Digital Commons Network^™

Endogenous Renal Adiponectin Drives Gluconeogenesis Through Enhancing Pyruvate And Fatty Acid Utilization, Toshiharu Onodera, May-Yun Wang, Joseph M Rutkowski, Stanislaw Deja, Shiuhwei Chen, Michael S Balzer, Dae-Seok Kim, Xuenan Sun, Yu A An, Bianca C Field, Charlotte Lee, Ei-Ichi Matsuo, Monika Mizerska, Ina Sanjana, Naoto Fujiwara, Christine M Kusminski, Ruth Gordillo, Laurent Gautron, Denise K Marciano, Ming Chang Hu, Shawn C Burgess, Katalin Susztak, Orson W Moe, Philipp E Scherer

Faculty, Staff and Student Publications

Adiponectin is a secretory protein, primarily produced in adipocytes. However, low but detectable expression of adiponectin can be observed in cell types beyond adipocytes, particularly in kidney tubular cells, but its local renal role is unknown. We assessed the impact of renal adiponectin by utilizing male inducible kidney tubular cell-specific adiponectin overexpression or knockout mice. Kidney-specific adiponectin overexpression induces a doubling of phosphoenolpyruvate carboxylase expression and enhanced pyruvate-mediated glucose production, tricarboxylic acid cycle intermediates and an upregulation of fatty acid oxidation (FAO). Inhibition of FAO reduces the adiponectin-induced enhancement of glucose production, highlighting the role of FAO in the induction …

Impairment Of Serine Transport Across The Blood-Brain Barrier By Deletion Of Slc38a5 Causes Developmental Delay And Motor Dysfunction, Inna Radzishevsky, Maali Odeh, Oded Bodner, Salman Zubedat, Lihi Shaulov, Maxim Litvak, Kayoko Esaki, Takeo Yoshikawa, Bella Agranovich, Wen-Hong Li, Alex Radzishevsky, Eyal Gottlieb, Avi Avital, Herman Wolosker

Faculty, Staff and Student Publications

Brain L-serine is critical for neurodevelopment and is thought to be synthesized solely from glucose. In contrast, we found that the influx of L-serine across the blood-brain barrier (BBB) is essential for brain development. We identified the endothelial Slc38a5, previously thought to be a glutamine transporter, as an L-serine transporter expressed at the BBB in early postnatal life. Young Slc38a5 knockout (KO) mice exhibit developmental alterations and a decrease in brain L-serine and D-serine, without changes in serum or liver amino acids. Slc38a5-KO brains exhibit accumulation of neurotoxic deoxysphingolipids, synaptic and mitochondrial abnormalities, and decreased neurogenesis at the dentate gyrus. …

Oncolytic Virus M1 Functions As A Bifunctional Checkpoint Inhibitor To Enhance The Antitumor Activity Of Dc Vaccine, Jia Dan, Jing Cai, Yingqian Zhong, Chaoqun Wang, Shanyu Huang, Ying Zeng, Zhen Fan, Cuiying Xu, Linyi Hu, Jiayu Zhang, Jun Hu, Ying Liu, Xingwen Su, Wenbo Zhu, Guangmei Yan, Jiankai Liang, Yuan Lin

Faculty, Staff and Student Publications

Although promising, dendritic cell (DC) vaccines still provide limited clinical benefits, mainly due to the immunosuppressive tumor microenvironment (TME) and the lack of tumor-associated antigens (TAAs). Oncolytic virus therapy is an ideal strategy to overcome immunosuppression and expose TAAs; therefore, they may work synergistically with DC vaccines. In this study, we demonstrate that oncolytic virus M1 (OVM) can enhance the antitumor effects of DC vaccines across diverse syngeneic mouse tumor models by increasing the infiltration of CD8+ effector T cells in the TME. Mechanically, we show that tumor cells counteract DC vaccines through the SIRPα-CD47 immune checkpoint, while OVM can …

Neuroprotective Activity Of Enantiomers Of Salsolinol And N-Methyl-(R)-Salsolinol: In Vitro And In Silico Studies, Magdalena Kurnik-Łucka, Gniewomir Latacz, Adam Bucki, Mario Rivera-Meza, Nadia Khan, Jahnobi Konwar, Kamil Skowron, Marcin Kołaczkowski, Krzysztof Gil

