild-type p53. Our key findings are that (i) BMH-21 selectively induces apoptosis and cell growth inhibition of pancreatic cancer cells with no effect on normal human pancreatic ductal epithelial cells; (ii) BMH-21 degrades RPA194; (iii) BMH-21 inhibits recruitment of both RPA194 and RPA135 on rDNA …

Immunogenicity And Efficacy Of A Rabies-Based Vaccine Against Highly Pathogenic Influenza H5n1 Virus, Nir Paran, Christoph Wirblich, Randy Albrecht, Leila Zabihi Diba, Alessandro Tarquinio, Drishya Kurup, Charalambos C. Solomides, Adolfo García-Sastre, Matthias J. Schnell

Department of Microbiology and Immunology Faculty Papers

The recent spillover of highly pathogenic influenza A/H5N1 (HPAI-H5N1) viruses to cattle, other mammals, and humans poses a major risk to animal and human health. Virus adaptation to new species highlights the need for effective vaccines for animals and humans. We recently developed a rabies virus-based H5 vaccine encoding the HPAI-H5 antigen and presenting it on the surface of the rabies virus particle. To test the immunogenicity and efficacy of the vaccine in eliciting systemic and mucosal immune response, we vaccinated mice intramuscularly or intranasally with either live or inactivated and adjuvanted vaccine. The vaccine elicited neutralizing antibodies against RABV …

Rev-Erb-Alpha And -Beta Coordinately Regulate Astrocyte Reactivity And Proteostatic Function, Collin J Nadarajah, Michelle Y Li, Elsa I Quillin, Kevin Boyer, Julie M Dimitry, Yining Chen, Melvin W King, Ibrahim O Saliu, Jiyeon Lee, Patrick W Sheehan, Albert A Davis, Mitchell A Lazar, Guoyan Zhao, Erik S Musiek

2020-Current year OA Pubs

The molecular circadian clock is a ubiquitous transcriptional-translational feedback loop that regulates CNS function, glial responses, and neurodegenerative pathology. The nuclear receptors REV-ERB-α (

Osimertinib Activates A Tgf-Β2-Dependent Secretory Program That Drives Lung Adenocarcinoma Progression, Madhurima Ghosh, Chao Wu, Abhishek Kumar, Monique Nilsson, John V Heymach, Weina Zhao, Jiang Yu, Xin Liu, Na Ding, Shike Wang, Guan-Yu Xiao, Angelo Chen, Kate Grimley, William K Russell, Chad J Creighton, Xiaochao Tan, Jonathan M Kurie

Faculty, Staff and Student Publications

EGFR-mutant lung adenocarcinomas (LUADs) that are vulnerable to the EGFR antagonist osimertinib (Osi) eventually relapse, owing in part to the emergence of drug-tolerant persister (DTP) cells that arise through epigenetic mechanisms. Intratumoral DTP cells can herald a worse clinical outcome, but the way in which DTP cells influence LUAD progression remains unclear. Osi-resistant (OR) cells exhibit typical DTP cell features, including a propensity to undergo senescence and epithelial-mesenchymal transition (EMT), which can activate heightened secretory states. Therefore, we postulated that OR cells influence LUAD progression through paracrine mechanisms. To test this hypothesis, we utilized congenic pairs of EGFR-mutant LUAD cell …

Nrn1 As A Therapeutic Target For Alzheimer's Disease., Derian A Pugh, Gregory Cary, Kelsey M Greathouse, Lauren C Nassour-Caswell, Emma L Hobby, Nicholas T Seyfried, Jeremy H Herskowitz

Faculty Research 2026

INTRODUCTION: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

METHODS: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

RESULTS: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression …

Nrn1 As A Therapeutic Target For Alzheimer's Disease., Derian A Pugh, Gregory Cary, Kelsey M Greathouse, Lauren C Nassour-Caswell, Emma L Hobby, Nicholas T Seyfried, Jeremy H Herskowitz

Faculty Research 2026

INTRODUCTION: Neuritin-1 (NRN1) was identified as a synaptic protein associated with cognitive resilience to Alzheimer's disease (AD).

