Digital Commons Network^™

Scca1/Serpinb3 Suppresses Antitumor Immunity And Blunts Therapy-Induced T Cell Responses Via Stat-Dependent Chemokine Production, Liyun Chen, Victoria Shi, Songyan Wang, Lulu Sun, Rebecca Freeman, Jasmine Yang, Matthew J. Inkman, Subhajit Ghosh, Fiona Ruiz, Kay Jayachandran, Yi Huang, Jingqin Luo, Jin Zhang, Pippa Cosper, Clifford J Luke, Perry W. Grigsby, Julie K. Schwarz, Stephanie Markovina, Et Al.

2020-Current year OA Pubs

Patients with cancer who have high serum levels of squamous cell carcinoma antigen 1 (SCCA1, now referred to as SERPINB3) commonly experience treatment resistance and have a poor prognosis. Despite being a clinical biomarker, the modulation of SERPINB3 in tumor immunity is poorly understood. We found positive correlations of SERPINB3 with CXCL1, CXCL8 (CXCL8/9), S100A8, and S100A9 (S100A8/A9) myeloid cell infiltration through RNA-Seq analysis of human primary cervical tumors. Induction of SERPINB3 resulted in increased CXCL1/8 and S100A8/A9 expression, which promoted monocyte and myeloid-derived suppressor cell (MDSC) migration in vitro. In mouse models, Serpinb3a tumors showed increased MDSC and tumor-associated …

Striatal Mglu5-Mediated Synaptic Plasticity Is Independently Regulated By Location-Specific Receptor Pools And Divergent Signaling Pathways, Yuh-Jiin I Jong, Yukitoshi Izumi, Steven K Harmon, Charles F Zorumski, Karen L Ómalley

2020-Current year OA Pubs

Metabotropic glutamate receptor 5 (mGlu

Inhibition Of Microsomal Prostaglandin E2 Synthase Reduces Collagen Deposition In Melanoma Tumors And May Improve Immunotherapy Efficacy By Reducing T-Cell Exhaustion, Yasunari Fukuda, Sun-Hee Kim, Matias A Bustos, Sung-Nam Cho, Jason Roszik, Jared K Burks, Hong Kim, Dave S B Hoon, Elizabeth A Grimm, Suhendan Ekmekcioglu

Faculty, Staff and Student Publications

The arachidonic acid pathway participates in immunosuppression in various types of cancer. Our previous observation detailed that microsomal prostaglandin E2 synthase 1 (mPGES-1), an enzyme downstream of cyclooxygenase 2 (COX-2), limited antitumor immunity in melanoma; in addition, genetic depletion of mPGES-1 specifically enhanced immune checkpoint blockade therapy. The current study set out to distinguish the roles of mPGES-1 from those of COX-2 in tumor immunity and determine the potential of mPGES-1 inhibitors for reinforcing immunotherapy in melanoma. Genetic deletion of mPGES-1 showed different profiles of prostaglandin metabolites from that of COX-2 deletion. In our syngeneic mouse model, mPGES-1-deficient cells exhibited …

The Role Of Fas Receptor Methylation In Osteosarcoma Metastasis, Jiayi M Sun, Wing-Yuk Chow, Gufeng Xu, M John Hicks, Manjula Nakka, Jianhe Shen, Patrick Kwok Shing Ng, Aaron M Taylor, Alexander Yu, Jason E Farrar, Donald A Barkauskas, Richard Gorlick, Jaime M Guidry Auvil, Daniela Gerhard, Paul Meltzer, Rudy Guerra, Tsz-Kwong Man, Ching C Lau, On Behalf Of The Target Osteosarcoma Consortium

Faculty, Staff and Students Publications

Osteosarcoma is the most frequent primary malignant bone tumor with an annual incidence of about 400 cases in the United States. Osteosarcoma primarily metastasizes to the lungs, where FAS ligand (FASL) is constitutively expressed. The interaction of FASL and its cell surface receptor, FAS, triggers apoptosis in normal cells; however, this function is altered in cancer cells. DNA methylation has previously been explored as a mechanism for altering FAS expression, but no variability was identified in the CpG island (CGI) overlapping the promoter. Analysis of an expanded region, including CGI shores and shelves, revealed high variability in the methylation of …

