Digital Commons Network^™

Oral Delivery Of Xenon For Cardiovascular Protection, Xing Yin, Melanie R Moody, Valeria Hebert, Melvin E Klegerman, Yong-Jian Geng, Tammy R Dugas, David D Mcpherson, Hyunggun Kim, Shao-Ling Huang

Faculty, Staff and Student Publications

Cardiac hypertrophy often causes impairment of cardiac function. Xenon (Xe), a naturally occurring noble gas, is known to provide neurological and myocardial protection without side effects. The conventional method of Xe delivery by inhalation is not feasible on a chronic basis. We have developed an orally deliverable, effective Xe formulation for long-term administration. We employed 2-hydroxypropyl)-β-cyclodextrin (HPCD), which was dissolved in water to increase the Xe concentration in solution. The beneficial effects of long-term oral administration of Xe-enriched solutions on cardiovascular function were evaluated in vivo. HPCD increased Xe solubility from 0.22 mM to 0.67 mM (3.8-fold). Aged ApoE knockout …

Sciatic Nerve Cut And Repair Using Fibrin Glue In Adult Mice, Erica T. Akhter, Travis M. Rotterman, Arthur W. English, Francisco J. Alvarez

Neuroscience, Cell Biology & Physiology Faculty Publications

Peripheral nerve injury (PNI) is an excellent model for studying neural responses to injury and elucidating the mechanisms that can facilitate axon regeneration. As such, several animal models have been employed to study regenerative mechanisms after PNI, including Aplysia, zebrafish, rabbits, cats and rodents. This protocol describes how to perform a sciatic nerve injury and repair in mice, one of the most frequently used models to study mechanisms that facilitate recovery after PNI, and that takes advantage of the availability of many genetic models. In this protocol, we describe a method for using fibrin glue to secure the proximal …

Inhibition Of 4-Aminobutyrate Aminotransferase Protects Against Injury-Induced Osteoarthritis In Mice, Jie Shen, Cuicui Wang, Jun Ying, Taotao Xu, Audrey Mcalinden, Regis J. O'Keefe

Open Access Publications

Recently we demonstrated that ablation of the DNA methyltransferase enzyme, Dnmt3b, resulted in catabolism and progression of osteoarthritis (OA) in murine articular cartilage through a mechanism involving increased mitochondrial respiration. In this study, we identify 4-aminobutyrate aminotransferase (Abat) as a downstream target of Dnmt3b. Abat is an enzyme that metabolizes γ-aminobutyric acid to succinate, a key intermediate in the tricarboxylic acid cycle. We show that Dnmt3b binds to the Abat promoter, increases methylation of a conserved CpG sequence just upstream of the transcriptional start site, and inhibits Abat expression. Dnmt3b deletion in articular chondrocytes results in reduced methylation of the …

Multispectral Tracing In Densely Labeled Mouse Brain With Ntracer, Douglas H Roossien, John M Webb, Cristina Mazuski, Erik D Herzog, Et Al.

2010-2019 OA Pubs

SUMMARY: This note describes nTracer, an ImageJ plug-in for user-guided, semi-automated tracing of multispectral fluorescent tissue samples. This approach allows for rapid and accurate reconstruction of whole cell morphology of large neuronal populations in densely labeled brains.

AVAILABILITY AND IMPLEMENTATION: nTracer was written as a plug-in for the open source image processing software ImageJ. The software, instructional documentation, tutorial videos, sample image and sample tracing results are available at https://www.cai-lab.org/ntracer-tutorial.

SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Vincristine And Bortezomib Use Distinct Upstream Mechanisms To Activate A Common Sarm1-Dependent Axon Degeneration Program, Stefanie Geisler, Ryan A Doan, Galen C Cheng, Aysel Cetinkaya-Fisgin, Shay X Huang, Ahmet Höke, Jeffrey Milbrandt, Aaron Diantonio

Open Access Publications

Chemotherapy-induced peripheral neuropathy is one of the most prevalent dose-limiting toxicities of anticancer therapy. Development of effective therapies to prevent chemotherapy-induced neuropathies could be enabled by a mechanistic understanding of axonal breakdown following exposure to neuropathy-causing agents. Here, we reveal the molecular mechanisms underlying axon degeneration induced by 2 widely used chemotherapeutic agents with distinct mechanisms of action: vincristine and bortezomib. We showed previously that genetic deletion of SARM1 blocks vincristine-induced neuropathy and demonstrate here that it also prevents axon destruction following administration of bortezomib in vitro and in vivo. Using cultured neurons, we found that vincristine and bortezomib converge …

