Digital Commons Network^™

Blocking Senescence And Tolerogenic Function Of Dendritic Cells Induced By Γδ Treg Cells Enhances Tumor-Specific Immunity For Cancer Immunotherapy, Fusheng Si, Xia Liu, Yan Tao, Yuanqin Zhang, Feiya Ma, Eddy C Hsueh, Sidharth V Puram, Guangyong Peng

2020-Current year OA Pubs

BACKGROUND: Regulatory T (Treg) cells are a key component in maintaining the suppressive tumor microenvironment and immune suppression in different types of cancers. A precise understanding of the molecular mechanisms used by Treg cells for immune suppression is critical for the development of effective strategies for cancer immunotherapy.

METHODS: Senescence development and tolerogenic functions of dendritic cells (DCs) induced by breast cancer tumor-derived γδ Treg cells were fully characterized using real-time PCR, flow cytometry, western blot, and functional assays. Loss-of-function strategies with pharmacological inhibitor and/or neutralizing antibody were used to identify the potential molecule(s) and pathway(s) involved in DC senescence …

Subcellular Pathways Through Vglut3-Expressing Mouse Amacrine Cells Provide Locally Tuned Object-Motion-Selective Signals In The Retina, Karl Friedrichsen, Jen-Chun Hsiang, Chin-I Lin, Liam Mccoy, Katia Valkova, Daniel Kerschensteiner, Josh L Morgan

2020-Current year OA Pubs

VGluT3-expressing mouse retinal amacrine cells (VG3s) respond to small-object motion and connect to multiple types of bipolar cells (inputs) and retinal ganglion cells (RGCs, outputs). Because these input and output connections are intermixed on the same dendrites, making sense of VG3 circuitry requires comparing the distribution of synapses across their arbors to the subcellular flow of signals. Here, we combine subcellular calcium imaging and electron microscopic connectomic reconstruction to analyze how VG3s integrate and transmit visual information. VG3s receive inputs from all nearby bipolar cell types but exhibit a strong preference for the fast type 3a bipolar cells. By comparing …

Genetic Identification Of Three Cites-Listed Sharks Using A Paper-Based Lab-On-A-Chip (Loc), Guuske P. Tiktak, Alexandria Gabb, Margarita Brandt, Fernando R. Diz, Karla Bravo-Vasquez, Cesar Peñaherrera-Palma, Jonathan Valdiviezo-Rivera, Aaron Carlisle, Louise M. Melling, Bradley Cain, David Megson, Richard Preziosi, Kirsty J. Shaw

School of Biological and Marine Sciences

Threatened shark species are caught in large numbers by artisanal and commercial fisheries and traded globally. Monitoring both which shark species are caught and sold in fisheries, and the export of CITES-restricted products, are essential in reducing illegal fishing. Current methods for species identification rely on visual examination by experts or DNA barcoding techniques requiring specialist laboratory facilities and trained personnel. The need for specialist equipment and/or input from experts means many markets are currently not monitored. We have developed a paper-based Lab-on-A-Chip (LOC) to facilitate identification of three threatened and CITES-listed sharks, bigeye thresher (Alopias superciliosus), pelagic thresher (A. …