Cell Surface B2m-Free Human Leukocyte Antigen (Hla) Monomers And Dimers: Are They Neo-Hla Class And Proto-Hla?, Mepur H. Ravindranath, Narendranath M. Ravindranath, Senthamil R. Selvan, Fatiha El Hilali, Carly J. Amato-Menker, Edward J. Filippone

Division of Nephrology Faculty Papers

Cell surface HLA-I molecules (Face-1) consist of a polypeptide heavy chain (HC) with two groove domains (G domain) and one constant domain (C-domain) as well as a light chain, B2-microglobulin (B2m). However, HCs can also independently emerge unfolded on the cell surface without peptides as B2m-free HC monomers (Face-2), B2m-free HC homodimers (Face 3), and B2m-free HC heterodimers (Face-4). The transport of these HLA variants from ER to the cell surface was confirmed by antiviral antibiotics that arrest the release of newly synthesized proteins from the ER. Face-2 occurs at low levels on the normal cell surface of the lung, …

Ifit2 Restricts Murine Coronavirus Spread To The Spinal Cord White Matter And Its Associated Myelin Pathology, Madhav Sharma, Debanjana Chakravarty, Afaq Hussain, Ajay Zalavadia, Amy Burrows, Patricia Rayman, Nikhil Sharma, Lawrence C. Kenyon, Cornelia Bergmann, Ganes C. Sen, Jayasri Das Sarma

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Interferon-induced protein with tetratricopeptide repeats 2, Ifit2, is critical in restricting neurotropic murine-β-coronavirus, RSA59 infection. RSA59 intracranial injection of Ifit2-deficient (-/-) compared to wild-type (WT) mice results in impaired acute microglial activation, reduced CX3CR1 expression, limited migration of peripheral lymphocytes into the brain, and impaired virus control followed by severe morbidity and mortality. While the protective role of Ifit2 is established for acute viral encephalitis, less is known about its influence during the chronic demyelinating phase of RSA59 infection. To understand this, RSA59 infected Ifit2-/- and Ifit2+/+ (WT) were observed for neuropathological outcomes at day 5 (acute phase) and 30 …

Tissue-Specific Features Of The T Cell Repertoire After Allogeneic Hematopoietic Cell Transplantation In Human And Mouse, Susan Dewolf, Yuval Elhanati, Katherine Nichols, Nicholas R Waters, Chi L Nguyen, John B Slingerland, Natasia Rodriguez, Olga Lyudovyk, Paul A Giardina, Anastasia I Kousa, Hana Andrlová, Nick Ceglia, Teng Fei, Rajya Kappagantula, Yanyun Li, Nathan Aleynick, Priscilla Baez, Rajmohan Murali, Akimasa Hayashi, Nicole Lee, Brianna Gipson, Madhumitha Rangesa, Zoe Katsamakis, Anqi Dai, Amanda G Blouin, Maria Arcila, Ignas Masilionis, Ronan Chaligne, Doris M Ponce, Heather J Landau, Ioannis Politikos, Roni Tamari, Alan M Hanash, Robert R Jenq, Sergio A Giralt, Kate A Markey, Yanming Zhang, Miguel-Angel Perales, Nicholas D Socci, Benjamin D Greenbaum, Christine A Iacobuzio-Donahue, Travis J Hollmann, Marcel R M Van Den Brink, Jonathan U Peled

Faculty, Staff and Student Publications

T cells are the central drivers of many inflammatory diseases, but the repertoire of tissue-resident T cells at sites of pathology in human organs remains poorly understood. We examined the site-specificity of T cell receptor (TCR) repertoires across tissues (5 to 18 tissues per patient) in prospectively collected autopsies of patients with and without graft-versus-host disease (GVHD), a potentially lethal tissue-targeting complication of allogeneic hematopoietic cell transplantation, and in mouse models of GVHD. Anatomic similarity between tissues was a key determinant of TCR repertoire composition within patients, independent of disease or transplant status. The T cells recovered from peripheral blood …

