Life Sciences Commons^™

Epidemiology Of Non-Alcoholic Fatty Liver Disease And Risk Of Hepatocellular Carcinoma Progression, Krishna Chaitanya Thandra, Adam Barsouk, Kalyan Saginala, John Sukumar Aluru, Prashanth Rawla, Alexander Barsouk

Kimmel Cancer Center Faculty Papers

Non-alcoholic fatty liver disease (NAFLD) has become the most common chronic liver disease worldwide. Its incidence has grown alongside the increasing global prevalence of type 2 diabetes, obesity, and metabolic syndrome. The risk of progression to hepatocellular carcinoma for nonalcoholic steatohepatitis patients over 5 years is 8%, and despite targeted and immunotherapy treatment advances, HCC maintains a bleak 5-year survival of 19%. NAFLD’s primary risk factors are components of metabolic syndrome as well as possible sleep disturbances. NAFLD is most common among men 50-60 years of age, though incidence in women catches up after menopause. In the US, Hispanics are …

Biophysical Analysis Of Pseudomonas-Phage Pap3 Small Terminase Suggests A Mechanism For Sequence-Specific Dna-Binding By Lateral Interdigitation., Marzia Niazi, Tyler J. Florio, Ruoyu Yang, Ravi K. Lokareddy, Nicholas A. Swanson, Richard E. Gillilan, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The genome packaging motor of tailed bacteriophages and herpesviruses is a powerful nanomachine built by several copies of a large (TerL) and a small (TerS) terminase subunit. The motor assembles transiently at the portal vertex of an empty precursor capsid (or procapsid) to power genome encapsidation. Terminase subunits have been studied in-depth, especially in classical bacteriophages that infect Escherichia coli or Salmonella, yet, less is known about the packaging motor of Pseudomonas-phages that have increasing biomedical relevance. Here, we investigated the small terminase subunit from three Podoviridae phages that infect Pseudomonas aeruginosa. We found TerS is polymorphic in solution but …

Insights From Five Decades Of Biodevelopment And Long-Term Research At Area De Conservación Guanacaste, Costa Rica, Jeffrey A. Klemens

College of Life Sciences Faculty Papers

No abstract provided.

Hitting The Bullseye: Are Extracellular Vesicles On Target?, Nicole Noren Hooten, María Yáñez-Mó, Rachel M. Derita, Ashley Russell, Peter Quesenberry, Bharat Ramratnam, Paul D Robbins, Dolores Di Vizio, Sicheng Wen, Kenneth W Witwer, Lucia R Languino

Department of Cancer Biology Faculty Papers

No abstract provided.

A Label-Free Assay For Aminoacylation Of Trna, Howard Gamper, Ya-Ming Hou

Department of Biochemistry and Molecular Biology Faculty Papers

Aminoacylation of tRNA generates an aminoacyl-tRNA (aa-tRNA) that is active for protein synthesis on the ribosome. Quantification of aminoacylation of tRNA is critical to understand the mechanism of specificity and the flux of the aa-tRNA into the protein synthesis machinery, which determines the rate of cell growth. Traditional assays for the quantification of tRNA aminoacylation involve radioactivity, either with a radioactive amino acid or with a [3'-32P]-labeled tRNA. We describe here a label-free assay that monitors aminoacylation by biotinylation-streptavidin (SA) conjugation to the α-amine or the α-imine of the aminoacyl group on the aa-tRNA. The conjugated aa-tRNA product is readily …

Recognition Of An Α-Helical Hairpin In P22 Large Terminase By A Synthetic Antibody Fragment., Ravi K Lokareddy, Ying Hui Ko, Nathaniel Hong, Steven G Doll, Marcin Paduch, Michael Niederweis, Anthony A Kossiakoff, Gino Cingolani

Department of Biochemistry and Molecular Biology Faculty Papers

The genome-packaging motor of tailed bacteriophages and herpesviruses is a multisubunit protein complex formed by several copies of a large (TerL) and a small (TerS) terminase subunit. The motor assembles transiently at the portal protein vertex of an empty precursor capsid to power the energy-dependent packaging of viral DNA. Both the ATPase and nuclease activities associated with genome packaging reside in TerL. Structural studies of TerL from bacteriophage P22 have been hindered by the conformational flexibility of this enzyme and its susceptibility to proteolysis. Here, an unbiased, synthetic phage-display Fab library was screened and a panel of high-affinity Fabs against …

From Gene To Function: A Safe Laboratory Exercise Promoting The Learning Of The Central Dogma Of Biology For The Undergraduate Biology Curriculum., Manuela Tripepi, Morgan Clear, Jack Lyons Bondi, Elvira Brunelli, Arianna Berardi

College of Life Sciences Faculty Papers

No abstract provided.

