Digital Commons Network^™

Fibrosis Induced By Resident Macrophages Has Divergent Roles In Pancreas Inflammatory Injury And Pdac, John M Baer, Chong Zuo, Liang-I Kang, Angela Alarcon De La Lastra, Nicholas C Borcherding, Brett L Knolhoff, Savannah J Bogner, Yu Zhu, Liping Yang, Jennifer Laurent, Mark A Lewis, Nan Zhang, Ki-Wook Kim, Ryan C Fields, Wayne M Yokoyama, Jason C Mills, Li Ding, Gwendalyn J Randolph, David G Denardo

Faculty, Staff and Students Publications

Tissue-resident macrophages (TRMs) are long-lived cells that maintain locally and can be phenotypically distinct from monocyte-derived macrophages. Whether TRMs and monocyte-derived macrophages have district roles under differing pathologies is not understood. Here, we showed that a substantial portion of the macrophages that accumulated during pancreatitis and pancreatic cancer in mice had expanded from TRMs. Pancreas TRMs had an extracellular matrix remodeling phenotype that was important for maintaining tissue homeostasis during inflammation. Loss of TRMs led to exacerbation of severe pancreatitis and death, due to impaired acinar cell survival and recovery. During pancreatitis, TRMs elicited protective effects by triggering the accumulation …

Visualizing Dopamine Activity In Deletion Of D2 Receptors In Medium Spiny Neurons, Kunhee Lee

Dissertations, Theses, and Capstone Projects

Dopamine has been implicated in motivated behaviors and reinforcement learning. In this study, we are looking at the role of dopamine in allocating efforts when obtaining reward. Using Cre recombinase genetic tool, D2 receptors in striatal indirect pathway neurons were selectively deleted, and dopamine signal was recorded in ventral striatum using fiber photometry. Behaviorally, D2 receptor deletion resulted in less effort in a Progressive Ratio (PR) paradigm shown by decreased breakpoint, number of presses, and reward pellets earned. Due to the previous evidence that dopamine positively modulates effort, we hypothesized that there would be less dopamine release in D2 deleted …

Greater Male Variability In Daily Energy Expenditure Develops Through Puberty, Lewis G Halsey, Vincent Careau, Philip N Ainslie, Heliodoro Alemán-Mateo, Lene F Andersen, Liam J Anderson, Leonore Arab, Issad Baddou, Linda Bandini, Kweku Bedu-Addo, Ellen E Blaak, Stephane Blanc, Alberto G Bonomi, Carlijn V C Bouten, Pascal Bovet, Soren Brage, Maciej S Buchowski, Nancy Butte, Stephan G Camps, Regian Casper, Graeme L Close, Lisa H Colbert, Jamie A Cooper, Richard Cooper, Prasangi Dabare, Sai Krupa Das, Peter S W Davies, Sanjoy Deb, Christine Delisle Nyström, William Dietz, Lara R Dugas, Simon Eaton, Ulf Ekelund, Asmaa El Hamdouchi, Sonja Entringer, Terrence Forrester, Barry W Fudge, Melanie Gillingham, Annelies H Goris, Michael Gurven, Hinke Haisma, Catherine Hambly, Daniel Hoffman, Marije B Hoos, Sumei Hu, Noorjehan Joonas, Annemiek Joosen, Peter Katzmarzyk, Kitty P Kempen, Misaka Kimura, William E Kraus, Wantanee Kriengsinyos, Rebecca Kuriyan, Robert F Kushner, Estelle V Lambert, Pulani Lanerolle, Christel L Larsson, Nader Lessan, Marie Löf, Corby Martin, Eric Matsiko, Gerwin A Meijer, James C Morehen, James P Morton, Aviva Must, Marian Neuhouser, Theresa A Nicklas, Robert M Ojiambo, Kirsi H Pietilainen, Yannis P Pitsiladis, Jacob Plange-Rhule, Guy Plasqui, Ross L Prentice, Roberto Rabinovich, Susan B Racette, David A Raichen, Eric Ravussin, Leanne Redman, John J Reilly, Rebecca Reynolds, Susan Roberts, Jennifer C Rood, Dulani Samaranayake, Luís B Sardinha, Albertine J Scuitt, Analiza M Silva, Srishti Sinha, Anders M Sjödin, Eric Stice, Albert Stunkard, Samuel S Urlacher, Mauro Eduardo Valencia, Giulio Valenti, Ludo M Van Etten, Edgar A Van Mil, Jeanine A Verbunt, Jonathan C K Wells, George Wilson, Brian Wood, Tsukasa Yoshida, Xueying Zhang, Alexia Murphy-Alford, Cornelia Loechl, Amy Luke, Herman Pontzer, Jennifer Rood, Hiroyuki Sagayama, Klaas R Westerterp, William W Wong, Yosuke Yamada, John R Speakman

