Digital Commons Network^™

Α4 Nicotinic Acetylcholine Receptors In Lipopolysaccharide-Related Lung Inflammation, J. Ritzenthaler, Walter H. Watson, Jesse Roman

Division of Pulmonary, Allergy, and Critical Care Medicine Faculty Papers

Sepsis remains an important healthcare challenge. The lungs are often affected in sepsis, resulting in acute lung injury characterized by inflammation. Mechanisms involving lipopolysaccharide (LPS) stimulation of toll-like receptor (TLR) signaling with induction of proinflammatory pathways have been implicated in this process. To date, however, studies targeting these pathways have failed to improve outcomes. We have found that LPS may also promote lung injury through the activation of α4 nicotinic acetylcholine receptors (α4 nAChRs) in immune cells. We observed increased expression of α4 nAChRs in human THP-1 monocytic cells exposed to LPS (100 ng/mL, 24 h). We also observed that …

Current Understanding Of The Impact Of United States Military Airborne Hazards And Burn Pit Exposures On Respiratory Health, Janeen Trembley, Paul Barach, Julie Tomáška, Jedidah Poole, Pamela Ginex, Robert Miller, Jacob Lindheimer, Anthony Szema, Kimberly Gandy, Trishul Siddharthan, Jason Kirkness, Joshua Nixon, Rosie Lopez Torres, Mark Klein, Timothy Nurkiewicz, Tammy Butterick

College of Population Health Faculty Papers

Millions of United States (U.S.) troops deployed to the Middle East and Southwest Asia were exposed to toxic airborne hazards and/or open-air burn pits. Burn pit emissions contain particulate matter combined with toxic gasses and heavy metals. Ongoing research has demonstrated that exposures to the airborne hazards from military burn pits have profound and lasting health and wellness consequences. Research on the long-term health consequences of exposure to open burn pits has been limited. Work continues to understand the scope of the health impacts and the underlying pathobiology following exposures and to establish care standards. The U.S. Sergeant First Class …

Glucose Metabolism Controls Monocyte Homeostasis And Migration But Has No Impact On Atherosclerosis Development In Mice, Alexandre Gallerand, Gyu Seong Heo, Hannah Luehmann, Yongjian Liu, Et Al.

2020-Current year OA Pubs

Monocytes directly contribute to atherosclerosis development by their recruitment to plaques in which they differentiate into macrophages. In the present study, we ask how modulating monocyte glucose metabolism could affect their homeostasis and their impact on atherosclerosis. Here we investigate how circulating metabolites control monocyte behavior in blood, bone marrow and peripheral tissues of mice. We find that serum glucose concentrations correlate with monocyte numbers. In diet-restricted mice, monocytes fail to metabolically reprogram from glycolysis to fatty acid oxidation, leading to reduced monocyte numbers in the blood. Mechanistically, Glut1-dependent glucose metabolism helps maintain CD115 membrane expression on monocytes and their …

Nonclinical Profile Of Pf-06952229 (Mdv6058), A Novel Tgfβri/Activin Like Kinase 5 Inhibitor Supports Clinical Evaluation In Cancer, Mausumee Guha, Stephane Thibault, Son Pham, Sebastian Bernales, Rama Pai, Francisco J Herrera, Theodore R Johnson, Allison Vitsky, Tina Fernando, Martin Finkelstein

Faculty, Staff and Student Publications

The development of transforming growth factor βreceptor inhibitors (TGFβRi) as new medicines has been affected by cardiac valvulopathy and arteriopathy toxicity findings in nonclinical toxicology studies. PF-06952229 (MDV6058) selected using rational drug design is a potent and selective TGFβRI inhibitor with a relatively clean off-target selectivity profile and good pharmacokinetic properties across species. PF-06952229 inhibited clinically translatable phospho-SMAD2 biomarker (≥60%) in human and cynomolgus monkey peripheral blood mononuclear cells, as well as in mouse and rat splenocytes. Using an optimized, intermittent dosing schedule (7-day on/7-day off/cycle; 5 cycles), PF-06952229 demonstrated efficacy in a 63-day syngeneic …