Dysregulation Of Ryr Calcium Channel Causes The Onset Of Mitochondrial Retrograde Signaling, Anindya Roy Chowdhury, Satish Srinivasan, György Csordás, György Hajnóczky, Narayan G Avadhani

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

This study shows that multiple modes of mitochondrial stress generated by partial mtDNA depletion or cytochrome c oxidase disruption cause ryanodine receptor channel (RyR) dysregulation, which instigates the release of Ca2+ in the cytoplasm of C2C12 myoblasts and HCT116 carcinoma cells. We also observed a reciprocal downregulation of IP3R channel activity and reduced mitochondrial uptake of Ca2+. Ryanodine, an RyR antagonist, abrogated the mitochondrial stress-mediated increase in [Ca2+]c and the entire downstream signaling cascades of mitochondrial retrograde signaling. Interestingly, ryanodine also inhibited mitochondrial stress-induced invasive behavior in mtDNA-depleted C2C12 cells and HCT116 carcinoma cells. In addition, co-immunoprecipitation shows reduced FKBP12 …

Phosphorylation Of Cyclophilin D At Serine 191 Regulates Mitochondrial Permeability Transition Pore Opening And Cell Death After Ischemia-Reperfusion, Stephen Hurst, Fabrice Gonnot, Maya Dia, Claire Crola Da Silva, Ludovic Gomez, Shey-Shing Sheu

Department of Medicine Faculty Papers

The mitochondrial permeability transition pore (mPTP) plays a critical role in the pathogenesis of cardiovascular diseases, including ischemia/reperfusion injury. Although the pore structure is still unresolved, the mechanism through which cyclophilin D (CypD) regulates mPTP opening is the subject of intensive studies. While post-translational modifications of CypD have been shown to modulate pore opening, specific phosphorylation sites of CypD have not yet been identified. We hypothesized here that phosphorylation of CypD on a serine residue controls mPTP opening and subsequent cell death at reperfusion. We combined in silico analysis with in vitro and genetic manipulations to determine potential CypD phosphorylation …

Deacetylation Of Hsd17b10 By Sirt3 Regulates Cell Growth And Cell Resistance Under Oxidative And Starvation Stresses., Lu Liu, Shuaiyi Chen, Miao Yu, Chenxu Ge, Mengmeng Ren, Boya Liu, Xin Yang, Thomas W Christian, Ya-Ming Hou, Junhua Zou, Wei-Guo Zhu, Jianyuan Luo

Department of Biochemistry and Molecular Biology Faculty Papers

17-beta-hydroxysteroid dehydrogenase 10 (HSD17B10) plays an important role in mitochondrial fatty acid metabolism and is also involved in mitochondrial tRNA maturation. HSD17B10 missense mutations cause HSD10 mitochondrial disease (HSD10MD). HSD17B10 with mutations identified from cases of HSD10MD show loss of function in dehydrogenase activity and mitochondrial tRNA maturation, resulting in mitochondrial dysfunction. It has also been implicated to play roles in the development of Alzheimer disease (AD) and tumorigenesis. Here, we found that HSD17B10 is a new substrate of NAD-dependent deacetylase Sirtuin 3 (SIRT3). HSD17B10 is acetylated at lysine residues K79, K99 and K105 by the acetyltransferase CBP, and the …

Insulin-Like Growth Factor 2 Mrna-Binding Protein 3 Modulates Aggressiveness Of Ewing Sarcoma By Regulating The Cd164-Cxcr4 Axis, Caterina Mancarella, Giulia Caldoni, Irene Ribolsi, Alessandro Parra, Maria Cristina Manara, Arthur M Mercurio, Andrea Morrione, Katia Scotlandi

