Digital Commons Network^™

Neurotransmitter Signaling In Molecular And Behavioral Immune Responses To Pathogens In C Elegans, Benson Otarigho, Alejandro Aballay

Faculty, Staff and Student Publications

Neurotransmitter signaling pathways play major roles in both molecular and behavioral defenses against pathogen invasion, shaping the ability of Caenorhabditis elegans to sense and respond to environmental challenges. Given the conservation of neurotransmitter signaling pathways, their understanding may not only provide insights into the neurobiology of C. elegans but also has broader implications for our understanding of neural-immune interactions and host defense mechanisms in higher organisms. In this review, we discussed the literature on various neurotransmitter signaling pathways, including serotonergic, dopaminergic/octopaminergic, GABAergic, and glutamatergic pathways, and how these pathways modulate molecular and behavioral immune defense against pathogens.

The Colonic Crypt: Cellular Dynamics And Signaling Pathways In Homeostasis And Cancer, Anh L. Nguyen, Molly A. Lausten, Bruce M. Boman

College of Life Sciences Faculty Papers

The goal of this review is to expand our understanding of how the cellular organization of the normal colonic crypt is maintained and elucidate how this intricate architecture is disrupted during tumorigenesis. Additionally, it will focus on implications for new therapeutic strategies targeting Epithelial-Mesenchymal Transition (EMT). The colonic crypt is a highly structured epithelial unit that functions in maintaining homeostasis through a complex physiological function of diverse cell types: SCs, transit-amplifying (TA) progenitors, goblet cells, absorptive colonocytes, Paneth-like cells, M cells, tuft cells, and enteroendocrine cells. These cellular subpopulations are spatially organized and regulated by multiple crucial signaling pathways, including …

Human Toxocariasis, Susana Lopez-Alamillo, Pravallika Padyala, Megan Carey, Megan M Duffey, Jill E Weatherhead

Faculty, Staff and Students Publications

Human toxocariasis is a globally prevalent zoonotic parasitic infection caused by larvae of Toxocara species, primarily Toxocara canis and Toxocara cati. Toxocariasis is commonly transmitted to humans through the ingestion of embryonated Toxocara eggs found in contaminated soil, water, or on surfaces contaminated with animal feces. Unlike in dogs and cats, humans are not definitive hosts for Toxocara spp., and, as a result, Toxocara larvae do not complete their life cycle in humans. Instead, following accidental oral ingestion of embryonated eggs, Toxocara larvae undergo an aberrant larval migratory cycle to various organs including the lungs, liver, muscles, and central …

Retinoid-X-Receptor As A Mediator Of Poststroke Recovery By Reversing Age-Associated Phenotypes Of Microglia/Hematogenous Macrophages, Shun-Ming Ting, Xiurong Zhao, Guanghua Sun, Mercedes Ricote, Jaroslaw Aronowski

Faculty, Staff and Student Publications

After stroke, microglia and hematogenous macrophages, together referred to as MΦ, clear dead cells and cellular debris in the infarcted brain through phagocytosis as an essential part of the recovery process. However, the phagocytic capability of MΦ declines with age. Furthermore, aged MΦ become overactivated in response to stroke, enhancing secondary brain injury. In this study, we demonstrated that by reversing the age-related dysfunctions in MΦ through activating the retinoid X receptor (RXR), the recovery after stroke in the aged brain could be improved. Using RNA-sequencing, we compared the transcriptomes between MΦ isolated from the brains of young and aged …

Infectious Prions In Brains And Muscles Of Domestic Pigs Experimentally Challenged With The Bse, Scrapie, And Cwd Agents, Francisca Bravo-Risi, Fraser Brydon, Angela Chong, Kane Spicker, Justin J Greenlee, Glenn Telling, Claudio Soto, Sandra Pritzkow, Marcelo A Barria, Rodrigo Morales

Faculty, Staff and Student Publications

Experimental studies suggest that animal species not previously described as naturally infected by prions are susceptible to prion diseases affecting sheep, cattle, and deer. These interspecies transmissions may generate prions with unknown host ranges. Pigs are susceptible to prions from different origins, including deer chronic wasting disease (CWD), sheep scrapie, and bovine spongiform encephalopathy (BSE). Here, we studied prions in brains and muscles from pigs previously infected with these different prion sources. Specifically, we measured the total prion protein (PrP) and PK-resistant PrP by western blot. Seeding activity in these tissues was evaluated using the protein misfolding cyclic amplification (PMCA) …

