Digital Commons Network^™

Olaparib And Radiotherapy Induce Type I Interferon- And Cd8+ T Cell-Dependent Sensitization To Immunotherapy In Pancreatic Cancer, Victoria M Valvo, Qiang Zhang, Long Jiang, Erin A Holcomb, Ashley N Pearson, Anna G Edmunds, Hailey G Faulkner, Jadyn G James, Akshay Tate, Amanda K Huber, Zhuwen Wang, Yupei Guo, David Karnak, Leslie A Parsels, Joshua D Parsels, Yu L Lei, Alnawaz Rehemtulla, Heng Lin, Eileen S Carpenter, Daniel R Wahl, Vaibhav Sahai, Theodore S Lawrence, Michael D Green, Meredith A Morgan

Faculty, Staff and Student Publications

PARP inhibitors sensitize pancreatic ductal adenocarcinoma (PDAC) to radiation by inducing DNA damage and replication stress. These mechanisms also have the potential to enhance radiation-induced type I interferon (T1IFN) mediated anti-tumoral immune responses. We hypothesized that the PARP inhibitor olaparib would also potentiate radiation-induced T1IFN to promote anti-tumor immune responses and sensitization of otherwise resistant PDAC to immunotherapy. To test this hypothesis, we assessed the effects of olaparib and radiation on T1IFN production and sensitivity to αPD-L1 immunotherapy, as well as on the tumor microenvironment by single-cell RNA sequencing (scRNA-seq). We found that olaparib enhanced T1IFN production following radiation and …

Eph Receptors Activate Myeloid Checkpoint Receptor Lilrb5 To Support Tumor Development, Yubo He, Chengcheng Zhang, Lingxiao Tan, Mi Deng, Xiaoye Liu, Ryan Huang, Xing Yang, Jingjing Xie, Qi Lou, Meng Fang, Caroline Smith, Samuel John, Wei Xiong, Xin Li, Cheryl Lewis, Jade Homsi, Ankit Gupta, Ningyan Zhang, Zhiqiang An, Cheng Cheng Zhang

Faculty, Staff and Student Publications

Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of patients with cancer. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. In this study, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte Ig-like receptor family B 5 (LILRB5) and LILRB2. These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid …

Deep Learning Based Rapid X-Ray Fluorescence Signal Extraction And Image Reconstruction For Preclinical Benchtop X-Ray Fluorescence Computed Tomography Applications, Amrit Kaphle, Sandun Jayarathna, Sang Hyun Cho

Faculty, Staff and Student Publications

Recent research advances have resulted in an experimental benchtop X-ray fluorescence computed tomography (XFCT) system that likely meets the imaging dose/scan time constraints for benchtop XFCT imaging of live mice injected with gold nanoparticles (GNPs). For routine in vivo benchtop XFCT imaging, however, additional challenges, most notably the need for rapid/near-real-time handling of X-ray fluorescence (XRF) signal extraction and XFCT image reconstruction, must be successfully addressed. Here we propose a novel end-to-end deep learning (DL) framework that integrates a one-dimensional convolutional neural network (1D CNN) for rapid XRF signal extraction with a U-Net model for XFCT image reconstruction. We trained …

Restoration Of The Tumor Suppressor Function Of Y220c-Mutant P53 By Rezatapopt, A Small-Molecule Reactivator, Anna M Puzio-Kuter, Lizhong Xu, Mary Kate Mcbrayer, Romyr Dominique, Hongju H Li, Bruce J Fahr, Alyssa M Brown, Amy E Wiebesiek, Brandon M Russo, Chris L Mulligan, Hong Yang, Josh Battaglia, Kimberly A Robell, Dafydd H Thomas, Kuo-Sen Huang, Alexander Solovyov, Benjamin D Greenbaum, Jonathan D Oliner, Thomas W Davis, Melissa L Dumble, Melissa L Johnson, Shunbin Xiong, Peirong Yang, Guillermina Lozano, Marc M Fellous, Binh T Vu, Alison M Schram, Arnold J Levine, Masha V Poyurovsky