The Socioeconomic And Environmental Niche Of Protected Areas Reveals Global Conservation Gaps And Opportunities, David Mouillot, Laure Velez, Camille Albouy, Nicolas Casajus, Joachim Claudet, Vincent Delbar, Rodolphe Devillers, Tom B Letessier, Nicolas Loiseau, Stéphanie Manel, Laura Mannocci, Jessica Meeuwig, Nicolas Mouquet, Ana Nuno, Louise O'Connor, Valeriano Parravicini, Julien Renaud, Raphael Seguin, Marc Troussellier, Wilfried Thuiller

School of Biological and Marine Sciences

The global network of protected areas has rapidly expanded in the past decade and is expected to cover at least 30% of land and sea by 2030 to halt biodiversity erosion. Yet, the distribution of protected areas is highly heterogeneous on Earth and the social-environmental preconditions enabling or hindering protected area establishment remain poorly understood. Here, using fourteen socioeconomic and environmental factors, we characterize the multidimensional niche of terrestrial and marine protected areas, which we use to accurately establish, at the global scale, whether a particular location has preconditions favourable for paestablishment. We reveal that protected areas, particularly the most …

Frugal Engineering-Inspired Wearable Augmented Reality Goggle System Enables Fluorescence-Guided Cancer Surgery, Leonid Shmuylovich, Christine M O'Brien, Karen Nwosu, Samuel Achilefu

2020-Current year OA Pubs

Disparities in surgical outcomes often result from subjective decisions dictated by surgical training, experience, and available resources. To improve outcomes, surgeons have adopted advancements in robotics, endoscopy, and intra-operative imaging including fluorescence-guided surgery (FGS), which highlights tumors and anatomy in real-time. However, technical, economic, and logistic challenges hinder widespread adoption of FGS beyond high-resource centers. To overcome these impediments, we combined laser diodes, Raspberry Pi cameras and computers, off-the-shelf optical components, and 3D-printed parts to make a battery-powered, compact, dual white light and NIR imaging system that has comparable performance to existing bulkier, pricier, and wall-powered technologies. We combined these …

Divergent Sensory Pathways Of Sneezing And Coughing, Haowu Jiang, Huan Cui, Mengyu Chen, Fengxian Li, Xiaolei Shen, Changxiong J Guo, George E Hoekel, Yuyan Zhu, Liang Han, Kangyun Wu, Michael J Holtzman, Qin Liu

2020-Current year OA Pubs

Sneezing and coughing are primary symptoms of many respiratory viral infections and allergies. It is generally assumed that sneezing and coughing involve common sensory receptors and molecular neurotransmission mechanisms. Here, we show that the nasal mucosa is innervated by several discrete populations of sensory neurons, but only one population (MrgprC11

Therapeutic Targeting Of Differentiation-State Dependent Metabolic Vulnerabilities In Diffuse Midline Glioma., Nneka E. Mbah, Amy L. Myers, Peter Sajjakulnukit, Chan Chung, Joyce K. Thompson, Hanna S. Hong, Heather Giza, Derek Dang, Zeribe C. Nwosu, Mengrou Shan, Stefan R. Sweha, Daniella D. Maydan, Brandon Chen, Li Zhang, Brian Magnuson, Zirui Zhu, Megan Radyk, Brooke Lavoie, Viveka Nand Yadav, Imhoi Koo, Andrew D. Patterson, Daniel R. Wahl, Luigi Franchi, Sameer Agnihotri, Carl J. Koschmann, Sriram Venneti, Costas A. Lyssiotis

Manuscripts, Articles, Book Chapters and Other Papers

H3K27M diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPG), exhibit cellular heterogeneity comprising less-differentiated oligodendrocyte precursors (OPC)-like stem cells and more differentiated astrocyte (AC)-like cells. Here, we establish in vitro models that recapitulate DMG-OPC-like and AC-like phenotypes and perform transcriptomics, metabolomics, and bioenergetic profiling to identify metabolic programs in the different cellular states. We then define strategies to target metabolic vulnerabilities within specific tumor populations. We show that AC-like cells exhibit a mesenchymal phenotype and are sensitized to ferroptotic cell death. In contrast, OPC-like cells upregulate cholesterol biosynthesis, have diminished mitochondrial oxidative phosphorylation (OXPHOS), and are accordingly more …