Dhx33 Interacts With Ap-2Β To Regulate Bcl-2 Gene Expression And Promote Cancer Cell Survival, Jiuling Wang, Weimin Feng, Zhen Yuan, Jason D. Weber, Yandong Zhang

Open Access Publications

The RNA helicase DHX33 has been found to be overexpressed in human cancers, where it promotes cancer development. Previous reports have shown that DHX33 deficiency caused cancer cell apoptosis, but the underlying mechanism remains unknown. In this study, we discovered that DHX33 regulates Bcl-2 family protein expression. In multiple human cancer cell lines, DHX33 was found to stimulate the transcription of

Developing Drug Therapies: Cognitive Damage In Mice Following Brain Radiation, Rachel Yuska

The Journal of Purdue Undergraduate Research

Pediatric brain cancer patients are at a high risk for radiation-induced cognitive impairment due to white matter changes in the brain. Half of six-month radiotherapy survivors develop significant changes in white matter. Previous research has shown that a mouse model can be used to show similar cognitive and behavioral deficits in human patients. The purpose of this work is to evaluate the effectiveness of two drug therapies, Donepezil and 3,3-Diindolylmethane (DIM), that could be used to either protect the brain from radiation injury or cure the cognitive injury and behavioral deficits that result from whole-brain irradiation. This project consisted of …

Imaging Of Glucose Metabolism By 13c-Mri Distinguishes Pancreatic Cancer Subtypes In Mice, Shun Kishimoto, Jeffrey R. Brender, Daniel R. Crooks, Shingo Matsumoto, Tomohiro Seki, Nobu Oshima, Hellmut Merkle, Penghui Lin, Galen Reed, Albert P. Chen, Jan Henrik Ardenkjaer-Larsen, Jeeva Munasinghe, Keita Saito, Kazutoshi Yamamoto, Peter L. Choyke, James Mitchell, Andrew N. Lane, Teresa W. M. Fan, W. Marston Linehan, Murali C. Krishna

Center for Environmental and Systems Biochemistry Faculty Publications

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from …

Understanding The Axonal Response To Injury By In Vivo Imaging In The Mouse Spinal Cord: A Tale Of Two Branches., Binhai Zheng, Ariana O Lorenzana, Le Ma

Department of Neuroscience Faculty Papers

Understanding the basic properties of how axons respond to injury in the mammalian central nervous system (CNS) is of fundamental value for developing strategies to promote neural repair. Axons possess complex morphologies with stereotypical branching patterns. However, current knowledge of the axonal response to injury gives little consideration to axonal branches, nor do strategies to promote axon regeneration. This article reviews evidence from in vivo spinal cord imaging that axonal branches markedly impact the degenerative and regenerative responses to injury. At a major bifurcation point, depending on whether one or both axonal branches are injured, neurons may choose either a …

Effect Of Supplemental Prebiotics, Probiotics And Bioactive Proteins On The Microbiome Composition And Gut Physiology In C57bl6/J Mice, Ye Li

All Graduate Theses and Dissertations, Spring 1920 to Summer 2023

The composition and metabolic activity of the microbiome affect many aspects of health, and there is current interest in dietary constituents that may affect this system. The purpose of this study was to evaluate the effects of a mix of probiotics, a mix of prebiotics and a bioactive protein fraction on the microbiome, when fed to mice individually and in combination. Mice were fed the total western diet (TWD) supplemented with prebiotics, probiotics, and Tri-Factor (bioactive proteins) individually and in combination for four weeks. Subsequently, effects on the composition of gut microbiome, gut short chain fatty acids (SCFAs) concentration, gut …

Host And Viral Mechanisms Of Congenital Zika Syndrome, Brooke Liang, José Paulo Guida, Maria Laura Costa Do Nascimento, Indira U Mysorekar