Faculty, Staff and Student Publications

Restoration of the tumor suppressor function of tumor-associated p53 mutants, including the Y220C substitution, has posed a significant challenge for therapeutic discovery. In this study, we describe rezatapopt (PC14586), part of a series of compounds designed to reactivate the p53 Y220C mutant. These compounds restore p53 tumor suppressor function by correcting its conformation and enabling it to bind DNA and activate downstream target genes, thus inducing antiproliferative changes in tumor cells. Our findings are supported by biochemical and structural analysis, in vitro and in vivo transcriptomics, and functional data, revealing the recovery of multiple aspects of the wild-type p53 program. …

Xbp1s-Edem2 Prevents The Onset And Development Of Hfpef By Ameliorating Cardiac Lipotoxicity, Oveena Fonseka, Rida Raja, Claire Ross, Sanskruti R Gare, Jiayan Zhang, Susanne S Hille, Katharine King, Andrea Ruiz-Velasco, Namrita Kaur, Xinyi Chen, Jessica M Miller, Riham R E Abouleisa, Qinghui Ou, Zhiyong Zou, Xiangjun Zhao, Cristian Sotomayor-Flores, Derk Frank, Eileithyia Swanton, Martin R Pool, Sara Missaglia, Daniela Tavian, Gabriele G Schiattarella, Tao Wang, Luigi Venetucci, Christian Pinali, Martin K Rutter, Bernard D Keavney, Elizabeth J Cartwright, Tamer M A Mohamed, Oliver J Müller, Wei Liu

Center for Medical Ethics and Health Policy Staff Publications

Background: Morbidity and mortality of heart failure with preserved ejection fraction (HFpEF) is increased in metabolic disorders. However, options for preventing and treating these prevalent outcomes are limited. Intramyocardial lipotoxicity contributes to cardiac dysfunction. Here, we investigate the mechanisms underlying EDEM2 (endoplasmic reticulum degradation-enhancing alpha-mannosidase-like protein 2) regulation of cardiac lipid homeostasis and assess strategies that inhibit the incidence and progression of HFpEF.

Methods: Metabolic stress was induced in C57BL/6 male mice using a high-fat diet and Nω-nitro-L-arginine methyl ester. The recombinant adeno-associated virus 9 delivery system was used for loss- and gain-of-function studies. Palmitic acid and oleic acid …

Maternal Loss Of Mouse Nlrp2 Alters The Transcriptome And Dna Methylome In Gv Oocytes And Impairs Zygotic Genome Activation In Embryos, Zahra Anvar, Michael D Jochum, Imen Chakchouk, Momal Sharif, Hannah Demond, Alvin K To, Daniel C Kraushaar, Ying-Wooi Wan, Michael C Mari, Simon Andrews, Gavin Kelsey, Ignatia B Van Den Veyver

Center for Medical Ethics and Health Policy Staff Publications

Background: NLRP2 is a subcortical maternal complex (SCMC) protein of mammalian oocytes and preimplantation embryos. SCMC proteins are encoded by maternal effect genes and play a pivotal role in the maternal-to-zygotic transition (MZT), early embryogenesis, and epigenetic (re)programming. Maternal inactivation of genes encoding SCMC proteins has been linked to infertility and subfertility in mice and humans, but the underlying molecular mechanisms for the diverse functions of SCMC proteins, and specifically the role of NLRP2, are incompletely understood.

Results: We profiled the DNA methylome of pre-ovulatory germinal-vesicle (GV) oocytes from Nlrp2-null, heterozygous (Het), and wild-type (WT) female mice and assessed the …

Mutant P53 Gain Of Function: Why Many See It, Why Some Do Not, Guillermina Lozano, Carol Prives, Kanaga Sabapathy

Faculty, Staff and Student Publications

Mutations in the TP53 tumor-suppressor gene in human cancer are unique in that 60% to 70% are of the missense variety, resulting in a full-length protein that is often highly expressed in patients' tumors. These missense mutant proteins often exhibit pro-oncogenic activities (referred to as gain of function) in mouse models and human cell lines and correlate with poor cancer prognosis in some cases.