Inhibition Of The Ufd-1-Npl-4 Complex Triggers An Aberrant Immune Response In Caenorhabditis Elegans, Rajneesh Rao, Alejandro Aballay, Jogender Singh

Faculty, Staff and Student Publications

The UFD-1 (ubiquitin fusion degradation 1)-NPL-4 (nuclear protein localization homolog 4) heterodimer is involved in extracting ubiquitinated proteins from several plasma membrane locations, including the endoplasmic reticulum. This heterodimer complex helps in the degradation of ubiquitinated proteins via the proteasome with the help of the AAA+ATPase CDC-48. While the ubiquitin-proteasome system is known to have important roles in maintaining innate immune responses, the role of the UFD-1-NPL-4 complex in regulating immunity remains elusive. In this study, we investigate the role of the UFD-1-NPL-4 complex in maintaining

Therapeutic Restoration Of Mitochondria-Endoplasmic Reticulum Cross Talk For Osteoarthritis, Mingzhuang Hou, Yifan Ma, Yaoge Deng, Yubin Wu, Yanrun Zhu, Yang Liu, Xiaoping Li, Lili Yu, Zirui He, Yifan Wang, Shiyan Dong, Xiaowei Xia, Jianfeng Yu, Chenqi Yu, Kang Kang, Yingjie Lu, Lili Sun, Betty Y S Kim, Yuan Yuan, Yijian Zhang, Wen Jiang, Xuesong Zhu

Faculty, Staff and Student Publications

Osteoarthritis is a prevalent joint disease in the aging population. The hallmark of osteoarthritis is the degeneration of the joint cartilage, characterized by changes in chondrocytes including mitochondrial dysfunction. However, the precise mechanisms of how this affects chondrocyte homeostasis and whether such processes can be explored as therapeutic targets for osteoarthritis remain unclear. Here, we show that impaired mitochondrial function and disrupted cartilage matrix metabolism due to loss of mitofusin-2 (MFN2) expression in chondrocytes leads to the development of osteoarthritis. Sirtuin-3 (SIRT3), a key regulator of mitochondrial function, plays a critical role in modulating MFN2 to restore mitochondrial dynamics, reduce …

Testis Expressed 50 Is Essential For Maintaining Sperm Acrosome Integrity During Epididymal Transit, Saori Haga, Kaori Nozawa, Ferheen Abbasi, Katarzyna Kent, Naoko Nagasawa, Tsutomu Endo, Haruhiko Miyata, Masahito Ikawa, Martin M Matzuk, Yoshitaka Fujihara

Faculty, Staff and Students Publications

In mammals, sperm formation is completed in the seminiferous tubules within the testis, and sperm maturation occurs during the epididymal transit of the spermatozoa. Sperm morphology drastically changes when abnormal spermatozoa migrate from the testis to the epididymis. Detailed molecular mechanisms for sperm survival in the epididymis have not been determined yet. Globozoospermia is a cause of male infertility and is characterized by round-headed spermatozoa without acrosomes, an abnormal sperm nuclear membrane, and sperm midpiece defects. Testis expressed 50 (Tex50) is a testis-enriched gene that is expressed in mice and humans. Using CRISPR-Cas9, we generated Tex50 knockout (KO) …

Computationally Resolved Neuroprogenitor Cell Biomarkers Associate With Human Disorders, Gerarda Cappuccio, William T Choi, Fatih Semerci, Jill A Rosenfeld, Toni Claire Tacorda, Guantong Qi, Anthony W Zoghbi, Yi Zhong, Hu Chen, Pengfei Liu, Zhandong Liu, Mirjana Maletić-Savatić