Open Access Publications

In 2015-2016, in the Americas, and especially in northeast Brazil, a significant number of cases of microcephaly and other congenital brain abnormalities were linked with an outbreak of Zika virus (ZIKV) infection in pregnant women. While maternal symptoms of ZIKV are generally mild and self-limiting, clinical presentation in fetuses and newborns infected is extensive and includes microcephaly, decreased cortical development, atrophy and hypoplasia of the cerebellum and cerebellar vermis, arthrogryposis, and polyhydramnios. The term congenital ZIKV syndrome (CZS) was introduced to describe the range of findings associated with maternal-fetal ZIKV transmission. ZIKV is primarily transmitted by

Developing Drug Therapies For Cognitive Damage In Mice Following Brain Radiation, Rachel Yuska

Purdue Undergraduate Research Conference

Pediatric brain cancer patients are at a high risk for radiation induced cognitive impairment due to white matter changes in the brain. Half of six-month radiotherapy survivors develop significant changes in white matter. Previous research has shown that a mouse model can be used to show similar cognitive and behavioral deficits shown in human patients. The purpose of this work is to evaluate the effectiveness of two drug therapies, Donepezil and 3,3-Diindolylmethane, (DIM), that could be used to either protect the brain from radiation injury or cure the cognitive injury and behavioral deficits that result from whole-brain irradiation. This project …

In Vivo Effectiveness And Safety Of Probiotics On Prophylaxis And Treatment Of Oral Candidiasis: A Systematic Review And Meta-Analysis, Lijun Hu, Mimi Zhou, Andrew L. Young, Weiwei Zhao, Zhimin Yan

All Dugoni School of Dentistry Faculty Articles

BACKGROUND: To systematically review and assess the in vivo effectiveness and safety of probiotics for prophylaxis and treating oral candidiasis.

METHODS: A literature search for studies published in English until August 1, 2018 was conducted in the following databases: PubMed, EMBASE, Cochrane Library, and Web of Science. Randomized controlled clinical trials and experimental mouse animal model studies comparing probiotics (at any dosage and in any form) with control groups (placebo, blank control or other agents) and reporting outcomes of the prophylactic and therapeutic effects were considered for inclusion. A descriptive study and, potentially, a meta-analysis were planned.

RESULTS: Six randomized …

Pathologic Gene Network Rewiring Implicates Ppp1r3a As A Central Regulator In Pressure Overload Heart Failure., Pablo Cordero, Victoria N Parikh, Elizabeth T Chin, Ayca Erbilgin, Michael J Gloudemans, Ching Shang, Yong Huang, Alex C Chang, Kevin S Smith, Frederick Dewey, Kathia Zaleta, Michael Morley, Jeff Brandimarto, Nicole Glazer, Daryl Waggott, Aleksandra Pavlovic, Mingming Zhao, Christine S Moravec, W H Wilson Tang, Jamie Skreen, Christine Malloy, Sridhar Hannenhalli, Hongzhe Li, Scott Ritter, Mingyao Li, Daniel Bernstein, Andrew Connolly, Hakon Hakonarson, Aldons J Lusis, Kenneth B Margulies, Anna A Depaoli-Roach, Stephen B Montgomery, Matthew T Wheeler, Thomas Cappola, Euan A Ashley

Articles, Abstracts, and Reports

Heart failure is a leading cause of mortality, yet our understanding of the genetic interactions underlying this disease remains incomplete. Here, we harvest 1352 healthy and failing human hearts directly from transplant center operating rooms, and obtain genome-wide genotyping and gene expression measurements for a subset of 313. We build failing and non-failing cardiac regulatory gene networks, revealing important regulators and cardiac expression quantitative trait loci (eQTLs). PPP1R3A emerges as a regulator whose network connectivity changes significantly between health and disease. RNA sequencing after PPP1R3A knockdown validates network-based predictions, and highlights metabolic pathway regulation associated with increased cardiomyocyte size and …

Environmental Microcystin Targets The Microbiome And Increases The Risk Of Intestinal Inflammatory Pathology Via Nox2 In Underlying Murine Model Of Nonalcoholic Fatty Liver Disease, Sutapa Sarkar, Diana Kimono, Muayad Albadrani, Ratanesh K. Seth, Philip Busbee, Hasan Alghetaa, Dwayne E. Porter, Geoff I. Scott, Bryan Brooks, Mitzi Nagarkatti, Prakash Nagarkatti, Saurabh Chatterjee