A Novel Cardiomyopathy Phenotype Linked To A Chd7 Missense Variant, In Young Park, Chih-Wei Hsu, Karim Bouazoune, Christina E Espindola, Madeline Hannah Mclaughlin Armond, Cristian Coarfa, Sandra L Grimm, James F Martin, Donna M Martin, Cheryl Lyn Walker

Center for Medical Ethics and Health Policy Staff Publications

Loss of function in the chromatin remodeler CHD7 causes CHARGE syndrome, characterized by variable penetrance and diverse abnormalities. However, establishing genotype-phenotype correlations has been challenging, as most CHD7 inactivating mutations are null alleles. Through CHD7 missense variant analysis at potential phosphorylation sites, we identified T730 (T720 in mice) as a critical residue associated with pathogenesis. Using a CHD7 T730 missense variant (Chd7T720A) and a frameshift null allele (Chd7fs) in a mouse model, we found that Chd7fs/fs mice were non-viable, while Chd7fs/+ mice exhibited haploinsufficiency-related circling behavior. Notably, Chd7fs/T720A mice died before postnatal …

Phage-Induced Protection Against Lethal Bacterial Reinfection, Yikun Xing, Haroldo J Hernandez Santos, Ling Qiu, Samantha R Ritter, Jacob J Zulk, Rachel Lahowetz, Kathryn A Patras, Austen L Terwilliger, Anthony W Maresso

Faculty, Staff and Students Publications

Bacteriophages, or phages, are viruses that target and infect bacteria. Due to a worldwide rise in antimicrobial resistance (AMR), phages have been proposed as a promising alternative to antibiotics for the treatment of resistant bacterial infections. Up to this point in history, phage use in preclinical animal studies, clinical trials, and emergency-use compassionate care cases has centered around the original observation from 1915 showing phage as lytic agent, and thus a treatment that kills bacteria. Here, we describe an activity associated with phage therapy that extends beyond lytic activity that results in long-term protection against reinfection. This activity is potent, …

An Antibody Biomarker Associated With Onchocerca Volvulus Microfilariae Identified By Proteomic Analysis Of Parasite Tissues Isolated From Paraffin Embedded O. Volvulus Nodules By Laser Capture Microdissection, Sarah E Greene, Kerstin Fischer, Lucia S Di Maggio, Bruce A Rosa, Yuefang Huang, Irina Diekmann, Byoung-Kyu Cho, Jessica Lukowski, Young A Goo, Makedonka Mitreva, Nicholas Opoku, Gary J Weil, Peter U Fischer

2020-Current year OA Pubs

Onchocerciasis (river blindness), a neglected tropical disease caused by the filarial nematode Onchocerca volvulus, impacts millions of people in sub-Saharan Africa. The WHO coordinates global efforts to eliminate onchocerciasis and has prioritized development of improved diagnostic tests to aid these efforts. To find new microfilarial-associated diagnostic targets to help identify active infections, we used laser capture microdissection to isolate embryonic stages from histologic sections of O. volvulus worms in subcutaneous nodules excised from onchocerciasis patients. Proteomic analysis identified 2,512 O. volvulus proteins in those tissues, including 264 found only in the microfilariae (Mf). From this pool of diagnostic candidates, we …

A Multimodal Therapeutic Strategy For Inflammatory Bowel Disease Using Microrna-146a Mimic Encapsulated In Lipid Nanoparticles., Kanika Suri, Vishnu Hosur, Rohit Panchakshari, Mansoor M Amiji