Faculty, Staff and Student Publications

There is considerably greater variation in metabolic rates between men than between women, in terms of basal, activity and total (daily) energy expenditure (EE). One possible explanation is that EE is associated with male sexual characteristics (which are known to vary more than other traits) such as musculature and athletic capacity. Such traits might be predicted to be most prominent during periods of adolescence and young adulthood, when sexual behaviour develops and peaks. We tested this hypothesis on a large dataset by comparing the amount of male variation and female variation in total EE, activity EE and basal EE, at …

The Transcription Factor Chrebp Links Mitochondrial Lipidomes To Mitochondrial Morphology And Progression Of Diabetic Kidney Disease, Li Li, Jianyin Long, Koki Mise, Naravat Poungavrin, Philip L Lorenzi, Iqbal Mahmud, Lin Tan, Pradip K Saha, Yashpal S Kanwar, Benny H Chang, Farhad R Danesh

Faculty, Staff and Students Publications

A substantial body of evidence has established the contributions of both mitochondrial dynamics and lipid metabolism to the pathogenesis of diabetic kidney disease (DKD). However, the precise interplay between these two key metabolic regulators of DKD is not fully understood. Here, we uncover a link between mitochondrial dynamics and lipid metabolism by investigating the role of carbohydrate-response element-binding protein (ChREBP), a glucose-responsive transcription factor and a master regulator of lipogenesis, in kidney podocytes. We find that inducible podocyte-specific knockdown of ChREBP in diabetic db/db mice improves key biochemical and histological features of DKD in addition to significantly reducing mitochondrial fragmentation. …

Rna Interference Targeting Angptl3 For Triglyceride And Cholesterol Lowering: Phase 1 Basket Trial Cohorts, Gerald F Watts, Christian Schwabe, Russell Scott, Patrick A Gladding, David Sullivan, John Baker, Peter Clifton, James Hamilton, Bruce Given, Stacey Melquist, Rong Zhou, Ting Chang, Javier San Martin, Daniel Gaudet, Ira J Goldberg, Joshua W Knowles, Robert A Hegele, Christie M Ballantyne

Faculty, Staff and Students Publications

Elevated triglycerides and non-high-density lipoprotein cholesterol (HDL-C) are risk factors for atherosclerotic cardiovascular disease (ASCVD). ARO-ANG3 is an RNA interference therapy that targets angiopoietin-like protein 3 (ANGPTL3), a regulator of lipoprotein metabolism. This first-in-human, phase 1, randomized, placebo-controlled, open-label trial investigated single and repeat ARO-ANG3 doses in four cohorts of fifty-two healthy participants and one cohort of nine participants with hepatic steatosis, part of a basket trial. Safety (primary objective) and pharmacokinetics (in healthy participants) and pharmacodynamics (secondary objectives) of ARO-ANG3 were evaluated. ARO-ANG3 was generally well tolerated, with similar frequencies of treatment-emergent adverse events in active and placebo groups. …

Global Sumoylation In Mouse Oocytes Maintains Oocyte Identity And Regulates Chromatin Remodeling And Transcriptional Silencing At The End Of Folliculogenesis, Shawn M Briley, Avery A Ahmed, Tessa E Steenwinkel, Peixin Jiang, Sean M Hartig, Karen Schindler, Stephanie A Pangas