Faculty, Staff and Student Publications

Salsolinol (1-methyl-1,2,3,4-tetrahydroisoquinoline-6,7-diol) is a close structural analogue of dopamine with an asymmetric center at the C1 position, and its presence in vivo, both in humans and rodents, has already been proven. Yet, given the fact that salsolinol colocalizes with dopamine-rich regions and was first detected in the urine of Parkinson's disease patients, its direct role in the process of neurodegeneration has been proposed. Here, we report that

Macrocephaly And Developmental Delay Caused By Missense Variants In Rab5c, Klaas Koop, Weimin Yuan, Federico Tessadori, Wilmer R Rodriguez-Polanco, Jeremy Grubbs, Bo Zhang, Matt Osmond, Gail Graham, Sarah Sawyer, Erin Conboy, Francesco Vetrini, Kayla Treat, Rafal Płoski, Victor Murcia Pienkowski, Anna Kłosowska, Elizabeth Fieg, Joel Krier, Coralie Mallebranche, Ziegler Alban, Kimberly A Aldinger, Deborah Ritter, Ellen Macnamara, Bonnie Sullivan, John Herriges, Joseph T Alaimo, Catherine Helbig, Colin A Ellis, Clare Van Eyk, Jozef Gecz, Daniel Farrugia, Ikeoluwa Osei-Owusu, Lesley Adès, Marie-Jose Van Den Boogaard, Sabine Fuchs, Jeroen Bakker, Karen Duran, Zachary D Dawson, Anika Lindsey, Huiyan Huang, Dustin Baldridge, Gary A Silverman, Barth D Grant, David Raizen, Undiagnosed Diseases Network, Gijs Van Haaften, Stephen C Pak, Holger Rehmann, Tim Schedl, Peter Van Hasselt

Faculty, Staff and Students Publications

Rab GTPases are important regulators of intracellular vesicular trafficking. RAB5C is a member of the Rab GTPase family that plays an important role in the endocytic pathway, membrane protein recycling and signaling. Here we report on 12 individuals with nine different heterozygous de novo variants in RAB5C. All but one patient with missense variants (n = 9) exhibited macrocephaly, combined with mild-to-moderate developmental delay. Patients with loss of function variants (n = 2) had an apparently more severe clinical phenotype with refractory epilepsy and intellectual disability but a normal head circumference. Four missense variants were investigated experimentally. In vitro biochemical …

Hippo Pathway Knockdown Gene Therapy In The Heart, Todd R Heallen, James F Martin

The Texas Heart Institute Journal

No abstract provided.

Regulation Of Postnatal Cardiomyocyte Maturation By An Rna Splicing Regulator Rbfox1, Jijun Huang, Josh Z Lee, Christoph D Rau, Arash Pezhouman, Tomohiro Yokota, Hiromi Miwa, Matthew Feldman, Tsz Kin Kong, Ziyue Yang, Woan Ting Tay, Ivan Pushkarsky, Kyungsoo Kim, Shan S Parikh, Shreya Udani, Boon Seng Soh, Chen Gao, Linsey Stiles, Orian S Shirihai, Bjorn C Knollmann, Reza Ardehali, Dino Di Carlo, Yibin Wang

Faculty, Staff and Students Publications

No abstract provided.

Molecular And Sequencing Study And Identification Of Novel Sem-Type In Beta-Hemolytic Streptococci Involving The Upper Respiratory Tract In Iran, Sina Moghaddam, Samad Lotfollahzadeh, Taghi Zahraei Salehi, Ali Hassanpour, Hamid Tavanaei Manesh, Iraj Ashrafi Tamai

Faculty, Staff and Students Publications

BACKGROUND: Beta-hemolytic streptococci involving the upper respiratory tract cause strangles and strangles-like diseases in horses and cause severe economic damage to the equestrian club each year. Therefore, careful epidemiological study of these bacteria, evaluation of phylogenetic connections and SeM-typing can be useful to determine the source and epidemiological characteristics of the disease outbreak. Isolates were analyzed using molecular and phylogenetic methods and to determine antibiotic resistance pattern in Iranian isolates. Molecular and phylogenetic methods were used to evaluate Iranian streptococcal isolates, and the similarity of the Iranian SeM-97 sequence with other alleles was assessed using the Neighbor-joining method with the …

