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Full-Text Articles in Medicine and Health Sciences

Dynamic Fecal Microbiota Transfer From Mice With Western Diet-Induced Severe Colitis And Colon Tumorigenesis Did Not Exacerbate Colitis Symptoms Or Colon Tumorigenesis In Recipient Mice Fed Either The Ain93g Diet Or The Total Western Diet, Abby D. Benninghoff Jan 2023

Dynamic Fecal Microbiota Transfer From Mice With Western Diet-Induced Severe Colitis And Colon Tumorigenesis Did Not Exacerbate Colitis Symptoms Or Colon Tumorigenesis In Recipient Mice Fed Either The Ain93g Diet Or The Total Western Diet, Abby D. Benninghoff

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Consumption of the total Western diet (TWD) in mice has been shown to increase gut inflammation, promote colon tumorigenesis, and alter the fecal microbiome composition in mice as com-pared to mice fed a healthy diet, AIN93G (AIN). However, it is unclear whether the gut micro-biome contributes directly to colitis-associated CRC in this model. The objective of this study was to determine whether dynamic fecal microbiota transfer (FMT) from host mice fed either AIN or TWD basal diets would alter colitis symptoms or colitis-associated CRC in recipient mice, which were fed either AIN or TWD directly using a 2x2 factorial experiment …


A Rodent Model For Dirofilaria Immitis, Canine Heartworm: Parasite Growth, Development, And Drug Sensitivity In Nsg Mice, Jessica A. Hess, Mark L. Eberhard, Marcelo Segura-Lepe, Kathrin Grundner-Culemann, Barbara Kracher, Jeffrey Shryock, John Harrington, David Abraham Jan 2023

A Rodent Model For Dirofilaria Immitis, Canine Heartworm: Parasite Growth, Development, And Drug Sensitivity In Nsg Mice, Jessica A. Hess, Mark L. Eberhard, Marcelo Segura-Lepe, Kathrin Grundner-Culemann, Barbara Kracher, Jeffrey Shryock, John Harrington, David Abraham

Department of Microbiology and Immunology Faculty Papers

Heartworm disease, caused by Dirofilaria immitis, remains a significant threat to canines and felines. The development of parasites resistant to macrocyclic lactones (ML) has created a significant challenge to the control of the infection. The goal of this study was to determine if mice lacking a functional immune response would be susceptible to D. immitis. Immunodeficient NSG mice were susceptible to the infection, sustaining parasites for at least 15 weeks, with infective third-stage larvae molting and developing into the late fourth-stage larvae. Proteomic analysis of host responses to the infection revealed a complex pattern of changes after infection, with at …


Identification Of Collaborative Cross Mouse Strains Permissive To Salmonella Enterica Serovar Typhi Infection, Kishore Alugupalli, Sudeep Kothari, Matthew P Cravens, Justin A Walker, Darren T Dougharty, Gregory S. Dickinson, Louis A Gatto, Andreas J Bäumler, Tamding Wangdi, Darla R Miller, Fernando Pardo-Manuel De Villena, Linda D Siracusa Jan 2023

Identification Of Collaborative Cross Mouse Strains Permissive To Salmonella Enterica Serovar Typhi Infection, Kishore Alugupalli, Sudeep Kothari, Matthew P Cravens, Justin A Walker, Darren T Dougharty, Gregory S. Dickinson, Louis A Gatto, Andreas J Bäumler, Tamding Wangdi, Darla R Miller, Fernando Pardo-Manuel De Villena, Linda D Siracusa

Department of Microbiology and Immunology Faculty Papers

Salmonella enterica serovar Typhi is the causative agent of typhoid fever restricted to humans and does not replicate in commonly used inbred mice. Genetic variation in humans is far greater and more complex than that in a single inbred strain of mice. The Collaborative Cross (CC) is a large panel of recombinant inbred strains which has a wider range of genetic diversity than laboratory inbred mouse strains. We found that the CC003/Unc and CC053/Unc strains are permissive to intraperitoneal but not oral route of S. Typhi infection and show histopathological changes characteristic of human typhoid. These CC strains are immunocompetent, …


An Entosis-Like Process Induces Mitotic Disruption In Pals1 Microcephaly Pathogenesis, Noelle A Sterling, Jun Young Park, Raehee Park, Seo-Hee Cho, Seonhee Kim Jan 2023

An Entosis-Like Process Induces Mitotic Disruption In Pals1 Microcephaly Pathogenesis, Noelle A Sterling, Jun Young Park, Raehee Park, Seo-Hee Cho, Seonhee Kim

Center for Translational Medicine Faculty Papers

Entosis is cell cannibalism utilized by tumor cells to engulf live neighboring cells for pro- or anti-tumorigenic purposes. It is unknown whether this extraordinary cellular event can be pathogenic in other diseases such as microcephaly, a condition characterized by a smaller than normal brain at birth. We find that mice mutant for the human microcephaly-causing gene Pals1, which exhibit diminished cortices due to massive cell death, also exhibit nuclei enveloped by plasma membranes inside of dividing cells. These cell-in-cell (CIC) structures represent a dynamic process accompanied by lengthened mitosis and cytokinesis abnormalities. As shown in tumor cells, ROCK inhibition completely …