Faculty Research 2025

Dysregulated microRNAs (miRNAs) have significant potential as diagnostic tools for various chronic diseases; however, their therapeutic applications remain largely unexplored. Given their capacity to regulate multiple pathways, miRNAs are promising candidates for treating pleiotropic diseases, such as inflammatory bowel disease (IBD). In our study, we conducted a comprehensive review of the literature of miRNA-146 levels in the inflamed tissues of IBD patients and murine colitis models. Initially, we quantified the expression of miRNA-146a and miRNA-146b in the colons of mice using the dextran sodium sulfate (DSS)-inducedacute model of IBD. We selected miRNA-146a for further study due to its anti-inflammatory properties …

Mutation Of Smarca4 Induces Cancer Cell-Intrinsic Defects In The Enhancer Landscape And Resistance To Immunotherapy, Yawen Wang, Ismail M Meraz, Md Qudratullah, Sasikumar Kotagiri, Yanyan Han, Yuanxin Xi, Jing Wang, Kadir C Akdemir, Jack A Roth, Yonathan Lissanu

Faculty, Staff and Student Publications

Cancer genomic studies have identified frequent alterations in genes encoding components of the SWI/SNF chromatin remodeling complex, including SMARCA4 and ARID1A. Importantly, clinical reports indicate that SMARCA4-mutant lung cancers respond poorly to immunotherapy and have dismal prognosis. In this study, we corroborated the clinical findings by using immune-humanized, syngeneic, and genetically engineered mouse models of lung cancer harboring SMARCA4 deficiency. Specifically, models with SMARCA4 loss showed decreased response to anti-PD-1 immunotherapy associated with significantly reduced infiltration of dendritic cells and CD4+ T cells into the tumor microenvironment. SMARCA4 loss in tumor cells led to profound downregulation of STING1, IL1β, and …

Suppression Of Brca1 Facilitates Kidney Regeneration, Kaira A Church, Xunian Zhou, Raghu Kalluri

Faculty, Staff and Student Publications

Maladaptive repair following kidney injury leads to the development of kidney disease. In this issue of JEM, Ajay et al. (https://doi.org/10.1084/jem.20231107) uncover the role of breast cancer susceptibility gene 1 (BRCA1) in cell cycle arrest, DNA damage, and cell senescence, preventing maladaptive repair.

Drosha: A New Tumor Suppressor In Pineoblastoma, Zhixuan Huang, Xueli Ren, Jian Hu

Faculty, Staff and Student Publications

In this Outlook, Huang et al. discuss a study in this issue of Genes & Development by Fraire et al. that shows that a deficiency in miRNA processors Drosha and Dicer and consequent cell cycle gene derepression promote pineoblastoma development. The authors highlight the heterogeneity of pineoblastoma's pathogenic mechanisms and its implications for therapeutic interventions in the clinic.

Switching On The Evolutionary Potential Of Pancreatic Cancer: The Tumor Suppressor Functions Of Pbrm1, Luigi Perelli, Giannicola Genovese

Faculty, Staff and Student Publications

Cell plasticity is a hallmark of cancer, enabling tumor cells to acquire multiple phenotypes responsible for tumor progression, metastasis, and therapy resistance. In this issue of the JCI, Kawai and colleagues leveraged genetically engineered mouse models (GEMM) of pancreatic ductal adenocarcinoma (PDAC) to demonstrate that loss of Pbrm1, a member of the SWI/SNF complex, drives dedifferentiation and aggressive tumor features. Pbrm1 loss activated a program of epithelial-to-mesenchymal transition (EMT) and allowed the emergence of poorly differentiated histologies that are commonly associated with high recurrence rate and dismal prognosis. These findings reveal the role of the SWI/SNF complex during PDAC evolution …

Hyaluronan Network Remodeling By Zeb1 And Itih2 Enhances The Motility And Invasiveness Of Cancer Cells, Sieun Lee, Jihye Park, Seongran Cho, Eun Ju Kim, Seonyeong Oh, Younseo Lee, Sungsoo Park, Keunsoo Kang, Dong Hoon Shin, Song Yi Ko, Jonathan M Kurie, Young-Ho Ahn

