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Parenchymal Border Macrophages Regulate Tau Pathology And Tau-Mediated Neurodegeneration, Antoine Drieu, Siling Du, Michal Kipnis, Megan E Bosch, Jasmin Herz, Choonghee Lee, Hong Jiang, Melissa Manis, Jason D Ulrich, Jonathan Kipnis, David M Holtzman, Maud Gratuze Nov 2023

Parenchymal Border Macrophages Regulate Tau Pathology And Tau-Mediated Neurodegeneration, Antoine Drieu, Siling Du, Michal Kipnis, Megan E Bosch, Jasmin Herz, Choonghee Lee, Hong Jiang, Melissa Manis, Jason D Ulrich, Jonathan Kipnis, David M Holtzman, Maud Gratuze

2020-Current year OA Pubs

Parenchymal border macrophages (PBMs) reside close to the central nervous system parenchyma and regulate CSF flow dynamics. We recently demonstrated that PBMs provide a clearance pathway for amyloid-β peptide, which accumulates in the brain in Alzheimer's disease (AD). Given the emerging role for PBMs in AD, we explored how tau pathology affects the CSF flow and the PBM populations in the PS19 mouse model of tau pathology. We demonstrated a reduction of CSF flow, and an increase in an MHCII

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Protective Effects Of Epigallocatechin-3-Gallate Counteracting The Chronic Hypobaric Hypoxia-Induced Myocardial Injury In Plain-Grown Rats At High Altitude, Haotian Chen, Chen Chen, Yuhui Qin, Lei Wang, Jie Zheng, Fabao Gao Nov 2023

Protective Effects Of Epigallocatechin-3-Gallate Counteracting The Chronic Hypobaric Hypoxia-Induced Myocardial Injury In Plain-Grown Rats At High Altitude, Haotian Chen, Chen Chen, Yuhui Qin, Lei Wang, Jie Zheng, Fabao Gao

2020-Current year OA Pubs

Exposure to hypobaric hypoxia (HH) environment causes stress to the body, especially the oxygen-consuming organs. Chronic HH conditions have adverse effects on the myocardium. Thus, we conducted this experiment and aim to evaluate such adverse effects and explore the therapeutic role of epigallocatechin-3-gallate (EGCG) in rats' heart under chronic HH conditions. For that purpose, we transported rats from plain to a real HH environment at high altitude for establishing the HH model. At high altitude, animals were treated with EGCG while the salidroside was used as the positive control. General physiological data were collected, and routine blood test results were …

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Cux1-Related Neurodevelopmental Disorder: Deep Insights Into Phenotype-Genotype Spectrum And Underlying Pathology, Henry Oppermann, Christina A Gurnett, Et Al. Nov 2023

Cux1-Related Neurodevelopmental Disorder: Deep Insights Into Phenotype-Genotype Spectrum And Underlying Pathology, Henry Oppermann, Christina A Gurnett, Et Al.

2020-Current year OA Pubs

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1

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Long Non-Coding Rna Snhg8 Drives Stress Granule Formation In Tauopathies, Reshma Bhagat, Miguel A Minaya, Arun Renganathan, Muneshwar Mehra, Jacob Marsh, Rita Martinez, Abdallah M Eteleeb, Alissa L Nana, Salvatore Spina, William W Seeley, Lea T Grinberg, Celeste M Karch Nov 2023

Long Non-Coding Rna Snhg8 Drives Stress Granule Formation In Tauopathies, Reshma Bhagat, Miguel A Minaya, Arun Renganathan, Muneshwar Mehra, Jacob Marsh, Rita Martinez, Abdallah M Eteleeb, Alissa L Nana, Salvatore Spina, William W Seeley, Lea T Grinberg, Celeste M Karch

2020-Current year OA Pubs

Tauopathies are a heterogenous group of neurodegenerative disorders characterized by tau aggregation in the brain. In a subset of tauopathies, rare mutations in the MAPT gene, which encodes the tau protein, are sufficient to cause disease; however, the events downstream of MAPT mutations are poorly understood. Here, we investigate the role of long non-coding RNAs (lncRNAs), transcripts >200 nucleotides with low/no coding potential that regulate transcription and translation, and their role in tauopathy. Using stem cell derived neurons from patients carrying a MAPT p.P301L, IVS10 + 16, or p.R406W mutation and CRISPR-corrected isogenic controls, we identified transcriptomic changes that occur …