METHODS: Target risk score and cell type expression profiles were generated for NRN1 using methods developed by the Emory-Sage-SGC-JAX Target Enablement to Accelerate Therapy Development for Alzheimer's Disease (TREAT-AD) Center and Seattle Alzheimer's Disease Brain Cell Atlas (SEA-AD). Antibody characterization was conducted using Western blots and densitometry to assess the relative protein abundances of NRN1 in rodents, humans, and cell models.

RESULTS: NRN1 has a TREAT-AD target risk score of 3.29 out of 5. Based on single-nucleus RNA sequencing from SEA-AD, NRN1 expression …

Somatic Deficiency Of The Human E3 Ubiquitin Ligase Cbl In Leukocytes Impairs B Cell But Not T Cell Development And Function., Taja Vatovec, Anna-Lena Neehus, Katherine J L Jackson, Danielle T Avery, Ivan Bagarić, Lucia Erazo, Carlos A Arango-Franco, Masato Ogishi, Syed F Ahmed, Axel Cederholm, Amanda J Russell, Erika Della Mina, Dena Al-Rifai, Rowena Bull, Lori Buetow, Steicy Sobrino, Allison Zhang, Lara Wahlster, Marine Michelet, Nima Parvaneh, Jessica Peel, Federica Barzaghi, Davide Leardini, Quentin Philippot, Francesco Saettini, Jacques Dutrieux, Benedicte De Muylder, Francesca Vendemini, Francesco Baccelli, Albert Catala, Eleonora Gambineri, Marinella Veltroni, Vignesh Pandiarajan, Yurena Aguilar, Filomeen Haerynck, Michael Elliott, Stuart Turville, Fabienne Brillot, Taushif Khan, Filippo Consonni, Laureline Berteloot, William A Sewell, Geetha Rao, Laetitia Largeaud, Francesca Conti, Cecile Roullion, Cécile Masson, Francesco Pegoraro, Tianyi Ye, Samantha Joubran, Emily Villalpando, Boris Bessot, Yoann Seeleuthner, Tom Le Voyer, Jérémie Rosain, Hailun Li, Zarah Janda, Edoardo Muratore, Camille Soudée, Eric Delabesse, Claire Goulvestre, Mohammad Shahrooei, Anne Puel, Isabelle André, Christine Bole-Feysot, Laurent Abel, Miriam Erlacher, Vivien Béziat, Chantal Lagresle-Peyrou, Remi Cheynier, Emmanuelle Six, Nico Marr, Marlène Pasquet, Laia Alsina, Christopher C Goodnow, Nils Landegren, Alessandro Aiuti, Peng Zhang, Riccardo Masetti, Danny T Huang, Cindy S Ma, Jean-Laurent Casanova, Vijay G Sankaran, Jacinta Bustamante, Stuart G Tangye, Jonathan Bohlen

Faculty Research 2026

The E3 ubiquitin ligase Casitas B-lineage lymphoma (CBL) promotes positive selection and antigen responses in mouse T lymphocytes by ubiquitinating ZAP70. Conversely, mouse CBL and CBL-B mutually redundantly regulate SYK ubiquitination and B cell receptor signaling. Here we studied individuals with somatically homozygous CBL loss-of-function variants in leukocytes. Human CBL is largely redundant for the development and function of human T cells. Conversely, B cell development is altered at the immature stage, with a tenfold increase in transitional cells, enhanced survival of autoreactive clones and impaired tolerance manifested by autoantibody production. B cell maturation is intrinsically impaired by reduced apoptosis …

A Scalable Organoid Model Of Urothelial Aging For Metabolic Interrogation, Infection Modeling, And Reversal Of Age-Associated Changes, Adwaita R Parab, Arnold M Salazar, Steven J Bark, Margarita Divenko, Vasanta Putluri, D'Feau J Lieu, Aadya S Singh, Nagireddy Putluri, Indira U Mysorekar

Faculty, Staff and Students Publications

Aging leads to a progressive decline in overall bladder function resulting in lower urinary tract symptoms and increased susceptibility to infections. However, tissue-specific mechanisms of aging, specifically the contributions of the urothelium, remain elusive. Here, we introduce mouse bladder epithelium-derived organoids (mBEDOs) as a scalable platform to model urothelial aging. mBEDOs from aged mice recapitulate key features of age-associated cellular reprogramming, including oxidative stress, senescence, and DNA damage. We demonstrate the utility of mBEDOs for modeling Uropathogenic Escherichia coli (UPEC) infection, generating assembloids between mBEDOs and macrophages to model epithelial-immune interactions, and genetic perturbation. Using the mBEDO platform, we also …

