Biochemistry, Biophysics, and Structural Biology Commons^™

Unraveling The Anti-Inflammatory And Cardioprotective Mechanism Of Prenylated Stilbenoids From Peanut Hairy Root Cultures In Vitro And In Vivo, Md Rokib Hasan

Student Theses and Dissertations

Stilbenoids are a non-flavonoid class of polyphenols that are important for their potential medicinal applications. Resveratrol, ione of the most well-studied compounds of this group, has various medicinal properties including anti-inflammatory, antioxidant, anti-cancer and many other properties. Prenylated stilbenoids which include arachidin-1 and arachidin-3 are produced as a defense response to biotic and abiotic stresses in peanut (Arachis hypogaea). Prenylation has been shown to enhance the biological activities of polyphenolic compounds and thus arachidins may have higher anti-inflammatory activity than resveratrol in addition to many other potential health applications. However, the molecular mechanism of the arachidins as an anti-inflammatory and …

Prostacyclin Promotes Degenerative Pathology In A Model Of Alzheimer’S Disease, Tasha R. Womack, Craig T. Vollert, Odochi Ohia-Nwoko, Monika Schmitt, Saghi Montazari, Tina L. Beckett, David Mayerich, M. Paul Murphy, Jason L. Eriksen

Molecular and Cellular Biochemistry Faculty Publications

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder that is the most common form of dementia in aged populations. A substantial amount of data demonstrates that chronic neuroinflammation can accelerate neurodegenerative pathologies. In AD, chronic neuroinflammation results in the upregulation of cyclooxygenase and increased production of prostaglandin H2, a precursor for many vasoactive prostanoids. While it is well-established that many prostaglandins can modulate the progression of neurodegenerative disorders, the role of prostacyclin (PGI2) in the brain is poorly understood. We have conducted studies to assess the effect of elevated prostacyclin biosynthesis in a mouse model of AD. Upregulated prostacyclin expression …

Retinal Horizontal Cells Use Different Synaptic Sites For Global Feedforward And Local Feedback Signaling, Christian Behrens, Shubhash Chandra Yadav, Maria M Korympidou, Yue Zhang, Silke Haverkamp, Stephan Irsen, Anna Schaedler, Xiaoyu Lu, Zhuohe Liu, Jan Lause, François St-Pierre, Katrin Franke, Anna Vlasits, Karin Dedek, Robert G Smith, Thomas Euler, Philipp Berens, Timm Schubert

Faculty, Staff and Students Publications

In the outer plexiform layer (OPL) of the mammalian retina, cone photoreceptors (cones) provide input to more than a dozen types of cone bipolar cells (CBCs). In the mouse, this transmission is modulated by a single horizontal cell (HC) type. HCs perform global signaling within their laterally coupled network but also provide local, cone-specific feedback. However, it is unknown how HCs provide local feedback to cones at the same time as global forward signaling to CBCs and where the underlying synapses are located. To assess how HCs simultaneously perform different modes of signaling, we reconstructed the dendritic trees of five …

Imaging-Based Screening Of Deubiquitinating Proteases Identifies Otubain-1 As A Stabilizer Of C-Myc, Shannon E Moree, Laure Maneix, Polina Iakova, Fabio Stossi, Ergun Sahin, Andre Catic

Faculty, Staff and Students Publications

The ubiquitin-proteasome pathway precisely controls the turnover of transcription factors in the nucleus, playing an important role in maintaining appropriate quantities of these regulatory proteins. The transcription factor c-MYC is essential for normal development and is a critical cancer driver. Despite being highly expressed in several tissues and malignancies, the c-MYC protein is also continuously targeted by the ubiquitin-proteasome pathway, which can either facilitate or inhibit c-MYC degradation. Deubiquitinating proteases can remove ubiquitin chains from target proteins and rescue them from proteasomal digestion. This study sought to determine novel elements of the ubiquitin-proteasome pathway that regulate c-MYC levels. We performed …