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Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channel 3 Promotes Hcc Development In A Female-Biased Manner, Yueqi Zhang, Xinhui Liu, Kairui Sun, Yue Luo, Jack Yang, Aimin Li, Matti Kiupel, Stefanie Fenske, Martin Biel, Qing-Sheng Mi, Hongbing Wang, Hua Xiao Oct 2023

Hyperpolarization-Activated Cyclic Nucleotide-Gated Cation Channel 3 Promotes Hcc Development In A Female-Biased Manner, Yueqi Zhang, Xinhui Liu, Kairui Sun, Yue Luo, Jack Yang, Aimin Li, Matti Kiupel, Stefanie Fenske, Martin Biel, Qing-Sheng Mi, Hongbing Wang, Hua Xiao

Dermatology Articles

Sex differences in hepatocellular carcinoma (HCC) development are regulated by sex and non-sex chromosomes, sex hormones, and environmental factors. We previously reported that Ncoa5(+/-) mice develop HCC in a male-biased manner. Here we show that NCOA5 expression is reduced in male patient HCCs while the expression of an NCOA5-interacting tumor suppressor, TIP30, is lower in female HCCs. Tip30 heterozygous deletion does not change HCC incidence in Ncoa5(+/-) male mice but dramatically increases HCC incidence in Ncoa5(+/-) female mice, accompanied by hepatic hyperpolarization-activated cyclic nucleotide-gated cation channel 3 (HCN3) overexpression. HCN3 overexpression cooperates with MYC to promote mouse HCC development, whereas …

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Anthocyanins: Molecular Aspects On Their Neuroprotective Activity, César A Zaa, Álvaro J Marcelo, Zhiqiang An, José L Medina-Franco, Marco A Velasco-Velázquez Oct 2023

Anthocyanins: Molecular Aspects On Their Neuroprotective Activity, César A Zaa, Álvaro J Marcelo, Zhiqiang An, José L Medina-Franco, Marco A Velasco-Velázquez

Faculty, Staff and Student Publications

Anthocyanins are a type of flavonoids that give plants and fruits their vibrant colors. They are known for their potent antioxidant properties and have been linked to various health benefits. Upon consumption, anthocyanins are quickly absorbed and can penetrate the blood-brain barrier (BBB). Research based on population studies suggests that including anthocyanin-rich sources in the diet lower the risk of neurodegenerative diseases. Anthocyanins exhibit neuroprotective effects that could potentially alleviate symptoms associated with such diseases. In this review, we compiled and discussed a large body of evidence supporting the neuroprotective role of anthocyanins. Our examination encompasses human studies, animal models, …

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A Small-Molecule Inhibitor Of Topbp1 Exerts Anti-Myc Activity And Synergy With Parp Inhibitors, Fang-Tsyr Lin, Kang Liu, Lidija A Wilhelms Garan, Helena Folly-Kossi, Yongcheng Song, Shwu-Jiuan Lin, Weei-Chin Lin Oct 2023

A Small-Molecule Inhibitor Of Topbp1 Exerts Anti-Myc Activity And Synergy With Parp Inhibitors, Fang-Tsyr Lin, Kang Liu, Lidija A Wilhelms Garan, Helena Folly-Kossi, Yongcheng Song, Shwu-Jiuan Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

We have previously identified TopBP1 (topoisomerase IIβ-binding protein 1) as a promising target for cancer therapy, given its role in the convergence of Rb, PI(3)K/Akt, and p53 pathways. Based on this, we conducted a large-scale molecular docking screening to identify a small-molecule inhibitor that specifically targets the BRCT7/8 domains of TopBP1, which we have named 5D4. Our studies show that 5D4 inhibits TopBP1 interactions with E2F1, mutant p53, and Cancerous Inhibitor of Protein Phosphatase 2A. This leads to the activation of E2F1-mediated apoptosis and the inhibition of mutant p53 gain of function. In addition, 5D4 disrupts the interaction of TopBP1 …

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Diversity In Homeostatic Calcium Set Points Predicts Retinal Ganglion Cell Survival Following Optic Nerve Injury In Vivo, Sean Mccracken, Michael J Fitzpatrick, Allison L Hall, Zelun Wang, Daniel Kerschensteiner, Josh L Morgan, Philip R Williams Oct 2023

Diversity In Homeostatic Calcium Set Points Predicts Retinal Ganglion Cell Survival Following Optic Nerve Injury In Vivo, Sean Mccracken, Michael J Fitzpatrick, Allison L Hall, Zelun Wang, Daniel Kerschensteiner, Josh L Morgan, Philip R Williams