Duncan NRI Faculty and Staff Publications

Adult hippocampal neurogenesis, the process of generating new neurons, relies on a rare population of neural stem and progenitor cells (NPCs) within the dentate gyrus complex microenvironment. Discovering the specific genes that define these cells is vital yet challenging due to overlapping expression patterns, limiting detection of rare cell populations using traditional approaches. By employing the computational digital sorting algorithm (DSA) that deconvolves complex gene expression data based on pattern recognition, we identified 129 genes enriched in murine NPCs. We validated these genes against published single-cell RNA sequencing (scRNA-seq) data and discovered that 25 human orthologs were known to cause …

Endothelin B Receptor Inhibition Rescues Aging-Dependent Neuronal Regenerative Decline, Rui Feng, Sarah F Rosen, Irshad Ansari, Sebastian John, Michael B Thomsen, Oshri Avraham, Cedric G Geoffroy, Valeria Cavalli

2020-Current year OA Pubs

Peripheral sensory neurons regenerate their axons after injury to regain function, but this ability declines with age. The mechanisms behind this decline are not fully understood. While excessive production of endothelin 1 (ET-1), a potent vasoconstrictor, is linked to many diseases that increase with age, the role of ET-1 and its receptors in axon regeneration is unknown. Using single-cell RNA sequencing, we show that satellite glial cells (SGCs), which completely envelop the sensory neuron soma residing in the dorsal root ganglia (DRG), express the endothelin B receptor (ETBR), while ET-1 is expressed by endothelial cells. Inhibition of ETBR ex vivo …

Fatty Acid 2-Hydroxylase Facilitates Rotavirus Uncoating And Endosomal Escape, Enkai Li, Ruochen Zang, Takahiro Kawagishi, Wei Zhang, Kruthika Iyer, Gaopeng Hou, Qiru Zeng, Rita M Meganck, Susan R Ross, Xin Wang, Xiong Su, Siyuan Ding

2020-Current year OA Pubs

Despite the clinical significance of many nonenveloped viruses, the molecular mechanisms of their internalization and membrane penetration are not well understood. Rotaviruses (RVs) are nonenveloped double-stranded RNA viruses and the leading cause of severe dehydrating diarrhea in infants and young children. We identified fatty acid 2-hydroxylase (encoded by

Dissecting The Effect Of Mitochondrial Bcat Inhibition In Methylmalonic Acidemia, Madeline G Hemmingsen, Guo-Fang Zhang, Yunhan Ma, Hannah Marchuk, Kalyani R Patel, Tong Chen, Xinning Li, Mark Chapman, Sabrina Collias, Dolores H Lopez-Terrada, James Beasley, Ashlee R Stiles, Randy J Chandler, Charles P Venditti, Sarah P Young, Mercedes Barzi, Beatrice Bissig-Choisat, Doug Krafte, Christopher B Newgard, Karl-Dimiter Bissig

Faculty, Staff and Students Publications

Methylmalonic acidemia (MMA) is a severe metabolic disorder affecting multiple organs because of a distal block in branched-chain amino acid (BCAA) catabolism. Standard of care is limited to protein restriction and supportive care during metabolic decompensation. Severe cases require liver/kidney transplantation, and there is a clear need for better therapy. Here, we investigated the effects of a small molecule branched-chain amino acid transaminase (BCAT) inhibitor in human MMA hepatocytes and an MMA mouse model. Mitochondrial BCAT is the first step in BCAA catabolism, and reduction of flux through an early enzymatic step is successfully used in other amino acid metabolic …

Interindividual Genetic Differences Drive Discordance Between Serum Calcidiol And Calcitriol Concentrations In Females., Elizabeth K Hutchins, Changran Niu, Jing Xue, Debin Wan, Carolina V Campos, Molly Warren, Megan M Knuth, Michael B Whalen, Venkata S Voruganti, Rafiou Agoro, James C Fleet, Bruce D Hammock, Folami Ideraabdullah

Faculty Research 2025

Vitamin D insufficiency (VDI) is primarily determined by serum levels of calcidiol, which serves as a biomarker for the less abundant but most potent bioactive metabolite, calcitriol. However, population studies often show discordance between calcidiol and calcitriol. Here, a genetically diverse population of 7 inbred mouse strains was used to investigate the role of interindividual genetic differences in driving calcidiol-to-calcitriol discordance under vitamin D sufficient (VDS) vs depleted (VDD) conditions. We found high interstrain variability in calcitriol that was discordant with calcidiol under VDS and VDD conditions. However, under VDS conditions, stratification by calcitriol level revealed that strains with serum …