Cyclic Amp-Dependent Regulation Of Ryanodine Receptors In Healthy And Diseased Hearts, Mohit M Hulsurkar, Isabelle Ong, Joshua A Keefe, Issam H Abu-Taha, Dobromir Dobrev, Xander H T Wehrens

Faculty, Staff and Students Publications

Cyclic adenosine monophosphate (cAMP) is a critical second messenger in cardiomyocytes, regulating essential cellular functions. Upon G-protein-coupled receptor stimulation, adenylyl cyclase (AC) synthesizes cAMP, which phosphodiesterase (PDE) enzymes subsequently degrade. Recent studies challenge the traditional view of uniform cAMP signaling, revealing nanodomain-specific regulation within cardiomyocytes. This localized cAMP signaling modulates key Ca2+-handling proteins, including ryanodine receptor type-2 (RyR2), through channel-bound protein kinases and PDEs. Additionally, nucleoside-diphosphate kinases (NDPKs), particularly NDPK-C, contribute to cAMP synthesis and RyR2 regulation. Elevated NDPK-C levels in failing hearts correlate with increased cAMP levels, enhanced sarcoplasmic reticulum Ca2+ release, and cardiac arrhythmias. Furthermore, cAMP influences the …

Progressive Neuroinflammation And Deficits In Motor Function In A Mouse Model With An Epg5 Pathogenic Variant Of Vici Syndrome., Bradley Thornton, Alexandra G. Hardinger, Laramie Pence, Priyanka Prem Kumar, Nikolas Connolly, Scott J. Weir, Jay L. Vivian

Manuscripts, Articles, Book Chapters and Other Papers

Vici syndrome (VS) is a rare pediatric genetic disorder characterized by profound developmental delay, seizures, immune deficits, cardiomyopathy and progressive motor dysfunction. This devastating condition is caused by pathogenic variants in the EPG5 gene, which encodes a regulator of autophagy, leading to the accumulation of toxic intracellular material and widespread cellular dysfunction. Less-severe EPG5 pathogenic variants have recently been linked to rare familial forms of Parkinson's disease, suggesting deficits in EPG5 function drive a range of neurodegenerative disorders. Currently, there are no effective treatments for any disorders associated with pathogenic variants of EPG5. The underlying cellular mechanisms driving the progressive …

Pair-Feeding Study Designs Can Create Biases And Inflate Type I Error Rates: A Simulation Study, Wasiuddin Najam, Daniel E Kpormegbey, Deependra K Thapa, Bret Rust, Lilian Golzarri-Arroyo, Lance H Baumgard, Louis Wai-Tong Fan, Joseph G Ibrahim, Edith J Mayorga, David B Allison

Children’s Nutrition Research Center Staff Publications

Objective: Pair-feeding is a study design element where one group's food intake is provided to another group to assess whether a treatment effect is independent of food intake. Investigators often assume equivalent food intake across experimental conditions and exclude it from the statistical analysis. However, the impact of this practice on type I error (T1Er) rates has not been quantified.

Methods: We conducted a Monte Carlo simulation in which animals were assigned baseline weights and food intakes, then randomized to non-pair-fed or pair-fed groups. Daily food intake for both groups was initially drawn from the baseline food intake distribution. For …

Rethinking The Centrality Of Brain Areas In Understanding Functional Organization, Benjamin Yost Hayden, Sarah R Heilbronner, Seng Bum Michael Yoo

Faculty, Staff and Students Publications

Parcellation of the cerebral cortex into functionally modular brain areas is foundational to cognitive and systems neuroscience. Here, we question the central status of brain areas from the perspectives of neuroanatomy and electrophysiology. We argue that the major ostensible determinants of brain function, such as cytoarchitecture and connectivity, seldom produce convergent parcellations. Brain areas themselves are just one of several equally important organizing principles; others include macroscale gradients, distributed networks, layers, columns and patches. We further argue that the evidence for a close correspondence between areal parcellation and cognitive function is weaker than is generally supposed. Indeed, many important cognitive …