2020-Current year OA Pubs

Retinal ganglion cell (RGC) degeneration drives vision loss in blinding conditions. RGC death is often triggered by axon degeneration in the optic nerve. Here, we study the contributions of dynamic and homeostatic Ca

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Mycobacterium Tuberculosis Carrying The Rifampicin Drug-Resistance-Conferring Rpob Mutation H445y Is Associated With Suppressed Immunity Through Type I Interferons, Suhas Bobba, Nicole C Howard, Shibali Das, Mushtaq Ahmed, Linrui Tang, Shyamala Thirunavukkarasu, Michelle H Larsen, Barun Mathema, Maziar Divangahi, Shabaana A Khader Oct 2023

Mycobacterium Tuberculosis Carrying The Rifampicin Drug-Resistance-Conferring Rpob Mutation H445y Is Associated With Suppressed Immunity Through Type I Interferons, Suhas Bobba, Nicole C Howard, Shibali Das, Mushtaq Ahmed, Linrui Tang, Shyamala Thirunavukkarasu, Michelle H Larsen, Barun Mathema, Maziar Divangahi, Shabaana A Khader

2020-Current year OA Pubs

This study highlights the impact of specific rifampicin-resistance-conferring mutations on the host immune response to

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Toll-Like Receptor 4 And Cd11b Expressed On Microglia Coordinate Eradication Of Candida Albicans Cerebral Mycosis, Yifan Wu, Shuqi Du, Lynn H Bimler, Kelsey E Mauk, Léa Lortal, Nessim Kichik, James S Griffiths, Radim Osicka, Lizhen Song, Katherine Polsky, Lydia Kasper, Peter Sebo, Jill Weatherhead, J Morgan Knight, Farrah Kheradmand, Hui Zheng, Jonathan P Richardson, Bernhard Hube, Julian R Naglik, David B Corry Oct 2023

Toll-Like Receptor 4 And Cd11b Expressed On Microglia Coordinate Eradication Of Candida Albicans Cerebral Mycosis, Yifan Wu, Shuqi Du, Lynn H Bimler, Kelsey E Mauk, Léa Lortal, Nessim Kichik, James S Griffiths, Radim Osicka, Lizhen Song, Katherine Polsky, Lydia Kasper, Peter Sebo, Jill Weatherhead, J Morgan Knight, Farrah Kheradmand, Hui Zheng, Jonathan P Richardson, Bernhard Hube, Julian R Naglik, David B Corry

Faculty, Staff and Students Publications

The fungal pathogen Candida albicans is linked to chronic brain diseases such as Alzheimer's disease (AD), but the molecular basis of brain anti-Candida immunity remains unknown. We show that C. albicans enters the mouse brain from the blood and induces two neuroimmune sensing mechanisms involving secreted aspartic proteinases (Saps) and candidalysin. Saps disrupt tight junction proteins of the blood-brain barrier (BBB) to permit fungal brain invasion. Saps also hydrolyze amyloid precursor protein (APP) into amyloid β (Aβ)-like peptides that bind to Toll-like receptor 4 (TLR4) and promote fungal killing in vitro while candidalysin engages the integrin CD11b (Mac-1) on microglia. …

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Constitutive Interleukin-7 Cytokine Signaling Enhances The Persistence Of Epstein-Barr Virus-Specific T-Cells, Sandhya Sharma, Tim Sauer, Bilal A Omer, Thomas Shum, Lisa A Rollins, Cliona M Rooney Oct 2023

Constitutive Interleukin-7 Cytokine Signaling Enhances The Persistence Of Epstein-Barr Virus-Specific T-Cells, Sandhya Sharma, Tim Sauer, Bilal A Omer, Thomas Shum, Lisa A Rollins, Cliona M Rooney

Faculty, Staff and Students Publications

The efficacy of therapeutic T-cells is limited by a lack of positive signals and excess inhibitory signaling in tumor microenvironments. We previously showed that a constitutively active IL7 receptor (C7R) enhanced the persistence, expansion, and anti-tumor activity of T-cells expressing chimeric antigen receptors (CARs), and C7R-modified GD2.CAR T-cells are currently undergoing clinical trials. To determine if the C7R could also enhance the activity of T-cells recognizing tumors via their native T-cell receptors (TCRs), we evaluated its effects in Epstein–Barr virus (EBV)-specific T-cells (EBVSTs) that have produced clinical benefits in patients with EBV-associated malignancies. EBVSTs were generated by stimulation of peripheral …