Extensive Identification Of Genes Involved In Congenital And Structural Heart Disorders And Cardiomyopathy, Nadine Spielmann, Gregor Miller, Tudor I Oprea, Chih-Wei Hsu, Gisela Fobo, Goar Frishman, Corinna Montrone, Hamed Haseli Mashhadi, Jeremy Mason, Violeta Munoz Fuentes, Stefanie Leuchtenberger, Andreas Ruepp, Matias Wagner, Dominik S Westphal, Cordula Wolf, Agnes Görlach, Adrián Sanz-Moreno, Yi-Li Cho, Raffaele Teperino, Stefan Brandmaier, Sapna Sharma, Isabella Rikarda Galter, Manuela A Östereicher, Lilly Zapf, Philipp Mayer-Kuckuk, Jan Rozman, Lydia Teboul, Rosie K A Bunton-Stasyshyn, Heather Cater, Michelle Stewart, Skevoulla Christou, Henrik Westerberg, Amelia M Willett, Janine M Wotton, Willson B Roper, Audrey E Christiansen, Christopher S Ward, Jason D Heaney, Corey L Reynolds, Jan Prochazka, Lynette Bower, David Clary, Mohammed Selloum, Ghina Bou About, Olivia Wendling, Hugues Jacobs, Sophie Leblanc, Hamid Meziane, Tania Sorg, Enrique Audain, Arthur Gilly, Nigel W Rayner, Impc Consortium, Genomics England Research Consortium;, Marc-Phillip Hitz, Eleftheria Zeggini, Eckhard Wolf, Radislav Sedlacek, Steven A Murray, Karen L Svenson, Robert E Braun, Jaqueline K White, Lois Kelsey, Xiang Gao, Toshihiko Shiroishi, Ying Xu, Je Kyung Seong, Fabio Mammano, Glauco P Tocchini-Valentini, Arthur L Beaudet, Terrence F Meehan, Helen Parkinson, Damian Smedley, Ann-Marie Mallon, Sara E Wells, Harald Grallert, Wolfgang Wurst, Susan Marschall, Helmut Fuchs, Steve D M Brown, Ann M Flenniken, Lauryl M J Nutter, Colin Mckerlie, Yann Herault, K C Kent Lloyd, Mary E Dickinson, Valerie Gailus-Durner, Martin Hrabe De Angelis

Faculty, Staff and Students Publications

Clinical presentation of congenital heart disease is heterogeneous, making identification of the disease-causing genes and their genetic pathways and mechanisms of action challenging. By using in vivo electrocardiography, transthoracic echocardiography and microcomputed tomography imaging to screen 3,894 single-gene-null mouse lines for structural and functional cardiac abnormalities, here we identify 705 lines with cardiac arrhythmia, myocardial hypertrophy and/or ventricular dilation. Among these 705 genes, 486 have not been previously associated with cardiac dysfunction in humans, and some of them represent variants of unknown relevance (VUR). Mice with mutations in Casz1, Dnajc18, Pde4dip, Rnf38 or Tmem161b genes show developmental cardiac structural abnormalities, …

Detecting Anomalies In Retinal Diseases Using Generative, Discriminative, And Self-Supervised Deep Learning, Philippe Burlina, William Paul, T Y Alvin Liu, Neil M Bressler

Faculty, Staff and Students Publications

IMPORTANCE: Anomaly detectors could be pursued for retinal diagnoses based on artificial intelligence systems that may not have access to training examples for all retinal diseases in all phenotypic presentations. Possible applications could include screening of population for any retinal disease rather than a specific disease such as diabetic retinopathy, detection of novel retinal diseases or novel presentations of common retinal diseases, and detection of rare diseases with little or no data available for training.

OBJECTIVE: To study the application of anomaly detection to retinal diseases.