Bi-Allelic Acbd6 Variants Lead To A Neurodevelopmental Syndrome With Progressive And Complex Movement Disorders, Rauan Kaiyrzhanov, Aboulfazl Rad, Sheng-Jia Lin, Aida Bertoli-Avella, Wouter W Kallemeijn, Annie Godwin, Maha S Zaki, Kevin Huang, Tracy Lau, Cassidy Petree, Stephanie Efthymiou, Ehsan Ghayoor Karimiani, Maja Hempel, Elizabeth A Normand, Sabine Rudnik-Schöneborn, Ulrich A Schatz, Marc P Baggelaar, Muhammad Ilyas, Tipu Sultan, Javeria Raza Alvi, Manizha Ganieva, Ben Fowler, Ruxandra Aanicai, Gulsen Akay Tayfun, Abdulaziz Al Saman, Abdulrahman Alswaid, Nafise Amiri, Nilufar Asilova, Vorasuk Shotelersuk, Patra Yeetong, Matloob Azam, Meisam Babaei, Gholamreza Bahrami Monajemi, Pouria Mohammadi, Saeed Samie, Selina Husna Banu, Jorge Pinto Basto, Fanny Kortüm, Mislen Bauer, Peter Bauer, Christian Beetz, Masoud Garshasbi, Awatif Hameed Issa, Wafaa Eyaid, Hind Ahmed, Narges Hashemi, Kazem Hassanpour, Isabella Herman, Sherozjon Ibrohimov, Ban A Abdul-Majeed, Maria Imdad, Maksudjon Isrofilov, Qassem Kaiyal, Suliman Khan, Brian Kirmse, Janet Koster, Charles Marques Lourenço, Tadahiro Mitani, Oana Moldovan, David Murphy, Maryam Najafi, Davut Pehlivan, Maria Eugenia Rocha, Vincenzo Salpietro, Miriam Schmidts, Adel Shalata, Mohammad Mahroum, Jawabreh Kassem Talbeya, Robert W Taylor, Dayana Vazquez, Annalisa Vetro, Hans R Waterham, Mashaya Zaman, Tina A Schrader, Wendy K Chung, Renzo Guerrini, James R Lupski, Joseph Gleeson, Mohnish Suri, Yalda Jamshidi, Kailash P Bhatia, Barbara Vona, Michael Schrader, Mariasavina Severino, Matthew Guille, Edward W Tate, Gaurav K Varshney, Henry Houlden, Reza Maroofian

Faculty, Staff and Students Publications

The acyl-CoA-binding domain-containing protein 6 (ACBD6) is ubiquitously expressed, plays a role in the acylation of lipids and proteins and regulates the N-myristoylation of proteins via N-myristoyltransferase enzymes (NMTs). However, its precise function in cells is still unclear, as is the consequence of ACBD6 defects on human pathophysiology. Using exome sequencing and extensive international data sharing efforts, we identified 45 affected individuals from 28 unrelated families (consanguinity 93%) with bi-allelic pathogenic, predominantly loss-of-function (18/20) variants in ACBD6. We generated zebrafish and Xenopus tropicalis acbd6 knockouts by CRISPR/Cas9 and characterized the role of ACBD6 on protein N-myristoylation with myristic acid alkyne …

De Novo Variants In Fryl Are Associated With Developmental Delay, Intellectual Disability, And Dysmorphic Features, Xueyang Pan, Alice M Tao, Shenzhao Lu, Mengqi Ma, Shabab B Hannan, Rachel Slaugh, Sarah Drewes Williams, Lauren O'Grady, Oguz Kanca, Richard Person, Melissa T Carter, Konrad Platzer, Franziska Schnabel, Rami Abou Jamra, Amy E Roberts, Jane W Newburger, Anya Revah-Politi, Jorge L Granadillo, Alexander P A Stegmann, Margje Sinnema, Andrea Accogli, Vincenzo Salpietro, Valeria Capra, Lina Ghaloul-Gonzalez, Martina Brueckner, Marleen E H Simon, David A Sweetser, Kevin E Glinton, Susan E Kirk, Baylor College Of Medicine Center For Precision Medicine Models, Michael F Wangler, Shinya Yamamoto, Wendy K Chung, Hugo J Bellen

Faculty, Staff and Students Publications

FRY-like transcription coactivator (FRYL) belongs to a Furry protein family that is evolutionarily conserved from yeast to humans. The functions of FRYL in mammals are largely unknown, and variants in FRYL have not previously been associated with a Mendelian disease. Here, we report fourteen individuals with heterozygous variants in FRYL who present with developmental delay, intellectual disability, dysmorphic features, and other congenital anomalies in multiple systems. The variants are confirmed de novo in all individuals except one. Human genetic data suggest that FRYL is intolerant to loss of function (LoF). We find that the fly FRYL ortholog, furry (fry), is …

Intestinal Cell Diversity And Treatment Responses In A Parasitic Nematode At Single Cell Resolution, Rahul Tyagi, Bruce A Rosa, Amanda Swain, Maxim N Artyomov, Douglas P Jasmer, Makedonka Mitreva

2020-Current year OA Pubs

BACKGROUND: Parasitic nematodes, significant pathogens for humans, animals, and plants, depend on diverse organ systems for intra-host survival. Understanding the cellular diversity and molecular variations underlying these functions holds promise for developing novel therapeutics, with specific emphasis on the neuromuscular system's functional diversity. The nematode intestine, crucial for anthelmintic therapies, exhibits diverse cellular phenotypes, and unraveling this diversity at the single-cell level is essential for advancing knowledge in anthelmintic research across various organ systems.