Faculty Publications

With increased climate change pressures likely to influence harmful algal blooms, exposure to microcystin, a known hepatotoxin and a byproduct of cyanobacterial blooms can be a risk factor for NAFLD associated comorbidities. Using both in vivo and in vitro experiments we show that microcystin exposure in NAFLD mice cause rapid alteration of gut microbiome, rise in bacterial genus known for mediating gut inflammation and lactate production. Changes in the microbiome were strongly associated with inflammatory pathology in the intestine, gut leaching, tight junction protein alterations and increased oxidative tyrosyl radicals. Increased lactate producing bacteria from the altered microbiome was associated …

Intracellular Retention Of Mutant Lysyl Oxidase Leads To Aortic Dilation In Response To Increased Hemodynamic Stress, Vivian S Lee, Carmen M Halabi, Thomas J Broekelmann, Philip C Trackman, Nathan O Stitziel, Robert P Mecham

Open Access Publications

Heterozygous missense mutations in lysyl oxidase (LOX) are associated with thoracic aortic aneurysms and dissections. To assess how LOX mutations modify protein function and lead to aortic disease, we studied the factors that influence the onset and progression of vascular aneurysms in mice bearing a Lox mutation (p.M292R) linked to aortic dilation in humans. We show that mice heterozygous for the M292R mutation did not develop aneurysmal disease unless challenged with increased hemodynamic stress. Vessel dilation was confined to the ascending aorta although both the ascending and descending aortae showed changes in vessel wall structure, smooth muscle cell number and …

Preoperative Stimulation Of Resolution And Inflammation Blockade Eradicates Micrometastases., Dipak Panigrahy, Allison Gartung, Jun Yang, Haixia Yang, Molly M Gilligan, Megan L Sulciner, Swati S Bhasin, Diane R Bielenberg, Jaimie Chang, Birgitta A Schmidt, Julia Piwowarski, Anna Fishbein, Dulce Soler-Ferran, Matthew A Sparks, Steven J Staffa, Vidula Sukhatme, Bruce D Hammock, Mark W Kieran, Sui Huang, Manoj Bhasin, Charles N Serhan, Vikas P Sukhatme

Articles, Abstracts, and Reports

Cancer therapy is a double-edged sword, as surgery and chemotherapy can induce an inflammatory/immunosuppressive injury response that promotes dormancy escape and tumor recurrence. We hypothesized that these events could be altered by early blockade of the inflammatory cascade and/or by accelerating the resolution of inflammation. Preoperative, but not postoperative, administration of the nonsteroidal antiinflammatory drug ketorolac and/or resolvins, a family of specialized proresolving autacoid mediators, eliminated micrometastases in multiple tumor-resection models, resulting in long-term survival. Ketorolac unleashed anticancer T cell immunity that was augmented by immune checkpoint blockade, negated by adjuvant chemotherapy, and dependent on inhibition of the COX-1/thromboxane A2 …

Xx Sex Chromosome Complement Promotes Atherosclerosis In Mice, Yasir Alsiraj, Xuqi Chen, Sean E. Thatcher, Ryan E. Temel, Lei Cai, Eric M. Blalock, Wendy Katz, Heba M. Ali, Michael C. Petriello, Pan Deng, Andrew J. Morris, Xuping Wang, Aldons J. Lusis, Arthur P. Arnold, Karen Reue, Katherine L. Thompson, Patrick Tso, Lisa A. Cassis

Pharmacology and Nutritional Sciences Faculty Publications

Men and women differ in circulating lipids and coronary artery disease (CAD). While sex hormones such as estrogens decrease CAD risk, hormone replacement therapy increases risk. Biological sex is determined by sex hormones and chromosomes, but effects of sex chromosomes on circulating lipids and atherosclerosis are unknown. Here, we use mouse models to separate effects of sex chromosomes and hormones on atherosclerosis, circulating lipids and intestinal fat metabolism. We assess atherosclerosis in multiple models and experimental paradigms that distinguish effects of sex chromosomes, and male or female gonads. Pro-atherogenic lipids and atherosclerosis are greater in XX than XY mice, indicating …