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The Trna Methyltransferase Trmb Is Critical For Acinetobacter Baumannii Stress Responses And Pulmonary Infection, Jenna C Mcguffey, Clay D Jackson-Litteken, Gisela Di Venanzio, Aubree A Zimmer, Jessica M Lewis, Jesus S Distel, Kyusik Q Kim, Hani S Zaher, Juan Alfonzo, Nichollas E Scott, Mario F Feldman Oct 2023

The Trna Methyltransferase Trmb Is Critical For Acinetobacter Baumannii Stress Responses And Pulmonary Infection, Jenna C Mcguffey, Clay D Jackson-Litteken, Gisela Di Venanzio, Aubree A Zimmer, Jessica M Lewis, Jesus S Distel, Kyusik Q Kim, Hani S Zaher, Juan Alfonzo, Nichollas E Scott, Mario F Feldman

2020-Current year OA Pubs

As deficiencies in tRNA modifications have been linked to human diseases such as cancer and diabetes, much research has focused on the modifications' impacts on translational regulation in eukaryotes. However, the significance of tRNA modifications in bacterial physiology remains largely unexplored. In this paper, we demonstrate that the m

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Tgf-Β1 In Aplysia: Role In Long-Term Changes In The Excitability Of Sensory Neurons And Distribution Of Tβr-Ii-Like Immunoreactivity, Muhammad S Khan, Eun Kim, Quentin Le Hingrat, Adam Kleinman, Alessandro Ferrari, Jose C Sammartino, Elena Percivalle, Cuiling Xu, Shaohua Huang, Thomas W Kenniston, Irene Cassaniti, Fausto Baldanti, Ivona Pandrea, Andrea Gambotto, Cristian Apetrei Oct 2023

Tgf-Β1 In Aplysia: Role In Long-Term Changes In The Excitability Of Sensory Neurons And Distribution Of Tβr-Ii-Like Immunoreactivity, Muhammad S Khan, Eun Kim, Quentin Le Hingrat, Adam Kleinman, Alessandro Ferrari, Jose C Sammartino, Elena Percivalle, Cuiling Xu, Shaohua Huang, Thomas W Kenniston, Irene Cassaniti, Fausto Baldanti, Ivona Pandrea, Andrea Gambotto, Cristian Apetrei

Faculty, Staff and Student Publications

The study provides important insights into the immunogenicity and efficacy of a tetravalent protein subunit vaccine candidate against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The vaccine induced both humoral and cellular immune responses in nonhuman primates with controlled SIVagm infection and was able to generate Omicron variant-specific antibodies without specifically vaccinating with Omicron. These findings suggest that the tetravalent composition of the vaccine candidate could provide broad protection against multiple SARS-CoV-2 variants while minimizing the risk of immune escape and the emergence of new variants. Additionally, the use of rhesus macaques with controlled SIVsab infection may better represent vaccine …

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Diaph1-Mfn2 Interaction Regulates Mitochondria-Sr/Er Contact And Modulates Ischemic/Hypoxic Stress, Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy Oct 2023

Diaph1-Mfn2 Interaction Regulates Mitochondria-Sr/Er Contact And Modulates Ischemic/Hypoxic Stress, Gautham Yepuri, Lisa M Ramirez, Gregory G Theophall, Sergei V Reverdatto, Nosirudeen Quadri, Syed Nurul Hasan, Lei Bu, Devi Thiagarajan, Robin Wilson, Raquel López Díez, Paul F Gugger, Kaamashri Mangar, Navneet Narula, Stuart D Katz, Boyan Zhou, Huilin Li, Aleksandr B Stotland, Roberta A Gottlieb, Ann Marie Schmidt, Alexander Shekhtman, Ravichandran Ramasamy

Faculty, Staff and Student Publications

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. …

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The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao Oct 2023

The Lin28b/Wnt5a Axis Drives Pancreas Cancer Through Crosstalk Between Cancer Associated Fibroblasts And Tumor Epithelium, Zhaoqi Shu, Minghe Fan, Bo Tu, Zhiheng Tang, Haojie Wang, Haimeng Li, Hengchao Li, Meng Yuan, Jingru Bai, Sihan Huo, Lina Wang, Wei-Guo Zhu, Wei Wang, Xiaoyun Liu, Shaokun Shu, Ying Zhao