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Ewing sarcoma (EWS) is the second most common bone and soft tissue-associated malignancy in children and young adults. It is driven by the fusion oncogene EWS/FLI1 and characterized by rapid growth and early metastasis. We have previously discovered that the mRNA binding protein IGF2BP3 constitutes an important biomarker for EWS as high expression of IGF2BP3 in primary tumors predicts poor prognosis of EWS patients. We additionally demonstrated that IGF2BP3 enhances anchorage-independent growth and migration of EWS cells suggesting that IGF2BP3 might work as molecular driver and predictor of EWS progression. The aim of this study was to further define the …

An Epistatic Interaction Between Pre-Natal Smoke Exposure And Socioeconomic Status Has A Significant Impact On Bronchodilator Drug Response In African American Youth With Asthma., J Magaña, M G Contreras, K L Keys, O Risse-Adams, P C Goddard, A M Zeiger, A C Y Mak, J R Elhawary, L A Samedy-Bates, E Lee, N Thakur, D Hu, C Eng, S Salazar, S Huntsman, T Hu, E G Burchard, M J White

Department of Medicine Faculty Papers

Background: Asthma is one of the leading chronic illnesses among children in the United States. Asthma prevalence is higher among African Americans (11.2%) compared to European Americans (7.7%). Bronchodilator medications are part of the first-line therapy, and the rescue medication, for acute asthma symptoms. Bronchodilator drug response (BDR) varies substantially among different racial/ethnic groups. Asthma prevalence in African Americans is only 3.5% higher than that of European Americans, however, asthma mortality among African Americans is four times that of European Americans; variation in BDR may play an important role in explaining this health disparity. To improve our understanding of disparate …

Defective Early Innate Immune Response To Ectromelia Virus In The Draining Lymph Nodes Of Aged Mice Due To Impaired Dendritic Cell Accumulation., Colby Stotesbury, Eric B Wong, Lingjuan Tang, Brian Montoya, Cory J Knudson, Carolina R Melo-Silva, Luis J Sigal

Department of Microbiology and Immunology Faculty Papers

It is known that aging decreases natural resistance to viral diseases due to dysfunctional innate and adaptive immune responses, but the nature of these dysfunctions, particularly in regard to innate immunity, is not well understood. We have previously shown that C57BL/6J (B6) mice lose their natural resistance to footpad infection with ectromelia virus (ECTV) due to impaired maturation and recruitment of natural killer (NK) cells to the draining popliteal lymph node (dLN). More recently, we have also shown that in young B6 mice infected with ECTV, the recruitment of NK cells is dependent on a complex cascade whereby migratory dendritic …

Profiling The Circulating Mrna Transcriptome In Human Liver Disease, Aejaz Sayeed, Brielle E Dalvano, David E Kaplan, Usha Viswanathan, John Kulp, Alhaji H Janneh, Lu-Yu Hwang, Adam Ertel, Cataldo Doria, Timothy Block

Department of Cancer Biology Faculty Papers

The human circulation contains cell-free DNA and non-coding microRNA (miRNA). Less is known about the presence of messenger RNA (mRNA). This report profiles the human circulating mRNA transcriptome in people with liver cirrhosis (LC) and hepatocellular carcinoma (HCC) to determine whether mRNA analytes can be used as biomarkers of liver disease. Using RNAseq and RT-qPCR, we investigate circulating mRNA in plasma from HCC and LC patients and demonstrate detection of transcripts representing more than 19,000 different protein coding genes. Remarkably, the circulating mRNA expression levels were similar from person to person over the 21 individuals whose samples were analyzed by …

Training New Providers Dobhoff Tube Insertion During Covid-19: Rapid Training And A Novel “Opt In” Approach To Learning, Michele Decastro, Msn, Crnp, Heather M. Etzl, Msn, Rn, Cbc, Jacqueline E. Crawford, Ms, Rn, Accns-P

Health Equity and Quality Improvement (HEQI) Summit

As increasing numbers of Covid-19 patients were admitted to the hospital and progressed thru their disease course, the Division of Hospital Medicine noted an increased need for enteral feeding access for their patients. At the same time, the Nutritional Support Clinical Nurse Specialists were seeing an increase in requests for assistance with use of Cortrak technology for insertion of Dobhoff tube (DHT) insertion for high risk patients diagnosed with Covid-19.