Phosphorylation-Driven Epichaperome Assembly Is A Regulator Of Cellular Adaptability And Proliferation., Tanaya Roychowdhury, Seth W Mcnutt, Chiranjeevi Pasala, Hieu Nguyen, Daniel T Thornton, Sahil Sharma, Luke Botticelli, Chander S Digwal, Suhasini Joshi, Nan Yang, Palak Panchal, Souparna Chakrabarty, Sadik Bay, Vladimir Markov, Charlene Kwong, Jeanine Lisanti, Sun Young Chung, Stephen D Ginsberg, Pengrong Yan, Elisa De Stanchina, Adriana Corben, Shanu Modi, Mary Alpaugh, Giorgio Colombo, Hediye Erdjument-Bromage, Thomas A Neubert, Robert J Chalkley, Peter R Baker, Alma L Burlingame, Anna Rodina, Gabriela Chiosis, Feixia Chu

College of Science & Mathematics Departmental Research

The intricate network of protein-chaperone interactions is crucial for maintaining cellular function. Recent discoveries have unveiled the existence of specialized chaperone assemblies, known as epichaperomes, which serve as scaffolding platforms that orchestrate the reconfiguration of protein-protein interaction networks, thereby enhancing cellular adaptability and proliferation. This study explores the structural and regulatory aspects of epichaperomes, with a particular focus on the role of post-translational modifications (PTMs) in their formation and function. A key finding is the identification of specific PTMs on HSP90, particularly at residues Ser226 and Ser255 within an intrinsically disordered region, as critical determinants of epichaperome assembly. Our data …

Pediatric Cardiac Xenotransplantation And Expanded Access: Ethical Considerations, Daniel J Hurst, Christopher Bobier, Anthony Merlocco, Luz A Padilla, Daniel Rodger, David Cleveland, John D Cleveland

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Due to the current organ shortage waitlist, alternatives to allotransplantation are necessary. Xenotransplantation is currently being pursued as one such alternative in adults in need of kidney or heart transplantation. Cardiac xenotransplantation of genetically modified pig hearts has been conducted twice in adults under the United States Food and Drug Administration (FDA) expanded access criteria. Because of the shortage of transplantable hearts for children as well as the lack of mechanical circulatory support in this population, pediatric researchers are exploring FDA expanded access in high-risk neonates and infants who lack alternative options for survival. The adult cardiac xenotransplantation experience with …

A Combination Of Four Toxoplasma Gondii Nuclear-Targeted Effectors Protects Against Interferon Gamma-Driven Human Host Cell Death, Brittany Henry, Aubrey J Phillips, L David Sibley, Alex Rosenberg

2020-Current year OA Pubs

In both mice and humans, Type II interferon gamma (IFNγ) is crucial for the regulation of

Characterization Of Non-Standard Viral Genomes During Arenavirus Infections Identifies Prominent S Rna Intergenic Region Deletions, Matthew Hackbart, Carolina B López

2020-Current year OA Pubs

Arenaviruses, a family of negative-sense RNA viruses spread by rodents, are a leading cause of severe hemorrhagic fever in humans. Due to a paucity of antivirals and vaccines for arenaviruses, there is a need to identify new mechanisms for interfering with arenavirus replication. In several negative-sense RNA viruses, natural viral interference results from the production of non-standard viral genomes (nsVGs) that activate the innate immune system and/or compete for essential viral products. Although it is well established that arenaviruses produce strong interfering activities, it is unknown if they produce interfering nsVGs. Here, we show that arenaviruses produce deletions within the …