Faculty, Staff and Student Publications

Bidirectional signal transduction between tumor epithelial cells and tumor microenvironment (TME) is important for tumor development. Here we show that Lin28b/let-7 pathway is indispensable for modulating the expression of Wnt5a in tumor epithelium, which could be secreted and then up-regulates Lin28b in cancer-associated fibroblasts (CAFs). Moreover, we demonstrate that Lin28b in CAFs promoted growth of PDAC by inducing cytokine PCSK9's production. Using an orthotopic mouse model of PDAC, we find that depletion of Lin28b in CAFs reduced tumor weight, highlighting the importance of Lin28b in PDAC stroma. Thus, our study shows that the Lin28b-Wnt5a axis plays a critical role in …

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Irf1 Regulates Self-Renewal And Stress Responsiveness To Support Hematopoietic Stem Cell Maintenance, Alexandra J S Rundberg Nilsson, Hongxu Xian, Shabnam Shalapour, Jörg Cammenga, Michael Karin Oct 2023

Irf1 Regulates Self-Renewal And Stress Responsiveness To Support Hematopoietic Stem Cell Maintenance, Alexandra J S Rundberg Nilsson, Hongxu Xian, Shabnam Shalapour, Jörg Cammenga, Michael Karin

Faculty, Staff and Student Publications

Hematopoietic stem cells (HSCs) are tightly controlled to maintain a balance between blood cell production and self-renewal. While inflammation-related signaling is a critical regulator of HSC activity, the underlying mechanisms and the precise functions of specific factors under steady-state and stress conditions remain incompletely understood. We investigated the role of interferon regulatory factor 1 (IRF1), a transcription factor that is affected by multiple inflammatory stimuli, in HSC regulation. Our findings demonstrate that the loss of IRF1 from mouse HSCs significantly impairs self-renewal, increases stress-induced proliferation, and confers resistance to apoptosis. In addition, given the frequent abnormal expression of IRF1 in …

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Rna-Based Translation Activators For Targeted Gene Upregulation, Yang Cao, Huachun Liu, Shannon S Lu, Krysten A Jones, Anitha P Govind, Okunola Jeyifous, Christine Q Simmons, Negar Tabatabaei, William N Green, Jimmy L Holder, Soroush Tahmasebi, Alfred L George, Bryan C Dickinson Oct 2023

Rna-Based Translation Activators For Targeted Gene Upregulation, Yang Cao, Huachun Liu, Shannon S Lu, Krysten A Jones, Anitha P Govind, Okunola Jeyifous, Christine Q Simmons, Negar Tabatabaei, William N Green, Jimmy L Holder, Soroush Tahmasebi, Alfred L George, Bryan C Dickinson

Duncan NRI Faculty and Staff Publications

Technologies capable of programmable translation activation offer strategies to develop therapeutics for diseases caused by insufficient gene expression. Here, we present "translation-activating RNAs" (taRNAs), a bifunctional RNA-based molecular technology that binds to a specific mRNA of interest and directly upregulates its translation. taRNAs are constructed from a variety of viral or mammalian RNA internal ribosome entry sites (IRESs) and upregulate translation for a suite of target mRNAs. We minimize the taRNA scaffold to 94 nucleotides, identify two translation initiation factor proteins responsible for taRNA activity, and validate the technology by amplifying SYNGAP1 expression, a haploinsufficiency disease target, in patient-derived cells. …

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Impacting T-Cell Fitness In Multiple Myeloma: Potential Roles For Selinexor And Xpo1 Inhibitors, Adam Binder, Christopher Walker, Tomer Mark, Muhamed Baljevic Oct 2023

Impacting T-Cell Fitness In Multiple Myeloma: Potential Roles For Selinexor And Xpo1 Inhibitors, Adam Binder, Christopher Walker, Tomer Mark, Muhamed Baljevic

Department of Medical Oncology Faculty Papers

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate …

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Localized Cardiac Small Molecule Trajectories And Persistent Chemical Sequelae In Experimental Chagas Disease, Zongyuan Liu, Rebecca Ulrich Vonbargen, April L Kendricks, Kate Wheeler, Ana Carolina Leão, Krithivasan Sankaranarayanan, Danya A Dean, Shelley S Kane, Ekram Hossain, Jeroen Pollet, Maria Elena Bottazzi, Peter J Hotez, Kathryn M Jones, Laura-Isobel Mccall Oct 2023