Inherited Human Itk Deficiency Impairs Ifn-Γ Immunity And Underlies Tuberculosis, Masato Ogishi, Rui Yang, Rémy Rodriguez, Dominic P Golec, Emmanuel Martin, Quentin Philippot, Jonathan Bohlen, Simon J Pelham, Andrés Augusto Arias, Taushif Khan, Manar Ata, Fatima Al Ali, Flore Rozenberg, Xiao-Fei Kong, Maya Chrabieh, Candice Laine, Wei-Te Lei, Ji Eun Han, Yoann Seeleuthner, Zenia Kaul, Emmanuelle Jouanguy, Vivien Béziat, Leila Youssefian, Hassan Vahidnezhad, V Koneti Rao, Bénédicte Neven, Claire Fieschi, Davood Mansouri, Mohammad Shahrooei, Sevgi Pekcan, Gulsum Alkan, Melike Emiroğlu, Hüseyin Tokgöz, Jouni Uitto, Fabian Hauck, Jacinta Bustamante, Laurent Abel, Sevgi Keles, Nima Parvaneh, Nico Marr, Pamela L Schwartzberg, Sylvain Latour, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis Jan 2023

Inherited Human Itk Deficiency Impairs Ifn-Γ Immunity And Underlies Tuberculosis, Masato Ogishi, Rui Yang, Rémy Rodriguez, Dominic P Golec, Emmanuel Martin, Quentin Philippot, Jonathan Bohlen, Simon J Pelham, Andrés Augusto Arias, Taushif Khan, Manar Ata, Fatima Al Ali, Flore Rozenberg, Xiao-Fei Kong, Maya Chrabieh, Candice Laine, Wei-Te Lei, Ji Eun Han, Yoann Seeleuthner, Zenia Kaul, Emmanuelle Jouanguy, Vivien Béziat, Leila Youssefian, Hassan Vahidnezhad, V Koneti Rao, Bénédicte Neven, Claire Fieschi, Davood Mansouri, Mohammad Shahrooei, Sevgi Pekcan, Gulsum Alkan, Melike Emiroğlu, Hüseyin Tokgöz, Jouni Uitto, Fabian Hauck, Jacinta Bustamante, Laurent Abel, Sevgi Keles, Nima Parvaneh, Nico Marr, Pamela L Schwartzberg, Sylvain Latour, Jean-Laurent Casanova, Stéphanie Boisson-Dupuis

Department of Dermatology and Cutaneous Biology Faculty Papers

Inborn errors of IFN-γ immunity can underlie tuberculosis (TB). We report three patients from two kindreds without EBV viremia or disease but with severe TB and inherited complete ITK deficiency, a condition associated with severe EBV disease that renders immunological studies challenging. They have CD4+ αβ T lymphocytopenia with a concomitant expansion of CD4-CD8- double-negative (DN) αβ and Vδ2- γδ T lymphocytes, both displaying a unique CD38+CD45RA+T-bet+EOMES- phenotype. Itk-deficient mice recapitulated an expansion of the γδ T and DN αβ T lymphocyte populations in the thymus and spleen, respectively. Moreover, the patients' T lymphocytes secrete small amounts of IFN-γ in …


Microrna-1 Attenuates The Growth And Metastasis Of Small Cell Lung Cancer Through Cxcr4/Foxm1/Rrm2 Axis, Parvez Khan, Jawed A. Siddiqui, Prakash Kshirsagar Dr., Ramakanth Chirravuri Venkata, Shailendra K. Maurya, Tamara Mirzapoiazova, Naveenkumar Perumal, Sanjib Chaudhary, Ranjana K. Kanchan, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A. Talmon, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder K. Batra, Mohd W. Nasser Jan 2023

Microrna-1 Attenuates The Growth And Metastasis Of Small Cell Lung Cancer Through Cxcr4/Foxm1/Rrm2 Axis, Parvez Khan, Jawed A. Siddiqui, Prakash Kshirsagar Dr., Ramakanth Chirravuri Venkata, Shailendra K. Maurya, Tamara Mirzapoiazova, Naveenkumar Perumal, Sanjib Chaudhary, Ranjana K. Kanchan, Mahek Fatima, Md Arafat Khan, Asad Ur Rehman, Imayavaramban Lakshmanan, Sidharth Mahapatra, Geoffrey A. Talmon, Prakash Kulkarni, Apar Kishor Ganti, Maneesh Jain, Ravi Salgia, Surinder K. Batra, Mohd W. Nasser

Journal Articles: Biochemistry & Molecular Biology

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive lung cancer subtype that is associated with high recurrence and poor prognosis. Due to lack of potential drug targets, SCLC patients have few therapeutic options. MicroRNAs (miRNAs) provide an interesting repertoire of therapeutic molecules; however, the identification of miRNAs regulating SCLC growth and metastasis and their precise regulatory mechanisms are not well understood.

METHODS: To identify novel miRNAs regulating SCLC, we performed miRNA-sequencing from donor/patient serum samples and analyzed the bulk RNA-sequencing data from the tumors of SCLC patients. Further, we developed a nanotechnology-based, highly sensitive method to detect microRNA-1 (miR-1, …


Diverse Monogenic Subforms Of Human Spermatogenic Failure, Liina Nagirnaja, Wu-Lin Charng, Christina A Gurnett, Kenan R Omurtag, Et Al. Dec 2022

Diverse Monogenic Subforms Of Human Spermatogenic Failure, Liina Nagirnaja, Wu-Lin Charng, Christina A Gurnett, Kenan R Omurtag, Et Al.