An Emerging Multi-Omic Understanding Of The Genetics Of Opioid Addiction., Eric O Johnson, Heidi S Fisher, Kyle A Sullivan, Olivia Corradin, Sandra Sanchez-Roige, Nathan C Gaddis, Yasmine N Sami, Alice Townsend, Erica Teixeira Prates, Mirko Pavicic, Peter Kruse, Elissa J Chesler, Abraham A Palmer, Vanessa Troiani, Jason A. Bubier, Daniel A Jacobson, Brion S Maher

Faculty Research 2024

Opioid misuse, addiction, and associated overdose deaths remain global public health crises. Despite the tremendous need for pharmacological treatments, current options are limited in number, use, and effectiveness. Fundamental leaps forward in our understanding of the biology driving opioid addiction are needed to guide development of more effective medication-assisted therapies. This Review focuses on the omics-identified biological features associated with opioid addiction. Recent GWAS have begun to identify robust genetic associations, including variants in OPRM1, FURIN, and the gene cluster SCAI/PPP6C/RABEPK. An increasing number of omics studies of postmortem human brain tissue examining biological features (e.g., histone modification and gene …

Advancing Stem Cell Technologies For Conservation Of Wildlife Biodiversity., Ashlee M Hutchinson, Ruth Appeltant, Tom Burdon, Qiuye Bao, Rhishikesh Bargaje, Andrea Bodnar, Stuart Chambers, Pierre Comizzoli, Laura Cook, Yoshinori Endo, Bob Harman, Katsuhiko Hayashi, Thomas Hildebrandt, Marisa L Korody, Uma Lakshmipathy, Jeanne F Loring, Clara Munger, Alex H M Ng, Ben Novak, Manabu Onuma, Sara Ord, Monique Paris, Andrew J Pask, Francisco Pelegri, Martin Pera, Ryan Phelan, Benyamin Rosental, Oliver A Ryder, Woranop Sukparangsi, Gareth Sullivan, Nicole Liling Tay, Nikki Traylor-Knowles, Shawn Walker, Antonia Weberling, Deanne J Whitworth, Suzannah A Williams, Jessye Wojtusik, Jun Wu, Qi-Long Ying, Thomas P Zwaka, Timo N Kohler

Faculty Research 2024

Wildlife biodiversity is essential for healthy, resilient and sustainable ecosystems. For biologists, this diversity also represents a treasure trove of genetic, molecular and developmental mechanisms that deepen our understanding of the origins and rules of life. However, the rapid decline in biodiversity reported recently foreshadows a potentially catastrophic collapse of many important ecosystems and the associated irreversible loss of many forms of life on our planet. Immediate action by conservationists of all stripes is required to avert this disaster. In this Spotlight, we draw together insights and proposals discussed at a recent workshop hosted by Revive & Restore, which gathered …

Reproduction Has Immediate Effects On Female Mortality, But No Discernible Lasting Physiological Impacts: A Test Of The Disposable Soma Theory, Sharon E Mitchell, Megan Simpson, Lena Coulet, Solenn Gouedard, Catherine Hambly, Juliano Morimoto, David B Allison, John R Speakman

Children’s Nutrition Research Center Staff Publications

The disposable soma theory (DST) posits that organisms age and die because of a direct trade-off in resource allocation between reproduction and somatic maintenance. DST predicts that investments in reproduction accentuate somatic damage which increase senescence and shortens lifespan. Here, we directly tested DST predictions in breeding and nonbreeding female C57BL/6J mice. We measured reproductive outputs, body composition, daily energy expenditure, and oxidative stress at peak lactation and over lifetime. We found that reproduction had an immediate and negative effect on survival due to problems encountered during parturition for some females. However, there was no statistically significant residual effect on …

Cdk12 Loss Drives Prostate Cancer Progression, Transcription-Replication Conflicts, And Synthetic Lethality With Paralog Cdk13, Jean Ching-Yi Tien, Jie Luo, Yu Chang, Yuping Zhang, Yunhui Cheng, Xiaoju Wang, Jianzhang Yang, Rahul Mannan, Somnath Mahapatra, Palak Shah, Xiao-Ming Wang, Abigail J Todd, Sanjana Eyunni, Caleb Cheng, Ryan J Rebernick, Lanbo Xiao, Yi Bao, James Neiswender, Rachel Brough, Stephen J Pettitt, Xuhong Cao, Stephanie J Miner, Licheng Zhou, Yi-Mi Wu, Estefania Labanca, Yuzhuo Wang, Abhijit Parolia, Marcin Cieslik, Dan R Robinson, Zhen Wang, Felix Y Feng, Jonathan Chou, Christopher J Lord, Ke Ding, Arul M Chinnaiyan