Induction Of Yin Yang 1 (Yy1) Overexpression In Mature Adipocytes Promotes Dysfunctional Adipose Tissue And Systemic Insulin Resistance In Mice, Line Pedersen, Christy M Gliniak, Thomas Myhre Dale, Qingzhang Zhu, Chao Li, Jan-Bernd Funcke, Clair Crewe, Jiahui Luo, Lauren Palluth, Yi Zhu, Philipp E Scherer

Faculty, Staff and Students Publications

The ubiquitous transcription factor Ying Yang 1 (YY1) plays a fundamental role in multiple biological processes and is believed to regulate up to 10 % of all human genes. In thermogenic brown adipose tissue, YY1 has been linked to controlling mitochondrial gene expression and regulating cellular oxidative respiration, protecting against diet-induced obesity and alterations in energy balance. The role of YY1 in non-thermogenic, white adipose tissue, on the other hand, remains largely unknown. Here, we show that adipocyte-specific induction of YY1 promotes dysfunctional adipose tissue and systemic insulin resistance in mice. Long-term YY1 induction in mature adipocytes leads to reduced …

Therapeutic Potential Of C1-Inhibitor In Vascular Diseases And Beyond, Linda Sundler Björkman, Harish Eswaran, Steven P Grover

Faculty, Staff and Student Publications

C1INH (C1-inhibitor) is a multifunctional SERPIN (serine protease inhibitor) that functions as a major negative regulator of the complement, coagulation, and kallikrein-kinin systems. C1INH products were originally developed for the treatment of hereditary angioedema associated with C1INH deficiency. A growing body of literature indicates that C1INH products may find utility in the management of several other disease states. In this review, we detail the key biological activities of C1INH and consider the pathophysiological role of C1INH targets in many conditions. The therapeutic potential of exogenous C1INH is highlighted in the settings of thromboembolism, ischemia-reperfusion injury, sepsis, transplantation, and coronavirus disease …

Presenilin L166p Mutation, A Model Of Familial Alzheimer's Disease, Leads To Early Onset Bone Loss, Vidyani Suryadevara, Connor J Krehbial, Anuradha K Valiya, Melinda Vang, Julian Balanta-Melo, Pierre P Eleniste, Sumana Posritong, Jung Min Hong, Katie Chester, Gabriel M Pagnotti, Teresita Bellido, Monte S Willis, Angela Bruzzaniti

Faculty, Staff and Student Publications

Accelerated bone loss has been reported in the early stages of Alzheimer's disease (AD) as indicated by reduced bone mineral density and increased fracture risk in these patients, compared to healthy individuals. In the present study, we investigated bone loss in mouse models of familial Alzheimer's disease harboring the Presenilin 1 (L166P) knock-in mutation (PSEN1 KI), with or without the human amyloid precursor protein transgene (hAPP Tg+) known to induce brain amyloid pathology by 6 months. Female and not male 12-month PSEN1/hAPP Tg+ mice exhibited reduced whole-body bone mineral density and bone mineral content, compared to sex-matched controls. Consistent with …

Decellularized Extracellular Matrix Scaffolds To Engineer The Dormant Landscape Of Microscopic Colorectal Cancer Liver Metastasis, Sabrina N Vandenheuvel, Lucia L Nash, Abigail J Clevenger, Claudia A Collier, Oscar R Benavides, Sanjana Roy, Brinlee Goggans, Aelita Salikhova, Anvitha Tharakesh, Svasti Haricharan, Amber N Stratman, Scott Kopetz, Alex J Walsh, Shreya A Raghavan

Faculty, Staff and Student Publications

Recurrent liver-metastatic colorectal cancer contributes to high mortality. Recurrence occurs when dormant, microscopic residual disease survives initial treatment to escape dormancy. In their dormant, microscopic state within the liver, these metastatic lesions are undetectable by clinical diagnostic imaging until they form overt, chemoresistant metastases. Therefore, understanding the molecular mechanisms underlying dormancy in colorectal cancer liver metastases is a significant knowledge gap, motivating the engineering of nuanced in vitro models of disease. The current work presents an engineered model of liver-metastatic colorectal cancer dormancy. Decellularized extracellular matrix (dECM) scaffolds are used to provide microscopic colorectal cancer cell clusters with a biomimetic, …