Localized Cardiac Small Molecule Trajectories And Persistent Chemical Sequelae In Experimental Chagas Disease, Zongyuan Liu, Rebecca Ulrich Vonbargen, April L Kendricks, Kate Wheeler, Ana Carolina Leão, Krithivasan Sankaranarayanan, Danya A Dean, Shelley S Kane, Ekram Hossain, Jeroen Pollet, Maria Elena Bottazzi, Peter J Hotez, Kathryn M Jones, Laura-Isobel Mccall

Faculty, Staff and Students Publications

Post-infectious conditions present major health burdens but remain poorly understood. In Chagas disease (CD), caused by Trypanosoma cruzi parasites, antiparasitic agents that successfully clear T. cruzi do not always improve clinical outcomes. In this study, we reveal differential small molecule trajectories between cardiac regions during chronic T. cruzi infection, matching with characteristic CD apical aneurysm sites. Incomplete, region-specific, cardiac small molecule restoration is observed in animals treated with the antiparasitic benznidazole. In contrast, superior restoration of the cardiac small molecule profile is observed for a combination treatment of reduced-dose benznidazole plus an immunotherapy, even with less parasite burden reduction. Overall, …

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New Bibliographies Help Answer Questions About Animals And Metals In The Book Of Mormon Oct 2023

New Bibliographies Help Answer Questions About Animals And Metals In The Book Of Mormon

Insights: The Newsletter of the Neal A. Maxwell Institute for Religious Scholarship

The Book of Mormon mentions animals and metals that do not seem to fit into the conventional scholarly view of animals and metals in the New World. Two new study aids prepared by John L. Sorenson and available through F.A.R.M.S. provide information that will help students of the Book of Mormon examine and perhaps resolve these problems.

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Identification Of Chronic Wasting Disease Prions In Decaying Tongue Tissues From Exhumed White-Tailed Deer, Paulina Soto, Francisca Bravo-Risi, Rebeca Benavente, Stuart Lichtenberg, Mitch Lockwood, J Hunter Reed, Rodrigo Morales Oct 2023

Identification Of Chronic Wasting Disease Prions In Decaying Tongue Tissues From Exhumed White-Tailed Deer, Paulina Soto, Francisca Bravo-Risi, Rebeca Benavente, Stuart Lichtenberg, Mitch Lockwood, J Hunter Reed, Rodrigo Morales

Faculty, Staff and Student Publications

Chronic wasting disease (CWD) prions cause fatal neuropathies in farmed and free-ranging cervids. The deposition of prions in natural and humanmade environmental components has been implicated as a major mechanism mediating CWD spread in wild and captive populations. Prions can be deposited in the environment through excreta, tissues, and carcasses from pre-clinical and clinical animals. Furthermore, burial of CWD-positive animals may reduce but not completely mitigate prion spread from carcasses into the surrounding environment. Here, we analyzed exhumed, decaying deer carcasses for the presence of CWD prions. By analyzing tongue tissues through the protein misfolding cyclic amplification (PMCA) technique, we …

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Uracil-Dna Glycosylase Of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently Of Its Catalytic Residues, Kyle R Smith, Somnath Paul, Qiwen Dong, Orchi Anannya, Darby G Oldenburg, J Craig Forrest, Kevin M Mcbride, Laurie T Krug Oct 2023

Uracil-Dna Glycosylase Of Murine Gammaherpesvirus 68 Binds Cognate Viral Replication Factors Independently Of Its Catalytic Residues, Kyle R Smith, Somnath Paul, Qiwen Dong, Orchi Anannya, Darby G Oldenburg, J Craig Forrest, Kevin M Mcbride, Laurie T Krug

Faculty, Staff and Student Publications

Herpesviruses are large double-stranded DNA viruses that encode core replication proteins and accessory factors involved in nucleotide metabolism and DNA repair. Mammalian uracil-DNA glycosylases (UNG) excise deleterious uracil residues from their genomic DNA. Each herpesvirus UNG studied to date has demonstrated conservation of the enzymatic function to excise uracil residues from DNA. We previously reported that a murine gammaherpesvirus (MHV68) with a stop codon in ORF46 (ORF46.stop) that encodes for vUNG was defective in lytic replication and latency in vivo. However, a mutant virus that expressed a catalytically inactive vUNG (ORF46.CM) had no replication defect unless coupled with additional …

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Catalase Produced By Candida Albicans Protects Streptococcus Mutans From H2o2 Stress-One More Piece In The Cross-Kingdom Synergism Puzzle, Callahan Katrak, Bruna A Garcia, Louise M Dornelas-Figueira, Mary Nguyen, Robert B Williams, Michael C Lorenz, Jacqueline Abranches Oct 2023