Faculty, Staff and Student Publications

Biallelic loss of cyclin-dependent kinase 12 (CDK12) defines a metastatic castration-resistant prostate cancer (mCRPC) subtype. It remains unclear, however, whether CDK12 loss drives prostate cancer (PCa) development or uncovers pharmacologic vulnerabilities. Here, we show Cdk12 ablation in murine prostate epithelium is sufficient to induce preneoplastic lesions with lymphocytic infiltration. In allograft-based CRISPR screening, Cdk12 loss associates positively with Trp53 inactivation but negatively with Pten inactivation. Moreover, concurrent Cdk12/Trp53 ablation promotes proliferation of prostate-derived organoids, while Cdk12 knockout in Pten-null mice abrogates prostate tumor growth. In syngeneic systems, Cdk12/Trp53-null allografts exhibit luminal morphology and immune checkpoint blockade sensitivity. Mechanistically, Cdk12 inactivation …

Yap1 Status Defines Two Intrinsic Subtypes Of Lcnec With Distinct Molecular Features And Therapeutic Vulnerabilities, C Allison Stewart, Lixia Diao, Yuanxin Xi, Runsheng Wang, Kavya Ramkumar, Alejandra G Serrano, Azusa Tanimoto, B Leticia Rodriguez, Benjamin B Morris, Li Shen, Bingnan Zhang, Yan Yang, Samera H Hamad, Robert J Cardnell, Alberto Duarte, Moushumi Sahu, Veronica Y Novegil, Bernard E Weissman, Michael Frumovitz, Neda Kalhor, Luisa Solis Soto, Pedro Da Rocha, Natalie Vokes, Don L Gibbons, Jing Wang, John V Heymach, Bonnie Glisson, Lauren Averett Byers, Carl M Gay

Faculty, Staff and Student Publications

Purpose: Large cell neuroendocrine carcinoma (LCNEC) is a high-grade neuroendocrine malignancy that, like small cell lung cancer (SCLC), is associated with the absence of druggable oncogenic drivers and dismal prognosis. In contrast to SCLC, however, there is little evidence to guide optimal treatment strategies, which are often adapted from SCLC and non-small cell lung cancer approaches.

Experimental design: To better define the biology of LCNEC, we analyzed cell line and patient genomic data and performed IHC and single-cell RNA sequencing of core needle biopsies from patients with LCNEC and preclinical models.

Results: In this study, we demonstrate that the presence …

Biochemical And Structural Insights Into A 5′ To 3′ Rna Ligase Reveal A Potential Role In Trna Ligation, Yingjie Hu, Victor A Lopez, Hengyi Xu, James P Pfister, Bing Song, Kelly A Servage, Masahiro Sakurai, Benjamin T Jones, Joshua T Mendell, Tao Wang, Jun Wu, Alan M Lambowitz, Diana R Tomchick, Krzysztof Pawłowski, Vincent S Tagliabracci

Faculty, Staff and Student Publications

ATP-grasp superfamily enzymes contain a hand-like ATP-binding fold and catalyze a variety of reactions using a similar catalytic mechanism. More than 30 protein families are categorized in this superfamily, and they are involved in a plethora of cellular processes and human diseases. Here, we identify C12orf29 (RLIG1) as an atypical ATP-grasp enzyme that ligates RNA. Human RLIG1 and its homologs autoadenylate on an active site Lys residue as part of a reaction intermediate that specifically ligates RNA halves containing a 5’-phosphate and a 3’-hydroxyl. RLIG1 binds tRNA in cells and can ligate tRNA within the anticodon loop in vitro. Transcriptomic …