Gene Context Drift Identifies Drug Targets To Mitigate Cancer Treatment Resistance, Amir Jassim, Birgit V Nimmervoll, Sabrina Terranova, Erica Nathan, Linda Hu, Jessica T Taylor, Katherine E Masih, Lisa Ruff, Matilde Duarte, Elizabeth Cooper, Gunjan Katyal, Melika Akhbari, Reuben J Gilbertson, Jennifer C Coleman, Joseph S Toker, Colton Terhune, Gabriel Balmus, Stephen P Jackson, Hailong Liu, Tao Jiang, Michael D Taylor, Kui Hua, Jean E Abraham, Mariella G Filbin, Anthony Hill, Anarita Patrizi, Neil Dani, Aviv Regev, Maria K Lehtinen, Richard J Gilbertson

Faculty, Staff and Students Publications

Cancer treatment often fails because combinations of different therapies evoke complex resistance mechanisms that are hard to predict. We introduce REsistance through COntext DRift (RECODR): a computational pipeline that combines co-expression graph networks of single-cell RNA sequencing profiles with a graph-embedding approach to measure changes in gene co-expression context during cancer treatment. RECODR is based on the idea that gene co-expression context, rather than expression level alone, reveals important information about treatment resistance. Analysis of tumors treated in preclinical and clinical trials using RECODR unmasked resistance mechanisms -invisible to existing computational approaches- enabling the design of highly effective combination treatments …

Identification Of Cobra And Viper Bites In Southern India Using Enzyme-Linked Immunosorbent Assay, Tejeswara Rao Asuru, Raskin Erusan Rajagopal, Albert Rajendran, Gulistan Parveen, Anushka Das, Pabitha Devi, Swapan K Dasgupta, Shantaraman Kalyanaraman, Prasenjit Guchhait, Perumal Thiagarajan

Faculty, Staff and Students Publications

Introduction: Snakebite-related deaths are major concerns in populations worldwide that lack access to medical care. Current treatment of snakebites includes administration of polyspecific and polyvalent heterologous equine antiserum. Swift diagnosis of the species of snake responsible is essential to initiate a specific treatment.

Methods: We generated murine monoclonal and rabbit polyclonal antibodies against the venom of the 3 most common venomous snakes in southern India: the Russell viper, the saw-scaled viper, and the Indian cobra. We developed an enzyme-linked immunosorbent assay to distinguish the snake by analyzing the exudates from the snakebite wound.

Results: Monoclonal antibody EC3 reacts specifically with …

Chemo-Rast With Bortezomib Inhibits Multiple Myeloma Relapse, Anchal Ghai, Alexander Zheleznyak, Christopher Egbulefu, Nicole Blasi, Kvar Black, Rui Tang, Matthew L Cooper, Kiran Vij, Ravi Vij, John Dipersio, Monica Shokeen, Samuel Achilefu

2020-Current year OA Pubs

No abstract provided.

Post-Translational Modification Of H2b C-Terminal Helix Regulates Nucleosome Interactions And Chromatin Signaling, Yani Zhao, Anh Nguyen, Eyla C Arteaga, Aleksandra Skrajna, Krzysztof Krajewski, Dennis Goldfarb, Robert K Mcginty

2020-Current year OA Pubs

Histone H2B contains a highly conserved C-terminal (H2B αC) helix that has been implicated in chromatin interactions and dynamics. The H2B αC helix comprising residues 105-125 is positioned adjacent to a major site of nucleosome interactions called the acidic patch. Despite individual structural studies highlighting interactions between chromatin proteins and the H2B αC helix, the general role of the helix in mediating nucleosome recognition has not been explored. Moreover, many post-translational modifications (PTMs) have been identified within the H2B αC helix, but significant gaps exist in our understanding of their regulatory potential. In this study, we employed nucleosome affinity proteomics …