RESULTS: Here, using novel single-cell transcriptomics datasets, we delineate cellular diversity within the intestine of adult female Ascaris suum, a parasitic nematode species that infects animals …

Vista Checkpoint Inhibition By Ph-Selective Antibody Sns-101 With Optimized Safety And Pharmacokinetic Profiles Enhances Pd-1 Response, Thomas Thisted, Yoshiko Takeuchi, Robert D Schreiber, Et Al.

2020-Current year OA Pubs

VISTA, an inhibitory myeloid-T-cell checkpoint, holds promise as a target for cancer immunotherapy. However, its effective targeting has been impeded by issues such as rapid clearance and cytokine release syndrome observed with previous VISTA antibodies. Here we demonstrate that SNS-101, a newly developed pH-selective VISTA antibody, addresses these challenges. Structural and biochemical analyses confirmed the pH-selectivity and unique epitope targeted by SNS-101. These properties confer favorable pharmacokinetic and safety profiles on SNS-101. In syngeneic tumor models utilizing human VISTA knock-in mice, SNS-101 shows in vivo efficacy when combined with a PD-1 inhibitor, modulates cytokine and chemokine signaling, and alters the …

Antibody-Mediated Targeting Of Human Microglial Leukocyte Ig-Like Receptor B4 Attenuates Amyloid Pathology In A Mouse Model, Jinchao Hou, Yun Chen, Zhangying Cai, Gyu Seong Heo, Carla M Yuede, Zuoxu Wang, Kent Lin, Fareeha Saadi, Tihana Trsan, Aivi T Nguyen, Eleni Constantopoulos, Rachel A Larsen, Yiyang Zhu, Nicole D Wagner, Nolan Mclaughlin, Xinyi Cynthia Kuang, Alexander D Barrow, Dian Li, Yingyue Zhou, Shoutang Wang, Susan Gilfillan, Michael L Gross, Simone Brioschi, Yongjian Liu, David M Holtzman, Marco Colonna

The Brown Foundation: Institute of Molecular Medicine

Microglia help limit the progression of Alzheimer’s disease (AD) by constraining amyloid-β (Aβ) pathology, effected through a balance of activating and inhibitory intracellular signals delivered by distinct cell surface receptors. Human leukocyte Ig-like receptor B4 (LILRB4) is an inhibitory receptor of the immunoglobulin (Ig) superfamily that is expressed on myeloid cells and recognizes apolipoprotein E (ApoE) among other ligands. Here, we find that LILRB4 is highly expressed in microglia of patients with AD. Using mice that accumulate Aβ and carry a transgene encompassing a portion of the LILR region that includes LILRB4, we corroborated abundant LILRB4 expression in microglia …

Nodal Variants Are Associated With A Continuum Of Laterality Defects From Simple D-Transposition Of The Great Arteries To Heterotaxy, Zain Dardas, Jawid M Fatih, Angad Jolly, Moez Dawood, Haowei Du, Christopher M Grochowski, Edward G Jones, Shalini N Jhangiani, Xander H T Wehrens, Pengfei Liu, Weimin Bi, Eric Boerwinkle, Jennifer E Posey, Donna M Muzny, Richard A Gibbs, James R Lupski, Zeynep Coban-Akdemir, Shaine A Morris

Faculty, Staff and Student Publications

BACKGROUND: NODAL signaling plays a critical role in embryonic patterning and heart development in vertebrates. Genetic variants resulting in perturbations of the TGF-β/NODAL signaling pathway have reproducibly been shown to cause laterality defects in humans. To further explore this association and improve genetic diagnosis, the study aims to identify and characterize a broader range of NODAL variants in a large number of individuals with laterality defects.

METHODS: We re-analyzed a cohort of 321 proband-only exomes of individuals with clinically diagnosed laterality congenital heart disease (CHD) using family-based, rare variant genomic analyses. To this cohort we added 12 affected subjects with …

Harnessing Rna Technology To Advance Therapeutic Vaccine Antigens Against Chagas Disease, Chiara Mancino, Jeroen Pollet, Assaf Zinger, Kathryn M Jones, Maria José Villar, Ana Carolina Leao, Rakesh Adhikari, Leroy Versteeg, Rakhi Tyagi Kundu, Ulrich Strych, Federica Giordano, Peter J Hotez, Maria Elena Bottazzi, Francesca Taraballi, Cristina Poveda