Reactive Microglia And Il1Β/Il-1r1-Signaling Mediate Neuroprotection In Excitotoxin-Damaged Mouse Retina, Levi Todd, Isabella Palazzo, Lilianna Suarez, Xiaoyu Liu, Leo Volkov, Thanh V Hoang, Warren A Campbell, Seth Blackshaw, Ning Quan, Andy J Fischer

Open Access Publications

BACKGROUND: Microglia and inflammation have context-specific impacts upon neuronal survival in different models of central nervous system (CNS) disease. Herein, we investigate how inflammatory mediators, including microglia, interleukin 1 beta (IL1β), and signaling through interleukin 1 receptor type 1 (IL-1R1), influence the survival of retinal neurons in response to excitotoxic damage.

METHODS: Excitotoxic retinal damage was induced via intraocular injections of NMDA. Microglial phenotype and neuronal survival were assessed by immunohistochemistry. Single-cell RNA sequencing was performed to obtain transcriptomic profiles. Microglia were ablated by using clodronate liposome or PLX5622. Retinas were treated with IL1β prior to NMDA damage and cell …

Cyclin C Regulated Oxidative Stress Responsive Transcriptome In Mus Musculus Embryonic Fibroblasts, David C Stieg, Kai-Ti Chang, Katrina F Cooper, Randy Strich

Rowan-Virtua School of Osteopathic Medicine Departmental Research

The transcriptional changes that occur in response to oxidative stress help direct the decision to maintain cell viability or enter a cell death pathway. Cyclin C-Cdk8 is a conserved kinase that associates with the RNA polymerase II Mediator complex that stimulates or represses transcription depending on the locus. In response to oxidative stress, cyclin C, but not Cdk8, displays partial translocation into the cytoplasm. These findings open the possibility that cyclin C relocalization is a regulatory mechanism governing oxidative stress-induced transcriptional changes. In the present study, the cyclin C-dependent transcriptome was determined and compared to transcriptional changes occurring in oxidatively …

Altered Detrusor Contractility And Voiding Patterns In Mice Lacking The Mechanosensitive Trek-1 Channel., Ricardo H. Pineda, Joseph Hypolite, Sanghee Lee, Alonso Carrasco, Nao Iguchi, Randall B. Meacham, Anna P. Malykhina

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: Previously published results from our laboratory identified a mechano-gated two-pore domain potassium channel, TREK-1, as a main mechanosensor in the smooth muscle of the human urinary bladder. One of the limitations of in vitro experiments on isolated human detrusor included inability to evaluate in vivo effects of TREK-1 on voiding function, as the channel is also expressed in the nervous system, and may modulate micturition via neural pathways. Therefore, in the present study, we aimed to assess the role of TREK-1 channel in bladder function and voiding patterns in vivo by using TREK-1 knockout (KO) mice.

METHODS: Adult C57BL/6 …

A High-Throughput Screen Indicates Gemcitabine And Jak Inhibitors May Be Useful For Treating Pediatric Aml, Christina D. Drenberg, Anang Shelat, Jinjun Dang, Anitria Cotton, Shelley J. Orwick, Mengyu Li, Jae Yoon Jeon, Qiang Fu, Daelynn R. Buelow, Marissa Pioso, Shuiying Hu, Hiroto Inaba, Raul C. Ribeiro, Jeffrey E. Rubnitz, Tanja A. Gruber, R. Kiplin Guy, Sharyn D. Baker

Pharmaceutical Sciences Faculty Publications

Improvement in survival has been achieved for children and adolescents with AML but is largely attributed to enhanced supportive care as opposed to the development of better treatment regimens. High risk subtypes continue to have poor outcomes with event free survival rates < 40% despite the use of high intensity chemotherapy in combination with hematopoietic stem cell transplant. Here we combine high-throughput screening, intracellular accumulation assays, and in vivo efficacy studies to identify therapeutic strategies for pediatric AML. We report therapeutics not currently used to treat AML, gemcitabine and cabazitaxel, have broad anti-leukemic activity across subtypes and are more effective relative to the AML standard of care, cytarabine, both in vitro and in vivo. JAK inhibitors are selective for acute megakaryoblastic leukemia and significantly prolong survival in multiple preclinical models. Our approach provides advances in the development of treatment strategies for pediatric AML.