2020-Current year OA Pubs

Non-obstructive azoospermia (NOA) is the most severe form of male infertility and typically incurable. Defining the genetic basis of NOA has proven challenging, and the most advanced classification of NOA subforms is not based on genetics, but simple description of testis histology. In this study, we exome-sequenced over 1000 clinically diagnosed NOA cases and identified a plausible recessive Mendelian cause in 20%. We find further support for 21 genes in a 2-stage burden test with 2072 cases and 11,587 fertile controls. The disrupted genes are primarily on the autosomes, enriched for undescribed human "knockouts", and, for the most part, have …


Impact Of Cd4 T Cells On Intratumoral Cd8 T-Cell Exhaustion And Responsiveness To Pd-1 Blockade Therapy In Mouse Brain Tumors, Saad M. Khan, Rupen Desai, Andrew Coxon, Alexandra Livingstone, Gavin P Dunn, Allegra Petti, Tanner M Johanns Dec 2022

Impact Of Cd4 T Cells On Intratumoral Cd8 T-Cell Exhaustion And Responsiveness To Pd-1 Blockade Therapy In Mouse Brain Tumors, Saad M. Khan, Rupen Desai, Andrew Coxon, Alexandra Livingstone, Gavin P Dunn, Allegra Petti, Tanner M Johanns

2020-Current year OA Pubs

BACKGROUND: Glioblastoma is a fatal disease despite aggressive multimodal therapy. PD-1 blockade, a therapy that reinvigorates hypofunctional exhausted CD8 T cells (T

METHODS: Single-cell RNA sequencing was performed on flow sorted tumor-infiltrating lymphocytes from female C57/BL6 mice implanted with each model, with and without PD-1 blockade therapy. CD8

RESULTS: The CD8 T-cell compartment of the models is composed of heterogenous CD8 T

CONCLUSIONS: Here, we describe that dysfunctional CD4 T cells are associated with terminal CD8 T-cell exhaustion, suggesting CD4 T cells impact PD-1 blockade efficacy by controlling the severity of exhaustion. Given that CD4 lymphopenia is frequently observed in …


Human Nk Cells Confer Protection Against Hiv-1 Infection In Humanized Mice, Can M. Sungur, Qiankun Wang, Ayşe N. Ozantürk, Hongbo Gao, Aaron J. Schmitz, Marina Cella, Wayne M. Yokoyama, Liang Shan Dec 2022

Human Nk Cells Confer Protection Against Hiv-1 Infection In Humanized Mice, Can M. Sungur, Qiankun Wang, Ayşe N. Ozantürk, Hongbo Gao, Aaron J. Schmitz, Marina Cella, Wayne M. Yokoyama, Liang Shan

2020-Current year OA Pubs

The role of NK cells against HIV-1 infections remains to be elucidated in vivo. While humanized mouse models potentially could be used to directly evaluate human NK cell responses during HIV-1 infection, improved functional development of human NK cells in these hosts is needed. Here, we report the humanized MISTRG-6-15 mouse model, in which NK cells were quick to expand and exhibit degranulation, cytotoxicity, and proinflammatory cytokine production in nonlymphoid organs upon HIV-1 infection but had reduced functionality in lymphoid organs. Although HIV-1 infection induced functional impairment of NK cells, antiretroviral therapy reinvigorated NK cells in response to HIV-1 rebound …


Gata1 Controls Numbers Of Hematopoietic Progenitors And Their Response To Autoimmune Neuroinflammation, Daniel Hwang, Larissa Ishikawa, Maryam S. Seyedsadr, Elisabeth R. Mari, Ezgi Kasimoglu, Ziver Sahin, Alexandra Boehm, Soohwa Jang, Javad Rasouli, Courtney Vaccaro, Michael Gonzalez, Hakon Hakonarson, Mohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric Dec 2022

Gata1 Controls Numbers Of Hematopoietic Progenitors And Their Response To Autoimmune Neuroinflammation, Daniel Hwang, Larissa Ishikawa, Maryam S. Seyedsadr, Elisabeth R. Mari, Ezgi Kasimoglu, Ziver Sahin, Alexandra Boehm, Soohwa Jang, Javad Rasouli, Courtney Vaccaro, Michael Gonzalez, Hakon Hakonarson, Mohamad Rostami, Guang-Xian Zhang, Bogoljub Ciric

Department of Neurology Faculty Papers

GATA-binding factor 1 (GATA1) is a transcription factor that governs the development and function of multiple hematopoietic cell lineages. GATA1 is expressed in hematopoietic stem and progenitor cells (HSPCs) and is essential for erythroid lineage commitment; however, whether it plays a role in hematopoietic stem cell (HSC) biology and the development of myeloid cells, and what that role might be, remains unclear. We initially set out to test the role of eosinophils in experimental autoimmune encephalomyelitis (EAE), a model of central nervous system autoimmunity, using mice lacking a double GATA-site (ΔdblGATA), which lacks eosinophils due to the deletion of the …


Tenotomy-Induced Muscle Atrophy Is Sex-Specific And Independent Of Nfκb, Gretchen A Meyer, Stavros Thomopoulos, Yousef Abu-Amer, Karen C Shen Dec 2022

Tenotomy-Induced Muscle Atrophy Is Sex-Specific And Independent Of Nfκb, Gretchen A Meyer, Stavros Thomopoulos, Yousef Abu-Amer, Karen C Shen