Sall4 And Gata4 Induce Cardiac Fibroblast Transition Towards A Partially Multipotent State With Cardiogenic Potential, Hong Gao, Saliha Pathan, Beverly R E A Dixon, Aarthi Pugazenthi, Megumi Mathison, Tamer M A Mohamed, Todd K Rosengart, Jianchang Yang

Faculty, Staff and Students Publications

Cardiac cellular fate transition holds remarkable promise for the treatment of ischemic heart disease. We report that overexpressing two transcription factors, Sall4 and Gata4, which play distinct and overlapping roles in both pluripotent stem cell reprogramming and embryonic heart development, induces a fraction of stem-like cells in rodent cardiac fibroblasts that exhibit unlimited ex vivo expandability with clonogenicity. Transcriptomic and phenotypic analyses reveal that around 32 ± 6.4% of the expanding cells express Nkx2.5, while 13 ± 3.6% express Oct4. Activated signaling pathways like PI3K/Akt, Hippo, Wnt, and multiple epigenetic modification enzymes are also detected. Under suitable conditions, these cells …

Molecular Detection And Genomic Characterization Of Samak Micromys Paramyxovirus-1 And -2 In Micromys Minutus, Republic Of Korea, Augustine Natasha, Sarah E Pye, Carolina B López, Et Al.

2020-Current year OA Pubs

BACKGROUND: The discovery of viruses in small mammalian populations, particularly rodents, has expanded the family Paramyxoviridae. The overlap in habitats between rodents and humans increases the risk of zoonotic events, underscoring the importance of active surveillance. Rodent species, such as Apodemus agrarius, are natural hosts for Paramyxoviridae in the Republic of Korea (ROK). However, it is unknown whether Paramyxoviridae is present in Micromys minutus, another common rodent.

METHOD: Here, we screened M. minutus collected from the Gangwon Province in the ROK for paramyxoviruses using nested polymerase chain reaction and confirm positive samples by next-generation metagenomic sequencing. Complete paramyxovirus genomes were …

Magnetoelectrics For Implantable Bioelectronics: Progress To Date, Fatima Alrashdan, Kaiyuan Yang, Jacob T Robinson

Faculty, Staff and Students Publications

The coupling of magnetic and electric properties manifested in magnetoelectric (ME) materials has unlocked numerous possibilities for advancing technologies like energy harvesting, memory devices, and medical technologies. Due to this unique coupling, the magnetic properties of these materials can be tuned by an electric field; conversely, their electric polarization can be manipulated through a magnetic field. Over the past seven years, our lab work has focused on leveraging these materials to engineer implantable bioelectronics for various neuromodulation applications. One of the main challenges for bioelectronics is to design miniaturized solutions that can be delivered with minimally invasive procedures and yet …

Immuno-Scanning Electron Microscopy Of Islet Primary Cilia, Sanja Sviben, Alexander J Polino, Isabella L Melena, Jing W Hughes

2020-Current year OA Pubs

The definitive demonstration of protein localization on primary cilia has been a challenge for cilia biologists. Primary cilia are solitary thread-like projections that have a specialized protein composition, but as the ciliary structure overlays the cell membrane and other cell parts, the identity of ciliary proteins are difficult to ascertain by conventional imaging approaches like immunofluorescence microscopy. Surface scanning electron microscopy combined with immunolabeling (immuno-SEM) bypasses some of these indeterminacies by unambiguously showing protein expression in the context of the three-dimensional ultrastructure of the cilium. Here, we apply immuno-SEM to specifically identify proteins on the primary cilia of mouse and …

Molecular Detection And Genomic Characterization Of Samak Micromys Paramyxovirus-1 And -2 In Micromys Minutus, Republic Of Korea, Augustine Natasha, Sarah E Pye, Carolina B López, Qq Et Al.

2020-Current year OA Pubs

BACKGROUND: The discovery of viruses in small mammalian populations, particularly rodents, has expanded the family Paramyxoviridae. The overlap in habitats between rodents and humans increases the risk of zoonotic events, underscoring the importance of active surveillance. Rodent species, such as Apodemus agrarius, are natural hosts for Paramyxoviridae in the Republic of Korea (ROK). However, it is unknown whether Paramyxoviridae is present in Micromys minutus, another common rodent.