An Obligatory Role For Club Cells In Preventing Obliterative Bronchiolitis In Lung Transplants, Zhiyi Liu, Fuyi Liao, Davide Scozzi, Yuka Furuya, Kaitlyn N Pugh, Ramsey Hachem, Delphine L Chen, Marlene Cano, Jonathan M Green, Alexander S Krupnick, Daniel Kreisel, Anne Karina T Perl, Howard J Huang, Steven L Brody, Andrew E Gelman

Open Access Publications

Obliterative bronchiolitis (OB) is a poorly understood airway disease characterized by the generation of fibrotic bronchiolar occlusions. In the lung transplant setting, OB is a pathological manifestation of bronchiolitis obliterans syndrome (BOS), which is a major impediment to long-term recipient survival. Club cells play a key role in bronchiolar epithelial repair, but whether they promote lung transplant tolerance through preventing OB remains unclear. We determined if OB occurs in mouse orthotopic lung transplants following conditional transgene-targeted club cell depletion. In syngeneic lung transplants club cell depletion leads to transient epithelial injury followed by rapid club cell-mediated repair. In contrast, allogeneic …

Steroid Receptor Coactivator-1 Modulates The Function Of Pomc Neurons And Energy Homeostasis, Yongjie Yang, Agatha A Van Der Klaauw, Liangru Zhu, Tessa M Cacciottolo, Yanlin He, Lukas K J Stadler, Chunmei Wang, Pingwen Xu, Kenji Saito, Antentor Hinton, Xiaofeng Yan, Julia M Keogh, Elana Henning, Matthew C Banton, Audrey E Hendricks, Elena G Bochukova, Vanisha Mistry, Katherine L Lawler, Lan Liao, Jianming Xu, Stephen O'Rahilly, Qingchun Tong, Uk10k Consortium, Inês Barroso, Bert W O'Malley, I Sadaf Farooqi, Yong Xu

Children’s Nutrition Research Center Staff Publications

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function …

Gasdermin Pores Permeabilize Mitochondria To Augment Caspase-3 Activation During Apoptosis And Inflammasome Activation., Corey Rogers, Dan A. Erkes, Alexandria Nardone, Andrew E. Aplin, Teresa Fernandes-Alnemri, Emad S. Alnemri

Department of Biochemistry and Molecular Biology Faculty Papers

Gasdermin E (GSDME/DFNA5) cleavage by caspase-3 liberates the GSDME-N domain, which mediates pyroptosis by forming pores in the plasma membrane. Here we show that GSDME-N also permeabilizes the mitochondrial membrane, releasing cytochrome c and activating the apoptosome. Cytochrome c release and caspase-3 activation in response to intrinsic and extrinsic apoptotic stimuli are significantly reduced in GSDME-deficient cells comparing with wild type cells. GSDME deficiency also accelerates cell growth in culture and in a mouse model of melanoma. Phosphomimetic mutation of the highly conserved phosphorylatable Thr6 residue of GSDME, inhibits its pore-forming activity, thus uncovering a potential mechanism by which GSDME …

A Mixture Of U.S. Food And Drug Administration-Approved Monoaminergic Drugs Protects The Retina From Light Damage In Diverse Models Of Night Blindness, Henri Leinonen, Elliot H. Choi, Anthony Gardella, Vladimir J. Kefalov, Krzysztof Palczewski

Open Access Publications

Purpose: The purpose of this study was to test the extent of light damage in different models of night blindness and apply these paradigms in testing the therapeutic efficacy of combination therapy by drugs acting on the Gi, Gs, and Gq protein-coupled receptors.