Lewy Body Dementia Promotion By Air Pollutants, Xiaodi Zhang, Haiqing Liu, Xiao Wu, Longgang Jia, Kundlik Gadhave, Lena Wang, Kevin Zhang, Hanyu Li, Rong Chen, Ramhari Kumbhar, Ning Wang, Chantelle E Terrillion, Bong Gu Kang, Bin Bai, Minhan Park, Ma Cristine Faye Denna, Shu Zhang, Wenqiang Zheng, Denghui Ye, Xiaoli Rong, Liu Yang, Lili Niu, Han Seok Ko, Weiyi Peng, Lingtao Jin, Mingyao Ying, Liana S Rosenthal, David W Nauen, Alex Pantelyat, Mahima Kaur, Kezia Irene, Liuhua Shi, Rahel Feleke, Sonia García-Ruiz, Mina Ryten, Valina L Dawson, Francesca Dominici, Rodney J Weber, Xuan Zhang, Pengfei Liu, Ted M Dawson, Shizhong Han, Xiaobo Mao

Faculty, Staff and Student Publications

Evidence links air pollution to dementia, yet its role in Lewy body dementia (LBD) remains unclear. Here we showed in a cohort of 56.5 million individuals across the U.S. that PM2.5 exposure raises LBD risk. Mechanistically, we found PM2.5 exposure led to brain atrophy in wild-type mice, an effect not seen in α-synuclein (αSyn)-deficient mice. PM2.5 exposure generated a highly pathogenic αSyn strain, PM-PFF, with enhanced proteinase K-resistance and neurotoxicity, resembling αSyn LBD strains. PM2.5 samples from China, the U.S., and Europe consistently induced proteinase-resistant αSyn strains and in vivo pathology. Transcriptomic analyses revealed shared responses between PM2.5-exposed mice and …

Human Papillomavirus Integration Induces Oncogenic Host Gene Fusions In Oropharyngeal Cancers, Nusrat Khan, Keiko Akagi, Shiming Jiang, Joe Dan Dunn, Bo Jiang, Weihong Xiao, Madison P O'Hara, Li Shen, Qi Wang, Vakul Mohanty, Jing Wang, Sara Goodwin, Jamie L Hutchins, Kevin R Coombes, Jagannadha K Sastry, David E Symer, Maura L Gillison

Faculty, Staff and Student Publications

HPV integration disrupts host genomic structure and expression, but whether these alterations promote cancer development remains unclear. Multiple genomic analyses of oropharyngeal cancers identified several host fusion genes, including recurrent FGFR3-TACC3 fusions, expressed from rearranged genomic loci adjacent to HPV integration sites. Evolutionary modeling implicated integration of virus concatemers into the host genome as a common initiating event in fusion formation. Co-expression of HPV16 E6/E7 and FGFR3-TACC3, but neither alone, was sufficient for tumor development in both xenograft and syngeneic mouse models and led to unique transcriptional programs implicated in carcinogenesis. FGFR3-TACC3 expression decreased the ubiquitination and degradation of …

An Allele-Agnostic Mutant-Kras Inhibitor Suppresses Tumor Maintenance Signals And Reprograms Tumor Immunity In Pancreatic Cancer, Kathleen M Mcandrews, Francesca Paradiso, Clint A Stalnecker, Benson S Chellakkan, Fredrik I Thege, David H Peng, Barbara A Moreno Diaz, Hikaru Sugimoto, Sarah I Patel, Krishnan K Mahadevan, Michelle L Kirtley, Danielle Wills, Amari M Sockwell, Andre Luis F Fonseca, Yunhe Liu, Kimal I Rajapakshe, Nathaniel G Yee, Phuong Thao Tran, Huda Alchikh Omar, Antonio Tedeschi, Fiorella Schischlik-Siegl, Andrew S Boghossian, Matthew G Rees, Melissa M Ronan, Jennifer A Roth, Dorothea Rudolph, Martin Aichinger, Florian Ebner, Artem V Artemov, Jesse Lipp, Laura Pisarsky, Valerie Laura Herrmann, John Park, Jörg F Rippmann, Otmar Schaaf, Vanessa Chandler, Mariah Williams, Charles E Deckard, Linghua Wang, Channing J Der, Christopher Vellano, Paola A Guerrero, Timothy P Heffernan, Raghu Kalluri, Anirban Maitra