Faculty, Staff and Students Publications

Meiotically competent oocytes in mammals undergo cyclic development during folliculogenesis. Oocytes within ovarian follicles are transcriptionally active, producing and storing transcripts required for oocyte growth, somatic cell communication and early embryogenesis. Transcription ceases as oocytes transition from growth to maturation and does not resume until zygotic genome activation. Although SUMOylation, a post-translational modification, plays multifaceted roles in transcriptional regulation, its involvement during oocyte development remains poorly understood. In this study, we generated an oocyte-specific knockout of Ube2i, encoding the SUMO E2 enzyme UBE2I, using Zp3-cre+ to determine how loss of oocyte SUMOylation during folliculogenesis affects oocyte development. Ube2i Zp3-cre+ female …

A Defect In Mitochondrial Fatty Acid Synthesis Impairs Iron Metabolism And Causes Elevated Ceramide Levels, Debdeep Dutta, Oguz Kanca, Seul Kee Byeon, Paul C Marcogliese, Zhongyuan Zuo, Rishi V Shridharan, Jun Hyoung Park, Undiagnosed Diseases Networ, Guang Lin, Ming Ge, Gali Heimer, Jennefer N Kohler, Matthew T Wheeler, Benny A Kaipparettu, Akhilesh Pandey, Hugo J Bellen

Faculty, Staff and Students Publications

In most eukaryotic cells, fatty acid synthesis (FAS) occurs in the cytoplasm and in mitochondria. However, the relative contribution of mitochondrial FAS (mtFAS) to the cellular lipidome is not well defined. Here we show that loss of function of Drosophila mitochondrial enoyl coenzyme A reductase (Mecr), which is the enzyme required for the last step of mtFAS, causes lethality, while neuronal loss of Mecr leads to progressive neurodegeneration. We observe a defect in Fe-S cluster biogenesis and increased iron levels in flies lacking mecr, leading to elevated ceramide levels. Reducing the levels of either iron or ceramide suppresses the neurodegenerative …

Loss Of The Maternal Effect Gene Nlrp2 Alters The Transcriptome Of Ovulated Mouse Oocytes And Impacts Expression Of Histone Demethylase Kdm1b, Zahra Anvar, Imen Chakchouk, Momal Sharif, Sangeetha Mahadevan, Eleni Theodora Nasiotis, Li Su, Zhandong Liu, Ying-Wooi Wan, Ignatia B Van Den Veyver

Faculty, Staff and Students Publications

The subcortical maternal complex (SCMC) is a multiprotein complex in oocytes and preimplantation embryos that is encoded by maternal effect genes. The SCMC is essential for zygote-to-embryo transition, early embryogenesis, and critical zygotic cellular processes, including spindle positioning and symmetric division. Maternal deletion of Nlrp2, which encodes an SCMC protein, results in increased early embryonic loss and abnormal DNA methylation in embryos. We performed RNA sequencing on pools of meiosis II (MII) oocytes from wild-type and Nlrp2-null female mice that were isolated from cumulus-oocyte complexes (COCs) after ovarian stimulation. Using a mouse reference genome-based analysis, we found 231 …

Revisiting The Use Of Antibiotics To Prevent Copd Exacerbation: Is Doxycycline The Answer?, Muhammad Adrish, Nicola A Hanania

Faculty, Staff and Students Publications

No abstract provided.

Treatment Of Low Back Pain Elicited By Middle Cluneal Neuralgia: Case Report And Literature Review Of Interventional Treatments, Colton Reeh, Royce Copeland, Loc Lam, Christian Vangeison, Andrea M Trescot, Emanuel Narcis Husu

Faculty, Staff and Students Publications

Background: Cluneal neuralgia is increasingly becoming recognized as an etiology of low back pain. The majority of the literature on cluneal nerve interventions describes modalities targeting the superior cluneal nerves with little emphasis on the middle cluneal nerves.

Case report: A 21-year-old woman with a medical history of congenital myelomeningocele with tethered cord at L5-S1, status post 3 decompressive releases, presented to the clinic with chronic low back pain and associated sacroiliac paresthesia. Over 11 months, she underwent 7 ultrasound-guided bilateral middle cluneal nerve blocks, without corticosteroid, resulting in significant, immediate pain relief sustained for 4 to 6 weeks.