Center for Medical Ethics and Health Policy Staff Publications

Chagas disease (CD) (American trypanosomiasis caused by Trypanosoma cruzi) is a parasitic disease endemic in 21 countries in South America, with increasing global spread. When administered late in the infection, the current antiparasitic drugs do not prevent the onset of cardiac illness leading to chronic Chagasic cardiomyopathy. Therefore, new therapeutic vaccines or immunotherapies are under development using multiple platforms. In this study, we assessed the feasibility of developing an mRNA-based therapeutic CD vaccine targeting two known T. cruzi vaccine antigens (Tc24—a flagellar antigen and ASP-2—an amastigote antigen). We present the mRNA engineering steps, preparation, and stability of the lipid …

Gabaergic/Glycinergic And Glutamatergic Neurons Mediate Distinct Neurodevelopmental Phenotypes Of Stxbp1 Encephalopathy, Joo Hyun Kim, Wu Chen, Eugene S Chao, Armando Rivera, Heet Naresh Kaku, Kevin Jiang, Dongwon Lee, Hongmei Chen, Jaimie M Vega, Teresa V Chin, Kevin Jin, Kelly T Nguyen, Sheldon S Zou, Zain Moin, Shawn Nguyen, Mingshan Xue 薛名杉

Faculty, Staff and Students Publications

An increasing number of pathogenic variants in presynaptic proteins involved in the synaptic vesicle cycle are being discovered in neurodevelopmental disorders. The clinical features of these synaptic vesicle cycle disorders are diverse, but the most prevalent phenotypes include intellectual disability, epilepsy, movement disorders, cerebral visual impairment, and psychiatric symptoms ( Verhage and Sørensen, 2020; Bonnycastle et al., 2021; John et al., 2021; Melland et al., 2021). Among this growing list of synaptic vesicle cycle disorders, the most frequent is STXBP1 encephalopathy caused by de novo heterozygous pathogenic variants in syntaxin-binding protein 1 (STXBP1, also known as …

Neutrophil Elastase Remodels Mammary Tumors To Facilitate Lung Metastasis, Amriti R Lulla, Said Akli, Cansu Karakas, Joseph A Caruso, Lucas D Warma, Natalie W Fowlkes, Xiayu Rao, Jing Wang, Kelly K Hunt, Stephanie S Watowich, Khandan Keyomarsi

Faculty, Staff and Student Publications

Metastatic disease remains the leading cause of death due to cancer, yet the mechanism(s) of metastasis and its timely detection remain to be elucidated. Neutrophil elastase (NE), a serine protease secreted by neutrophils, is a crucial mediator of chronic inflammation and tumor progression. In this study, we used the PyMT model (NE+/+ and NE-/-) of breast cancer to interrogate the tumor-intrinsic and -extrinsic mechanisms by which NE can promote metastasis. Our results showed that genetic ablation of NE significantly reduced lung metastasis and improved metastasis-free survival. RNA-sequencing analysis of primary tumors indicated differential regulation of tumor-intrinsic actin cytoskeleton signaling pathways …

Antigen-Clustered Nanovaccine Achieves Long-Term Tumor Remission By Promoting B/Cd 4 T Cell Crosstalk, Chengyi Li, Ryan Clauson, Luke F Bugada, Fang Ke, Bing He, Zhixin Yu, Hongwei Chen, Binyamin Jacobovitz, Hongxiang Hu, Polina Chuikov, Brett Dallas Hill, Syed M Rizvi, Yudong Song, Kai Sun, Pasieka Axenov, Daniel Huynh, Xinyi Wang, Lana Garmire, Yu Leo Lei, Irina Grigorova, Fei Wen, Marilia Cascalho, Wei Gao, Duxin Sun

Faculty, Staff and Student Publications

Current cancer vaccines using T cell epitopes activate antitumor T cell immunity through dendritic cell/macrophage-mediated antigen presentation, but they lack the ability to promote B/CD4 T cell crosstalk, limiting their anticancer efficacy. We developed antigen-clustered nanovaccine (ACNVax) to achieve long-term tumor remission by promoting B/CD4 T cell crosstalk. The topographic features of ACNVax were achieved using an iron nanoparticle core attached with an optimal number of gold nanoparticles, where the clusters of HER2 B/CD4 T cell epitopes were conjugated on the gold surface with an optimal intercluster distance of 5-10 nm. ACNVax effectively trafficked to lymph nodes and cross-linked with …