Catalase Produced By Candida Albicans Protects Streptococcus Mutans From H2o2 Stress-One More Piece In The Cross-Kingdom Synergism Puzzle, Callahan Katrak, Bruna A Garcia, Louise M Dornelas-Figueira, Mary Nguyen, Robert B Williams, Michael C Lorenz, Jacqueline Abranches

Faculty, Staff and Student Publications

Co-infection with Streptococcus mutans and Candida albicans is associated with dental caries, and their co-cultivation results in enhanced biofilm matrix production that contributes to increased virulence and caries risk. Moreover, the catalase-negative S. mutans demonstrates increased oxidative stress tolerance when co-cultivated in biofilms with C. albicans, a catalase-producing yeast. Here, we sought to obtain mechanistic insights into the increased H2O2 tolerance of S. mutans when co-cultivated with clinical isolates of Candida glabrata, Candida tropicalis, and C. albicans. Additionally, the C. albicans SC5314 laboratory strain, its catalase mutant (SC5314Δcat1), and S. mutans UA159 and its glucosyltransferase B/C …

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Quantitative Analyses Of T Cell Motion In Tissue Reveals Factors Driving T Cell Search In Tissues, David J. Torres, Paulus Mrass, Janie Byrum, Arrick Gonzales, Dominick N. Martinez, Evelyn Juarez, Emily Thompson, Vaiva Vezys, Melanie E. Moses, Judy L. Cannon Oct 2023

Quantitative Analyses Of T Cell Motion In Tissue Reveals Factors Driving T Cell Search In Tissues, David J. Torres, Paulus Mrass, Janie Byrum, Arrick Gonzales, Dominick N. Martinez, Evelyn Juarez, Emily Thompson, Vaiva Vezys, Melanie E. Moses, Judy L. Cannon

Pathology Research and Scholarship

T cells are required to clear infection, and T cell motion plays a role in how quickly a T cell finds its target, from initial naive T cell activation by a dendritic cell to interaction with target cells in infected tissue. To better understand how different tissue environments affect T cell motility, we compared multiple features of T cell motion including speed, persistence, turning angle, directionality, and confinement of T cells moving in multiple murine tissues using microscopy. We quantitatively analyzed naive T cell motility within the lymph node and compared motility parameters with activated CD8 T cells moving within …

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Inhibition Of Retinoic Acid Signaling In Proximal Tubular Epithelial Cells Protects Against Acute Kidney Injury, Min Yang, Lauren N. Lopez, Maya Brewer, Rachel Delgado, Anna Menshikh, Kelly Clouthier, Yuantee Zhu, Thitinee Vanichapol, Haichun Yang, Raymond C. Harris, Leslie Gewin, Craig R. Brooks, Alan J. Davidson, Mark De Caestecker Oct 2023

Inhibition Of Retinoic Acid Signaling In Proximal Tubular Epithelial Cells Protects Against Acute Kidney Injury, Min Yang, Lauren N. Lopez, Maya Brewer, Rachel Delgado, Anna Menshikh, Kelly Clouthier, Yuantee Zhu, Thitinee Vanichapol, Haichun Yang, Raymond C. Harris, Leslie Gewin, Craig R. Brooks, Alan J. Davidson, Mark De Caestecker

2020-Current year OA Pubs

Retinoic acid receptor (RAR) signaling is essential for mammalian kidney development but, in the adult kidney, is restricted to occasional collecting duct epithelial cells. We now show that there is widespread reactivation of RAR signaling in proximal tubular epithelial cells (PTECs) in human sepsis-associated acute kidney injury (AKI) and in mouse models of AKI. Genetic inhibition of RAR signaling in PTECs protected against experimental AKI but was unexpectedly associated with increased expression of the PTEC injury marker Kim1. However, the protective effects of inhibiting PTEC RAR signaling were associated with increased Kim1-dependent apoptotic cell clearance, or efferocytosis, and this was …

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Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee Oct 2023

Dual Targeted Extracellular Vesicles Regulate Oncogenic Genes In Advanced Pancreatic Cancer, Chi-Ling Chiang, Yifan Ma, Ya-Chin Hou, Junjie Pan, Sin-Yu Chen, Ming-Hsien Chien, Zhi-Xuan Zhang, Wei-Hsiang Hsu, Xinyu Wang, Jingjing Zhang, Hong Li, Lili Sun, Shannon Fallen, Inyoul Lee, Xing-Yu Chen, Yeh-Shiu Chu, Chi Zhang, Tai-Shan Cheng, Wen Jiang, Betty Y S Kim, Eduardo Reategui, Robert Lee, Yuan Yuan, Hsiao-Chun Liu, Kai Wang, Michael Hsiao, Chi-Ying F Huang, Yan-Shen Shan, Andrew S Lee, L James Lee