DESIGN, SETTING, AND PARTICIPANTS: High-resolution retinal images from the publicly available EyePACS data set …

Randomized Phase Iii Bmt Ctn Trial Of Calcineurin Inhibitor-Free Chronic Graft-Versus-Host Disease Interventions In Myeloablative Hematopoietic Cell Transplantation For Hematologic Malignancies, Leo Luznik, Marcelo C Pasquini, Brent Logan, Robert J Soiffer, Juan Wu, Steven M Devine, Nancy Geller, Sergio Giralt, Helen E Heslop, Mary M Horowitz, Richard J Jones, Mark R Litzow, Adam Mendizabal, Lori Muffly, Eneida R Nemecek, Lynn O'Donnell, Richard J O'Reilly, Raquel Palencia, Johannes Schetelig, Leyla Shune, Scott R Solomon, Sumithira Vasu, Vincent T Ho, Miguel-Angel Perales

Faculty, Staff and Students Publications

PURPOSE: Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).

METHODS: This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or …

Race/Ethnicity And Birthplace As Risk Factors For Gastric Intestinal Metaplasia In A Multiethnic United States Population, Mimi C Tan, Taher Jamali, Theresa H Nguyen, Amy Galvan, Robert J Sealock, Anam Khan, Neda Zarrin-Khameh, Ashley Holloman, Ourania Kampagianni, David Henriquez Ticas, Yan Liu, Hashem B El-Serag, Aaron P Thrift

Faculty, Staff and Students Publications

INTRODUCTION: Several US subgroups have increased risk of gastric cancer and gastric intestinal metaplasia (GIM) and may benefit from targeted screening. We evaluated demographic and clinical risk factors for GIM and examined the interaction between race/ethnicity and birthplace on GIM risk.

METHODS: We identified patients who had undergone esophagogastroduodenoscopy with gastric biopsy from 3/2006-11/2016 using the pathology database at a safety net hospital in Houston, Texas. Cases had GIM on ≥1 gastric biopsy histopathology, whereas controls lacked GIM on any biopsy. We estimated odds ratios and 95% confidence intervals (CI) for associations with GIM risk using logistic regression and developed …

Maximum Dose Food Challenges Reveal Transient Sustained Unresponsiveness In Peanut Oral Immunotherapy (Poimd Study), Carla M Davis, Aikaterini Anagnostou, Sridevi Devaraj, Daisy T Vita, Fabian Rivera, Kathleen Pitts, Melissa Hearrell, Charles Minard, Danielle Guffey, Meera Gupta, Levi Watkin, Jordan S Orange, Sara Anvari

Faculty, Staff and Students Publications

BACKGROUND: The maximum tolerated dose of peanut protein following peanut oral immunotherapy (POIT) is unknown because most research studies have not examined very high thresholds.

OBJECTIVE: To define the maximum dose tolerated by patients on POIT and severity of allergic reactions after a 1-month period of treatment discontinuation.

METHODS: In a phase 2 3-year POIT open-label study, we enrolled participants age 5 to 13 years with a 1-year build-up period followed by a 2-year daily maintenance dose of 3900 mg with assessment of the maximum tolerated dose using double-blind placebo-controlled food challenges (DBPCFCs) of 26,225 mg cumulative dose of peanut …

Comparative Performance Of Risk Prediction Models For Hepatitis B-Related Hepatocellular Carcinoma In The United States, Hyun-Seok Kim, Xian Yu, Jennifer Kramer, Aaron P Thrift, Pete Richardson, Yao-Chun Hsu, Avegail Flores, Hashem B El-Serag, Fasiha Kanwal

Faculty, Staff and Students Publications

BACKGROUND & AIMS: Guidelines recommend hepatocellular carcinoma (HCC) surveillance in patients with chronic HBV infection. Several HCC risk prediction models are available to guide surveillance decisions, but their comparative performance remains unclear.

METHODS: Using a retrospective cohort of patients with HBV treated with nucleos(t)ide analogues at 130 Veterans Administration facilities between 9/1/2008 and 12/31/2018, we calculated risk scores from 10 HCC risk prediction models (REACH-B, PAGE-B, m-PAGE-B, CU-HCC, HCC-RESCUE, CAMD, APA-B, REAL-B, AASL-HCC, RWS-HCC). We estimated the models' discrimination and calibration. We calculated HCC incidence in risk categories defined by the reported cut-offs for all models.