Conclusions: …

A Novel Grk3-Hdac2 Regulatory Pathway Is A Key Direct Link Between Neuroendocrine Differentiation And Angiogenesis In Prostate Cancer Progression, Samira Naderinezhad, Guoliang Zhang, Zheng Wang, Dayong Zheng, Mohit Hulsurkar, Michael Bakhoum, Ning Su, Han Yang, Tao Shen, Wenliang Li

Faculty, Staff and Students Publications

The mechanisms underlying the progression of prostate cancer (PCa) to neuroendocrine prostate cancer (NEPC), an aggressive PCa variant, are largely unclear. Two prominent NEPC phenotypes are elevated NE marker expression and heightened angiogenesis. Identifying the still elusive direct molecular links connecting angiogenesis and neuroendocrine differentiation (NED) is crucial for our understanding and targeting of NEPC. Here we found that histone deacetylase 2 (HDAC2), whose role in NEPC has not been reported, is one of the most upregulated epigenetic regulators in NEPC. HDAC2 promotes both NED and angiogenesis. G protein-coupled receptor kinase 3 (GRK3), also upregulated in NEPC, is a critical …

Maternal Metabolism Influences Neural Tube Closure, Rachel A Keuls, Richard H Finnell, Ronald J Parchem

Faculty, Staff and Students Publications

Changes in maternal nutrient availability due to diet or disease significantly increase the risk of neural tube defects (NTDs). Because the incidence of metabolic disease continues to rise, it is urgent that we better understand how altered maternal nutrient levels can influence embryonic neural tube development. Furthermore, primary neurulation occurs before placental function during a period of histiotrophic nutrient exchange. In this review we detail how maternal metabolites are transported by the yolk sac to the developing embryo. We discuss recent advances in understanding how altered maternal levels of essential nutrients disrupt development of the neuroepithelium, and identify points of …

Equine Bronchial Epithelial Cells Are Susceptible To Cell Entry With A Sars-Cov-2 Pseudovirus But Reveal Low Replication Efficiency, Rebecca M Legere, Angelica R Allegro, Yvonne Affram, Bibiana Petri Da Silveira, Jennifer L Fridley, Kelsey M Wells, Numan Oezguen, Robert C Burghardt, Gus A Wright, Jeroen Pollet, Angela I Bordin, Paul De Figueiredo, Julian L Leibowitz, Noah D Cohen

Faculty, Staff and Students Publications

Objective: To examine the susceptibility of cultured primary equine bronchial epithelial cells (EBECs) to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pseudovirus relative to human bronchial epithelial cells (HBECs).

Sample: Primary EBEC cultures established from healthy adult horses and commercially sourced human bronchial epithelial cells (HBECs) were used as a positive control.

Methods: Angiotensin-converting enzyme 2 (ACE2) expression by EBECs was demonstrated using immunofluorescence, western immunoblot, and flow cytometry. EBECs were transduced with a lentivirus pseudotyped with the SARS-CoV-2 spike protein that binds to ACE2 and expresses the enhanced green fluorescent protein (eGFP) as a reporter. Cells were transduced …

Polygenic Genetic Variation Affecting Antibody Formation Underlies Hypertensive Renal Injury In The Stroke-Prone Spontaneously Hypertensive Rat, Isha S Dhande, Yaming Zhu, Aniket S Joshi, M John Hicks, Michael C Braun, Peter A Doris

Faculty, Staff and Students Publications

During development of the spontaneously hypertensive rat (SHR), several distinct but closely related lines were generated. Most lines are resistant to hypertensive renal disease. However, the SHR-A3 line (stroke-prone SHR) experiences end-organ injury (EOI) and provides a model of injury susceptibility that can be used to uncover genetic causation. In the present study, we generated a congenic line in which three distinct disease loci in SHR-A3 are concurrently replaced with homologous loci from an injury-resistant SHR line (SHR-B2). Verification that all three loci were homozygously replaced in this triple congenic line [SHR-A3(Trip B2)] while the genetic background of SHR-A3 was …

Characterizing Control Of Memory Cd8 T Cell Differentiation By Btb-Zf Transcription Factor Zbtb20, Nicholas K Preiss, Yasmin Kamal, Owen M Wilkins, Chenyang Li, Fred W Kolling, Heidi W Trask, Young-Kwang Usherwood, Chao Cheng, Hildreth R Frost, Edward J Usherwood