Orthostatic Hypotension, Hypertension Treatment, And Cardiovascular Disease: An Individual Participant Meta-Analysis, Stephen P Juraschek, Jiun-Ruey Hu, Jennifer L Cluett, Anthony M Ishak, Carol Mita, Lewis A Lipsitz, Lawrence J Appel, Nigel S Beckett, Ruth L Coleman, William C Cushman, Barry R Davis, Greg Grandits, Rury R Holman, Edgar R Miller, Ruth Peters, Jan A Staessen, Addison A Taylor, Lutgarde Thijs, Jackson T Wright, Kenneth J Mukamal

Faculty, Staff and Students Publications

IMPORTANCE: There are ongoing concerns about the benefits of intensive vs standard blood pressure (BP) treatment among adults with orthostatic hypotension or standing hypotension.

OBJECTIVE: To determine the effect of a lower BP treatment goal or active therapy vs a standard BP treatment goal or placebo on cardiovascular disease (CVD) or all-cause mortality in strata of baseline orthostatic hypotension or baseline standing hypotension.

DATA SOURCES: Individual participant data meta-analysis based on a systematic review of MEDLINE, EMBASE, and CENTRAL databases through May 13, 2022.

STUDY SELECTION: Randomized trials of BP pharmacologic treatment (more intensive BP goal or active agent) with …

Association Between Whole Blood-Derived Mitochondrial Dna Copy Number, Low-Density Lipoprotein Cholesterol, And Cardiovascular Disease Risk, Xue Liu, Xianbang Sun, Yuankai Zhang, Wenqing Jiang, Meng Lai, Kerri L Wiggins, Laura M Raffield, Lawrence F Bielak, Wei Zhao, Achilleas Pitsillides, Jeffrey Haessler, Yinan Zheng, Thomas W Blackwell, Jie Yao, Xiuqing Guo, Yong Qian, Bharat Thyagarajan, Nathan Pankratz, Stephen S Rich, Kent D Taylor, Patricia A Peyser, Susan R Heckbert, Sudha Seshadri, Eric Boerwinkle, Megan L Grove, Nicholas B Larson, Jennifer A Smith, Ramachandran S Vasan, Annette L Fitzpatrick, Myriam Fornage, Jun Ding, April P Carson, Goncalo Abecasis, Josée Dupuis, Alexander Reiner, Charles Kooperberg, Lifang Hou, Bruce M Psaty, James G Wilson, Daniel Levy, Jerome I Rotter, Joshua C Bis, Claudia L Satizabal, Dan E Arking, Chunyu Liu

Faculty, Staff and Student Publications

Background The relationship between mitochondrial DNA copy number (mtDNA CN) and cardiovascular disease remains elusive. Methods and Results We performed cross-sectional and prospective association analyses of blood-derived mtDNA CN and cardiovascular disease outcomes in 27 316 participants in 8 cohorts of multiple racial and ethnic groups with whole-genome sequencing. We also performed Mendelian randomization to explore causal relationships of mtDNA CN with coronary heart disease (CHD) and cardiometabolic risk factors (obesity, diabetes, hypertension, and hyperlipidemia).

Sptan1/Numb Axis Senses Cell Density To Restrain Cell Growth And Oncogenesis Through Hippo Signaling, Dongxue Su, Yuxi Li, Weiji Zhang, Huan Gao, Yao Cheng, Yongqiang Hou, Junhong Li, Yi Ye, Zhangjian Lai, Zhe Li, Haitao Huang, Jiaxin Li, Jinhuan Li, Mengyu Cheng, Cheng Nian, Na Wu, Zhien Zhou, Yunzhi Xing, Yu Zhao, He Liu, Jiayu Tang, Qinghua Chen, Lixin Hong, Wengang Li, Zhihai Peng, Bin Zhao, Randy L Johnson, Pingguo Liu, Wanjin Hong, Lanfen Chen, Dawang Zhou