2020-Current year OA Pubs

The nuclear factor-κB (NFκB) pathway is a major thoroughfare for skeletal muscle atrophy and is driven by diverse stimuli. Targeted inhibition of NFκB through its canonical mediator IKKβ effectively mitigates loss of muscle mass across many conditions, from denervation to unloading to cancer. In this study, we used gain- and loss-of-function mouse models to examine the role of NFκB in muscle atrophy following rotator cuff tenotomy - a model of chronic rotator cuff tear. IKKβ was knocked down or constitutively activated in muscle-specific inducible transgenic mice to elicit a twofold gain or loss of NFκB signaling. Surprisingly, neither knockdown of …


Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output In Dnmt3a-Mutant Clonal Hematopoiesis, Jennifer M Sanmiguel, Elizabeth Eudy, Matthew A Loberg, Kira A Young, Jayna J Mistry, Kristina D Mujica, Logan S Schwartz, Timothy M Stearns, Grant A Challen, Jennifer J Trowbridge Dec 2022

Distinct Tumor Necrosis Factor Alpha Receptors Dictate Stem Cell Fitness Versus Lineage Output In Dnmt3a-Mutant Clonal Hematopoiesis, Jennifer M Sanmiguel, Elizabeth Eudy, Matthew A Loberg, Kira A Young, Jayna J Mistry, Kristina D Mujica, Logan S Schwartz, Timothy M Stearns, Grant A Challen, Jennifer J Trowbridge

2020-Current year OA Pubs

UNLABELLED: Clonal hematopoiesis resulting from the enhanced fitness of mutant hematopoietic stem cells (HSC) associates with both favorable and unfavorable health outcomes related to the types of mature mutant blood cells produced, but how this lineage output is regulated is unclear. Using a mouse model of a clonal hematopoiesis-associated mutation, DNMT3AR882/+ (Dnmt3aR878H/+), we found that aging-induced TNFα signaling promoted the selective advantage of mutant HSCs and stimulated the production of mutant B lymphoid cells. The genetic loss of the TNFα receptor TNFR1 ablated the selective advantage of mutant HSCs without altering their lineage output, whereas the loss of TNFR2 resulted …


The Lack Of Natural Igm Increases Susceptibility And Impairs Anti-Vi Polysaccharide Igg Responses In A Mouse Model Of Typhoid, Akhil S. Alugupalli, Matthew P. Cravens, Justin A. Walker, Dania Gulandijany, Gregory S. Dickinson, Genevieve Lewis, Gudrun F. Debes, Dieter M. Schifferli, Andreas J. Bäumler, Kishore R. Alugupalli Dec 2022

The Lack Of Natural Igm Increases Susceptibility And Impairs Anti-Vi Polysaccharide Igg Responses In A Mouse Model Of Typhoid, Akhil S. Alugupalli, Matthew P. Cravens, Justin A. Walker, Dania Gulandijany, Gregory S. Dickinson, Genevieve Lewis, Gudrun F. Debes, Dieter M. Schifferli, Andreas J. Bäumler, Kishore R. Alugupalli

Department of Microbiology and Immunology Faculty Papers

Circulating IgM present in the body prior to any apparent Ag exposure is referred to as natural IgM. Natural IgM provides protective immunity against a variety of pathogens. Salmonella enterica serovar Typhi (S. Typhi) is the causative agent of typhoid fever in humans. Because mice are not permissive to S. Typhi infection, we employed a murine model of typhoid using S. enterica serovar Typhimurium expressing the Vi polysaccharide (ViPS) of S. Typhi (S. Typhimurium strain RC60) to evaluate the role of natural IgM in pathogenesis. We found that natural mouse IgM binds to S. Typhi and S. Typhimurium. The severity …


Macrophage Depletion Blocks Congenital Sarm1-Dependent Neuropathy, Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt Dec 2022

Macrophage Depletion Blocks Congenital Sarm1-Dependent Neuropathy, Caitlin B Dingwall, Amy Strickland, Sabrina W Yum, Aldrin Ky Yim, Jian Zhu, Peter L. Wang, Yurie Yamada, Robert E. Schmidt, Yo Sasaki, A. Joseph Bloom, Aaron Diantonio, Jeffrey Milbrandt

2020-Current year OA Pubs

Axon loss contributes to many common neurodegenerative disorders. In healthy axons, the axon survival factor NMNAT2 inhibits SARM1, the central executioner of programmed axon degeneration. We identified 2 rare NMNAT2 missense variants in 2 brothers afflicted with a progressive neuropathy syndrome. The polymorphisms resulted in amino acid substitutions V98M and R232Q, which reduced NMNAT2 NAD+-synthetase activity. We generated a mouse model to mirror the human syndrome and found that Nmnat2V98M/R232Q compound-heterozygous CRISPR mice survived to adulthood but developed progressive motor dysfunction, peripheral axon loss, and macrophage infiltration. These disease phenotypes were all SARM1-dependent. Remarkably, macrophage depletion therapy blocked and reversed …


Piperine Attenuates Cigarette Smoke-Induced Oxidative Stress, Lung Inflammation, And Epithelial-Mesenchymal Transition By Modulating The Sirt1/Nrf2 Axis, Pritam Saha, Sneha Durugkar, Siddhi Jain, P A Shantanu, Samir R Panda, Aishwarya Jala, Sharad Gokhale, Pawan Sharma, V G M Naidu Nov 2022