Local Delivery Of Mir-27a* Using Ultrasound-Targeted Microbubble Cavitation Inhibits Squamous Cell Carcinoma Growth, Nikhil S Chari, Cheng Chen, Thiruganesh Ramasamy, Xucai Chen, Geetika Wadhwa, Anurag N Paranjape, Stephen Y Lai, Flordeliza S Villanueva

Faculty, Staff and Student Publications

Objective: Ultrasound-targeted microbubble (MB) cavitation (UTMC) is an image-guided therapeutic oligonucleotide delivery platform utilizing intravenously injected gas-filled ultrasound contrast agents, which carry the therapeutic on the MB shell. During transit of MBs in the microcirculation of target tissue, ultrasound causes MB oscillation, facilitating endocytosis-independent payload uptake within insonified cells. Here, we tested the hypothesis that UTMC-mediated miR-27a* delivery will reduce tumor growth rate and result in accumulation of miR-27a* within tumor cells and the tumor microenvironment.

Methods: We used UTMC to deliver miR-27a* to SCC-VII cells in vitro and in SCC-VII mouse tumor models. Pulsed ultrasound was delivered during intravenous …

Investigating The Oxygen Dependence Of Flash-Rt Using Electron Paramagnetic Resonance Imaging, Trey Waldrop, Grace Murley, Brett Velasquez, Elise Konradsson, Denae Neill, Luke Connell, Alan Lopez Hernandez, Abagail Delahoussaye, F William Schuler, Jorge De La Cerda, Ziyi Li, Mark D Pagel, Emil Schüler

Faculty, Staff and Student Publications

Purpose: The FLASH effect occurs when radiation given at ultra-high dose rates spares healthy tissue while achieving isoeffective tumor control relative to conventional (CONV) dose rate irradiation. Limited data has implicated oxygen in the FLASH effect. This study investigated the effect of tissue oxygen tension (pO2) on gastrointestinal (GI) FLASH sparing in mice.

Methods: pO2 was quantified in vivo by electron paramagnetic resonance imaging (EPRI)- noninvasive oximetry through spin probe injection and magnetic resonance co-registration- and a phosphorescent quenching microsensor. B6(Cg)-Tyrc-2 J/J female mice were imaged while breathing 10%, 21%, and 95% oxygen. C57BL/6 mice of both sexes underwent microsensor …

Tbr2-Dependent Parallel Pathways Regulate The Development Of Distinct Iprgc Subtypes, Takae Kiyama, Ching-Kang Chen, Halit Y Altay, Yu-Jiun Chen, Leviette Sigala, Dan Su, Steven Eliason, Brad A Amendt, Chai-An Mao

Faculty, Staff and Student Publications

The intrinsically photosensitive retinal ganglion cells (ipRGC) are the conduit between the retina and brain regions responsible for non-image-forming and image-forming vision. In mice, six ipRGC subtypes have been discovered based on morphological characteristics, functions, and molecular profiles. All ipRGCs arise from Tbr2-expressing RGCs during developmental stages and subsequently diverge and differentiate into the six mature, distinct subtypes in adult retinas. However, the cellular and molecular mechanisms controlling the formation and maturation of the six ipRGC subtypes remain elusive. Here, we demonstrate that two Tbr2-dependent transcription factors, Iroquois‑related homeobox 1 (Irx1) and T-box containing factor 20 (Tbx20), are key downstream …

Neurological Recovery After Ich Is Mediated By The Aryl Hydrocarbon Receptor-Bilirubin Interplay Through Improved Erythrophagocytosis, Xiurong Zhao, Shun-Ming Ting, Guanghua Sun, Jaroslaw Aronowski

Faculty, Staff and Student Publications

Hematoma clearance after ICH is a pro-hemostatic process aiming at repair/recovery and is achieved through microglia/macrophages (MMΦ)-mediated erythrophagocytosis. Upon the engulfment of masses of erythrocytes and toxic hemolysis products, hemoglobin and heme, phagocytes convert them to bilirubin (BrB). Bilirubin is essentially not soluble in water and when overproduced, it precipitates within the cell causing injury. Thus, keeping bilirubin soluble and at a low intracellular level is needed for proper function of MMΦ. Here, using cultured microglia (MG), we found that intracellular formation of BrB in microglia during erythrophagocytosis coincides with the activation of transcription factor AhR, and AhR target genes …