Flowering Plant Composition Shapes Pathogen Infection Intensity And Reproduction In Bumble Bee Colonies., Lynn S. Adler, Nicholas A. Barber, Olivia M. Biller, Rebecca E. Irwin

Department of Occupational Therapy Faculty Papers

Pathogens pose significant threats to pollinator health and food security. Pollinators can transmit diseases during foraging, but the consequences of plant species composition for infection is unknown. In agroecosystems, flowering strips or hedgerows are often used to augment pollinator habitat. We used canola as a focal crop in tents and manipulated flowering strip composition using plant species we had previously shown to result in higher or lower bee infection in short-term trials. We also manipulated initial colony infection to assess impacts on foraging behavior. Flowering strips using high-infection plant species nearly doubled bumble bee colony infection intensity compared to low-infection …

Methylation Of Salmonella Typhimurium Flagella Promotes Bacterial Adhesion And Host Cell Invasion, Julia A Horstmann, Michele Lunelli, Hélène Cazzola, Johannes Heidemann, Caroline Kühne, Pascal Steffen, Sandra Szefs, Claire Rossi, Ravi K Lokareddy, Chu Wang, Laurine Lemaire, Kelly T Hughes, Charlotte Uetrecht, Hartmut Schlüter, Guntram A Grassl, Theresia E B Stradal, Yannick Rossez, Michael Kolbe, Marc Erhardt

Department of Biochemistry and Molecular Biology Faculty Papers

The long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of …

Methylation Of Salmonella Typhimurium Flagella Promotes Bacterial Adhesion And Host Cell Invasion., Julia A Horstmann, Michele Lunelli, Hélène Cazzola, Johannes Heidemann, Caroline Kühne, Pascal Steffen, Sandra Szefs, Claire Rossi, Ravi K Lokareddy, Chu Wang, Laurine Lemaire, Kelly T Hughes, Charlotte Uetrecht, Hartmut Schlüter, Guntram A Grassl, Theresia E B Stradal, Yannick Rossez, Michael Kolbe, Marc Erhardt

Department of Biochemistry and Molecular Biology Faculty Papers

The long external filament of bacterial flagella is composed of several thousand copies of a single protein, flagellin. Here, we explore the role played by lysine methylation of flagellin in Salmonella, which requires the methylase FliB. We show that both flagellins of Salmonella enterica serovar Typhimurium, FliC and FljB, are methylated at surface-exposed lysine residues by FliB. A Salmonella Typhimurium mutant deficient in flagellin methylation is outcompeted for gut colonization in a gastroenteritis mouse model, and methylation of flagellin promotes bacterial invasion of epithelial cells in vitro. Lysine methylation increases the surface hydrophobicity of flagellin, and enhances flagella-dependent adhesion of …

Microrna Expression Profiling Of Normal And Malignant Human Colonic Stem Cells Identifies, Vignesh Viswanathan, Lynn Opdenaker, Shirin Modarai, Jeremy Z Fields, Gregory Gonye, Bruce M Boman

Department of Pharmacology and Experimental Therapeutics Faculty Papers

MicroRNAs (miRNAs) have a critical role in regulating stem cells (SCs) during development, and because aberrant expression of miRNAs occurs in various cancers, our goal was to determine if dysregulation of miRNAs is involved in the SC origin of colorectal cancer (CRC). We previously reported that aldehyde dehydrogenase (ALDH) is a marker for normal and malignant human colonic SCs and tracks SC overpopulation during colon tumorigenesis. MicroRNA expression was studied in ALDH-positive SCs from normal and malignant human colon tissues by Nanostring miRNA profiling. Our findings show that: (1) A unique miRNA signature distinguishes ALDH-positive CRC cells from ALDH-positive normal …

Functional Blockade Of E-Selectin In Tumor-Associated Vessels Enhances Anti-Tumor Effect Of Doxorubicin In Breast Cancer, Yoshihiro Morita, Macall Leslie, Hiroyasu Kameyama, Ganesh L R Lokesh, Norihisa Ichimura, Rachel Davis, Natalie Hills, Nafis Hasan, Roy Zhang, Yuji Kondo, David G Gorenstein, David E Volk, Inna Chervoneva, Hallgeir Rui, Takemi Tanaka