Piperine Attenuates Cigarette Smoke-Induced Oxidative Stress, Lung Inflammation, And Epithelial-Mesenchymal Transition By Modulating The Sirt1/Nrf2 Axis, Pritam Saha, Sneha Durugkar, Siddhi Jain, P A Shantanu, Samir R Panda, Aishwarya Jala, Sharad Gokhale, Pawan Sharma, V G M Naidu

Center for Translational Medicine Faculty Papers

Piperine (PIP) is a major phytoconstituent in black pepper which is responsible for various pharmacological actions such as anti-inflammatory, antioxidant, and antitumor activity. To investigate the effects and mechanisms of PIP on cigarette smoke (CS)-induced lung pathology using both in-vitro and in-vivo models. BEAS-2B and A549 cells were exposed to CS extract (CSE) for 48 h; BALB/c mice were exposed to CS (9 cigarettes/day, 4 days) to induce features of airway disease. PIP at doses of (0.25, 1.25, and 6.25 µM, in vitro; 1 and 10 mg/kg, in vivo, i.n) and DEX (1 µM, in vitro; 1 mg/kg, in vivo, …


Determining Epigenetic Memory In Kidney Proximal Tubule Cell Derived Induced Pluripotent Stem Cells Using A Quadruple Transgenic Reprogrammable Mouse, Gabriel Khelifi, Theresa Chow, Jennifer Whiteley, Victoire Fort, Benjamin D Humphreys, Samer M I Hussein, Ian M Rogers Nov 2022

Determining Epigenetic Memory In Kidney Proximal Tubule Cell Derived Induced Pluripotent Stem Cells Using A Quadruple Transgenic Reprogrammable Mouse, Gabriel Khelifi, Theresa Chow, Jennifer Whiteley, Victoire Fort, Benjamin D Humphreys, Samer M I Hussein, Ian M Rogers

2020-Current year OA Pubs

The majority of nucleated somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs). The process of reprogramming involves epigenetic remodelling to turn on pluripotency-associated genes and turn off lineage-specific genes. Some evidence shows that iPSCs retain epigenetic marks of their cell of origin and this "epigenetic memory" influences their differentiation potential, with a preference towards their cell of origin. Here, we reprogrammed proximal tubule cells (PTC) and tail tip fibroblasts (TTF), from a reprogrammable mouse to iPSCs and differentiated the iPSCs to renal progenitors to understand if epigenetic memory plays a role in renal differentiation. This model allowed …


Cortex-Wide Response Mode Of Vip-Expressing Inhibitory Neurons By Reward And Punishment, Zoltán Szadai, Hyun-Jae Pi, Quentin Chevy, Katalin Ócsai, Dinu F Albeanu, Balázs Chiovini, Gergely Szalay, Gergely Katona, Adam Kepecs, Balázs Rózsa Nov 2022

Cortex-Wide Response Mode Of Vip-Expressing Inhibitory Neurons By Reward And Punishment, Zoltán Szadai, Hyun-Jae Pi, Quentin Chevy, Katalin Ócsai, Dinu F Albeanu, Balázs Chiovini, Gergely Szalay, Gergely Katona, Adam Kepecs, Balázs Rózsa

2020-Current year OA Pubs

Neocortex is classically divided into distinct areas, each specializing in different function, but all could benefit from reinforcement feedback to inform and update local processing. Yet it remains elusive how global signals like reward and punishment are represented in local cortical computations. Previously, we identified a cortical neuron type, vasoactive intestinal polypeptide (VIP)-expressing interneurons, in auditory cortex that is recruited by behavioral reinforcers and mediates disinhibitory control by inhibiting other inhibitory neurons. As the same disinhibitory cortical circuit is present virtually throughout cortex, we wondered whether VIP neurons are likewise recruited by reinforcers throughout cortex. We monitored VIP neural activity …


Muscle-Specific Ablation Of Glucose Transporter 1 (Glut1) Does Not Impair Basal Or Overload-Stimulated Skeletal Muscle Glucose Uptake, Shawna L Mcmillin, Parker L Evans, William M Taylor, Luke A Weyrauch, Tyler J Sermersheim, Steven S Welc, Monique R Heitmeier, Richard C Hresko, Paul W Hruz, Francoise Koumanov, Geoffrey D Holman, E Dale Abel, Carol A Witczak Nov 2022

Muscle-Specific Ablation Of Glucose Transporter 1 (Glut1) Does Not Impair Basal Or Overload-Stimulated Skeletal Muscle Glucose Uptake, Shawna L Mcmillin, Parker L Evans, William M Taylor, Luke A Weyrauch, Tyler J Sermersheim, Steven S Welc, Monique R Heitmeier, Richard C Hresko, Paul W Hruz, Francoise Koumanov, Geoffrey D Holman, E Dale Abel, Carol A Witczak

2020-Current year OA Pubs

Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle [


Interferon Partly Dictates A Divergent Transcriptional Response In Poxvirus-Infected And Bystander Inflammatory Monocytes, Carolina R Melo-Silva, Marisa I Roman, Cory J Knudson, Lingjuan Tang, Ren-Huan Xu, Michel Tassetto, Patrick Dolan, Raul Andino, Luis J. Sigal Nov 2022

Interferon Partly Dictates A Divergent Transcriptional Response In Poxvirus-Infected And Bystander Inflammatory Monocytes, Carolina R Melo-Silva, Marisa I Roman, Cory J Knudson, Lingjuan Tang, Ren-Huan Xu, Michel Tassetto, Patrick Dolan, Raul Andino, Luis J. Sigal