RESULTS: Of 3,101 patients …

Repurposing Metformin And Antifolates For The Treatment Of Hepatocellular Carcinoma, Sherouk Mohamed Tawfik

Theses and Dissertations

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancers worldwide, continues to maintain high levels of resistance to standard therapy. As clinical data revealed poor response rates, the need for developing new methods has increased to improve the overall wellbeing of patients with HCC. Due to its safety, wide availability and previously reported anti-cancer effects, metformin (MET) serves to be a possible therapeutic agent when combined with other well-known anti-cancer agents. The aim of this study was to investigate the potential anti-cancer effects of MET, an anti-diabetic agent, when combined with two antifolate drugs: trimethoprim (TMP) or methotrexate …

Conformational Flexibility And Local Frustration In The Functional States Of The Sars-Cov-2 Spike B.1.1.7 And B.1.351 Variants: Mutation-Induced Allosteric Modulation Mechanism Of Functional Dynamics And Protein Stability, Gennady M. Verkhivker

Mathematics, Physics, and Computer Science Faculty Articles and Research

Structural and functional studies of the SARS-CoV-2 spike proteins have recently determined distinct functional states of the B.1.1.7 and B.1.351 spike variants, providing a molecular framework for understanding the mechanisms that link the effect of mutations with the enhanced virus infectivity and transmissibility. A detailed dynamic and energetic analysis of these variants was undertaken in the present work to quantify the effects of different mutations on functional conformational changes and stability of the SARS-CoV-2 spike protein. We employed the efficient and accurate coarse-grained (CG) simulations of multiple functional states of the D614G mutant, B.1.1.7 and B.1.351 spike variants to characterize …

Maternal Choline Supplementation And High-Fat Feeding Interact To Influence Dna Methylation In Offspring In A Time-Specific Manner, Hunter W. Korsmo, Bhoomi Dave, Steven E. Trasino, Anjana Saxena, Jia Liu, Jorge Matias Caviglia, Kaydine Edwards, Moshe Dembitzer, Shameera Sheeraz, Sarah Khaldi, Xinyin Jiang

Advanced Science Research Center

Maternal methyl donor supplementation during pregnancy has demonstrated lasting influence on offspring DNA methylation. However, it is unknown whether an adverse postnatal environment, such as high-fat (HF) feeding, overrides the influence of prenatal methyl donor supplementation on offspring epigenome. In this study, we examined whether maternal supplementation of choline (CS), a methyl donor, interacts with prenatal and postnatal HF feeding to alter global and site-specific DNA methylation in offspring. We fed wild-type C57BL/6J mouse dams a HF diet with or without CS throughout gestation. After weaning, the offspring were exposed to HF feeding for 6 weeks resembling a continued obesogenic …

A Crispr Toolbox For Generating Intersectional Genetic Mouse Models For Functional, Molecular, And Anatomical Circuit Mapping, Savannah J Lusk, Andrew Mckinney, Patrick J Hunt, Paul G Fahey, Jay Patel, Andersen Chang, Jenny J Sun, Vena K Martinez, Ping Jun Zhu, Jeremy R Egbert, Genevera Allen, Xiaolong Jiang, Benjamin R Arenkiel, Andreas S Tolias, Mauro Costa-Mattioli, Russell S Ray

Faculty, Staff and Students Publications

BACKGROUND: The functional understanding of genetic interaction networks and cellular mechanisms governing health and disease requires the dissection, and multifaceted study, of discrete cell subtypes in developing and adult animal models. Recombinase-driven expression of transgenic effector alleles represents a significant and powerful approach to delineate cell populations for functional, molecular, and anatomical studies. In addition to single recombinase systems, the expression of two recombinases in distinct, but partially overlapping, populations allows for more defined target expression. Although the application of this method is becoming increasingly popular, its experimental implementation has been broadly restricted to manipulations of a limited set of …

Evaluation Of Bioactive Properties Of Lipophilic Fractions Of Edible And Non-Edible Parts Of Nasturtium Officinale (Watercress) In A Model Of Human Malignant Melanoma Cells, Sotiris Kyriakou, Venetia Tragkola, Heba Alghol, Ioannis Anestopoulos, Tom Amery, Kyle Stewart, Paul G. Winyard, Dimitrios T. Trafalis, Rodrigo Franco, Aglaia Pappa, Mihalis I. Panayiotidis