Faculty, Staff and Students Publications

Members of the BTB-ZF transcription factor family regulate the immune system. Our laboratory identified that family member Zbtb20 contributes to the differentiation, recall responses, and metabolism of CD8 T cells. Here, we report a characterization of the transcriptional and epigenetic signatures controlled by Zbtb20 at single-cell resolution during the effector and memory phases of the CD8 T cell response. Without Zbtb20, transcriptional programs associated with memory CD8 T cell formation were up-regulated throughout the CD8 T response. A signature of open chromatin was associated with genes controlling T cell activation, consistent with the known impact on differentiation. In addition, memory …

New Records Of Ornithodoros Turicata (Ixodida: Argasidae) In Rural And Urban Sites In The Mexican States Of Aguascalientes And Zacatecas Indicate The Potential For Tick-Borne Relapsing Fever, Edwin Vázquez-Guerrero, José Luis González-Quiroz, María Lilia Domínguez-López, Alexander R Kneubehl, Aparna Krishnavajhala, Michael W Curtis, Alejandro Ponce-Mendoza, Paulina Estrada-De Los Santos, Job E Lopez, J Antonio Ibarra

Faculty, Staff and Students Publications

Soft ticks from the Ornithodoros genus are vectors of relapsing fever (RF) spirochetes around the world. In Mexico, they were originally described in the 19th century. However, few recent surveillance studies have been conducted in Mexico, and regions where RF spirochetes circulate remain vague. Here, the presence of soft ticks in populated areas was assessed in two sites from the Mexican states of Aguascalientes and Zacatecas. Argasidae ticks were collected, identified by morphology and mitochondrial 16S rDNA gene sequencing, and tested for RF borreliae. The specimens in both sites were identified as Ornithodoros turicata but no RF spirochetes were detected. …

Loss Of Growth Differentiation Factor 15 Exacerbates Lung Injury In Neonatal Mice, Faeq Al-Mudares, Manuel Cantu Gutierrez, Abiud Cantu, Weiwu Jiang, Lihua Wang, Xiaoyu Dong, Bhagavatula Moorthy, Eniko Sajti, Krithika Lingappan

Faculty, Staff and Students Publications

Growth differentiation factor 15 (GDF15) is a divergent member of the transforming growth factor-β (TGF-β) superfamily, and its expression increases under various stress conditions, including inflammation, hyperoxia, and senescence. GDF15 expression is increased in neonatal murine bronchopulmonary dysplasia (BPD) models, and GDF15 loss exacerbates oxidative stress and decreases cellular viability in vitro. Our overall hypothesis is that the loss of GDF15 will exacerbate hyperoxic lung injury in the neonatal lung in vivo. We exposed neonatal

A Membrane-Associated Mhc-I Inhibitory Axis For Cancer Immune Evasion, Xufeng Chen, Qiao Lu, Hua Zhou, Jia Liu, Bettina Nadorp, Audrey Lasry, Zhengxi Sun, Baoling Lai, Gergely Rona, Jiangyan Zhang, Michael Cammer, Kun Wang, Wafa Al-Santli, Zoe Ciantra, Qianjin Guo, Jia You, Debrup Sengupta, Ahmad Boukhris, Hongbing Zhang, Cheng Liu, Peter Cresswell, Patricia L M Dahia, Michele Pagano, Iannis Aifantis, Jun Wang

Faculty, Staff and Student Publications

Immune-checkpoint blockade has revolutionized cancer treatment, but some cancers such as acute myeloid leukemia (AML) do not respond or develop resistance. A potential mode of resistance is immune evasion of T-cell immunity involving aberrant MHC-I antigen presentation (AP). To map such mechanisms of resistance, we identified key MHC-I regulators using specific peptide-MHC-I-guided CRISPR/Cas9 screens in AML. The top-ranked negative regulators were surface protein Sushi Domain Containing 6 (SUSD6), Transmembrane Protein 127 (TMEM127), and the E3 ubiquitin ligase WWP2. SUSD6 is abundantly expressed in AML and multiple solid cancers, and its ablation enhanced MHC-I AP and reduced tumor growth in CD8+ …

A Single Dominant Locus Restricts Retrovirus Replication In Ybr/Ei Mice, Helen A Beilinson, Amanda Sevilleja, Jessica Spring, Fernando Benavides, Vera Beilinson, Nickolas Neokosmidis, Tatyana Golovkina