Department of Microbiology and Immunology Faculty Papers

Inflammatory monocytes (iMOs) and B cells are the main targets of the poxvirus ectromelia virus (ECTV) in the lymph nodes of mice and play distinct roles in surviving the infection. Infected and bystander iMOs control ECTV's systemic spread, preventing early death, while B cells make antibodies that eliminate ECTV. Our work demonstrates that within an infected animal that survives ECTV infection, intrinsic and bystander infection of iMOs and B cells differentially control the transcription of genes important for immune cell function and, perhaps, cell identity. Bystander cells upregulate metabolism, antigen presentation, and interferon-stimulated genes. Infected cells downregulate many cell-type-specific genes …


An Mtorc1 To Hri Signaling Axis Promotes Cytotoxicity Of Proteasome Inhibitors In Multiple Myeloma, Odai Darawshi, Barbara Muz, Et Al. Nov 2022

An Mtorc1 To Hri Signaling Axis Promotes Cytotoxicity Of Proteasome Inhibitors In Multiple Myeloma, Odai Darawshi, Barbara Muz, Et Al.

2020-Current year OA Pubs

Multiple myeloma (MM) causes approximately 20% of deaths from blood cancers. Notwithstanding significant therapeutic progress, such as with proteasome inhibitors (PIs), MM remains incurable due to the development of resistance. mTORC1 is a key metabolic regulator, which frequently becomes dysregulated in cancer. While mTORC1 inhibitors reduce MM viability and synergize with other therapies in vitro, clinically, mTORC1 inhibitors are not effective for MM. Here we show that the inactivation of mTORC1 is an intrinsic response of MM to PI treatment. Genetically enforced hyperactivation of mTORC1 in MM was sufficient to compromise tumorigenicity in mice. In vitro, mTORC1-hyperactivated MM cells gained …


Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis Nov 2022

Human Dectin-1 Deficiency Impairs Macrophage-Mediated Defense Against Phaeohyphomycosis, Rebecca A. Drummond, Jigar V. Desai, Amy P. Hsu, Vasileios Oikonomou, Donald C. Vinh, Joshua A. Acklin, Michael S. Abers, Magdalena A. Walkiewicz, Sarah L. Anzick, Muthulekha Swamydas, Simon Vautier, Mukil Natarajan, Andrew J. Oler, Daisuke Yamanaka, Katrin D. Mayer-Barber, Yoichiro Iwakura, David Bianchi, Brian Driscoll, Ken Hauck, Ahnika Kline, Nicholas S.P. Viall, Christa S. Zerbe, Elise M.N. Ferré, Monica M. Schmitt, Tom Dimaggio, Stefania Pittaluga, John A. Butman, Adrian M. Zelazny, Yvonne R. Shea, Cesar A. Arias, Cameron Ashbaugh, Maryam Mahmood, Zelalem Temesgen, Alexander G. Theofiles, Masayuki Nigo, Varsha Moudgal, Karen C. Bloch, Sean G. Kelly, M. Suzanne Whitworth, Ganesh Rao, Cindy J. Whitener, Neema Mafi, Juan Gea-Banacloche, Lawrence C. Kenyon, William R. Miller, Katia Boggian, Andrea Gilbert, Matthew Sincock, Alexandra F. Freeman, John E. Bennett, Rodrigo Hasbun, Constantinos M. Mikelis, Kyung J. Kwon-Chung, Yasmine Belkaid, Gordon D. Brown, Jean K. Lim, Douglas B. Kuhns, Steven M. Holland, Michail S. Lionakis

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Subcutaneous phaeohyphomycosis typically affects immunocompetent individuals following traumatic inoculation. Severe or disseminated infection can occur in CARD9 deficiency or after transplantation, but the mechanisms protecting against phaeohyphomycosis remain unclear. We evaluated a patient with progressive, refractory Corynespora cassiicola phaeohyphomycosis and found that he carried biallelic deleterious mutations in CLEC7A encoding the CARD9-coupled, β-glucan-binding receptor, Dectin-1. The patient's PBMCs failed to produce TNF-α and IL-1β in response to β-glucan and/or C. cassiicola. To confirm the cellular and molecular requirements for immunity against C. cassiicola, we developed a mouse model of this infection. Mouse macrophages required Dectin-1 and CARD9 for IL-1β and …


Inhibiting Ack1-Mediated Phosphorylation Of C-Terminal Src Kinase Counteracts Prostate Cancer Immune Checkpoint Blockade Resistance, Dhivya Sridaran, Surbhi Chouhan, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Shambhavi Bhagwat, Melissa Reimers, Eric H Kim, Manish K Thakur, Muhammad A Saeed, Russell K Pachynski, Markus A Seeliger, W Todd Miller, Felix Y Feng, Nupam P Mahajan Nov 2022

Inhibiting Ack1-Mediated Phosphorylation Of C-Terminal Src Kinase Counteracts Prostate Cancer Immune Checkpoint Blockade Resistance, Dhivya Sridaran, Surbhi Chouhan, Kiran Mahajan, Arun Renganathan, Cody Weimholt, Shambhavi Bhagwat, Melissa Reimers, Eric H Kim, Manish K Thakur, Muhammad A Saeed, Russell K Pachynski, Markus A Seeliger, W Todd Miller, Felix Y Feng, Nupam P Mahajan