Faculty, Staff and Student Publications

The loss of contact inhibition is a key step during carcinogenesis. The Hippo-Yes-associated protein (Hippo/YAP) pathway is an important regulator of cell growth in a cell density-dependent manner. However, how Hippo signaling senses cell density in this context remains elusive. Here, we report that high cell density induced the phosphorylation of spectrin α chain, nonerythrocytic 1 (SPTAN1), a plasma membrane-stabilizing protein, to recruit NUMB endocytic adaptor protein isoforms 1 and 2 (NUMB1/2), which further sequestered microtubule affinity-regulating kinases (MARKs) in the plasma membrane and rendered them inaccessible for phosphorylation and inhibition of the Hippo kinases sterile 20-like kinases MST1 and …

Excretory/Secretory Products From Trichinella Spiralis Adult Worms Ameliorate Myocardial Infarction By Inducing M2 Macrophage Polarization In A Mouse Model, Lingqin Wu, Wenhui Yin, Jutai Wen, Shuying Wang, Huihui Li, Xiaoli Wang, Weixiao Zhang, Shuyao Duan, Qiuyu Zhu, Erhe Gao, Shili Wu, Bin Zhan, Rui Zhou, Xiaodi Yang

Faculty, Staff and Students Publications

BACKGROUND: Ischemia-induced inflammatory response is the main pathological mechanism of myocardial infarction (MI)-caused heart tissue injury. It has been known that helminths and worm-derived proteins are capable of modulating host immune response to suppress excessive inflammation as a survival strategy. Excretory/secretory products from Trichinella spiralis adult worms (Ts-AES) have been shown to ameliorate inflammation-related diseases. In this study, Ts-AES were used to treat mice with MI to determine its therapeutic effect on reducing MI-induced heart inflammation and the immunological mechanism involved in the treatment.

METHODS: The MI model was established by the ligation of the left anterior descending coronary artery, …

Dna2 Nuclease Inhibition Confers Synthetic Lethality In Cancers With Mutant P53 And Synergizes With Parp Inhibitors, Helena Folly-Kossi, Joshua D Graves, Lidija A Wilhelms Garan, Fang-Tsyr Lin, Weei-Chin Lin

Faculty, Staff and Students Publications

UNLABELLED: The tumor suppressor p53 promotes tumor-suppressive activities including cell-cycle inhibition, apoptosis, senescence, autophagy, and DNA repair. However, somatic mutations in the TP53 gene are one of the most common alterations in human cancers. We previously showed that mutant p53 (mutp53) can bind TopBP1, an ATR activator, to attenuate its ATR-activating function. A partially defective ATR function caused by mutp53 makes cancer cells more vulnerable to inhibitors of other TopBP1-independent ATR activators, such as DNA2. DNA2 plays a role in homologous recombination (HR) repair by resecting DNA ends in double-strand breaks and preparing them for invasion of homologous duplex. Here …

A Single Nanobody Neutralizes Multiple Epochally Evolving Human Noroviruses By Modulating Capsid Plasticity, Wilhelm Salmen, Liya Hu, Marina Bok, Natthawan Chaimongkol, Khalil Ettayebi, Stanislav V Sosnovtsev, Kaundal Soni, B Vijayalakshmi Ayyar, Sreejesh Shanker, Frederick H Neill, Banumathi Sankaran, Robert L Atmar, Mary K Estes, Kim Y Green, Viviana Parreño, B V Venkataram Prasad

Faculty, Staff and Students Publications

Acute gastroenteritis caused by human noroviruses (HuNoVs) is a significant global health and economic burden and is without licensed vaccines or antiviral drugs. The GII.4 HuNoV causes most epidemics worldwide. This virus undergoes epochal evolution with periodic emergence of variants with new antigenic profiles and altered specificity for histo-blood group antigens (HBGA), the determinants of cell attachment and susceptibility, hampering the development of immunotherapeutics. Here, we show that a llama-derived nanobody M4 neutralizes multiple GII.4 variants with high potency in human intestinal enteroids. The crystal structure of M4 complexed with the protruding domain of the GII.4 capsid protein VP1 revealed …