Methods: Acute bright light exposure was used to test susceptibility to light damage in mice lacking the following crucial phototransduction proteins: rod transducin (GNAT1), cone transducin (GNAT2), visual arrestin 1 (ARR1), and rhodopsin kinase 1 (GRK1). Mice were intraperitoneally injected with either vehicle or drug combination consisting of metoprolol (β1-receptor antagonist), bromocriptine (dopamine family-2 receptor agonist) and …

Proteomic Alterations Of Hdl In Youth With Type 1 Diabetes And Their Associations With Glycemic Control: A Case-Control Study, Evgenia Gourgari, Junfeng Ma, Martin P. Playford, Nehal N. Mehta, Radoslav Goldman, Alan T. Remaley, Scott M. Gordon

Saha Cardiovascular Research Center Faculty Publications

Background: Patients with type 1 diabetes (T1DM) typically have normal or even elevated plasma high density lipoprotein (HDL) cholesterol concentrations; however, HDL protein composition can be altered without a change in cholesterol content. Alteration of the HDL proteome can result in dysfunctional HDL particles with reduced ability to protect against cardiovascular disease (CVD). The objective of this study was to compare the HDL proteomes of youth with T1DM and healthy controls (HC) and to evaluate the influence of glycemic control on HDL protein composition.

Methods: This was a cross-sectional case–control study. Blood samples were obtained from patients with T1DM and …

Alterations In Phosphorylation Of Hepatocyte Ribosomal Protein S6 Control Plasmodium Liver Stage Infection., Elizabeth K K Glennon, Laura S Austin, Nadia Arang, Heather S Kain, Fred D Mast, Kamalakannan Vijayan, John D Aitchison, Stefan H I Kappe, Alexis Kaushansky

Articles, Abstracts, and Reports

Plasmodium parasites are highly selective when infecting hepatocytes and induce many changes within the host cell upon infection. While several host cell factors have been identified that are important for liver infection, our understanding of what facilitates the maintenance of infection remains incomplete. Here, we describe a role for phosphorylated ribosomal protein S6 (Ser235/236) (p-RPS6) in Plasmodium yoelii-infected hepatocytes. Blocking RPS6 phosphorylation prior to infection decreases the number of liver stage parasites within 24 h. Infected hepatocytes exhibit elevated levels of p-RPS6 while simultaneously abrogating the induction of phosphorylation of RPS6 in response to insulin stimulation. This is in contrast …

H3k27m Induces Defective Chromatin Spread Of Prc2-Mediated Repressive H3k27me2/Me3 And Is Essential For Glioma Tumorigenesis., Ashot S. Harutyunyan, Brian Krug, Haifen Chen, Simon Papillon-Cavanagh, Michele Zeinieh, Nicolas De Jay, Shriya Deshmukh, Carol C L Chen, Jad Belle, Leonie G. Mikael, Dylan M. Marchione, Rui Li, Hamid Nikbakht, Bo Hu, Gael Cagnone, Warren A. Cheung, Abdulshakour Mohammadnia, Denise Bechet, Damien Faury, Melissa K. Mcconechy, Manav Pathania, Siddhant U. Jain, Benjamin Ellezam, Alexander G. Weil, Alexandre Montpetit, Paolo Salomoni, Tomi Pastinen, Chao Lu, Peter W. Lewis, Benjamin A. Garcia, Claudia L. Kleinman, Nada Jabado, Jacek Majewski

Manuscripts, Articles, Book Chapters and Other Papers

Lys-27-Met mutations in histone 3 genes (H3K27M) characterize a subgroup of deadly gliomas and decrease genome-wide H3K27 trimethylation. Here we use primary H3K27M tumor lines and isogenic CRISPR-edited controls to assess H3K27M effects in vitro and in vivo. We find that whereas H3K27me3 and H3K27me2 are normally deposited by PRC2 across broad regions, their deposition is severely reduced in H3.3K27M cells. H3K27me3 is unable to spread from large unmethylated CpG islands, while H3K27me2 can be deposited outside these PRC2 high-affinity sites but to levels corresponding to H3K27me3 deposition in wild-type cells. Our findings indicate that PRC2 recruitment and propagation on …

Germ Cell-Depleted Ovaries Improve Metabolic Health In Post-Reproductive Mice, Kyleigh Tyler

Research on Capitol Hill

Reproductive senescence is correlated with many deleterious heath conditions. In human females, the decline of health associated with reproductive function is termed “menopause.“ One of the declining health factors is metabolism.

In order to understand how ovaries contribute to metabolic health, we further studied the structure of ovaries. Within ovaries, there are two main types of cells:

• Germ Cells (oocyte): Play a central role in reproduction (egg)
• Somatic Cells: Supporting cells for germ cells

This study aimed to understand the relationship between germ cells and somatic cells and how this relationship influenced metabolism.