School of Veterinary and Biomedical Sciences: Faculty Publications

Watercress is an enriched source of phenethyl isothiocyanate (PEITC), among other phytochemicals, with an antioxidant capacity. The aim of this study was to (i) chemically characterize and (ii) biologically evaluate the profile of the main health-promoting compounds contained in edible (i.e., mixture of leaves and lateral buds) and non-edible (i.e., stems) parts of watercress in an in vitro model of malignant melanoma consisting of human malignant melanoma (A375), non-melanoma (A431) and keratinocyte (HaCaT) cells. The extraction of the main constituents of watercress was performed by subjecting the freeze-dried edible and non-edible samples through different extraction protocols, whereas their concentration was …

Antibody Responses Of Healthy Adults To The P27 Peptide Of Respiratory Syncytial Virus Fusion Protein, Brittani N Blunck, Letisha Aideyan, Xunyan Ye, Vasanthi Avadhanula, Laura Ferlic-Stark, Lynn Zechiedrich, Brian E Gilbert, Pedro A Piedra

Faculty, Staff and Students Publications

The respiratory syncytial virus (RSV) fusion (F) protein undergoes two furin-cleavage events to become fusion competent, resulting in the release of a twenty-seven amino acid peptide (p27). Recent studies indicate that the p27 region of the F protein was an immunodominant antigen in young children. In this study, we evaluated the kinetics of the serum antibody response to the p27 peptide following natural RSV reinfection in adults. Nineteen healthy adults under sixty-five years of age were enrolled during the 2018-2019 RSV season in Houston, TX. Blood was collected at three study visits and RSV infection status was defined by changes …

Self-Conscious Emotions And The Right Fronto-Temporal And Right Temporal Parietal Junction, Adriana Lavarco, Nathira Ahmad, Qiana Archer, Matthew Pardillo, Ray Nunez Castaneda, Anthony Minervini, Julian Keenan

Department of Biology Faculty Scholarship and Creative Works

For more than two decades, research focusing on both clinical and non-clinical populations has suggested a key role for specific regions in the regulation of self-conscious emotions. It is speculated that both the expression and the interpretation of self-conscious emotions are critical in humans for action planning and response, communication, learning, parenting, and most social encounters. Empathy, Guilt, Jealousy, Shame, and Pride are all categorized as self-conscious emotions, all of which are crucial components to one’s sense of self. There has been an abundance of evidence pointing to the right Fronto-Temporal involvement in the integration of cognitive processes underlying the …

Effect Of P2y12 Inhibitors On Survival Free Of Organ Support Among Non-Critically Ill Hospitalized Patients With Covid-19: A Randomized Clinical Trial, Jeffrey S Berger, Lucy Z Kornblith, Michelle N Gong, Harmony R Reynolds, Mary Cushman, Yu Cheng, Bryan J Mcverry, Keri S Kim, Renato D Lopes, Bassel Atassi, Scott Berry, Grant Bochicchio, Murillo De Oliveira Antunes, Michael E Farkouh, Yonatan Greenstein, Erinn M Hade, Kristin Hudock, Robert Hyzy, Pooja Khatri, Andrei Kindzelski, Bridget-Anne Kirwan, Lisa Baumann Kreuziger, Patrick R Lawler, Eric Leifer, Jose Lopez-Sendon Moreno, Jose Lopez-Sendon, James F Luther, Lilia Nigro Maia, John Quigley, Robert Sherwin, Lana Wahid, Jennifer Wilson, Judith S Hochman, Matthew D Neal, Activ-4a Investigators

Faculty, Staff and Students Publications

IMPORTANCE: Platelets represent a potential therapeutic target for improved clinical outcomes in patients with COVID-19.

OBJECTIVE: To evaluate the benefits and risks of adding a P2Y12 inhibitor to anticoagulant therapy among non-critically ill patients hospitalized for COVID-19.