Revisiting Asthma Obstructive Sleep Apnea Overlap: Current Knowledge And Future Needs, Damini Saxena, Ikuyo Imayama, Muhammad Adrish

Faculty, Staff and Students Publications

Asthma and obstructive sleep apnea are highly prevalent conditions with a high cost burden. In addition to shared risk factors, existing data suggest a bidirectional relationship between asthma and OSA, where each condition can impact the other. Patients with asthma often complain of sleep fragmentation, nocturnal asthma symptoms, daytime sleepiness, and snoring. The prevalence of OSA increases with asthma severity, as evidenced by multiple large studies. Asthma may lower the threshold for arousal in OSA, resulting in the hypopnea with arousal phenotype. Epidemiologic studies in adults have shown that OSA is associated with worse asthma severity, increased frequency of exacerbation, …

Investigating Associations Of Omega-3 Fatty Acids, Lung Function Decline, And Airway Obstruction, Bonnie K Patchen, Pallavi Balte, Traci M Bartz, R Graham Barr, Myriam Fornage, Mariaelisa Graff, David R Jacobs, Ravi Kalhan, Rozenn N Lemaitre, George O'Connor, Bruce Psaty, Jungkyun Seo, Michael Y Tsai, Alexis C Wood, Hanfei Xu, Jingwen Zhang, Sina A Gharib, Ani Manichaikul, Kari North, Lyn M Steffen, Josée Dupuis, Elizabeth Oelsner, Dana B Hancock, Patricia A Cassano

Faculty, Staff and Student Publications

Rationale: Inflammation contributes to lung function decline and the development of chronic obstructive pulmonary disease. Omega-3 fatty acids have antiinflammatory properties and may benefit lung health.

Objectives: To investigate associations of omega-3 fatty acids with lung function decline and incident airway obstruction in a diverse sample of adults from general-population cohorts.

Methods: Complementary study designs: 1) longitudinal study of plasma phospholipid omega-3 fatty acids and repeated FEV1 and FVC measures in the NHLBI Pooled Cohorts Study and 2) two-sample Mendelian randomization (MR) study of genetically predicted omega-3 fatty acids and lung function parameters.

Measurements and Main Results: The …

Stroke Recovery Is A Journey: Prediction And Potentials Of Motor Recovery After A Stroke From A Practical Perspective, Sheng Li

Faculty, Staff and Student Publications

Stroke recovery is a journey. Stroke survivors can face many consequences that may last the rest of their lives. Assessment of initial impairments allows reasonable prediction of biological spontaneous recovery at 3 to 6 months for a majority of survivors. In real-world clinical practice, stroke survivors continue to improve their motor function beyond the spontaneous recovery period, but management plans for maximal recovery are not well understood. A model within the international classification of functioning (ICF) theoretical framework is proposed to systematically identify opportunities and potential barriers to maximize and realize the potentials of functional recovery from the acute to …

A Retrospective, Observational Study Of 12 Cases Of Expanded-Access Customized Phage Therapy: Production, Characteristics, And Clinical Outcomes, Sabrina I Green, Justin R Clark, Haroldo H Santos, Kyle E Weesner, Keiko C Salazar, Saima Aslam, J William Campbell, Sarah B Doernberg, Emily Blodget, Michele I Morris, Gina A Suh, Karam Obeid, Fernanda P Silveira, Andrey A Filippov, Katrine L Whiteson, Barbara W Trautner, Austen L Terwilliger, Anthony Maresso

Faculty, Staff and Students Publications

BACKGROUND: Antimicrobial resistance (AMR) is undermining modern medicine, a problem compounded by bacterial adaptation to antibiotic pressures. Phages are viruses that infect bacteria. Their diversity and evolvability offer the prospect of their use as a therapeutic solution. Reported are outcomes of customized phage therapy for patients with difficult-to-treat antimicrobial resistant infections.