Faculty, Staff and Student Publications

Differential responses to viral infections are influenced by the genetic makeup of the host. Studies of resistance to retroviruses in human populations are complicated due to the inability to conduct proof-of-principle studies. Inbred mouse lines, which have a range of susceptible phenotypes to retroviruses, are an ideal tool to identify and characterize mechanisms of resistance and define their genetic underpinnings. YBR/Ei mice become infected with Mouse Mammary Tumor Virus, a mucosally transmitted murine retrovirus, but eliminate the virus from their pedigrees. Virus elimination correlates with a lack of virus-specific neonatal oral tolerance, which is a major mechanism for blocking the …

Loss Of Stearoyl-Coa Desaturase 2 Disrupts Inflammatory Response In Macrophages, Joseph B Lin, Amy Mora, Tzu Jui Wang, Andrea Santeford, Darksha Usmani, Marianne M Ligon, Indira U Mysorekar, Rajendra S Apte

Faculty, Staff and Students Publications

Macrophages are innate immune cells that patrol tissues and are the first responders to detect infection. They orchestrate the host immune response in eliminating invading pathogens and the subsequent transition from inflammation to tissue repair. Macrophage dysfunction contributes to age-related pathologies, including low-grade inflammation in advanced age that is termed "inflammaging." Our laboratory has previously identified that macrophage expression of a fatty acid desaturase, stearoyl-CoA desaturase 2 (SCD2), declines with age. Herein, we delineate the precise cellular effects of SCD2 deficiency in murine macrophages. We found that deletion of

Car-T Cells Targeting Cd38 And Lmp1 Exhibit Robust Antitumour Activity Against Nk/T Cell Lymphoma, Hongwen Li, Wenting Song, Jiazhuo Wu, Zhuangzhuang Shi, Yuyang Gao, Jiwei Li, Lijuan Han, Jianxiang Zhang, Zhaoming Li, Yong Li, Mingzhi Zhang

Faculty, Staff and Students Publications

BACKGROUND: Natural killer/T cell lymphoma (NKTCL) is an aggressive lymphoma with a poor prognosis. Chimeric antigen receptor-transduced T (CAR-T) cell therapy has become a promising immunotherapeutic strategy against haematologic malignancies.

METHODS: In this study, four CAR-T cell lines (CD38-CAR, LMP1-CAR, CD38-LMP1 tandem CAR 1 and CD38-LMP1 tandem CAR 2) were generated. The effect of CAR-T cells against NKTCL cells was evaluated both in vitro and in vivo. Expression of T cell activation markers and cytokines produced by CAR-T cells were detected by flow cytometry.

RESULTS: The four CAR-T cell lines could effectively eliminate malignant NKTCL cells. They could be activated …

Pimavanserin Treatment Increases Plasma Brain-Derived Neurotrophic Factor Levels In Rats, Ashutosh Tripathi, Henry A Nasrallah, Anilkumar Pillai

Faculty, Staff and Student Publications

BACKGROUND: Pimavanserin, a serotonin 5HT-2A receptor inverse agonist is the first-line, FDA-approved treatment of hallucinations and delusions associated with Parkinson's Disease psychosis (PDP), which occurs in up to 50% of PD patients. The neurobiological mechanism underlying the therapeutic effectiveness of Pimavanserin in PDP remains unknown. Several earlier studies have shown that treatment with 5HT-2A antagonists and other drugs acting on the serotonergic system such as SSRIs increase Brain derived neurotrophic factor (BDNF) levels in rodents. BDNF is synthesized as the precursor proBDNF, that undergoes cleavage intra or extracellularly to produce a mature BDNF (mBDNF) protein. mBDNF is believed to play …

Daam2 Phosphorylation By Ck2Α Negatively Regulates Wnt Activity During White Matter Development And Injury, Chih-Yen Wang, Zhongyuan Zuo, Juyeon Jo, Kyoung In Kim, Christine Madamba, Qi Ye, Sung Yun Jung, Hugo J Bellen, Hyun Kyoung Lee

Faculty, Staff and Students Publications

Wnt signaling plays a vital role in oligodendrocyte (OL) development and has been implicated as an adverse event for myelin repair after white matter injury. Emerging studies have shed light on multimodal roles of Wnt effectors in the OL lineage, but the underlying molecular mechanisms and modifiable targets in OL remyelination remain unclear. Using genetic mouse development and injury model systems, we delineate a unique stage-specific function of Daam2 in Wnt signaling and OL development via a S704/T705 phosphorylation mechanism and determine a different role of the kinase CK2α in the regulation of OL development and myelin regeneration.