Targeting Branched N-Glycans And Fucosylation Sensitizes Ovarian Tumors To Immune Checkpoint Blockade, Hao Nie, Pratima Saini, Taito Miyamoto, Liping Liao, Rafal J Zielinski, Heng Liu, Wei Zhou, Chen Wang, Brennah Murphy, Martina Towers, Tyler Yang, Yuan Qi, Toshitha Kannan, Andrew Kossenkov, Hiroaki Tateno, Daniel T Claiborne, Nan Zhang, Mohamed Abdel-Mohsen, Rugang Zhang

Faculty, Staff and Student Publications

Aberrant glycosylation is a crucial strategy employed by cancer cells to evade cellular immunity. However, it's unclear whether homologous recombination (HR) status-dependent glycosylation can be therapeutically explored. Here, we show that the inhibition of branched N-glycans sensitizes HR-proficient, but not HR-deficient, epithelial ovarian cancers (EOCs) to immune checkpoint blockade (ICB). In contrast to fucosylation whose inhibition sensitizes EOCs to anti-PD-L1 immunotherapy regardless of HR-status, we observe an enrichment of branched N-glycans on HR-proficient compared to HR-deficient EOCs. Mechanistically, BRCA1/2 transcriptionally promotes the expression of MGAT5, the enzyme responsible for catalyzing branched N-glycans. The branched N-glycans on HR-proficient tumors augment their …

A Compendium Of Multi-Omics Data Illuminating Host Responses To Lethal Human Virus Infections, Amie J Eisfeld, Larissa B Thackray, Qing Tan, Michael S Diamond, Et Al.

2020-Current year OA Pubs

Human infections caused by viral pathogens trigger a complex gamut of host responses that limit disease, resolve infection, generate immunity, and contribute to severe disease or death. Here, we present experimental methods and multi-omics data capture approaches representing the global host response to infection generated from 45 individual experiments involving human viruses from the Orthomyxoviridae, Filoviridae, Flaviviridae, and Coronaviridae families. Analogous experimental designs were implemented across human or mouse host model systems, longitudinal samples were collected over defined time courses, and global multi-omics data (transcriptomics, proteomics, metabolomics, and lipidomics) were acquired by microarray, RNA sequencing, or mass spectrometry analyses. For …

Nfĸb Signaling Drives Myocardial Injury Via Ccr2+ Macrophages In A Preclinical Model Of Arrhythmogenic Cardiomyopathy, Stephen P. Chelko, Vinay R. Penna, Morgan Engel, Emily A. Shiel, Ann M. Centner, Waleed Farra, Elisa N. Cannon, Maicon Landim-Vieira, Niccole Schaible, Kory Lavine, Jeffrey E. Saffitz

2020-Current year OA Pubs

Nuclear factor κ-B (NFκB) is activated in iPSC-cardiac myocytes from patients with arrhythmogenic cardiomyopathy (ACM) under basal conditions, and inhibition of NFκB signaling prevents disease in Dsg2mut/mut mice, a robust mouse model of ACM. Here, we used genetic approaches and single-cell RNA-Seq to define the contributions of immune signaling in cardiac myocytes and macrophages in the natural progression of ACM using Dsg2mut/mut mice. We found that NFκB signaling in cardiac myocytes drives myocardial injury, contractile dysfunction, and arrhythmias in Dsg2mut/mut mice. NFκB signaling in cardiac myocytes mobilizes macrophages expressing C-C motif chemokine receptor-2 (CCR2+ cells) to affected areas within the …

Network-Based Analysis Predicts Interacting Genetic Modifiers From A Meta-Mapping Study Of Spike-Wave Discharge In Mice., Montana Kay Lara, Jeffrey L Brabec, Amanda E Hernan, Rod C Scott, Anna L. Tyler, J Matthew Mahoney

Faculty Research 2024

Absence seizures are characterized by brief lapses in awareness accompanied by a hallmark spike-and-wave discharge (SWD) electroencephalographic pattern and are common to genetic generalized epilepsies (GGEs). While numerous genes have been associated with increased risk, including some Mendelian forms with a single causal allele, most cases of GGE are idiopathic and there are many unknown genetic modi- fiers of GGE influencing risk and severity. In a previous meta-mapping study, crosses between transgenic C57BL/6 and C3HeB/FeJ strains, each carrying one of three SWD-causing mutations (Gabrg2 tm1Spet(R43Q), Scn8a8j or Gria4spkw1), demonstrated an antagonistic epistatic interaction between loci on mouse chromosomes 2 and …