METHODS: We retrospectively assessed 12 cases of customized phage therapy from a phage production center. Phages were screened, purified, sequenced, characterized, and Food and Drug Administration-approved via the IND (investigational new drug) compassionate-care route. Outcomes were assessed as favorable or unfavorable by microbiologic and clinical standards. Infections were device-related …

Ppp1r12c Promotes Atrial Hypocontractility In Atrial Fibrillation, Srikanth Perike, Francisco J Gonzalez-Gonzalez, Issam Abu-Taha, Frederick W Damen, Laurin M Hanft, Ken S Lizama, Anahita Aboonabi, Andrielle E Capote, Yuriana Aguilar-Sanchez, Benjamin Levin, Zhenbo Han, Arvind Sridhar, Jacob Grand, Jody Martin, Joseph G Akar, Chad M Warren, R John Solaro, Sang-Ging Ong, Dawood Darbar, Kerry S Mcdonald, Craig J Goergen, Beata M Wolska, Dobromir Dobrev, Xander H T Wehrens, Mark D Mccauley

Faculty, Staff and Students Publications

Background: Atrial fibrillation (AF)-the most common sustained cardiac arrhythmia-increases thromboembolic stroke risk 5-fold. Although atrial hypocontractility contributes to stroke risk in AF, the molecular mechanisms reducing myofilament contractile function remain unknown. We tested the hypothesis that increased expression of PPP1R12C (protein phosphatase 1 regulatory subunit 12C)-the PP1 (protein phosphatase 1) regulatory subunit targeting MLC2a (atrial myosin light chain 2)-causes hypophosphorylation of MLC2a and results in atrial hypocontractility.

Methods: Right atrial appendage tissues were isolated from human patients with AF versus sinus rhythm controls. Western blots, coimmunoprecipitation, and phosphorylation studies were performed to examine how the PP1c (PP1 catalytic subunit)-PPP1R12C interaction …

Next-Generation Crispr Gene-Drive Systems Using Cas12a Nuclease, Sara Sanz Juste, Emily M Okamoto, Christina Nguyen, Xuechun Feng, Víctor López Del Amo

Faculty, Staff and Student Publications

One method for reducing the impact of vector-borne diseases is through the use of CRISPR-based gene drives, which manipulate insect populations due to their ability to rapidly propagate desired genetic traits into a target population. However, all current gene drives employ a Cas9 nuclease that is constitutively active, impeding our control over their propagation abilities and limiting the generation of alternative gene drive arrangements. Yet, other nucleases such as the temperature sensitive Cas12a have not been explored for gene drive designs in insects. to address this, we herein present a proof-of-concept gene-drive system driven by Cas12a that can be regulated …

Trio-Based Gwas Identifies Novel Associations And Subtype-Specific Risk Factors For Cleft Palate, Kelsey Robinson, Trenell J Mosley, Kenneth S Rivera-González, Christopher R Jabbarpour, Sarah W Curtis, Wasiu Lanre Adeyemo, Terri H Beaty, Azeez Butali, Carmen J Buxó, David J Cutler, Michael P Epstein, Lord J J Gowans, Jacqueline T Hecht, Jeffrey C Murray, Gary M Shaw, Lina Moreno Uribe, Seth M Weinberg, Harrison Brand, Mary L Marazita, Robert J Lipinski, Elizabeth J Leslie

Faculty, Staff and Student Publications

Cleft palate (CP) is one of the most common craniofacial birth defects; however, there are relatively few established genetic risk factors associated with its occurrence despite high heritability. Historically, CP has been studied as a single phenotype, although it manifests across a spectrum of defects involving the hard and/or soft palate. We performed a genome-wide association study using transmission disequilibrium tests of 435 case-parent trios to evaluate broad risks for any cleft palate (ACP) (n = 435), and subtype-specific risks for any cleft soft palate (CSP), (n = 259) and any cleft hard palate (CHP) (n = 125). We identified …

Widefield Imaging Of Rapid Pan-Cortical Voltage Dynamics With An Indicator Evolved For One-Photon Microscopy, Xiaoyu Lu, Yunmiao Wang, Zhuohe Liu, Yueyang Gou, Dieter Jaeger, François St-Pierre