Genetically Diverse Mouse Models Of Sars-Cov-2 Infection Reproduce Clinical Variation In Type I Interferon And Cytokine Responses In Covid-19., Shelly J Robertson, Olivia Bedard, Kristin L Mcnally, Carl Shaia, Chad S Clancy, Matthew Lewis, Rebecca M Broeckel, Abhilash I Chiramel, Jeffrey G Shannon, Gail L Sturdevant, Rebecca Rosenke, Sarah L Anzick, Elvira Forte, Christoph Preuss, Candice N Baker, Jeffrey M. Harder, Catherine Brunton, Steven C. Munger, Daniel P Bruno, Justin B Lack, Jacqueline M Leung, Amirhossein Shamsaddini, Paul Gardina, Daniel E Sturdevant, Jian Sun, Craig Martens, Steven M Holland, Nadia Rosenthal, Sonja M Best

Faculty Research 2023

Inflammation in response to severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection drives severity of coronavirus disease 2019 (COVID-19) and is influenced by host genetics. To understand mechanisms of inflammation, animal models that reflect genetic diversity and clinical outcomes observed in humans are needed. We report a mouse panel comprising the genetically diverse Collaborative Cross (CC) founder strains crossed to human ACE2 transgenic mice (K18-hACE2) that confers susceptibility to SARS-CoV-2. Infection of CC x K18-hACE2 resulted in a spectrum of survival, viral replication kinetics, and immune profiles. Importantly, in contrast to the K18-hACE2 model, early type I interferon (IFN-I) and regulated …

Global And Tissue-Specific Aging Effects On Murine Proteomes., Gregory R Keele, Ji-Gang Zhang, John Szpyt, Ron Korstanje, Steven P Gygi, Gary Churchill, Devin K Schweppe

Faculty Research 2023

Maintenance of protein homeostasis degrades with age, contributing to aging-related decline and disease. Previous studies have primarily surveyed transcriptional aging changes. To define the effects of age directly at the protein level, we perform discovery-based proteomics in 10 tissues from 20 C57BL/6J mice, representing both sexes at adult and late midlife ages (8 and 18 months). Consistent with previous studies, age-related changes in protein abundance often have no corresponding transcriptional change. Aging results in increases in immune proteins across all tissues, consistent with a global pattern of immune infiltration with age. Our protein-centric data reveal tissue-specific aging changes with functional …

Agrp Neurons Are Not Indispensable For Body Weight Maintenance In Adult Mice, Jing Cai, Jing Chen, Joshua Ortiz-Guzman, Jessica Huang, Benjamin R Arenkiel, Yuchen Wang, Yan Zhang, Yuyan Shi, Qingchun Tong, Cheng Zhan

Faculty, Staff and Student Publications

In addition to their role in promoting feeding and obesity development, hypothalamic arcuate agouti-related protein/neuropeptide Y (AgRP/NPY) neurons are widely perceived to be indispensable for maintaining normal feeding and body weight in adults, and consistently, acute inhibition of AgRP neurons is known to reduce short-term food intake. Here, we adopted complementary methods to achieve nearly complete ablation of arcuate AgRP/NPY neurons in adult mice and report that lesioning arcuate AgRP/NPY neurons in adult mice causes no apparent alterations in ad libitum feeding or body weight. Consistent with previous studies, loss of AgRP/NPY neurons blunts fasting refeeding. Thus, our studies show …

Age-Related Decline In Hippocampal Tyrosine Phosphatase Ptpro Is A Mechanistic Factor In Chemotherapy-Related Cognitive Impairment., Zhimeng Yao, Hongmei Dong, Jianlin Zhu, Liang Du, Yichen Luo, Qing Liu, Shixin Liu, Yusheng Lin, Lu Wang, Shuhong Wang, Wei Wei, Keke Zhang, Qingjun Huang, Xiaojun Yu, Weijiang Zhao, Haiyun Xu, Xiaofu Qiu, Yunlong Pan, Xingxu Huang, Sai-Ching Jim Yeung, Dianzheng Zhang, Hao Zhang