Genetic Diversity Promotes Resilience In A Mouse Model Of Alzheimer's Disease., Neelakshi Soni, Lindsay A Hohsfield, Kristine M Tran, Shimako Kawauchi, Amber Walker, Dominic Javonillo, Jimmy Phan, Dina Matheos, Celia Da Cunha, Asli Uyar, Giedre Milinkeviciute, Angela Gomez-Arboledas, Katelynn Tran, Catherine C Kaczorowski, Marcelo A Wood, Andrea J Tenner, Frank M Laferla, Gregory W. Carter, Ali Mortazavi, Vivek Swarup, Grant R Macgregor, Kim N Green

Faculty Research 2024

INTRODUCTION: Alzheimer's disease (AD) is a neurodegenerative disorder with multifactorial etiology, including genetic factors that play a significant role in disease risk and resilience. However, the role of genetic diversity in preclinical AD studies has received limited attention.

METHODS: We crossed five Collaborative Cross strains with 5xFAD C57BL/6J female mice to generate F1 mice with and without the 5xFAD transgene. Amyloid plaque pathology, microglial and astrocytic responses, neurofilament light chain levels, and gene expression were assessed at various ages.

RESULTS: Genetic diversity significantly impacts AD-related pathology. Hybrid strains showed resistance to amyloid plaque formation and neuronal damage. Transcriptome diversity was …

Unraveling The Genetics Of Arsenic Toxicity With Cellular Morphology Qtl., Callan O'Connor, Gregory R Keele, Whitney Martin, Tim J Stodola, Daniel M Gatti, Brian Hoffmann, Ron Korstanje, Gary Churchill, Laura G Reinholdt

Faculty Research 2024

The health risks that arise from environmental exposures vary widely within and across human populations, and these differences are largely determined by genetic variation and gene-by-environment (gene-environment) interactions. However, risk assessment in laboratory mice typically involves isogenic strains and therefore, does not account for these known genetic effects. In this context, genetically heterogenous cell lines from laboratory mice are promising tools for population-based screening because they provide a way to introduce genetic variation in risk assessment without increasing animal use. Cell lines from genetic reference populations of laboratory mice offer genetic diversity, power for genetic mapping, and potentially, predictive value …

In Vivo Tissue Distribution Of Polystyrene Or Mixed Polymer Microspheres And Metabolomic Analysis After Oral Exposure In Mice, Marcus M. Garcia, Aaron S. Romero, Seth D. Merkley, Jewel L. Meyer-Hagen, Charles Forbes, Eliane El Hayek, David P. Sciezka, Rachel Templeton, Jorge Gonzalez-Estrella, Yan Jin, Haiwei Gu, Angelica Benavidez, Russell P. Hunter, Selita Lucas, Guy Herbert, Kyle Joohyung Kim, Julia Yue Cui, Rama R. Gullapalli, Julie G. In, Matthew J. Campen, Eliseo F. Castillo

Pathology Research and Scholarship

BACKGROUND: Global plastic use has consistently increased over the past century with several different types of plastics now being produced. Much of these plastics end up in oceans or landfills leading to a substantial accumulation of plastics in the environment. Plastic debris slowly degrades into microplastics (MPs) that can ultimately be inhaled or ingested by both animals and humans. A growing body of evidence indicates that MPs can cross the gut barrier and enter into the lymphatic and systemic circulation leading to accumulation in tissues such as the lungs, liver, kidney, and brain. The impacts of mixed MPs exposure on …

A Machine Learning Approach For Quantifying Age-Related Histological Changes In The Mouse Kidney., Susan Sheehan, Seamus Mawe, Mandy Chen, Jenna Klug, Warren Ladiges, Ron Korstanje, J Matthew Mahoney

Faculty Research 2024

The ability to quantify aging-related changes in histological samples is important, as it allows for evaluation of interventions intended to effect health span. We used a machine learning architecture that can be trained to detect and quantify these changes in the mouse kidney. Using additional held out data, we show validation of our model, correlation with scores given by pathologists using the Geropathology Research Network aging grading scheme, and its application in providing reproducible and quantifiable age scores for histological samples. Aging quantification also provides the insights into possible changes in image appearance that are independent of specific geropathology-specified lesions. …