Faculty, Staff and Students Publications

Widefield imaging with genetically encoded voltage indicators (GEVIs) is a promising approach for understanding the role of large cortical networks in the neural coding of behavior. However, the limited performance of current GEVIs restricts their deployment for single-trial imaging of rapid neuronal voltage dynamics. Here, we developed a high-throughput platform to screen for GEVIs that combine fast kinetics with high brightness, sensitivity, and photostability under widefield one-photon illumination. Rounds of directed evolution produced JEDI-1P, a green-emitting fluorescent indicator with enhanced performance across all metrics. Next, we optimized a neonatal intracerebroventricular delivery method to achieve cost-effective and wide-spread JEDI-1P expression in …

Usp1 Promotes Cholangiocarcinoma Progression By Deubiquitinating Parp1 To Prevent Its Proteasomal Degradation, Deng Yong Zhang, Yan Zhu, Qiong Wu, Shuoshuo Ma, Yang Ma, Zheng Chao Shen, Zhonglin Wang, Wanliang Sun, Yong Chun Zhou, Dongdong Wang, Shuo Zhou, Zhong Liu, Lawrence N Kwong, Zheng Lu

Faculty, Staff and Student Publications

Despite its involvement in various cancers, the function of the deubiquitinase USP1 (ubiquitin-specific protease 1) is unexplored in cholangiocarcinoma (CCA). In this study, we provide evidence that USP1 promotes CCA progression through the stabilization of Poly (ADP-ribose) polymerase 1 (PARP1), consistent with the observation that both USP1 and PARP1 are upregulated in human CCA. Proteomics and ubiquitylome analysis of USP1-overexpressing CCA cells nominated PARP1 as a top USP1 substrate. Indeed, their direct interaction was validated by a series of immunofluorescence, co-immunoprecipitation (CO-IP), and GST pull-down assays, and their interaction regions were identified using deletion mutants. Mechanistically, USP1 removes the ubiquitin …

Functional Analysis Reveals Driver Cooperativity And Novel Mechanisms In Endometrial Carcinogenesis, Matthew Brown, Alicia Leon, Katarzyna Kedzierska, Charlotte Moore, Hayley L Belnoue-Davis, Susanne Flach, John P Lydon, Francesco J Demayo, Annabelle Lewis, Tjalling Bosse, Ian Tomlinson, David N Church

Faculty, Staff and Students Publications

High-risk endometrial cancer has poor prognosis and is increasing in incidence. However, understanding of the molecular mechanisms which drive this disease is limited. We used genetically engineered mouse models (GEMM) to determine the functional consequences of missense and loss of function mutations in Fbxw7, Pten and Tp53, which collectively occur in nearly 90% of high-risk endometrial cancers. We show that Trp53 deletion and missense mutation cause different phenotypes, with the latter a substantially stronger driver of endometrial carcinogenesis. We also show that Fbxw7 missense mutation does not cause endometrial neoplasia on its own, but potently accelerates carcinogenesis caused by Pten …

Dendritic Cells As Shepherds Of T Cell Immunity In Cancer, Mikael J Pittet, Mauro Di Pilato, Christopher Garris, Thorsten R Mempel

Faculty, Staff and Student Publications

In cancer patients, dendritic cells (DCs) in tumor-draining lymph nodes can present antigens to naive T cells in ways that break immunological tolerance. The clonally expanded progeny of primed T cells are further regulated by DCs at tumor sites. Intratumoral DCs can both provide survival signals to and drive effector differentiation of incoming T cells, thereby locally enhancing antitumor immunity; however, the paucity of intratumoral DCs or their expression of immunoregulatory molecules often limits antitumor T cell responses. Here, we review the current understanding of DC-T cell interactions at both priming and effector sites of immune responses. We place emerging …

Cd13 Facilitates Immune Cell Migration And Aggravates Acute Injury But Promotes Chronic Post-Stroke Recovery, Justin N Nguyen, Eric C Mohan, Gargee Pandya, Uzma Ali, Chunfeng Tan, Julia K Kofler, Linda Shapiro, Sean P Marrelli, Anjali Chauhan

Faculty, Staff and Student Publications

Introduction

Acute stroke leads to the activation of myeloid cells. These cells express adhesion molecules and transmigrate to the brain, thereby aggravating injury. Chronically after stroke, repair processes, including angiogenesis, are activated and enhance post-stroke recovery. Activated myeloid cells express CD13, which facilitates their migration into the site of injury. However, angiogenic blood vessels which play a role in recovery also express CD13. Overall, the specific contribution of CD13 to acute and chronic stroke outcomes is unknown.