How To Measure, Analyze, And Interpret Age-Related Changes In Caenorhabditis Elegans: Lessons For Mechanistic And Evolutionary Theories Of Aging, Zuzana Kocsisova, Brian M Egan, Andrea Scharf, Xavier Anderson, Franziska Pohl, Aaron Anderson, Kerry Kornfeld

2020-Current year OA Pubs

Aging is characterized by progressive degenerative changes in tissue organization and function, some of which increase the probability of mortality. Major goals of aging research are to elucidate the series of events that cause degenerative changes, and to identify environmental, pharmacological, and genetic factors that influence these changes; this information might lead to new strategies to extend health span and lifespan. Mechanistic studies of aging depend on accurate and precise descriptions of age-related changes, since these descriptions define the aging phenotype. Here, we review studies that describe age-related changes in C. elegans, including measurements of integrated functions such as behavior …

A Systemic Selective Modified Mrna Delivery Platform For Preventing Chemotherapy-Induced Cardiotoxicity, Jimeen Yoo, Mengcheng Shen, Et Al.

2020-Current year OA Pubs

Doxorubicin (Dox) is a widely employed chemotherapeutic agent, but its use is clinically limited by dose-accumulative cardiotoxicity. More specifically, Dox induces oxidative stress and causes pro-apoptotic ceramide accumulation in cardiomyocytes (CMs). Acid ceramidase (AC) modified mRNA (modRNA) has been shown to reduce ceramide levels and protect the heart following ischemic injury; however, therapeutic modRNA applications have been hindered by the need for invasive delivery. Here, we present a platform for minimally intrusive transmission of modRNA to the heart. This CM-selective modRNA translational system (cmSMRTs) is encapsulated in lipid nanoparticles for intravenous (IV) delivery to enable systemic administration with high cardiac …

Functional Genomic Analysis Of Non-Canonical Dna Regulatory Elements Of The Aryl Hydrocarbon Receptor, Shayan Shahriar, Tajhal D Patel, Manjula Nakka, Sandra L Grimm, Cristian Coarfa, Daniel A Gorelick

Faculty, Staff and Students Publications

The aryl hydrocarbon receptor (AHR) is a ligand-dependent transcription factor activated by environmental toxicants like halogenated and polycyclic aromatic hydrocarbons, which then binds to DNA and regulates gene expression. AHR is implicated in numerous physiological processes, including liver and immune function, cell cycle control, oncogenesis, and metabolism. Traditionally, AHR binds a consensus DNA sequence (GCGTG), the xenobiotic response element (XRE), recruits coregulators, and modulates gene expression. Yet, recent evidence suggests AHR can also regulate gene expression via a non-consensus sequence (GGGA), termed the non-consensus XRE (NC-XRE). The prevalence and functional significance of NC-XRE motifs in the genome have remained unclear. …

Combined Glycoprotein Mutations In Rabies Virus Promote Astrocyte Tropism And Protective Cns Immunity In Mice, Mirjam Anna Rita Bertoune, Corinna Kolbe, Ann-Cathrin Werner, Maren Steinmetz, Bernhard Dietzschold, Eberhard Weihe

Department of Microbiology and Immunology Faculty Papers

Rabies virus (RABV) causes fatal encephalitis once it invades the central nervous system (CNS), and treatment options are extremely limited at this stage. We investigated the recombinant RABV variants SPBN, SPBNGA (glycoprotein substitution R333E), SPBNGAK (R333E plus N194K), SPBNGAS (R333E plus N194S), and TriGAS (three copies of the R333E/N194S glycoprotein). We evaluated their cellular tropism and immune activation in an intracerebral mouse infection model using immunohistochemistry and confocal immunofluorescence. SPBNGAK (R333E/N194K) resulted in mixed neuronal and astrocytic infection and lethal disease. In contrast, the R333E/N194S mutations in the GAS variants were associated with reduced neuronal infection and apparent astrocyte-restricted infection …