Into The Wild: A Novel Wild-Derived Inbred Strain Resource Expands The Genomic And Phenotypic Diversity Of Laboratory Mouse Models., Beth L Dumont, Daniel Mario Gatti, Mallory A Ballinger, Dana Lin, Megan Phifer-Rixey, Michael J Sheehan, Taichi A Suzuki, Lydia K Wooldridge, Hilda Opoku Frempong, Raman Akinyanju Lawal, Gary Churchill, Cathleen Lutz, Nadia Rosenthal, Jacqueline K White, Michael W Nachman

Faculty Research 2024

The laboratory mouse has served as the premier animal model system for both basic and preclinical investigations for over a century. However, laboratory mice capture only a subset of the genetic variation found in wild mouse populations, ultimately limiting the potential of classical inbred strains to uncover phenotype-associated variants and pathways. Wild mouse populations are reservoirs of genetic diversity that could facilitate the discovery of new functional and disease-associated alleles, but the scarcity of commercially available, well-characterized wild mouse strains limits their broader adoption in biomedical research. To overcome this barrier, we have recently developed, sequenced, and phenotyped a set …

Gene Replacement-Alzheimer's Disease (Gr-Ad): Modeling The Genetics Of Human Dementias In Mice., Kellie Benzow, Kul Karanjeet, Adrian L Oblak, Gregory W. Carter, Michael Sasner, Michael D Koob

Faculty Research 2024

INTRODUCTION: Genetic studies conducted over the past four decades have provided us with a detailed catalog of genes that play critical roles in the etiology of Alzheimer's disease (AD) and related dementias (ADRDs). Despite this progress, as a field we have had only limited success in incorporating this rich complexity of human AD/ADRD genetics findings into our animal models of these diseases. Our primary goal for the gene replacement (GR)-AD project is to develop mouse lines that model the genetics of AD/ADRD as closely as possible.

METHODS: To do this, we are generating mouse lines in which the genes of …

Robust Capital Cost Optimization Of Generation And Multitimescale Storage Requirements For A 100% Renewable Australian Electricity Grid, Raheel A Shaikh, David J Vowles, Alex Dinovitser, Andrew Allison, Derek Abbott

Faculty, Staff and Student Publications

Transitioning from a fossil-fuel-dependent economy to one based on renewable energy requires significant investment and technological advancement. While wind and solar technologies provide lower cost electricity, enhanced energy storage and transmission infrastructure come at a cost for managing renewable intermittency. Energy storage systems vary in characteristics and costs, and future grids will incorporate multiple technologies, yet the optimal combination of storage technologies and the role of interconnectors in alleviating storage needs are not widely explored. This study focuses on optimal generation-storage capacity requirements to elucidate associated investments. We propose a multitimescale storage solution consisting of three storage categories and an …

Fda Overreach: Is Your Pet’S Health A “Major Question” To You?, Ross C. Reggio

Washington and Lee Law Review

Pharmacy compounding of drugs for companion animals and humans is as old as time. For hundreds of years, pharmacists created these drugs using active pharmaceutical ingredients, otherwise known as bulk drug substances, to address the medical needs of these patients. Congress recognized this longstanding practice when it enacted the Food, Drug, and Cosmetic Act (“FDCA”), with lawmakers then noting that while pharmacists, physicians, and veterinarians were already highly regulated by the states, mass-producing drug manufacturers were not regulated. The FDCA would regulate such manufacturers.

Thereafter, pharmacy compounding from bulk drug substances continued for decades after the FDCA’s enactment and without …

Asthmatic Patients With High Serum Amyloid A Have Proinflammatory Hdl: Implications For Augmented Systemic And Airway Inflammation., Xianglan Yao, Maryann Kaler, Xuan Qu, Rama Satyanarayana Raju Kalidhindi, Denis Sviridov, Amaury Dasseux, Eric Barr, Karen Keeran, Kenneth R. Jeffries, Zu-Xi Yu, Meixia Gao, Scott Gordon, Amisha V. Barochia, Joni Mills, Shahid Shahid, Nargues A. Weir, Or Kalchiem-Dekel, Patricia Theard, Martin P. Playford, Mario Stylianou, Wendy Fitzgerald, Alan T. Remaley, Stewart J. Levine

Physiology Faculty Publications

RATIONALE: Serum amyloid A (SAA) is bound to high-density lipoproteins (HDL) in blood. Although SAA is increased in the blood of patients with asthma, it is not known whether this modifies asthma severity.