PCOM Scholarly Works

Chemotherapy-related cognitive impairment (CRCI) or "chemo brain" is a devastating neurotoxic sequela of cancer-related treatments, especially for the elderly individuals. Here we show that PTPRO, a tyrosine phosphatase, is highly enriched in the hippocampus, and its level is tightly associated with neurocognitive function but declined significantly during aging. To understand the protective role of PTPRO in CRCI, a mouse model was generated by treating Ptpro-/- female mice with doxorubicin (DOX) because Ptpro-/- female mice are more vulnerable to DOX, showing cognitive impairments and neurodegeneration. By analyzing PTPRO substrates that are neurocognition-associated tyrosine kinases, we found that SRC and EPHA4 are …

Loss Of Function Mutation In Ank Causes Aberrant Mineralization And Acquisition Of Osteoblast-Like-Phenotype By The Cells Of The Intervertebral Disc, Takashi Ohnishi, Victoria Tran, Kimheak Sao, Pranay Ramteke, William Querido, Ruteja A. Barve, Koen Van De Wetering, Makarand V. Risbud

Department of Orthopaedic Surgery Faculty Papers

Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Metastatic Infiltration Of Nervous Tissue And Periosteal Nerve Sprouting In Multiple Myeloma-Induced Bone Pain In Mice And Human, Marta Diaz-Delcastillo, Oana Palasca, Tim T Nemler, Didde M Thygesen, Norma A Chávez-Saldaña, Juan A Vázquez-Mora, Lizeth Y Ponce Gomez, Lars Juhl Jensen, Holly Evans, Rebecca E Andrews, Aritri Mandal, David Neves, Patrick Mehlen, James P Caruso, Patrick M Dougherty, Theodore J Price, Andrew Chantry, Michelle A Lawson, Thomas L Andersen, Juan M Jimenez-Andrade, Anne-Marie Heegaard

Faculty, Staff and Student Publications

Multiple myeloma (MM) is a neoplasia of B plasma cells that often induces bone pain. However, the mechanisms underlying myeloma-induced bone pain (MIBP) are mostly unknown. Using a syngeneic MM mouse model, we show that periosteal nerve sprouting of calcitonin gene-related peptide (CGRP+) and growth associated protein 43 (GAP43+) fibers occurs concurrent to the onset of nociception and its blockade provides transient pain relief. MM patient samples also showed increased periosteal innervation. Mechanistically, we investigated MM induced gene expression changes in the dorsal root ganglia (DRG) innervating the MM-bearing bone of male mice and found alterations in pathways associated with …

Βii-Spectrin Is Required For Synaptic Positioning During Retinal Development, Debalina Goswami-Sewell, Caitlin Bagnetto, Cesiah C Gomez, Joseph T Anderson, Akash Maheshwari, Elizabeth Zuniga-Sanchez

Faculty, Staff and Students Publications

Neural circuit assembly is a multistep process where synaptic partners are often born at distinct developmental stages, and yet they must find each other and form precise synaptic connections with one another. This developmental process often relies on late-born neurons extending their processes to the appropriate layer to find and make synaptic connections to their early-born targets. The molecular mechanism responsible for the integration of late-born neurons into an emerging neural circuit remains unclear. Here, we uncovered a new role for the cytoskeletal protein βII-spectrin in properly positioning presynaptic and postsynaptic neurons to the developing synaptic layer. Loss of βII-spectrin …

Loss Of Function Mutation In Ank Causes Aberrant Mineralization And Acquisition Of Osteoblast-Like-Phenotype By The Cells Of The Intervertebral Disc, Takashi Ohnishi, Victoria Tran, Kimheak Sao, Pranay Ramteke, William Querido, Ruteja A Barve, Koen Van De Wetering, Makarand V Risbud