2020-Current year OA Pubs

Solid tumours are highly refractory to immune checkpoint blockade (ICB) therapies due to the functional impairment of effector T cells and their inefficient trafficking to tumours. T-cell activation is negatively regulated by C-terminal Src kinase (CSK); however, the exact mechanism remains unknown. Here we show that the conserved oncogenic tyrosine kinase Activated CDC42 kinase 1 (ACK1) is able to phosphorylate CSK at Tyrosine 18 (pY18), which enhances CSK function, constraining T-cell activation. Mice deficient in the Tnk2 gene encoding Ack1, are characterized by diminished CSK Y18-phosphorylation and spontaneous activation of CD8


Enterotoxigenic Escherichia Coli Heat-Labile Toxin Drives Enteropathic Changes In Small Intestinal Epithelia, Alaullah Sheikh, Brunda Tumala, Tim J Vickers, John C Martin, Bruce A Rosa, Subrata Sabui, Supratim Basu, Rita D Simoes, Makedonka Mitreva, Chad Storer, Erik Tyksen, Richard D Head, Wandy Beatty, Hamid M Said, James M Fleckenstein Nov 2022

Enterotoxigenic Escherichia Coli Heat-Labile Toxin Drives Enteropathic Changes In Small Intestinal Epithelia, Alaullah Sheikh, Brunda Tumala, Tim J Vickers, John C Martin, Bruce A Rosa, Subrata Sabui, Supratim Basu, Rita D Simoes, Makedonka Mitreva, Chad Storer, Erik Tyksen, Richard D Head, Wandy Beatty, Hamid M Said, James M Fleckenstein

2020-Current year OA Pubs

Enterotoxigenic E. coli (ETEC) produce heat-labile (LT) and/or heat-stable (ST) enterotoxins, and commonly cause diarrhea in resource-poor regions. ETEC have been linked repeatedly to sequelae in children including enteropathy, malnutrition, and growth impairment. Although cellular actions of ETEC enterotoxins leading to diarrhea are well-established, their contributions to sequelae remain unclear. LT increases cellular cAMP to activate protein kinase A (PKA) that phosphorylates ion channels driving intestinal export of salt and water resulting in diarrhea. As PKA also modulates transcription of many genes, we interrogated transcriptional profiles of LT-treated intestinal epithelia. Here we show that LT significantly alters intestinal epithelial gene …


Caspase-8 Inactivation Drives Autophagy-Dependent Inflammasome Activation In Myeloid Cells., Yung-Hsuan Wu, Shu-Ting Mo, I-Ting Chen, Fu-Yi Hsieh, Shie-Liang Hsieh, Jianke Zhang, Ming-Zong Lai Nov 2022

Caspase-8 Inactivation Drives Autophagy-Dependent Inflammasome Activation In Myeloid Cells., Yung-Hsuan Wu, Shu-Ting Mo, I-Ting Chen, Fu-Yi Hsieh, Shie-Liang Hsieh, Jianke Zhang, Ming-Zong Lai

Department of Microbiology and Immunology Faculty Papers

Caspase-8 activity controls the switch from cell death to pyroptosis when apoptosis and necroptosis are blocked, yet how caspase-8 inactivation induces inflammasome assembly remains unclear. We show that caspase-8 inhibition via IETD treatment in Toll-like receptor (TLR)-primed Fadd-/-Ripk3-/- myeloid cells promoted interleukin-1β (IL-1β) and IL-18 production through inflammasome activation. Caspase-8, caspase-1/11, and functional GSDMD, but not NLRP3 or RIPK1 activity, proved essential for IETD-triggered inflammasome activation. Autophagy became prominent in IETD-treated Fadd-/-Ripk3-/- macrophages, and inhibiting it attenuated IETD-induced cell death and IL-1β/IL-18 production. In contrast, inhibiting GSDMD or autophagy did not prevent IETD-induced septic …


Ornithine Decarboxylase Supports Ilc3 Responses In Infectious And Autoimmune Colitis Through Positive Regulation Of Il-22 Transcription, Vincent Peng, Siyan Cao, Tihana Trsan, Jennifer K Bando, Julian Avila-Pacheco, John L Cleveland, Clary Clish, Ramnik J Xavier, Marco Colonna Nov 2022

Ornithine Decarboxylase Supports Ilc3 Responses In Infectious And Autoimmune Colitis Through Positive Regulation Of Il-22 Transcription, Vincent Peng, Siyan Cao, Tihana Trsan, Jennifer K Bando, Julian Avila-Pacheco, John L Cleveland, Clary Clish, Ramnik J Xavier, Marco Colonna

2020-Current year OA Pubs

Group 3 innate lymphoid cells (ILC3s) are RORγT


A Human Stat3 Gain-Of-Function Variant Confers T Cell Dysregulation Without Predominant Treg Dysfunction In Mice, Erica G Schmitt, Kelsey A Toth, Samuel I Risma, Ana Kolicheski, Nermina Saucier, Rafael J. Feliciano Berríos, Zev J. Greenberg, Jennifer W. Leiding, Jack J. Bleesing, Akaluck Thatayatikom, Laura G. Schuettpelz, John R. Edwards, Tiphanie P. Vogel, Megan A Cooper Nov 2022