DESIGN, SETTING, AND PARTICIPANTS: An open-label, bayesian, adaptive randomized clinical trial including 562 non-critically ill patients hospitalized for COVID-19 was conducted between February 2021 and June 2021 at 60 hospitals in Brazil, Italy, Spain, and the US. The date of final 90-day follow-up was September 15, 2021.

INTERVENTIONS: Patients were randomized to a therapeutic dose of heparin plus a P2Y12 inhibitor (n = …

Ultrasound 96 Probe Device Protocol For Cancer Cell Treatment, Aisling Field, Brijesh K. Tiwari, James F. Curtin, Julie R M Mondala, Janith Wanigasekara

Articles

Ultrasound is a sound wave with frequencies ranging between 20 kHz and 20 MHz. Ultrasound is able to temporarily and repeatedly open the BBB safely and enhance chemotherapeutic delivery without adverse effects. This novel technique in drug delivery benefits from the powerful ability of ultrasound to produce cavitation activity. Cavitation is the generation and activity of gas-filled bubbles in a medium exposed to ultrasound. As the pressure wave passes through the media, gas bubbles expand at low pressure and contract at high pressure. This leads to oscillation which produces a circulating fluid flow known as microstreaming around the bubble with …

Characterizing The Amino Acid Activation Center Of The Naturally Editing-Deficient Aminoacyl-Trna Synthetase Phers In Mycoplasma Mobile, Nien-Ching Han, Arundhati Kavoor, Michael Ibba

Biology, Chemistry, and Environmental Sciences Faculty Articles and Research

To ensure correct amino acids are incorporated during protein synthesis, aminoacyl-tRNA synthetases (aaRSs) employ proofreading mechanisms collectively referred to as editing. Although editing is important for viability, editing-deficient aaRSs have been identified in host-dependent organisms. In Mycoplasma mobile, editing-deficient PheRS and LeuRS have been identified. We characterized the amino acid activation site of MmPheRS and identified a previously unknown hyperaccurate mutation, L287F. Additionally, we report that m-Tyr, an oxidation byproduct of Phe which is toxic to editing-deficient cells, is poorly discriminated by MmPheRS activation and is not subjected to editing. Furthermore, expressing MmPheRS and the hyperaccurate variants renders …

Harnessing Mycobacterium Bovis Bcg Trained Immunity To Control Human And Bovine Babesiosis, Reginaldo G. Bastos, Heba F. Alzan, Vignesh A. Rathinasamy, Brian M. Cooke, Odir A. Dellagostin, Raul G. Barletta, Carlos E. Suarez

School of Veterinary and Biomedical Sciences: Faculty Publications

Babesiosis is a disease caused by tickborne hemoprotozoan apicomplexan parasites of the genus Babesia that negatively impacts public health and food security worldwide. Development of effective and sustainable vaccines against babesiosis is currently hindered in part by the absence of definitive host correlates of protection. Despite that, studies in Babesia microti and Babesia bovis, major causative agents of human and bovine babesiosis, respectively, suggest that early activation of innate immune responses is crucial for vertebrates to survive acute infection. Trained immunity (TI) is defined as the development of memory in vertebrate innate immune cells, allowing more efficient responses to subsequent …

Mutations In Hcfc1 And Ronin Result In An Inborn Error Of Cobalamin Metabolism And Ribosomopathy, Tiffany Chern, Annita Achilleos, Xuefei Tong, Matthew C Hill, Alexander B Saltzman, Lucas C Reineke, Arindam Chaudhury, Swapan K Dasgupta, Yushi Redhead, David Watkins, Joel R Neilson, Perumal Thiagarajan, Jeremy B A Green, Anna Malovannaya, James F Martin, David S Rosenblatt, Ross A Poché