Department of Pharmacology and Experimental Therapeutics Faculty Papers

Chemotherapy is a mainstay of treatment for solid tumors. However, little is known about how therapy-induced immune cell infiltration may affect therapy response. We found substantial CD45+ immune cell density adjacent to E-selectin expressing inflamed vessels in doxorubicin (DOX)-treated residual human breast tumors. While CD45 level was significantly elevated in DOX-treated wildtype mice, it remained unchanged in DOX-treated tumors from E-selectin null mice. Similarly, intravenous administration of anti-E-selectin aptamer (ESTA) resulted in a significant reduction in CD45+ immune cell density in DOX-treated residual tumors, which coincided with a delay in tumor growth and lung metastasis in MMTV-pyMT mice. Additionally, both …

Levetiracetam Versus Phenytoin For The Treatment Of Established Status Epilepticus: A Systematic Review And Meta-Analysis Of Randomized Controlled Trials., Linjie Li, Yu Zhang, Lu Jia, Desheng Jia, Andrew Faramand, Weelic Chong, Yuan Fang, Lu Ma, Fang Fang

College of Life Sciences Faculty Papers

OBJECTIVES: To compare the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus.

METHODS: In this systematic review, we searched Medline, Embase, and Cochrane databases from their inception with no language restrictions until May 8, 2019 and updated on February 5, 2020, for randomized controlled trials comparing the efficacy and safety of levetiracetam and phenytoin for the treatment of established status epilepticus. A Meta-analysis was conducted to calculate the risk ratio (RR) using random-effects models.

RESULTS: We identified 7 trials with a total of 1028 participants. Levetiracetam was not associated with an increased rate of …

Antagonistic Regulation Of Circadian Output And Synaptic Development By Jetlag And The Dyschronic-Slowpoke Complex, Angelique Lamaze, James E.C. Jepson, Oghenerukevwe Akpoghiran, Kyunghee Koh

Department of Neuroscience Faculty Papers

Circadian output genes act downstream of the clock to promote rhythmic changes in behavior and physiology, yet their molecular and cellular functions are not well understood. Here we characterize an interaction between regulators of circadian entrainment, output, and synaptic development in Drosophila that influences clock-driven anticipatory increases in morning and evening activity. We previously showed the JETLAG (JET) E3 ubiquitin ligase resets the clock upon light exposure, whereas the PDZ protein DYSCHRONIC (DYSC) regulates circadian locomotor output and synaptic development. Surprisingly, we find that JET and DYSC antagonistically regulate synaptic development at the larval neuromuscular junction, and reduced JET activity …

Pan-Cancer Analysis Reveals Cooperativity Of Both Strands Of Microrna That Regulate Tumorigenesis And Patient Survival, Ramkrishna Mitra, Clare M. Adams, Wei Jiang, Evan J. Greenawalt, Christine M. Eischen

Department of Cancer Biology Faculty Papers

Recently, both 5p and 3p miRNA strands are being recognized as functional instead of only one, leaving many miRNA strands uninvestigated. To determine whether both miRNA strands, which have different mRNA-targeting sequences, cooperate to regulate pathways/functions across cancer types, we evaluate genomic, epigenetic, and molecular profiles of >5200 patient samples from 14 different cancers, and RNA interference and CRISPR screens in 290 cancer cell lines. We identify concordantly dysregulated miRNA 5p/3p pairs that coordinately modulate oncogenic pathways and/or cell survival/growth across cancers. Down-regulation of both strands of miR-30a and miR-145 recurrently increased cell cycle pathway genes and significantly reduced patient …

Microrna And Transcription Factor Co-Regulatory Networks And Subtype Classification Of Seminoma And Non-Seminoma In Testicular Germ Cell Tumors, Guimin Qin, Saurav Mallik, Ramkrishna Mitra, Aimin Li, Peilin Jia, Christine M. Eischen, Zhongming Zhao

Department of Cancer Biology Faculty Papers

Recent studies have revealed that feed-forward loops (FFLs) as regulatory motifs have synergistic roles in cellular systems and their disruption may cause diseases including cancer. FFLs may include two regulators such as transcription factors (TFs) and microRNAs (miRNAs). In this study, we extensively investigated TF and miRNA regulation pairs, their FFLs, and TF-miRNA mediated regulatory networks in two major types of testicular germ cell tumors (TGCT): seminoma (SE) and non-seminoma (NSE). Specifically, we identified differentially expressed mRNA genes and miRNAs in 103 tumors using the transcriptomic data from The Cancer Genome Atlas. Next, we determined significantly correlated TF-gene/miRNA and miRNA-gene/TF …