Medicine and Health Sciences Commons^™

Increased Mitochondrial Superoxide In The Brain, But Not Periphery, Sensitizes Mice To Angiotensin Ii-Mediated Hypertension., Adam J. Case, Jun Tian, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Angiotensin II (AngII) elicits the production of superoxide (O2(•-)) from mitochondria in numerous cell types within peripheral organs and in the brain suggesting a role for mitochondrial-produced O2(•-) in the pathogenesis of hypertension. However, it remains unclear if mitochondrial O2(•-) is causal in the development of AngII-induced hypertension, or if mitochondrial O2(•-) in the absence of elevated AngII is sufficient to increase blood pressure. Further, the tissue specific (i.e. central versus peripheral) redox regulation of AngII hypertension remains elusive. Herein, we hypothesized that increased mitochondrial O2(•-) in the absence of pro-hypertensive stimuli, such as AngII, elevates baseline systemic mean arterial …

Membrane-Active Epithelial Keratin 6a Fragments (Kamps) Are Unique Human Antimicrobial Peptides With A Non-Αβ Structure., Judy T.Y. Lee, Guangshun Wang, Yu Tong Tam, Connie Tam

Journal Articles: Pathology and Microbiology

Antibiotic resistance is a pressing global health problem that threatens millions of lives each year. Natural antimicrobial peptides and their synthetic derivatives, including peptoids and peptidomimetics, are promising candidates as novel antibiotics. Recently, the C-terminal glycine-rich fragments of human epithelial keratin 6A were found to have bactericidal and cytoprotective activities. Here, we used an improved 2-dimensional NMR method coupled with a new protocol for structural refinement by low temperature simulated annealing to characterize the solution structure of these kerain-derived antimicrobial peptides (KAMPs). Two specific KAMPs in complex with membrane mimicking sodium dodecyl sulfate (SDS) micelles displayed amphipathic conformations with only …

Il-10 Plays An Important Role In The Control Of Inflammation But Not In The Bacterial Burden In S. Epidermidis Cns Catheter Infection., Yenis M. Gutierrez-Murgas, Gwenn Skar, Danielle Ramirez, Matthew Beaver, Jessica N. Snowden

Journal Articles: Pathology and Microbiology

BACKGROUND: Shunt infection is a frequent and serious complication in the surgical treatment in hydrocephalus. Previous studies have shown an attenuated immune response to these biofilm-mediated infections. We proposed that IL-10 reduces the inflammatory response to Staphylococcus epidermidis (S. epidermidis) CNS catheter infection.

METHODS: In this study, a murine model of catheter-associated S. epidermidis biofilm infection in the CNS was generated based on a well-established similar model for S. aureus. The catheters were pre-coated with a clinically derived biofilm-forming strain of S. epidermidis (strain 1457) which were then stereotactically implanted into the lateral left ventricle of 8-week-old C57BL/6 and IL-10 …

Mitochondrial Superoxide Signaling Contributes To Norepinephrine-Mediated T-Lymphocyte Cytokine Profiles., Adam J. Case, Colton T. Roessner, Jun Tian, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Norepinephrine (NE) produces multifaceted regulatory patterns in T-lymphocytes. Recently, we have shown that NE utilizes redox signaling as evidenced by increased superoxide (O2●-) causally linked to the observed changes in these cells; however, the source of this reactive oxygen species (ROS) remains elusive. Herein, we hypothesized that the source of increased O2●- in NE-stimulated T-lymphocytes is due to disruption of mitochondrial bioenergetics. To address this hypothesis, we utilized purified mouse splenic CD4+ and CD8+ T-lymphocytes stimulated with NE and assessed O2●- levels, mitochondrial metabolism, cellular proliferation, and cytokine profiles. We demonstrate that the increase in O2●- levels in response to …

Nox2-Derived Oxidative Stress Results In Inefficacy Of Antibiotics Against Post-Influenza S. Aureus Pneumonia., Keer Sun, Vijaya Kumar Yajjala, Christopher Bauer, G. Talmon, Karl J. Fischer, Tammy Kielian, Dennis W. Metzger