Faculty, Staff and Student Publications

KRAS is among the most frequently mutated oncogenes in cancer, and for decades, efforts at pharmacological blockade of its function in solid cancers have been unsuccessful. A notable advance in this endeavor is the recent development of small molecule KRAS inhibitors, which enable direct targeting of the mutant oncoprotein. Here, we comprehensively evaluate the pre-clinical efficacy of BI-2493 a panKRASi, a first-in-class allele agnostic mutant KRAS inhibitor, in pancreatic ductal adenocarcinoma (PDAC). We report effective tumor growth suppression across a broad range of models, including cell lines, patient-derived xenografts (PDXs), syngeneic orthotopic models, and prolonged survival in genetically engineered mouse …

Nebulization Of An Mrna-Encoded Monoclonal Antibody For Passive Immunization Of Foals Against Rhodococcus Equi, Rebecca M Legere, Jeannine A Ott, Cristina Poveda, Daryll Vanover, Karin E R Borba, Jae Yeon Joo, Cameron L Martin, Bibiana P Da Silveira, Jocelyne M Bray, Kerstin Landrock, Gus A Wright, J Chistensen Blazier, Andrew E Hillhouse, Ashley L Benham-Duret, Brandon Mistretta, Rafaela L Klein, Sarah M Thompson, Amelia R Woolums, Michael F Criscitiello, Luc R Berghman, Angela I Bordin, Philip J Santangelo, Jeroen Pollet, Noah D Cohen

Faculty, Staff and Students Publications

Inhalation of Rhodococcus equi causes severe pneumonia in humans and animals worldwide, most commonly affecting horse foals. The standard for preventing R. equi pneumonia in foals is transfusion of hyperimmune plasma, which is expensive and carries the risk of adverse effects. Our goal was to passively immunize foals against R. equi by nebulizing mRNA encoding an equine monoclonal antibody (mAb) against the virulence-associated protein A (VapA) directly into the lungs. VapA-specific memory B cells from an immunized horse were used to identify and select the sequence for an equine immunoglobulin (Ig)G1 mAb. In vitro-transcribed mRNA encoding this sequence expressed …

Persistent Na+ Current Couples Spreading Depolarization To Seizures In Scn8a Gain-Of-Function Mice, Isamu Aiba, Yao Ning, Jeffrey L Noebels

Faculty, Staff and Students Publications

Spreading depolarization (SD) is a slowly propagating wave of massive cellular depolarization that transiently impairs the function of affected brain regions. Although SD typically arises as an isolated hemispheric event, we previously reported that reducing M-type potassium current (IKM) by ablation of Kcnq2 in forebrain excitatory neurons results in tightly coupled spontaneous bilateral seizure–SD complexes in the awake mouse cortex.

Here we find that enhanced persistent Na+ current attributable to gain-of-function mutations in Scn8a (N1768D/+, hereafter D/+) produces a similar compound cortical excitability phenotype. Chronic direct-current (DC)-band EEG recording detected spontaneous bilateral seizure–SD complexes accompanied by seizures with …

Absence Of Glaucoma In Tg-Myocy437h Mice Of Diverse Genetic Backgrounds., Nicholas G Tolman, Marina Simón, Felicia A Juarez, Chi Zhang, Zhivka I Hristova, Tionna Ouellette, Michael A Sellarole, Wilhelmine N Devries, Christa Montgomery, Simon W M John

Faculty Research 2025

PURPOSE: Mutations in the myocilin (MYOC) gene cause elevated intraocular pressure and glaucoma. To better understand the factors influencing susceptibility to glaucoma, we studied the MYOC mutation (MYOCY437H).

METHODS: We characterized ocular phenotypes in Tg-MYOCY437H mice on nine different mouse strain backgrounds.