Faculty, Staff and Student Publications

Pancreatic ductal adenocarcinoma (PDAC) tumours carry multiple gene mutations and respond poorly to treatments. There is currently an unmet need for drug carriers that can deliver multiple gene cargoes to target high solid tumour burden like PDAC. Here, we report a dual targeted extracellular vesicle (dtEV) carrying high loads of therapeutic RNA that effectively suppresses large PDAC tumours in mice. The EV surface contains a CD64 protein that has a tissue targeting peptide and a humanized monoclonal antibody. Cells sequentially transfected with plasmid DNAs encoding for the RNA and protein of interest by Transwell®-based asymmetric cell electroporation release abundant targeted …

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The Herbicide Glyphosate Inhibits Hippocampal Long-Term Potentiation And Learning Through Activation Of Pro-Inflammatory Signaling, Yukitoshi Izumi, Kazuko A O'Dell, Charles F Zorumski Oct 2023

The Herbicide Glyphosate Inhibits Hippocampal Long-Term Potentiation And Learning Through Activation Of Pro-Inflammatory Signaling, Yukitoshi Izumi, Kazuko A O'Dell, Charles F Zorumski

2020-Current year OA Pubs

Glyphosate, a herbicide marketed as Roundup, is widely used but there are concerns this exposure could impair cognitive function. In the CA1 region of rat hippocampal slices, we investigated whether glyphosate alters synaptic transmission and long-term potentiation (LTP), a cellular model of learning and memory. Our hypothesis is that glyphosate alters neuronal function and impairs LTP induction via activation of pro-inflammatory processes. Roundup depressed excitatory synaptic potentials(EPSPs) in a dose-dependent manner with complete suppression at 2000 mg/L. At concentrations ≤ 20 mg/L Roundup did not affect basal transmission, but 4 mg/L Roundup administered for 30 min inhibited LTP induction. Acute …

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Chek2 Signaling Is The Key Regulator Of Oocyte Survival After Chemotherapy., Chihiro Emori, Zachary Boucher, Ewelina Bolcun-Filas Oct 2023

Chek2 Signaling Is The Key Regulator Of Oocyte Survival After Chemotherapy., Chihiro Emori, Zachary Boucher, Ewelina Bolcun-Filas

Faculty Research 2023

Cancer treatments can damage the ovarian follicle reserve, leading to primary ovarian insufficiency and infertility among survivors. Checkpoint kinase 2 (CHEK2) deficiency prevents elimination of oocytes in primordial follicles in female mice exposed to radiation and preserves their ovarian function and fertility. Here, we demonstrate that CHEK2 also coordinates the elimination of oocytes after exposure to standard-of-care chemotherapy drugs. CHEK2 activates two downstream targets-TAp63 and p53-which direct oocyte elimination. CHEK2 knockout or pharmacological inhibition preserved ovarian follicle reserve after radiation and chemotherapy. However, the lack of specificity for CHEK2 among available inhibitors limits their potential for clinical development. These findings …

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Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey Oct 2023

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

Faculty, Staff and Student Publications

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

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Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey Oct 2023

Early Resveratrol Treatment Mitigates Joint Degeneration And Dampens Pain In A Mouse Model Of Pseudoachondroplasia (Psach), Jacqueline T Hecht, Alka C Veerisetty, Debabrata Patra, Mohammad G Hossain, Frankie Chiu, Claire Mobed, Francis H Gannon, Karen L Posey

2020-Current year OA Pubs

Pseudoachondroplasia (PSACH), a severe dwarfing condition associated with early-onset joint degeneration and lifelong joint pain, is caused by mutations in cartilage oligomeric matrix protein (COMP). The mechanisms underlying the mutant-COMP pathology have been defined using the MT-COMP mouse model of PSACH that has the common D469del mutation. Mutant-COMP protein does not fold properly, and it is retained in the rough endoplasmic reticulum (rER) of chondrocytes rather than being exported to the extracellular matrix (ECM), driving ER stress that stimulates oxidative stress and inflammation, driving a self-perpetuating cycle. CHOP (ER stress signaling protein) and TNFα inflammation drive high levels of mTORC1 …

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