METHOD: Here, we screened M. minutus collected from the Gangwon Province in the ROK for paramyxoviruses using nested polymerase chain reaction and confirm positive samples by next-generation metagenomic sequencing. Complete paramyxovirus genomes were …

Adipocyte Lipin 1 Expression Associates With Human Metabolic Health And Regulates Systemic Metabolism In Mice, Andrew Lapoint, Jason M. Singer, Daniel Ferguson, Trevor M. Shew, M. Katie Renkemeyer, Hector H. Palacios, Rachael L. Field, Gordon I. Smith, Mai He, Gary J Patti, Samuel Klein, Jonathan R. Brestoff, Brian N. Finck, Et Al.

2020-Current year OA Pubs

Dysfunctional adipose tissue is believed to promote the development of hepatic steatosis and systemic insulin resistance, but many of the mechanisms involved are still unclear. Lipin 1 catalyzes the conversion of phosphatidic acid to diacylglycerol, the penultimate step of triglyceride synthesis, which is essential for lipid storage. Herein we found that adipose tissue LPIN1 expression is decreased in people with obesity compared with lean subjects, and low LPIN1 expression correlated with multi-tissue insulin resistance and increased rates of hepatic de novo lipogenesis. Comprehensive metabolic and multiomic phenotyping demonstrated that adipocyte-specific Lpin1-/- mice had a metabolically unhealthy phenotype, including liver and …

Ovarian Cancer Metastasis: Looking Beyond The Surface, Emine Bayraktar, Sisy Chen, Sara Corvigno, Jinsong Liu, Anil K Sood

Faculty, Staff and Student Publications

Historically, ovarian cancer (OC) was thought to metastasize by surface-to-surface spread, but recent developments have yielded a new understanding of the paths of metastatic spread. Given the histologic and molecular heterogeneity of OC, we will focus on high-grade serous carcinoma (HGSC). Here, we provide a critical and more holistic view of the evidence supporting various routes of metastasis, including peritoneal, hematogenous, lymphatic, and nerve-related. Understanding the underlying mechanisms is necessary to improve treatment strategies for this challenging disease.

Sdeper: A Hybrid Machine Learning And Regression Method For Cell-Type Deconvolution Of Spatial Barcoding-Based Transcriptomic Data, Yunqing Liu, Ningshan Li, Ji Qi, Gang Xu, Jiayi Zhao, Nating Wang, Xiayuan Huang, Wenhao Jiang, Huanhuan Wei, Aurélien Justet, Taylor S Adams, Robert Homer, Amei Amei, Ivan O Rosas, Naftali Kaminski, Zuoheng Wang, Xiting Yan

Faculty, Staff and Students Publications

Spatial barcoding-based transcriptomic (ST) data require deconvolution for cellular-level downstream analysis. Here we present SDePER, a hybrid machine learning and regression method to deconvolve ST data using reference single-cell RNA sequencing (scRNA-seq) data. SDePER tackles platform effects between ST and scRNA-seq data, ensuring a linear relationship between them while addressing sparsity and spatial correlations in cell types across capture spots. SDePER estimates cell-type proportions, enabling enhanced resolution tissue mapping by imputing cell-type compositions and gene expressions at unmeasured locations. Applications to simulated data and four real datasets showed SDePER's superior accuracy and robustness over existing methods.