RESULTS: No glaucoma-related phenotypes were observed. We detected neither elevated intraocular pressure (daytime readings) nor optic nerve degeneration differences between wild type (WT) and Tg-MYOCY437H mice. This included an absence of Tg-MYOCY437H-induced phenotypes on a mixed B6SJL background that best reflected the original publications with this strain. We confirmed that this result was not due to an absence …

Chp1 Promotes Lipid Droplet Growth And Regulates The Localization Of Key Enzymes For Triacylglycerol Synthesis, Guang Yang, Ximing Du, Dougall Norris, Armella Zadoorian, Yuyuan Zheng, Mingming Gao, Andrew J Brown, Shane T Grey, Chun Zhou, Hongyuan Yang

Faculty, Staff and Student Publications

The glycerol-3-phosphate (G-3-P) pathway is central to the synthesis of triacylglycerols (TAGs) and glycerophospholipids, essential for membrane biogenesis and lipid storage. The first and rate-limiting step in this pathway is catalyzed by glycerol-3-phosphate acyltransferases (GPATs), with microsomal GPAT3 and GPAT4 being evolutionarily conserved and predominant in most tissues. While previous studies have implicated Calcineurin B homologous protein 1 (CHP1) as a cofactor for GPAT4, the broader role of CHP1 in regulating microsomal GPATs and TAG biosynthesis remains unclear. Here, we demonstrate that CHP1 is a critical regulator of both GPAT3 and GPAT4, essential for their stability, enzymatic activity, and lipid …

Targeting Aldh16a1 Mediated Thioredoxin Lysosomal Degradation To Enhance Ferroptosis Susceptibility In Smarca4-Deficient Nsclc, Guoshu Bi, Jiaqi Liang, Yunyi Bian, Guangyao Shan, Shencheng Ren, Haochun Shi, Xiaolong Huang, Junkan Zhu, Qun Wang, Wei Jiang, Boyi Gan, Cheng Zhan

Faculty, Staff and Student Publications

Ferroptosis, an iron-dependent form of cell death, holds promise for cancer therapy. However, the intricate link between ferroptosis and oncogenic mutations remains unclear. Here we show that SMARCA4, a well-established tumour suppressor whose deficiency is associated with poor prognosis and resistance to treatments, sensitizes non-small cell lung cancer (NSCLC) cells to ferroptosis. Mechanistically, SMARCA4 promotes chromatin accessibility and expression of ALDH16A1. Surprisingly, ALDH16A1 lacks ALDH enzymatic activity, but binds to the anti-ferroptotic oxidoreductase thioredoxin (TXN), facilitating its translocation to the lysosome and subsequent degradation. Meanwhile, ALDH16A1 directly inhibits TXN's oxidoreductase function by occluding its active site. We also show that …

Inhibition Of Mcl-1 And Mek Overcomes Mek Inhibitor Resistance In Triple-Negative And Inflammatory Breast Cancers, Mohd Mughees, Moises Tacam, Alex W Tan, Mary Kathryn Pitner, Lakesla R Iles, Xiaoding Hu, Emilly S Villodre, Bisrat G Debeb, Takahiro Kogawa, Bora Lim, Rachel M Layman, Wendy A Woodward, Naoto T Ueno, Debu Tripathy, Savitri Krishnamurthy, Yuan Qi, Lajos Pusztai, Jian Wang, Varsha Gandhi, Geoffrey Bartholomeusz, Chandra Bartholomeusz

Faculty, Staff and Student Publications

The MAPK pathway can drive resistance in highly aggressive breast cancers. Our previous work showed that the MEK inhibitor (MEKi) AZD6244 (selumetinib) prevented lung metastasis in a breast cancer xenograft model. In clinical studies, MEKis as single agents have had only modest activity against solid tumors due to the onset of resistance. Using synthetic lethality siRNA screening, we identified myeloid cell leukemia-1 (MCL-1) as a potential contributor to AZD6244 resistance. We hypothesized that MCL-1 promotes MEKi resistance in highly aggressive breast cancers and that MCL-1 inhibition overcomes AZD6244 resistance. We established two AZD6244-resistant cell lines: MDA-MB-231-R (triple-negative breast cancer) and …

Efficacy Of Atr Kinase Inhibitor Elimusertib Monotherapy Or Combination In Tumors With Dna Damage Response Pathway And Other Genomic Alterations, Kaushik Varadarajan, Christian X Cruz Pico, Kurt W Evans, Maria Gabriela Raso, Yasmeen Qamar Rizvi, Xiaofeng Zheng, Dhruv Chachad, Timothy P Diperi, Bailiang Wang, Stephen M Scott, Ming Zhao, Argun Akcakanat, Antje M Wengner, Timothy A Yap, Funda Meric-Bernstam