2020-Current year OA Pubs

Pathological mineralization of intervertebral disc is debilitating and painful and linked to disc degeneration in a subset of human patients. An adenosine triphosphate efflux transporter, progressive ankylosis (ANK) is a regulator of extracellular inorganic pyrophosphate levels and plays an important role in tissue mineralization. However, the function of ANK in intervertebral disc has not been fully explored. Herein we analyzed the spinal phenotype of Ank mutant mice (ank/ank) with attenuated ANK function. Micro-computed tomography and histological analysis showed that loss of ANK function results in the aberrant annulus fibrosus mineralization and peripheral disc fusions with cranial to caudal progression in …

Interleukin-1Β Disruption Protects Male Mice From Heart Failure With Preserved Ejection Fraction Pathogenesis, Balaji K. Srinivas, Aya Bourdi, Jacob D. O'Regan, Kumar D. Malavalli, Nour-Eddine Rhaleb, Souad Belmadani, Khalid Matrougui

Hypertension and Vascular Research Articles

Background: Heart failure with preserved ejection fraction (HFpEF) is a significant unmet need in cardiovascular medicine and remains an untreatable cardiovascular disease. The role and mechanism of interleukin-1β in HFpEF pathogenesis are poorly understood.

Methods and Results: C57/Bl6J and interleukin-1β(-/-) male mice were randomly divided into 4 groups. Groups 1 and 2: C57/Bl6J and interleukin-1β(-/-) mice were fed a regular diet for 4 months and considered controls. Groups 3 and 4: C57/Bl6 and interleukin-1β(-/-) mice were fed a high-fat diet with N[w]-nitro-l-arginine methyl ester (endothelial nitric oxide synthase inhibitor, 0.5 g/L) in the drinking water for 4 months. We measured …

Isoflurane Conditioning-Induced Delayed Cerebral Ischemia Protection In Subarachnoid Hemorrhage-Role Of Inducible Nitric Oxide Synthase, Meizi Liu, Keshav Jayaraman, Aaron J Norris, Ahmed Hussein, James W Nelson, Jogender Mehla, Deepti Diwan, Ananth Vellimana, Yousef Abu-Amer, Gregory J Zipfel, Umeshkumar Athiraman

2020-Current year OA Pubs

Background Recent evidence implicates inflammation as a key driver in delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage (SAH). Inducible nitric oxide synthase (iNOS) is one of the known major mediators of inflammation. We previously showed that an inhalational anesthetic, isoflurane, provides strong protection against delayed cerebral ischemia after SAH. Our current study aims to define the role of iNOS in isoflurane conditioning-induced protection against delayed cerebral ischemia in a mouse model of SAH. Methods and Results The experiments used 10- to 14-week-old male wild-type (C57BL/6) and iNOS global knockout mice. Anesthetic conditioning was initiated 1 hour after SAH with isoflurane …

Effects Of Probiotics On Colitis-Induced Exacerbation Of Alzheimer's Disease In, Bijayani Sahu, Lauren M Johnson, Mona Sohrabi, Anastasia A Usatii, Rachel M J Craig, Joshua B Kaelberer, Sathiya Priya Chandrasekaran, Harpreet Kaur, Suba Nookala, Colin K Combs

Faculty Research 2023

Alzheimer’s disease (AD) is characterized by progressive cognitive decline and is a leading cause of death in the United States. Neuroinflammation has been implicated in the progression of AD, and several recent studies suggest that peripheral immune dysfunction may influence the disease. Continuing evidence indicates that intestinal dysbiosis is an attribute of AD, and inflammatory bowel disease (IBD) has been shown to aggravate cognitive impairment. Previously, we separately demonstrated that an IBD-like condition exacerbates AD-related changes in the brains of the AppNL-G-F mouse model of AD, while probiotic intervention has an attenuating effect. In this study, we investigated the combination …