Journal Articles: Pathology and Microbiology

Clinical post-influenza Staphylococcus aureus pneumonia is characterized by extensive lung inflammation associated with severe morbidity and mortality even after appropriate antibiotic treatment. In this study, we show that antibiotics rescue nicotinamide adenine dinucleotide phosphate (NADPH) oxidase 2 (Nox2)-deficient mice but fail to fully protect WT animals from influenza and S. aureus coinfection. Further experiments indicate that the inefficacy of antibiotics against coinfection is attributable to oxidative stress-associated inflammatory lung injury. However, Nox2-induced lung damage during coinfection was not associated with aggravated inflammatory cytokine response or cell infiltration but rather caused by reduced survival of myeloid cells. Specifically, oxidative stress increased …

Ehd1 As A Positive Regulator Of Macrophage Colony-Stimulating Factor-1 Receptor, Luke R. Cypher

Theses & Dissertations

The master regulator of the macrophage development, differentiation, proliferation, survival, phagocytosis, cytokine secretion, motility, adhesion, migration, and spreading is the receptor tyrosine kinase (RTK) colony stimulating factor-1 receptor (CSF-1R). Aberrant CSF-1R signaling is present amongst a variety of highly prevalent and devastating human diseases in the United States such as atherosclerosis, cancer, inflammatory bowel disease, arthritis, and neuro-demyelination/neuro-degeneration. A better understanding of basic mechanisms that govern macrophage development and function is of vital importance in treating patients afflicted with these conditions/diseases. CSF-1R presentation on the macrophage cell surface is a required precursor for CSF1- induced RTK dimerization (activation) and downstream …

The Pathogenesis Of Natural Killer/T Cell Lymphoma, Bei Jiang

Theses & Dissertations

Extranodal natural killer/T-cell lymphomas (NKTCL) are uncommon lymphomas with poor prognosis. In order to gain a better understanding of the molecular pathogenesis of NKTCL, we obtained and compared the global gene expression profile, global somatic mutation profile, and global methylation profile of normal NK cells, malignant NK cell lines, and NKTCL patient samples. We showed that the JAK-STAT pathway was constitutively activated in NKTCL through the cooperation between activation of signal transducer and activator of transcription proteins (STATs) via activating mutations and inactivation of STAT suppressor protein suppressor of cytokine signaling 6 (SOCS6) through promoter hypermethylation. Activating STAT3 and STAT5B …

Exome-Based Variant Detection In Core Promoters., Yeong C. Kim, Jian Cui, Jiangtao Luo, Fengxia Xiao, Bradley Downs, San Ming Wang

Journal Articles: Genetics, Cell Biology & Anatomy

Core promoter controls the initiation of transcription. Core promoter sequence change can disrupt transcriptional regulation, lead to impairment of gene expression and ultimately diseases. Therefore, comprehensive characterization of core promoters is essential to understand normal and abnormal gene expression in biomedical studies. Here we report the development of EVDC (Exome-based Variant Detection in Core promoters) method for genome-scale analysis of core-promoter sequence variation. This method is based on the fact that exome sequences contain the sequences not only from coding exons but also from non-coding region including core promoters generated by random fragmentation in exome sequencing process. Using exome data …

Comparison Of A Powdered, Acidified Liquid, And Non-Acidified Liquid Human Milk Fortifier On Clinical Outcomes In Premature Infants., Melissa Thoene, Elizabeth Lyden, Kara Weishaar, Elizabeth Elliott, Ruomei Wu, Katelyn White, Hayley Timm, Ann Anderson-Berry