Faculty, Staff and Student Publications

The ataxia telangiectasia and RAD3-related (ATR) kinase functions with ataxia telangiectasia-mutated (ATM) kinase as a modulator of DNA damage response (DDR). We assessed the antitumor effects of the ATR inhibitor elimusertib (BAY-1895344) in patient-derived xenograft (PDX) models with DDR alterations. Antitumor activity was assessed by change in tumor volume (TV) from baseline. Responses were categorized as follows: partial response (PR), ≥30% decrease in TV; ≥20% increase in TV, progressive disease; and non-PR/progressive disease, stable disease (SD). Event-free survival was defined as time for tumor doubling (EFS-2). Of 21 PDX models tested, 11 had significant prolongation of EFS-2 with elimusertib monotherapy. …

Age-Dependent Brain Responses To Mechanical Stress Determine Resilience In A Chronic Lymphatic Drainage Impairment Model, Zachary Gursky, Zohaib Nisar Khan, Sunil Koundal, Ankita Bhardwaj, Joaquin Caceres Melgarejo, Kaiming Xu, Xinan Chen, Hung-Mo Lin, Xianfeng Gu, Hedok Lee, Jonathan Kipnis, Yoav Dori, Allen Tannenbaum, Laura Santambrogio, Helene Benveniste

2020-Current year OA Pubs

The outflow of 'dirty' brain fluids from the glymphatic system drains via the meningeal lymphatic vessels to the lymph nodes in the neck, primarily the deep cervical lymph nodes (dcLN). However, it is unclear whether dcLN drainage is essential for normal cerebral homeostasis. Using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and computational fluid dynamics, we studied the impact of long-term mechanical stress from compromised dcLN drainage on brain solute and fluid outflow in anesthetized rats. We found that in young, but not middle-aged, rats, impairment of dcLN drainage was linked to moderately increased intracranial pressure and the emergence of extracranial …

Commensal Colonization Of Candida Albicans In The Mouse Gastrointestinal Tract Is Mediated Via Expression Of Candidalysin And Adhesins, Kelsey E Mauk, Pedro Miramón, Michael C Lorenz, Léa Lortal, Julian R Naglik, Bernhard Hube, Lynn Bimler, Farrah Kheradmand, David B Corry

Faculty, Staff and Students Publications

The ubiquitous fungal pathogen Candida albicans has the potential to either asymptomatically colonize the gastrointestinal (GI) tract or become an invasive pathogen through mechanisms that remain incompletely understood. Here we explored the fungal, host, and environmental factors that influence the ability of C. albicans to colonize the mouse GI tract using a representative clinical strain, CLCA10. After a single gavage challenge (5 × 106 CFU C. albicans), specific pathogen-free (SPF) mice remained colonized with C. albicans strain CLCA10, but not other Candida species, for at least 58 days with the fungus confined largely to the gut luminal …

Identifying Genetic Determinants Of Outer Retinal Function In Mice Using A Large-Scale Gene-Targeted Screen., Janine M Wotton, Mark P. Krebs, Riccardo Sangermano, Jessica Wong, Cynthia Smith, Amelia M Willett, Douglas Howell, Abby Jones, Catherine Witmeyer, Jacob P Lowy, Michael Mcfarland, Stephen A Murray, Robert E Braun, Patsy M. Nishina, Eric A Pierce, Emily M Place, Kinga M Bujakowska, Neal S Peachey, Jacqueline K White

Faculty Research 2025

Electroretinography (ERG) provides a noninvasive functional measure of multiple cell types of the outer retina. We conducted an ERG-based screen of 530 single-gene knockout mouse strains generated as part of the International Mouse Phenotyping Consortium, representing 2.5% of all protein-coding genes, to identify genetic variants affecting retinal function. We identified 30 strains with significantly altered ERG amplitudes. Two of the genes identified, Cfap418 and Syne2, have been previously reported with outer retinal dysfunction, thereby serving as internal controls that validate our screening protocol. Of the remaining 28 genes newly associated with altered retinal function, the majority lacked a contemporaneous histopathology …