Anti-Mir-93-5p Therapy Prolongs Sepsis Survival By Restoring The Peripheral Immune Response, Mihnea P Dragomir, Enrique Fuentes-Mattei, Melanie Winkle, Keishi Okubo, Recep Bayraktar, Erik Knutsen, Aiham Qdaisat, Meng Chen, Yongfeng Li, Masayoshi Shimizu, Lan Pang, Kevin Liu, Xiuping Liu, Simone Anfossi, Huanyu Zhang, Ines Koch, Anh M Tran, Swati Mohapatra, Anh Ton, Mecit Kaplan, Matthew W Anderson, Spencer J Rothfuss, Robert Silasi, Ravi S Keshari, Manuela Ferracin, Cristina Ivan, Cristian Rodriguez-Aguayo, Gabriel Lopez-Berestein, Constantin Georgescu, Pinaki P Banerjee, Rafet Basar, Ziyi Li, David Horst, Catalin Vasilescu, Maria Teresa S Bertilaccio, Katayoun Rezvani, Florea Lupu, Sai-Ching Yeung, George A Calin

Faculty, Staff and Student Publications

Sepsis remains a leading cause of death for humans and currently has no pathogenesis-specific therapy. Hampered progress is partly due to a lack of insight into deep mechanistic processes. In the past decade, deciphering the functions of small noncoding miRNAs in sepsis pathogenesis became a dynamic research topic. To screen for new miRNA targets for sepsis therapeutics, we used samples for miRNA array analysis of PBMCs from patients with sepsis and control individuals, blood samples from 2 cohorts of patients with sepsis, and multiple animal models: mouse cecum ligation puncture-induced (CLP-induced) sepsis, mouse viral miRNA challenge, and baboon Gram+ and …

The Checkpoint Inhibitor Pd-1h/Vista Controls Osteoclast-Mediated Multiple Myeloma Bone Disease, Jing Fu, Shirong Li, Huihui Ma, Jun Yang, Gabriel M Pagnotti, Lewis M Brown, Stephen J Weiss, Markus Y Mapara, Suzanne Lentzsch

Faculty, Staff and Student Publications

Multiple myeloma bone disease is characterized by the development of osteolytic bone lesions. Recent work identified matrix metalloproteinase 13 as a myeloma-derived fusogen that induces osteoclast activation independent of its proteolytic activity. We now identify programmed death-1 homolog, PD-1H, as the bona fide MMP-13 receptor on osteoclasts. Silencing PD-1H or using Pd-1h-/- bone marrow cells abrogates the MMP-13-enhanced osteoclast fusion and bone-resorptive activity. Further, PD-1H interacts with the actin cytoskeleton and plays a necessary role in supporting c-Src activation and sealing zone formation. The critical role of PD-1H in myeloma lytic bone lesions was confirmed using a Pd-1h-/- myeloma bone …

Anoctamin 4 Channel Currents Activate Glucose-Inhibited Neurons In The Mouse Ventromedial Hypothalamus During Hypoglycemia, Longlong Tu, Jonathan C Bean, Yang He, Hailan Liu, Meng Yu, Hesong Liu, Nan Zhang, Na Yin, Junying Han, Nikolas A Scarcelli, Kristine M Conde, Mengjie Wang, Yongxiang Li, Bing Feng, Peiyu Gao, Zhao-Lin Cai, Makoto Fukuda, Mingshan Xue, Qingchun Tong, Yongjie Yang, Lan Liao, Jianming Xu, Chunmei Wang, Yanlin He, Yong Xu

Faculty, Staff and Student Publications

Glucose is the basic fuel essential for maintenance of viability and functionality of all cells. However, some neurons - namely, glucose-inhibited (GI) neurons - paradoxically increase their firing activity in low-glucose conditions and decrease that activity in high-glucose conditions. The ionic mechanisms mediating electric responses of GI neurons to glucose fluctuations remain unclear. Here, we showed that currents mediated by the anoctamin 4 (Ano4) channel are only detected in GI neurons in the ventromedial hypothalamic nucleus (VMH) and are functionally required for their activation in response to low glucose. Genetic disruption of the Ano4 gene in VMH neurons reduced blood …