Journal Articles: Medical Nutrition

We previously compared infant outcomes between a powdered human milk fortifier (P-HMF) vs. acidified liquid HMF (AL-HMF). A non-acidified liquid HMF (NAL-HMF) is now commercially available. The purpose of this study is to compare growth and outcomes of premature infants receiving P-HMF, AL-HMF or NAL-HMF. An Institutional Review Board (IRB) approved retrospective chart review compared infant outcomes (born < 2000 g) who received one of three HMF. Growth, enteral nutrition, laboratory and demographic data were compared. 120 infants were included (P-HMF = 46, AL-HMF = 23, NAL-HMF = 51). AL-HMF infants grew slower in g/day (median 23.66 vs. P-HMF 31.27, NAL-HMF 31.74 (p < 0.05)) and in g/kg/day, median 10.59 vs. 15.37, 14.03 (p < 0.0001). AL-HMF vs. NAL-HMF infants were smaller at 36 weeks gestational age (median 2046 vs. 2404 g, p < 0.05). However AL-HMF infants received more daily calories (p = 0.21) and protein (p < 0.0001), mean 129 cal/kg, 4.2 g protein/kg vs. P-HMF 117 cal/kg, 3.7 g protein/kg , NAL-HMF 120 cal/kg, 4.0 g protein/kg. AL-HMF infants exhibited lower carbon dioxide levels after day of life 14 and 30 (p < 0.0001, p = 0.0038). Three AL-HMF infants (13%) developed necrotizing enterocolitis (NEC) vs. no infants in the remaining groups (p = 0.0056). A NAL-HMF is the most optimal choice for premature human milk-fed infants in a high acuity neonatal intensive care unit (NICU).

Traumatic Brain Injury Increases Levels Of Mir-21 In Extracellular Vesicles: Implications For Neuroinflammation, Emily B. Harrison, Colleen G. Hochfelder, Benjamin G. Lamberty, Brittney M. Meays, Brenda M. Morsey, Matthew L. Kelso, Howard S. Fox, Sowmya V. Yelamanchili

Journal Articles: Pharmacology & Experimental Neuroscience

No abstract provided.

Metabolic Drift In The Aging Brain., Julijana Ivanisevic, Kelly L. Stauch, Michael Petrascheck, H. Paul Benton, Adrian A. Epstein, Mingliang Fang, Santhi Gorantla, Minerva Tran, Linh Hoang, Michael E. Kurczy, Michael D. Boska, Howard Gendelman, Howard S. Fox, Gary Siuzdak

Journal Articles: Pharmacology & Experimental Neuroscience

Brain function is highly dependent upon controlled energy metabolism whose loss heralds cognitive impairments. This is particularly notable in the aged individuals and in age-related neurodegenerative diseases. However, how metabolic homeostasis is disrupted in the aging brain is still poorly understood. Here we performed global, metabolomic and proteomic analyses across different anatomical regions of mouse brain at different stages of its adult lifespan. Interestingly, while severe proteomic imbalance was absent, global-untargeted metabolomics revealed an energymetabolic drift or significant imbalance in core metabolite levels in aged mouse brains. Metabolic imbalance was characterized by compromised cellular energy status (NAD decline, increased AMP/ATP, …

Proportion Of Heart Failure Patients Who Meet Criteria For Malnutrition Upon Hospital Admission Based On Aspen Guidelines, Sarah L. Johnson

Theses & Dissertations

Background: Current research estimates that approximately 50 percent of heart failure patients are categorized as malnourished. Heart failure patients are at increased risk of malnourishment due to increased catabolic processes that increase resting energy expenditure, decrease appetite, impair nutrient absorption, and lead to unintentional weight loss. The goal of standardized diagnostic criteria is to identify malnutrition early for more effective treatment. Current studies suggest the association of early diagnosis and nutrition intervention with increased positive patient outcomes and improved quality of life for heart failure (HF) patients. However, the proportion of patients with HF who meet criteria for malnutrition at …

Gross Anatomy Dissection Videos: Effect On Student Dissection Confidence And Laboratory Examination Scores, Kevin J. Selting