Faculty, Staff and Student Publications

Hyaluronan (HA) in the extracellular matrix promotes epithelial-mesenchymal transition (EMT) and metastasis; however, the mechanism by which the HA network constructed by cancer cells regulates cancer progression and metastasis in the tumor microenvironment (TME) remains largely unknown. In this study, inter-α-trypsin inhibitor heavy chain 2 (ITIH2), an HA-binding protein, was confirmed to be secreted from mesenchymal-like lung cancer cells when cocultured with cancer-associated fibroblasts. ITIH2 expression is transcriptionally upregulated by the EMT-inducing transcription factor ZEB1, along with HA synthase 2 (HAS2), which positively correlates with ZEB1 expression. Depletion of ITIH2 and HAS2 reduced HA matrix formation and the migration and …

Harnessing Electrophiles In Vivo: A Pilot Study In Swine Using A Hydrophobic Radiopaque Formulation Of 2-Propylpentanoyl Chloride, Erik Cressman, Danielle Stolley, Natalie Fowlkes, Edd Felix, Waldemar Priebe, Steve Parrish, David Fuentes

Faculty, Staff and Student Publications

Manipulating biology through chemistry is older than the discipline of chemistry itself. Traditionally, selectivity of oral or intravenous drugs relied on preferential drug-receptor binding. A novel approach exploiting image-guided techniques to impart spatial selectivity opens up a wide range of new possibilities for study and manipulation of biology. Motivated initially by the poor prognosis for solid tumors such as liver cancer, we demonstrate the use of an extreme form of in vivo chemistry for targeted delivery of 2-propylpentanoyl chloride in a swine model. The ensuing reaction in tissue devitalizes it by multiple mechanisms with lasting effects and, critically, demonstrates very …

Ocular Phenotyping Of Knockout Mice Identifies Genes Associated With Late Adult Retinal Phenotypes, Abraham Hang, Andy Shao, Michael Shea, Michel J Roux, Denise M Imai-Leonard, David J Adams, Takanori Amano, Oana V Amarie, Zorana Berberovic, Raphaël Bour, Lynette Bower, Brian C Leonard, Steve D Brown, Soo Young Cho, Sharon Clementson-Mobbs, Abigail J D'Souza, Mary Dickinson, Mohammad Eskandarian, Ann M Flenniken, Helmut Fuchs, Valerie Gailus-Durner, Jason Heaney, Yann Hérault, Martin Hrabe De Angelis, Chih-Wei Hsu, Shundan Jin, Russell Joynson, Yeon Kyung Kang, Haerim Kim, Hiroshi Masuya, Ki-Hoan Nam, Hyuna Noh, Lauryl M J Nutter, Marcela Palkova, Jan Prochazka, Miles Joseph Raishbrook, Fabrice Riet, Jason Salazar, John Richard Seavitt, Radislav Sedlacek, Mohammed Selloum, Kyoung Yul Seo, Je Kyung Seong, Hae-Sol Shin, Toshihiko Shiroishi, Tania Sorg, Michelle Stewart, Masaru Tamura, Heather Tolentino, Uchechukwu Udensi, Sara Wells, Wolfgang Wurst, Atsushi Yoshiki, Hamid Meziane, Glenn Yiu, Paul A Sieving, Louise Lanoue, K C Kent Lloyd, Colin Mckerlie, Ala Moshiri, International Mouse Phenotyping Consortium (Impc)

Center for Medical Ethics and Health Policy Staff Publications

Purpose: Analyze phenotypic data from knockout mice with late-adult retinal pathologic phenotypes to identify genes associated with development of adult-onset retinal diseases.