Apoe-Ε4 Synergizes With Sleep Disruption To Accelerate Aβ Deposition And Aβ-Associated Tau Seeding And Spreading, Chanung Wang, Aishwarya Nambiar, Michael R. Strickland, Choonghee Lee, Samira Parhizkar, Alec C. Moore, Erik S. Musiek, Jason D. Ulrich, David M. Holtzman

2020-Current year OA Pubs

Alzheimer's disease (AD) is the most common cause of dementia. The APOE-ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset AD. The APOE genotype modulates the effect of sleep disruption on AD risk, suggesting a possible link between apoE and sleep in AD pathogenesis, which is relatively unexplored. We hypothesized that apoE modifies Aβ deposition and Aβ plaque-associated tau seeding and spreading in the form of neuritic plaque-tau (NP-tau) pathology in response to chronic sleep deprivation (SD) in an apoE isoform-dependent fashion. To test this hypothesis, we used APPPS1 mice expressing human APOE-ε3 …

The Cerebellum Contributes To Generalized Seizures By Altering Activity In The Ventral Posteromedial Nucleus, Jaclyn Beckinghausen, Joshua Ortiz-Guzman, Tao Lin, Benjamin Bachman, Luis E Salazar Leon, Yu Liu, Detlef H Heck, Benjamin R Arenkiel, Roy V Sillitoe

Duncan NRI Faculty and Staff Publications

Thalamo-cortical networks are central to seizures, yet it is unclear how these circuits initiate seizures. We test whether a facial region of the thalamus, the ventral posteromedial nucleus (VPM), is a source of generalized, convulsive motor seizures and if convergent VPM input drives the behavior. To address this question, we devise an in vivo optogenetic mouse model to elicit convulsive motor seizures by driving these inputs and perform single-unit recordings during awake, convulsive seizures to define the local activity of thalamic neurons before, during, and after seizure onset. We find dynamic activity with biphasic properties, raising the possibility that heterogenous …

Mesenchymal Stem Cell-Extracellular Vesicle Therapy For Stroke: Scalable Production And Imaging Biomarker Studies, Jeong Pyo Son, Eun Hee Kim, Eun Kyoung Shin, Dong Hee Kim, Ji Hee Sung, Mi Jeong Oh, Jae Min Cha, Michael Chopp, Oh Young Bang

Neurology Articles

A major clinical hurdle to translate MSC-derived extracellular vesicles (EVs) is the lack of a method to scale-up the production of EVs with customized therapeutic properties. In this study, we tested whether EV production by a scalable 3D-bioprocessing method is feasible and improves neuroplasticity in animal models of stroke using MRI study. MSCs were cultured in a 3D-spheroid using a micro-patterned well. The EVs were isolated with filter and tangential flow filtration and characterized using electron microscopy, nanoparticle tracking analysis, and small RNA sequencing. Compared to conventional 2D culture, the production-reproduction of EVs (the number/size of particles and EV purity) …

Unique Transcriptional Profiles Underlie Osteosarcomagenesis Driven By Different P53 Mutants, Dhruv Chachad, Lalit R Patel, Carlos Vera Recio, Rasoul Pourebrahim, Elizabeth M Whitley, Wenyi Wang, Xiaoping Su, An Xu, Dung-Fang Lee, Guillermina Lozano

Faculty, Staff and Student Publications

Missense mutations in the DNA binding domain of p53 are characterized as structural or contact mutations based on their effect on the conformation of the protein. These mutations show gain-of-function (GOF) activities, such as promoting increased metastatic incidence compared with p53 loss, often mediated by the interaction of mutant p53 with a set of transcription factors. These interactions are largely context specific. To understand the mechanisms by which p53 DNA binding domain mutations drive osteosarcoma progression, we created mouse models, in which either the p53 structural mutant p53R172H or the contact mutant p53R245W are expressed specifically in osteoblasts, yielding osteosarcoma …