Entry Receptor Ldlrad3 Is Required For Venezuelan Equine Encephalitis Virus Peripheral Infection And Neurotropism Leading To Pathogenesis In Mice, Natasha M Kafai, Hana Janova, Matthew D Cain, Yael Alippe, Stefanie Muraro, Alan Sariol, Michelle Elam-Noll, Robyn S Klein, Michael S Diamond

The Brown Foundation: Institute of Molecular Medicine

Venezuelan equine encephalitis virus (VEEV) is an encephalitic alphavirus responsible for epidemics of neurological disease across the Americas. Low-density lipoprotein receptor class A domain-containing 3 (LDLRAD3) is a recently reported entry receptor for VEEV. Here, using wild-type and Ldlrad3-deficient mice, we define a critical role for LDLRAD3 in controlling steps in VEEV infection, pathogenesis, and neurotropism. Our analysis shows that LDLRAD3 is required for efficient VEEV infection and pathogenesis prior to and after central nervous system invasion. Ldlrad3-deficient mice survive intranasal and intracranial VEEV inoculation and show reduced infection of neurons in different brain regions. As LDLRAD3 is a determinant …

An Evolutionarily Nascent Architecture Underlying The Formation And Emergence Of Biomolecular Condensates, Nima Jaberi-Lashkari, Byron Lee, Fardin Aryan, Eliezer Calo

Faculty, Staff and Student Publications

Biomolecular condensates are implicated in core cellular processes such as gene regulation and ribosome biogenesis. Although the architecture of biomolecular condensates is thought to rely on collective interactions between many components, it is unclear how the collective interactions required for their formation emerge during evolution. Here, we show that the structure and evolution of a recently emerged biomolecular condensate, the nucleolar fibrillar center (FC), is explained by a single self-assembling scaffold, TCOF1. TCOF1 is necessary to form the FC, and it structurally defines the FC through self-assembly mediated by homotypic interactions of serine/glutamate-rich low-complexity regions (LCRs). Finally, introduction of TCOF1 …

Bcl-2 Inhibition Combined With Pparα Activation Synergistically Targets Leukemic Stem Cell-Like Cells In Acute Myeloid Leukemia, Chendi Xie, Hui Zhou, Dongmei Qin, Huijian Zheng, Yuanfang Tang, Wenjuan Li, Jie Zhou, Long Liu, Xinxin Yu, Hongpeng Duan, Yong Zhou, Zhifeng Li, Zhihong Fang, Yiming Luo, Bing Z Carter, Bing Xu, Jie Zha

Faculty, Staff and Student Publications

Persistence of leukemic stem cells (LSCs) is one of the determining factors to acute myeloid leukemia (AML) treatment failure and responsible for the poor prognosis of the disease. Hence, novel therapeutic strategies that target LSCs are crucial for treatment success. We investigated if targeting Bcl-2 and peroxisome proliferator activated receptor α (PPARα), two distinct cell survival regulating mechanisms could eliminate LSCs. This study demonstrate that the Bcl-2 inhibitor venetoclax combined with the PPARα agonist chiglitazar resulted in synergistic killing of LSC-like cell lines and CD34+ primary AML cells while sparing their normal counterparts. Furthermore, the combination regimen significantly suppressed AML …

High Foxa1 Levels Induce Er Transcriptional Reprogramming, A Pro-Metastatic Secretome, And Metastasis In Endocrine-Resistant Breast Cancer, Xiaoyong Fu, Resel Pereira, Chia-Chia Liu, Carmine De Angelis, Martin J Shea, Sarmistha Nanda, Lanfang Qin, Tamika Mitchell, Maria L Cataldo, Jamunarani Veeraraghavan, Vidyalakshmi Sethunath, Mario Giuliano, Carolina Gutierrez, Balázs Győrffy, Meghana V Trivedi, Ofir Cohen, Nikhil Wagle, Agostina Nardone, Rinath Jeselsohn, Mothaffar F Rimawi, C Kent Osborne, Rachel Schiff