Methods: The International Mouse Phenotyping Consortium (IMPC) database was queried for genes associated with abnormal retinal phenotypes in the late-adult knockout mouse pipeline (49-80 weeks postnatal age). We identified human orthologs and performed protein-protein analysis and biological pathways analysis with known inherited retinal disease (IRD) and age-related macular degeneration (AMD) genes using Search Tool for the Retrieval of Interacting Genes/Proteins (STRING), PLatform for Analysis of single cell Eye in a Disk (PLAE), Protein Analysis Through Evolutionary Relationships (PANTHER), …

Present And Future Of Microbiome-Targeting Therapeutics, Lauren E Lynch, Rachel Lahowetz, Christian Maresso, Austen Terwilliger, Jason Pizzini, Valeria Melendez Hebib, Robert A Britton, Anthony W Maresso, Geoffrey A Preidis

Children’s Nutrition Research Center Staff Publications

A large body of evidence suggests that single- and multiple-strain probiotics and synbiotics could have roles in the management of specific gastrointestinal disorders. However, ongoing concerns regarding the quality and heterogeneity of the clinical data, safety in vulnerable populations, and the lack of regulation of products containing live microbes are barriers to widespread clinical use. Safety and regulatory issues must be addressed and new technologies considered. One alternative future strategy is the use of synthetic bacterial communities, defined as manually assembled consortia of two or more bacteria originally derived from the human gastrointestinal tract. Synthetic bacterial communities can model functional, …

Identification Of A Seasonal Influenza Vaccine-Induced Broadly Protective Neuraminidase Antibody, Anders Madsen, Nisreen M A Okba, Tossapol Pholcharee, Hanover C Matz, Huibin Lv, Maria Ibanez Trullen, Julian Q Zhou, Jackson S Turner, Aaron J Schmitz, Fangjie Han, Stephen C Horvath, Sameer Kumar Malladi, Florian Krammer, Nicholas C Wu, Ali H Ellebedy

2020-Current year OA Pubs

Seasonal influenza viruses cause significant global illness and death annually, and the potential spillover of avian H5N1 poses a serious pandemic threat. Traditional influenza vaccines target the variable hemagglutinin (HA) protein, necessitating annual vaccine updates, while the slower-evolving neuraminidase (NA) presents a promising target for broader protection. We investigated the breadth of anti-NA B cell responses to seasonal influenza vaccination in humans. We screened plasmablast-derived monoclonal antibodies (mAbs) from three donors, identifying 11 clonally distinct NA mAbs from 268 vaccine-specific mAbs. Among these, mAb-297 showed exceptionally broad NA inhibition, effectively protecting mice against lethal doses of influenza A and B …

Innate Lymphoid Cells In Inflammatory Bowel Disease, Xin Yao, Kaiming Ma, Yangzhuangzhuang Zhu, Siyan Cao

2020-Current year OA Pubs

Inflammatory bowel disease (IBD), including Crohn's disease and ulcerative colitis, is a chronic inflammatory disorder of the gastrointestinal tract with rising incidence and an unclear etiology. Innate lymphoid cells (ILCs) have recently emerged as key regulators of mucosal immunity and tissue homeostasis and are increasingly implicated in IBD. Unlike adaptive lymphocytes, ILCs do not require antigen recognition and clonal expansion to respond rapidly to environmental cues and shape immune responses. In a healthy gut, ILCs maintain intestinal homeostasis by guarding the epithelial barrier, protecting against pathogens, and mounting proper responses to external insults. However, their altered differentiation, proliferation, recruitment, activation, …

Comparative Genomics Reveals Common Diversity And Adaptation To Harsh Environments In The Arabian Peninsula Indigenous Chickens., Abdulwahad Assiri, Adriana Vallejo-Trujillo, Mohammed Al-Abri, Hussain Bahbahani, Faisal Almathen, Abulgasim Ahbara, Waleed Al Marzooqi, Abdulfatai Tijjani, Raman Akinyanju Lawal, Olivier Hanotte

Faculty Research 2025

Identifying genomic regions under selection is crucial for comprehending the evolutionary history of the domestic chicken. Arabian Peninsula (AP) indigenous chickens are mostly found outdoors, being reared alongside other livestock for production purposes. These birds show high resilience to extreme temperatures (hot and cold), typical of the desert environment. The selection pressures responsible for unique local adaptations in these birds remain largely unidentified. Here, we aimed to investigate the genome diversity and structure of 15 indigenous chicken populations including 13 populations from the AP (n = 5), Ethiopia (n = 6), and the People's Republic of China (n = 2). …