A Human Stat3 Gain-Of-Function Variant Confers T Cell Dysregulation Without Predominant Treg Dysfunction In Mice, Erica G Schmitt, Kelsey A Toth, Samuel I Risma, Ana Kolicheski, Nermina Saucier, Rafael J. Feliciano Berríos, Zev J. Greenberg, Jennifer W. Leiding, Jack J. Bleesing, Akaluck Thatayatikom, Laura G. Schuettpelz, John R. Edwards, Tiphanie P. Vogel, Megan A Cooper

2020-Current year OA Pubs

Primary immune regulatory disorders (PIRD) represent a group of disorders characterized by immune dysregulation, presenting with a wide range of clinical disease, including autoimmunity, autoinflammation, or lymphoproliferation. Autosomal dominant germline gain-of-function (GOF) variants in STAT3 result in a PIRD with a broad clinical spectrum. Studies in patients have documented a decreased frequency of FOXP3+ Tregs and an increased frequency of Th17 cells in some patients with active disease. However, the mechanisms of disease pathogenesis in STAT3 GOF syndrome remain largely unknown, and treatment is challenging. We developed a knock-in mouse model harboring a de novo pathogenic human STAT3 variant (p.G421R) …


The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino Nov 2022

The Nogo Receptor Ngr2, A Novel Αvβ3 Integrin Effector, Induces Neuroendocrine Differentiation In Prostate Cancer, Fabio Quaglia, Shiv Ram Krishn, Khalid Sossey-Alaoui, Priyanka Shailendra Rana, Elzbieta Pluskota, Pyung Hun Park, Christopher D. Shields, Stephen Lin, Peter Mccue, Andrew V. Kossenkov, Yanqing Wang, David W. Goodrich, Sheng-Yu Ku, Himisha Beltran, William K. Kelly, Eva Corey, Maja Klose, Christine Bandtlow, Qin Liu, Dario C. Altieri, Edward F. Plow, Lucia R. Languino

Department of Cancer Biology Faculty Papers

Androgen deprivation therapies aimed to target prostate cancer (PrCa) are only partially successful given the occurrence of neuroendocrine PrCa (NEPrCa), a highly aggressive and highly metastatic form of PrCa, for which there is no effective therapeutic approach. Our group has demonstrated that while absent in prostate adenocarcinoma, the αVβ3 integrin expression is increased during PrCa progression toward NEPrCa. Here, we show a novel pathway activated by αVβ3 that promotes NE differentiation (NED). This novel pathway requires the expression of a GPI-linked surface molecule, NgR2, also known as Nogo-66 receptor homolog 1. We show here that NgR2 is upregulated by αVβ3, …


Uremic Myopathy And Mitochondrial Dysfunction In Kidney Disease, Eurico Serrano, Diana Whitaker-Menezes, Zhao Lin, Megan Roche, Maria Paula Martinez Cantarin Nov 2022

Uremic Myopathy And Mitochondrial Dysfunction In Kidney Disease, Eurico Serrano, Diana Whitaker-Menezes, Zhao Lin, Megan Roche, Maria Paula Martinez Cantarin

Kimmel Cancer Center Faculty Papers

Alterations in muscle structure and function in chronic kidney disease (CKD) patients are associated with poor outcomes. As key organelles in muscle cell homeostasis, mitochondrial metabolism has been studied in the context of muscle dysfunction in CKD. We conducted a study to determine the contribution of oxidative metabolism, glycolysis and fatty acid oxidation to the muscle metabolism in CKD. Mice developed CKD by exposure to adenine in the diet. Muscle of CKD mice showed significant weight loss compared to non-CKD mice, but only extensor digitorum longus (EDL) muscle showed a decreased number of fibers. There was no difference in the …


Single-Cell Multiomics Identifies Clinically Relevant Mesenchymal Stem-Like Cells And Key Regulators For Mpnst Malignancy, Lai Man Natalie Wu, Joshua Rubin, Et Al. Nov 2022

Single-Cell Multiomics Identifies Clinically Relevant Mesenchymal Stem-Like Cells And Key Regulators For Mpnst Malignancy, Lai Man Natalie Wu, Joshua Rubin, Et Al.

2020-Current year OA Pubs

Malignant peripheral nerve sheath tumor (MPNST), a highly aggressive Schwann cell (SC)-derived soft tissue sarcoma, arises from benign neurofibroma (NF); however, the identity, heterogeneity and origins of tumor populations remain elusive. Nestin


A New Mouse Model Of Charcot-Marie-Tooth 2j Neuropathy Replicates Human Axonopathy And Suggest Alteration In Axo-Glia Communication, Ghjuvan'ghjacumu Shackleford, Yo Sasaki, Et Al. Nov 2022

A New Mouse Model Of Charcot-Marie-Tooth 2j Neuropathy Replicates Human Axonopathy And Suggest Alteration In Axo-Glia Communication, Ghjuvan'ghjacumu Shackleford, Yo Sasaki, Et Al.

2020-Current year OA Pubs

Myelin is essential for rapid nerve impulse propagation and axon protection. Accordingly, defects in myelination or myelin maintenance lead to secondary axonal damage and subsequent degeneration. Studies utilizing genetic (CNPase-, MAG-, and PLP-null mice) and naturally occurring neuropathy models suggest that myelinating glia also support axons independently from myelin. Myelin protein zero (MPZ or P0), which is expressed only by Schwann cells, is critical for myelin formation and maintenance in the peripheral nervous system. Many mutations in MPZ are associated with demyelinating neuropathies (Charcot-Marie-Tooth disease type 1B [CMT1B]). Surprisingly, the substitution of threonine by methionine at position 124 of P0 …