Center for Medical Ethics and Health Policy Staff Publications

Aberrant activation of the forkhead protein FOXA1 is observed in advanced hormone-related cancers. However, the key mediators of high FOXA1 signaling remain elusive. We demonstrate that ectopic high FOXA1 (H-FOXA1) expression promotes estrogen receptor-positive (ER+) breast cancer (BC) metastasis in a xenograft mouse model. Mechanistically, H-FOXA1 reprograms ER-chromatin binding to elicit a core gene signature (CGS) enriched in ER+ endocrine-resistant (EndoR) cells. We identify Secretome14, a CGS subset encoding ER-dependent cancer secretory proteins, as a strong predictor for poor outcomes of ER+ BC. It is elevated in ER+ metastases vs. primary tumors, irrespective of ESR1 mutations. Genomic ER binding near …

A Comprehensive Drosophila Resource To Identify Key Functional Interactions Between Sars-Cov-2 Factors And Host Proteins, Annabel Guichard, Shenzhao Lu, Oguz Kanca, Daniel Bressan, Yan Huang, Mengqi Ma, Sara Sanz Juste, Jonathan C Andrews, Kristy L Jay, Marketta Sneider, Ruth Schwartz, Mei-Chu Huang, Danqing Bei, Hongling Pan, Liwen Ma, Wen-Wen Lin, Ankush Auradkar, Pranjali Bhagwat, Soo Park, Kenneth H Wan, Takashi Ohsako, Toshiyuki Takano-Shimizu, Susan E Celniker, Michael F Wangler, Shinya Yamamoto, Hugo J Bellen, Ethan Bier

Faculty, Staff and Students Publications

Development of effective therapies against SARS-CoV-2 infections relies on mechanistic knowledge of virus-host interface. Abundant physical interactions between viral and host proteins have been identified, but few have been functionally characterized. Harnessing the power of fly genetics, we develop a comprehensive Drosophila COVID-19 resource (DCR) consisting of publicly available strains for conditional tissue-specific expression of all SARS-CoV-2 encoded proteins, UAS-human cDNA transgenic lines encoding established host-viral interacting factors, and GAL4 insertion lines disrupting fly homologs of SARS-CoV-2 human interacting proteins. We demonstrate the utility of the DCR to functionally assess SARS-CoV-2 genes and candidate human binding partners. We show that …

Evaluation Of Antibacterial Efficacy Of Lawsonia Inermis Linn (Henna) On Periodontal Pathogens Using Agar Well Diffusion And Broth Microdilution Methods: An In-Vitro Study, Şevki Güler, Damla Torul, Sevda Kurt-Bayrakdar, Emine Kübra Tayyarcan, Çağrı Çamsarı, İsmail Hakkı Boyacı

BioMedicine

Background: Although widely explored in medicine, limited evidence exists in the literature regarding the efficacy of Lawsonia inermis Linn (henna) in the dental field. Aim: This study aimed to investigate the antibacterial effect of henna on Aggregatibacter actinomycetemcomitans and Porphyromonas gingivalis in vitro. Methods: The agar well diffusion and broth microdilution methods were used to evaluate the antibacterial effect of henna extracts. Dimethyl sulfoxide was used to prepare the ethanol extract of henna, and distilled water was used to prepare the water extract. For both ethanol and water extracts, 4 different concentrations were prepared as 15, 30, 60, and 120 …

Endometrial Fluid Biomarkers And Their Potential As Predictors Of Successful Embryo Implantation, Ana Rita Alves, Margarida Figueiredo Dias, Margarida Silvestre

BioMedicine

Background: Embryo implantation is a complex biological process which requires synchronized dialogue between the receptive endometrium and the blastocyst. The endometrium, however, is only receptive to embryo implantation for a very short period. Recurrent implantation failure (RIF) is a major challenge in assisted reproductive techniques mainly due to impaired receptivity, but there is still a need for a reliable and valid clinical test to assess endometrial receptiveness, especially at embryo transfer time. The aim of this review is to investigate what is currently known about the contribution of endometrial fluid (EF) to endometrial receptivity by identifying its potential biomarkers. Methods: …