The Impact Of Co-Housing On Murine Aging Studies., Alison Luciano, Gary Churchill

Faculty Research 2025

Analysis of preclinical lifespan studies often assume that outcome data from co-housed animals are independent. In practice, treatments, such as controlled feeding or putative life-extending compounds, are applied to whole housing units, and as a result, the outcomes are potentially correlated within housing units. We consider intra-class (here, intra-cage) correlation in three published and two unpublished lifespan studies of aged mice encompassing more than 20,000 observations. We show that the independence assumption underlying common analytic techniques does not hold in these data, particularly for traits associated with frailty. We describe and demonstrate various analytical tools available to accommodate this study …

Perioperative Fluid Therapy Impairs Lymphatic Pump Function In Male Rats, Rebecca C Harlow-Adamek, Reetu Singh, Randolph H Stewart, Cristine L Heaps, Glen A Laine, Charles S Cox, Ranjeet M Dongaonkar

The Brown Foundation: Institute of Molecular Medicine

Because of its life-saving benefits, perioperative IV fluid therapy remains a cornerstone of medical treatment. However, it also induces sustained edemagenic stress. The resulting persistent interstitial edema-excessive fluid accumulation in the interstitium-significantly delays recovery and worsens patient outcomes. Therefore, to gain a detailed understanding of the lymphatic functional consequences of perioperative fluid therapy, this study aimed to test the hypothesis that perioperative IV fluid therapy compromises lymphatic pump function within 3 days after major surgery. Following a midline laparotomy, animals received IV fluid therapy over 48 h during recovery (FLTP). Three days post-surgery, mesenteric lymphatic vessels from FLTP and sham …

Biomolecular Condensates In Immune Cell Fate, Srikanth Kodali, Caroline M Sands, Lei Guo, Yun Huang, Bruno Di Stefano

Faculty, Staff and Students Publications

Fate decisions during immune cell development require temporally precise changes in gene expression. Evidence suggests that the dynamic modulation of these changes is associated with the formation of diverse, membrane-less nucleoprotein assemblies that are termed biomolecular condensates. These condensates are thought to orchestrate fate-determining transcriptional and post-transcriptional processes by locally and transiently concentrating DNA or RNA molecules alongside their regulatory proteins. Findings have established a link between condensate formation and the gene regulatory networks that ensure the proper development of immune cells. Conversely, condensate dysregulation has been linked to impaired immune cell fates, including ageing and malignant transformation. This Review …

Mollusc And Crustacean Consumption In The First 1000 Days: A Scoping Review, Brietta M Oaks, Emmanuel A Gyimah, Eliza Kleban, Kathleen Ragsdale, Lora L Iannotti

2020-Current year OA Pubs

Mollusc and crustacean consumption in the first 1000 d may improve maternal and child health by providing essential nutrients. However, in some contexts, molluscs and crustaceans have been associated with allergies and environmental contamination, potentially leading to adverse health and development outcomes. It is unclear whether the health benefits of consuming molluscs and crustaceans, collectively classified as shellfish in nutrition, are outweighed by the potential risks to pregnant women and children. We conducted a scoping review (PROSPERO: CRD42022320454) in PubMed, Scopus and EBSCO Global Health of articles published between January 2000 and March 2022 that assessed shellfish consumption during pregnancy, …

Identification And Functional Assessment Of Candidate Causal Cis-Regulatory Variants Underlying Electrocardiographic Qt Interval Gwas Loci, Supraja Kadagandla, Lavanya Gunamalai, Dongwon Lee, Ashish Kapoor

The Brown Foundation: Institute of Molecular Medicine

Background: Identifying causal variants among tens or hundreds of associated variants at each locus in genome-wide association studies is challenging. As the vast majority of genome-wide association studies variants are noncoding, sequence variation at cis-regulatory elements (CREs) affecting transcriptional expression of specific genes is a widely accepted molecular hypothesis. Following this hypothesis, combined with the observation that open chromatin is a universal hallmark of all types of CREs, we aimed to identify candidate causal cis-regulatory variants underlying QT interval genome-wide association studies loci.