Faculty, Staff and Students Publications

Combined methylmalonic acidemia and homocystinuria (cblC) is the most common inborn error of intracellular cobalamin metabolism and due to mutations in Methylmalonic Aciduria type C and Homocystinuria (MMACHC). Recently, mutations in the transcriptional regulators HCFC1 and RONIN (THAP11) were shown to result in cellular phenocopies of cblC. Since HCFC1/RONIN jointly regulate MMACHC, patients with mutations in these factors suffer from reduced MMACHC expression and exhibit a cblC-like disease. However, additional de-regulated genes and the resulting pathophysiology is unknown. Therefore, we have generated mouse models of this disease. In addition to exhibiting loss of Mmachc, metabolic perturbations, and developmental defects previously …

Secretogranin Iii Stringently Regulates Pathological But Not Physiological Angiogenesis In Oxygen-Induced Retinopathy, Chang Dai, Prabuddha Waduge, Liyang Ji, Chengchi Huang, Ye He, Hong Tian, Elizabeth Zuniga-Sanchez, Amit Bhatt, Iok-Hou Pang, Guanfang Su, Keith A Webster, Wei Li

Faculty, Staff and Students Publications

Conventional angiogenic factors, such as vascular endothelial growth factor (VEGF), regulate both pathological and physiological angiogenesis indiscriminately, and their inhibitors may elicit adverse side effects. Secretogranin III (Scg3) was recently reported to be a diabetes-restricted VEGF-independent angiogenic factor, but the disease selectivity of Scg3 in retinopathy of prematurity (ROP), a retinal disease in preterm infants with concurrent pathological and physiological angiogenesis, was not defined. Here, using oxygen-induced retinopathy (OIR) mice, a surrogate model of ROP, we quantified an exclusive binding of Scg3 to diseased versus healthy developing neovessels that contrasted sharply with the ubiquitous binding of VEGF. Functional immunohistochemistry visualized …

Associations Between Resources And Practices Of Ild Centers And Outcomes In Patients With Idiopathic Pulmonary Fibrosis: Data From The Ipf-Pro Registry, Joao A De Andrade, Tejaswini Kulkarni, Megan L Neely, Anne S Hellkamp, Amy Hajari Case, Daniel A Culver, Kalpalatha Guntupalli, Shaun Bender, Craig S Conoscenti, Laurie D Snyder, Ipf-Pro Registry Investigators

Faculty, Staff and Students Publications

BACKGROUND: Performance benchmarks for the management of idiopathic pulmonary fibrosis (IPF) have not been established. We used data from the IPF-PRO Registry, an observational registry of patients with IPF managed at sites across the US, to examine associations between the characteristics of the enrolling sites and patient outcomes.

METHODS: An online survey was used to collect information on the resources, operations, and self-assessment practices of IPF-PRO Registry sites that enrolled ≥ 10 patients. Site variability in 1-year event rates of clinically relevant outcomes, including death, death or lung transplant, and hospitalization, was assessed. Models were adjusted for differences in patient …

Glycocalyx Mechanotransduction Mechanisms Are Involved In Renal Cancer Metastasis, Heriberto Moran, Limary M. Cancel, Peigen Huang, Sylvie Roberge, Tuoye Xu, John M. Tarbell, Lance L. Munn

Publications and Research

Mammalian cells, including cancer cells, are covered by a surface layer containing cell bound proteoglycans, glycoproteins, associated glycosaminoglycans and bound proteins that is commonly referred to as the glycocalyx. Solid tumors also have a dynamic fluid microenvironment with elevated interstitial flow. In the present work we further investigate the hypothesis that interstitial flow is sensed by the tumor glycocalyx leading to activation of cell motility and metastasis. Using a highly metastatic renal carcinoma cell line (SN12L1) and its low metastatic counterpart (SN12C) we demonstrate in vitro that the small molecule Suberoylanilide Hydroxamic Acid (SAHA) inhibits the heparan sulfate synthesis enzyme …

Plasma Induced Reactive Oxygen Species-Dependent Cytotoxicity In Glioblastoma 3d Tumourspheres, Janith Wanigasekara, Carlos Barcia, Patrick J. Cullen, Brijesh Tiwari, James F. Curtin