Effects Of Cadherin Mediated Contact Normalization On Oncogenic Src Kinase Mediated Gene Expression And Protein Phosphorylation, Rachel E Nicoletto, Cayla J Holdcraft, Ariel C Yin, Edward P Retzbach, Stephanie A Sheehan, Amanda A Greenspan, Christopher M Laugier, Jason Trama, Caifeng Zhao, Haiyan Zheng, Gary S Goldberg

Rowan-Virtua School of Osteopathic Medicine Departmental Research

Nontransformed cells form heterotypic cadherin junctions with adjacent transformed cells to inhibit tumor cell growth and motility. Transformed cells must override this form of growth control, called "contact normalization", to invade and metastasize during cancer progression. Heterocellular cadherin junctions between transformed and nontransformed cells are needed for this process. However, specific mechanisms downstream of cadherin signaling have not been clearly elucidated. Here, we utilized a β-catenin reporter construct to determine if contact normalization affects Wnt signaling in transformed cells. β-catenin driven GFP expression in Src transformed mouse embryonic cells was decreased when cultured with cadherin competent nontransformed cells compared to …

Bi-Directional Allosteric Pathway In Nmda Receptor Activation And Modulation, Paula A Bender, Subhajit Chakraborty, Ryan J Durham, Vladimir Berka, Elisa Carrillo, Vasanthi Jayaraman

Faculty, Staff and Student Publications

N-methyl-D-aspartate (NMDA) receptors are ionotropic glutamate receptors involved in learning and memory. NMDA receptors primarily comprise two GluN1 and two GluN2 subunits. The GluN2 subunit dictates biophysical receptor properties, including the extent of receptor activation and desensitization. GluN2A- and GluN2D-containing receptors represent two functional extremes. To uncover the conformational basis of their functional divergence, we utilize single-molecule fluorescence resonance energy transfer to probe the extracellular domains of these receptor subtypes under resting and ligand-bound conditions. We find that the conformational profile of the GluN2 amino-terminal domain correlates with the disparate functions of GluN2A- and GluN2D-containing receptors. Changes at the pre-transmembrane …

Long-Term Human Immune Reconstitution, T-Cell Development, And Immune Reactivity In Mice Lacking The Murine Major Histocompatibility Complex: Validation With Cellular And Gene Expression Profiles., Milita Darguzyte, Philipp Antczak, Daniel Bachurski, Patrick Hoelker, Nima Abedpour, Rahil Gholamipoorfard, Hans A Schlößer, Kerstin Wennhold, Martin Thelen, Maria A Garcia-Marquez, Johannes Koenig, Andreas Schneider, Tobias Braun, Frank Klawonn, Michael Damrat, Masudur Rahman, Jan-Malte Kleid, Sebastian J Theobald, Eugen Bauer, Constantin Von Kaisenberg, Steven R Talbot, Leonard D. Shultz, Brian Soper, Renata Stripecke

Faculty Research 2024

Background: Humanized mice transplanted with CD34+ hematopoietic cells (HPCs) are broadly used to study human immune responses and infections in vivo and for testing therapies pre-clinically. However, until now, it was not clear whether interactions between the mouse major histocompatibility complexes (MHCs) and/or the human leukocyte antigens (HLAs) were necessary for human T-cell development and immune reactivity. Methods: We evaluated the long-term (20- week) human hematopoiesis and human T-cell development in NOD Scid Gamma (NSG) mice lacking the expression of MHC class I and II (NSG-DKO). Triplicate experiments were performed with HPCs obtained from three donors, and humanization was confirmed …

Interleukin-1 Receptor-Associated Kinase 1 In Cancer Metastasis And Therapeutic Resistance: Mechanistic Insights And Translational Advances., Mariana K Najjar, Munazza S Khan, Chuling Zhuang, Ankush Chandra, Hui-Wen Lo

Faculty, Staff and Student Publications

Interleukin-1 Receptor Associated Kinase 1 (IRAK1) is a serine/threonine kinase that plays a critical role as a signaling transducer of the activated Toll-like receptor (TLR)/Interleukin-1 receptor (IL-1R) signaling pathway in both immune cells and cancer cells. Upon hyperphosphorylation by IRAK4, IRAK1 forms a complex with TRAF6, which results in the eventual activation of the NF-κB and MAPK pathways. IRAK1 can translocate to the nucleus where it phosphorylates STAT3 transcription factor, leading to enhanced IL-10 gene expression. In immune cells, activated IRAK1 coordinates innate immunity against pathogens and mediates inflammatory responses. In cancer cells, IRAK1 is frequently activated, and the activation …