Methods: Common variants in high linkage disequilibrium with genome-wide significant variants were identified using variant …

The Macrophage Sterol Transport Protein Orp2 Promotes Cholesterol Efflux And Prevents Foam Cell Formation And Atherosclerosis, Xiaowei Wang, Kenan Peng, Yudi Zhao, Liwen Qiu, Chenxi Liang, Yaqian Dou, Qianqian Dong, Xiaoting Ma, Jinye Tang, Yidan Ma, Lin Liu, Mingqi Zheng, Hongyuan Yang, Mingming Gao

Faculty, Staff and Student Publications

Cholesterol-loaded macrophage foam cells are a key feature of atherosclerotic plaques. Oxysterol-binding protein-related protein 2 (ORP2) facilitates the transport of cholesterol from lysosomes to the plasma membrane in cultured cell lines. However, the role of ORP2 in macrophages and its involvement in atherosclerosis remain unclear. In this study, we found ORP2 expression was reduced in atherosclerotic vessels and in macrophages exposed to oxidized LDL (ox-LDL). Myeloid-specific human ORP2 overexpression (hORP2MOE) mice were generated and crossed with atherosclerotic-prone ApoE−/− mice and then fed a high-fat diet (HFD) to induce atherosclerosis. Our results showed that myeloid-specific hORP2 overexpression significantly reduced the atherosclerotic …

Salicylamide Derivative Jmx0312 Protects Immunosuppressed Syrian Hamsters Against Adenovirus Lethal Challenge, Marta Carretero-Ledesma, Jun Li, Javier Martín-Escolano, Soraya Herrera-Espejo, Jimin Xu, Haiying Chen, Caridad Díaz-Navarro, Jerónimo Pachón, Javier Sánchez-Céspedes, Jia Zhou, María Eugenia Pachón-Ibáñez

Faculty, Staff and Student Publications

Despite the fact that human adenovirus (HAdV) causes severe infections in immunosuppressed and immunocompetent individuals, especially in children, there is currently no specific treatment for these infections. Previously we reported a new salicylamide analogue, JMX0312, as a potent inhibitor of HAdV infection with low cytotoxicity in vitro. Here we evaluate the in vivo efficacy and safety of this molecule in the immunosuppressed Syrian hamster model of HAdV infection. JMX0312 administration at a dose of 6.25 mg/kg did not affect the body weight of the animals, and reduced the viral load in liver and blood in a similar way than cidofovir. …

Glutamatergic Regulation Of Mirna-Containing Intraluminal Vesicle Trafficking And Extracellular Vesicle Secretion From Cortical Neurons, Marcela Bertolio, Qiyi Li, Francesca E Mowry, Kathryn E Reynolds, Rashed Alananzeh, Haichao Wei, Kyoeun Keum, Rachel Jarvis, Jiaqian Wu, Yongjie Yang

Faculty, Staff and Student Publications

Neuronal extracellular vesicles (microvesicles and exosomes) are emerging secreted vesicular signals that play important roles in the CNS. Currently, little is known about how glutamatergic signalling affects the subcellular localisation of exosome precursor intraluminal vesicles (ILVs), microRNA (miR) packaging into ILVs and in vivo spreading of neuronal EVs. By selectively labelling ILVs and exosomes (but not plasma membrane-derived MVs) with GFP-tagged human CD63 (hCD63-GFP) in cortical neurons, we found that glutamate stimulation significantly redistributes subcellular localisation of hCD63-GFP+ ILVs, especially decreasing its co-localisation with multi-vesicular body (MVB) marker Rab7 while substantially promoting EV secretion. Interestingly, glutamate stimulation only modestly alters …