Articles

The aim of this study was to determine the effects of a pin‐to‐plate cold atmospheric plasma (CAP) on U‐251 MG three‐dimensional (3D) glioblastoma spheroids under different conditions. 3D tumorspheres showed higher resistance to the CAP treatment compared to 2D monolayer cells. A single CAP treatment was able to induce cytotoxicity, while multiple CAP treatments augmented this effect. CAP was also able to induce cytotoxicity throughout the tumoursphere, and we identified that reactive oxygen species(ROS) plays a major role, while H2O2plays a partial role in CAP‐induced cytotoxicity in tumour-spheres. We conclude that ROS‐dependent cytotoxicity is induced uniformly throughout glioblastoma and epidermoid …

Aav5 Delivery Of Crispr-Cas9 Supports Effective Genome Editing In Mouse Lung Airway, Shun-Qing Liang, Christopher J Walkey, Alexa E Martinez, Qin Su, Mary E Dickinson, Dan Wang, William R Lagor, Jason D Heaney, Guangping Gao, Wen Xue

Faculty, Staff and Students Publications

Genome editing in the lung has the potential to provide long-term expression of therapeutic protein to treat lung genetic diseases. Yet efficient delivery of CRISPR to the lung remains a challenge. The NIH Somatic Cell Genome Editing (SCGE) Consortium is developing safe and effective methods for genome editing in disease tissues. Methods developed by consortium members are independently validated by the SCGE small animal testing center to establish rigor and reproducibility. We have developed and validated a dual adeno-associated virus (AAV) CRISPR platform that supports effective editing of a lox-stop-lox-Tomato reporter in mouse lung airway. After intratracheal injection of the …

Autophagosomes Fuse To Phagosomes And Facilitate The Degradation Of Apoptotic Cells In Caenorhabditis Elegans, Omar Peña-Ramos, Lucia Chiao, Xianghua Liu, Xiaomeng Yu, Tianyou Yao, Henry He, Zheng Zhou

Faculty, Staff and Students Publications

Autophagosomes are double-membrane intracellular vesicles that degrade protein aggregates, intracellular organelles, and other cellular components. During the development of the nematode Caenorhabditis elegans, many somatic and germ cells undergo apoptosis. These cells are engulfed and degraded by their neighboring cells. We discovered a novel role of autophagosomes in facilitating the degradation of apoptotic cells using a real-time imaging technique. Specifically, the double-membrane autophagosomes in engulfing cells are recruited to the surfaces of phagosomes containing apoptotic cells and subsequently fuse to phagosomes, allowing the inner vesicle to enter the phagosomal lumen. Mutants defective in the production of autophagosomes display significant …

Antioxidant Biomarkers And Nutraceutical Therapeutics In Neurodegeneration And Neurotrauma, Lilia A. Koza

Electronic Theses and Dissertations

Mild traumatic brain injury (mTBI), yielding a Glascow Coma Scale of 13-15, is the most commonly occurring severity of TBI. Pathology from mTBI consists of blood brain barrier disruption, neuroinflammation, oxidative stress, excitotoxicity, mitochondrial dysfunction, protein aggregation, axonal degeneration, and resulting neuronal death. These processes deplete the body’s endogenous antioxidant system. We report a retrospective analysis of antioxidant blood biomarkers in patients with a history of mTBI from a local sports medicine clinic, Resilience Code. We found persistent sex-specific antioxidant depletions in mTBI patients associated with worsened symptomology.

Certain populations, such as athletes, are at high risk for repetitive mTBI …

Organellar Zn2+ Homeostasis And The Role Of Trpml Channels In Neuronal Lysosome Physiology And Axonal Transport, Taylor Franklin Minckley

Electronic Theses and Dissertations

Zinc (Zn²⁺) is crucial for proper cellular function, and as such it is important to measure and track Zn²⁺ dynamics in living cells. Fluorescent sensors have been used to estimate Zn²⁺ content of subcellular compartments, but little is known about endolysosomal Zn2+ homeostasis. Similarly, although numerous sensors have been reported, it is unclear whether and how Zn²⁺ can be released from intracellular compartments into the cytosol due to a lack of probes that can detect physiological dynamics of cytosolic Zn²⁺. My dissertation started with comparing and characterizing different Zn²⁺ sensors including the …