Methods

CD13 expression was estimated in both mice and humans after the ischemic stroke. Young (8–12 weeks) male wild-type and global CD13 knockout …

Subventricular Zone Cytogenesis Provides Trophic Support For Neural Repair In A Mouse Model Of Stroke, Michael R Williamson, Stephanie P Le, Ronald L Franzen, Nicole A Donlan, Jill L Rosow, Mathilda S Nicot-Cartsonis, Alexis Cervantes, Benjamin Deneen, Andrew K Dunn, Theresa A Jones, Michael R Drew

Faculty, Staff and Students Publications

Stroke enhances proliferation of neural precursor cells within the subventricular zone (SVZ) and induces ectopic migration of newborn cells towards the site of injury. Here, we characterize the identity of cells arising from the SVZ after stroke and uncover a mechanism through which they facilitate neural repair and functional recovery. With genetic lineage tracing, we show that SVZ-derived cells that migrate towards cortical photothrombotic stroke in mice are predominantly undifferentiated precursors. We find that ablation of neural precursor cells or conditional knockout of VEGF impairs neuronal and vascular reparative responses and worsens recovery. Replacement of VEGF is sufficient to induce …

Paired Liver:Plasma Pfas Concentration Ratios From Adolescents In The Teen-Labs Study And Derivation Of Empirical And Mass Balance Models To Predict And Explain Liver Pfas Accumulationn, Brittney O Baumert, Fabian C Fischer, Flemming Nielsen, Philippe Grandjean, Scott Bartell, Nikos Stratakis, Douglas I Walker, Damaskini Valvi, Rohit Kohli, Thomas Inge, Justin Ryder, Todd Jenkins, Stephanie Sisley, Stavra Xanthakos, Sarah Rock, Michele A La Merrill, David Conti, Rob Mcconnell, Lida Chatzi

Faculty, Staff and Students Publications

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity, however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentrations ratios were perfectly explained (r2 > 0.99) in a multi-linear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this …

Opposing Roles For The Α Isoform Of The Catalytic Subunit Of Protein Phosphatase 1 In Inside-Out And Outside-In Integrin Signaling In Murine Platelets, Tanvir Khatlani, Subhashree Pradhan, Kimberly Langlois, Deepika Subramanyam, Rolando E Rumbaut, K Vinod Vijayan

Faculty, Staff and Students Publications

Platelet activation during hemostasis and thrombosis is facilitated by agonist-induced inside–out and integrin αIIbβ3-initiated outside–in signaling via protein kinases and phosphatases. Pharmacological inhibitor studies suggest that the serine/threonine protein phosphatase 1 (PP1) promotes platelet activation. However, since phosphatase inhibitors block all the isoforms of the catalytic subunit of PP1 (PP1c), the role of specific PP1c isoform in platelet signaling remains unclear. Here, we employed a platelet-specific PP1cα−/− mice to explore the contribution of a major PP1 isoform in platelet functions. Loss of PP1cα moderately decreased activation of integrin αIIbβ3, binding of soluble fibrinogen, and aggregation to low-dose thrombin, ADP, and …

Mathematical Modeling Of Radiotherapy: Impact Of Model Selection On Estimating Minimum Radiation Dose For Tumor Control, Achyudhan R Kutuva, Jimmy J Caudell, Kosj Yamoah, Heiko Enderling, Mohammad U Zahid

Faculty, Staff and Student Publications

INTRODUCTION: Radiation therapy (RT) is one of the most common anticancer therapies. Yet, current radiation oncology practice does not adapt RT dose for individual patients, despite wide interpatient variability in radiosensitivity and accompanying treatment response. We have previously shown that mechanistic mathematical modeling of tumor volume dynamics can simulate volumetric response to RT for individual patients and estimation personalized RT dose for optimal tumor volume reduction. However, understanding the implications of the choice of the underlying RT response model is critical when calculating personalized RT dose.

METHODS: In this study, we evaluate the mathematical implications and biological effects of 2 …