OBJECTIVE: We sought to define the clinical characteristics of patients with asthma who have high SAA levels and assess whether HDL from SAA-high patients with asthma is proinflammatory.

METHODS: SAA levels in serum from subjects with and without asthma were quantified by ELISA. HDLs isolated from subjects with asthma and high SAA levels were used to stimulate human monocytes and were intravenously administered to BALB/c mice.

RESULTS: …

Population Coding Of Strategic Variables During Foraging In Freely Moving Macaques, Neda Shahidi, Melissa Franch, Arun Parajuli, Paul Schrater, Anthony Wright, Xaq Pitkow, Valentin Dragoi

Faculty, Staff and Student Publications

Until now, it has been difficult to examine the neural bases of foraging in naturalistic environments because previous approaches have relied on restrained animals performing trial-based foraging tasks. Here we allowed unrestrained monkeys to freely interact with concurrent reward options while we wirelessly recorded population activity in the dorsolateral prefrontal cortex. The animals decided when and where to forage based on whether their prediction of reward was fulfilled or violated. This prediction was not solely based on a history of reward delivery, but also on the understanding that waiting longer improves the chance of reward. The task variables were continuously …

E-Cadherin Loss Drives Diffuse-Type Gastric Tumorigenesis Via Ezh2-Mediated Reprogramming, Gengyi Zou, Yuanjian Huang, Shengzhe Zhang, Kyung-Pil Ko, Bongjun Kim, Jie Zhang, Vishwa Venkatesan, Melissa P Pizzi, Yibo Fan, Sohee Jun, Na Niu, Huamin Wang, Shumei Song, Jaffer A Ajani, Jae-Il Park

Faculty, Staff and Student Publications

Diffuse-type gastric adenocarcinoma (DGAC) is a deadly cancer often diagnosed late and resistant to treatment. While hereditary DGAC is linked to CDH1 mutations, the role of CDH1/E-cadherin inactivation in sporadic DGAC tumorigenesis remains elusive. We discovered CDH1 inactivation in a subset of DGAC patient tumors. Analyzing single-cell transcriptomes in malignant ascites, we identified two DGAC subtypes: DGAC1 (CDH1 loss) and DGAC2 (lacking immune response). DGAC1 displayed distinct molecular signatures, activated DGAC-related pathways, and an abundance of exhausted T cells in ascites. Genetically engineered murine gastric organoids showed that Cdh1 knock-out (KO), KrasG12D, Trp53 KO (EKP) accelerates tumorigenesis with immune evasion …

Protective Effects Of The Postbiotic Lactobacillus Plantarum Md35 On Bone Loss In An Ovariectomized Mice Model, Ju-Yeong Myeong, Hye-Yeon Jung, Hyo-Seok Chae, Hyang Hyun Cho, Don-Kyu Kim, You-Jee Jang, Jae-Il Park

Faculty, Staff and Student Publications

Postmenopausal osteoporosis is caused by estrogen deficiency, which impairs bone homeostasis, resulting in increased osteoclastic resorption without a corresponding increase in osteoblastic activity. Postbiotics have several therapeutic properties, including anti-obesity, anti-diabetic, anti-inflammatory, and anti-osteoporotic effects. However, the beneficial effects of the postbiotic MD35 of Lactobacillus plantarum on bone have not been studied. In this study, we demonstrated that the postbiotic L. plantarum MD35, isolated from young radish water kimchi, influences osteoclast differentiation in mouse bone marrow-derived macrophage (BMM) culture. In addition, it was effective protecting against estrogen deficiency-induced bone loss in ovariectomized (OVX) mice, an animal model of postmenopausal osteoporosis. …

Influenza Incidence, Lineages, And Vaccine Effectiveness Estimates In Lima, Peru, 2023, Juan Gonzalo Acevedo-Rodriguez, Carlos Zamudio, Noah Kojima, Fiorella Krapp, Pablo Tsukayama, Victor Giancarlo Sal Y Rosas Celi, Dante Baldeon, Carmen Stefany Neciosup-Vera, Carlos Medina, Elsa Gonzalez-Lagos, Laura Castro, Ashley Fowlkes, Eduardo Azziz-Baumgartner, Eduardo Gotuzzo

Faculty, Staff and Student Publications

No abstract provided.