Bicc1 Drives Pancreatic Cancer Progression By Inducing Vegf-Independent Angiogenesis, Chongbiao Huang, Hui Li, Yang Xu, Chao Xu, Huizhi Sun, Zengxun Li, Yi Ge, Hongwei Wang, Tiansuo Zhao, Song Gao, Xiuchao Wang, Shengyu Yang, Peiqing Sun, Zhe Liu, Jing Liu, Antao Chang, Jihui Hao

Faculty, Staff and Student Publications

VEGF inhibitors are one of the most successful antiangiogenic drugs in the treatment of many solid tumors. Nevertheless, pancreatic adenocarcinoma (PAAD) cells can reinstate tumor angiogenesis via activation of VEGF-independent pathways, thereby conferring resistance to VEGF inhibitors. Bioinformatic analysis showed that BICC1 was one of the top genes involved in the specific angiogenesis process of PAAD. The analysis of our own cohort confirmed that BICC1 was overexpressed in human PAAD tissues and was correlated to increased microvessel density and tumor growth, and worse prognosis. In cells and mice with xenograft tumors, BICC1 facilitated angiogenesis in pancreatic cancer in a VEGF-independent …

Lrp1 Is Essential For Lethal Rift Valley Fever Hepatic Disease In Mice, Madeline M Schwarz, Safder S Ganaie, Annie Feng, Griffin Brown, Tenzin Yangdon, J Michael White, Ryan M Hoehl, Cynthia M Mcmillen, Rachael E Rush, Kaleigh A Connors, Xiaoxia Cui, Daisy W Leung, Takeshi Egawa, Gaya K Amarasinghe, Amy L Hartman

2020-Current year OA Pubs

Rift Valley fever virus (RVFV) is an emerging arbovirus found in Africa. While RVFV is pantropic and infects many cells and tissues, viral replication and necrosis within the liver play a critical role in mediating severe disease. The low-density lipoprotein receptor-related protein 1 (Lrp1) is a recently identified host factor for cellular entry and infection by RVFV. The biological significance of Lrp1, including its role in hepatic disease in vivo, however, remains to be determined. Because Lrp1 has a high expression level in hepatocytes, we developed a mouse model in which Lrp1 is specifically deleted in hepatocytes to test how …

Molecular Dissection And Testing Of Prss37 Function Through Lc-Ms/Ms And The Generation Of A Prss37 Humanized Mouse Model, Courtney Sutton, Kaori Nozawa, Katarzyna Kent, Alexander Saltzman, Mei Leng, Sureshbabu Nagarajan, Anna Malovannaya, Masahito Ikawa, Thomas X Garcia, Martin M Matzuk

Faculty, Staff and Students Publications

The quest for a non-hormonal male contraceptive pill for men still exists. Serine protease 37 (PRSS37) is a sperm-specific protein that when ablated in mice renders them sterile. In this study we sought to examine the molecular sequelae of PRSS37 loss to better understand its molecular function, and to determine whether human PRSS37 could rescue the sterility phenotype of knockout (KO) mice, allowing for a more appropriate model for drug molecule testing. To this end, we used CRISPR-EZ to create mice lacking the entire coding region of Prss37, used pronuclear injection to create transgenic mice expressing human PRSS37, intercrossed these …

Adenosine Metabolized From Extracellular Atp Ameliorates Organ Injury By Triggering A2br Signaling, Taha Kelestemur, Zoltán H Németh, Pal Pacher, Jennet Beesley, Simon C Robson, Holger K Eltzschig, György Haskó

Faculty, Staff and Student Publications

BACKGROUND: Trauma and a subsequent hemorrhagic shock (T/HS) result in insufficient oxygen delivery to tissues and multiple organ failure. Extracellular adenosine, which is a product of the extracellular degradation of adenosine 5' triphosphate (ATP) by the membrane-embedded enzymes CD39 and CD73, is organ protective, as it participates in signaling pathways, which promote cell survival and suppress inflammation through adenosine receptors including the A

METHODS: T/HS shock was induced by blood withdrawal from the femoral artery in wild-type, global knockout (CD39, CD73, A

RESULTS: T/HS upregulated the expression of CD39, CD73, and the A

CONCLUSION: In conclusion, the CD39-CD73-A