Theses & Dissertations

As medical colleges across the world experience cadaver shortages, faculty shortages, and decreased time allotted to teaching gross anatomy, a need for different teaching modalities has emerged. New ways of teaching are being studied to optimize efficiency and to acquire the same, or better, student outcomes as before the previously mentioned variables became prevalent. This was the stimulus for our research. Dissection videos were made, closely adhering to the dissections performed by Physician Assistant, Physical therapy, and Medical students at the University of Nebraska Medical Center (UNMC). The current Gross Anatomy course at UNMC involves four written examinations covering material …

Mechanisms Of Lateral-Inhibitory Feedback From Horizontal Cells To Cone Photoreceptors At The First Synapse Of The Retina, Ted J. Warren

Theses & Dissertations

Polarization of the horizontal cell (HC) membrane potential causes changes in the synaptic cleft pH that result in inhibitory feedback from HCs to cone photoreceptors (PRs). HCs average signals from many PRs and so negative feedback onto PR terminals from HCs subtracts the average luminance of the visual scene from the light responses of an individual cone. This feedback operates by changing the voltage-dependence and amplitude of the L-type Ca²⁺ current (I_Ca) that regulates synaptic release. Feedback regulation of PR Ca²⁺ channels involves protons but the mechanism by which this pH change occurs is unclear. We …

Genetic Predisposition And M1 Macrophage Polarization Created By Elastin-Derived Peptides Drive Abdominal Aortic Aneurysm Formation, Matthew A. Dale

Theses & Dissertations

Abdominal aortic aneurysm (AAA) is a dynamic vascular disease characterized by inflammatory cell invasion and extracellular matrix (ECM) degradation. Evidence has demonstrated a profound influence of genetic background on AAA formation. The work presented herein discusses two studies: the first demonstrates how genetic components can enhance the susceptibility to AAA formation and the second demonstrates how ECM degradation enhances AAA progression by influencing inflammatory cell phenotypes. An understanding of the pathways involved in AAA pathogenesis can help not only to identify potential patients at risk of AAA development, a heritable disease in which the incriminating component has yet to be …

Vitamin A Compounds In Mothers And Infants At Birth, Jenna M. Paseka

Theses & Dissertations

OBJECTIVE: Little is known about the vitamin A status in mothers and infants at birth in the United States. The main objective of this study is to determine associations between maternal and infant serum retinol, provitamin A carotenoids, and non-provitamin A carotenoids. The secondary aim is to explore the relationship between maternal intake and maternal and infant serum levels of vitamin A compounds.

METHODS: This was a prospective cohort of 34 mothers and their infants admitted to the neonatal intensive care unit (NICU). Maternal and cord blood samples were collected at delivery. Serum retinol, lutein + zeaxanthin, β-cryptoxanthin, lycopene, α-carotene, …

Moving Towards Effective Therapeutic Strategies For Neuronal Ceroid Lipofuscinosis., Ryan D. Geraets, Seung Yon Koh, Michelle L. Hastings, Tammy Kielian, David A. Pearce, Jill M. Weimer

Journal Articles: Pathology and Microbiology

The Neuronal Ceroid Lipofuscinoses (NCLs) are a family of autosomal recessive neurodegenerative disorders that annually affect 1:100,000 live births worldwide. This family of diseases results from mutations in one of 14 different genes that share common clinical and pathological etiologies. Clinically, the diseases are subcategorized into infantile, late-infantile, juvenile and adult forms based on their age of onset. Though the disease phenotypes may vary in their age and order of presentation, all typically include progressive visual deterioration and blindness, cognitive impairment, motor deficits and seizures. Pathological hallmarks of NCLs include the accumulation of storage material or ceroid in the lysosome, …

Nrp2 Transcriptionally Regulates Its Downstream Effector Wdfy1., Samikshan Dutta, Sohini Roy, Navatha S. Polavaram, Gustavo B. Baretton, Michael H. Muders, Surinder K. Batra, K Datta

Journal Articles: Biochemistry & Molecular Biology

Neuropilins (NRPs) are cell surface glycoproteins that often act as co-receptors for plexins and VEGF family receptors. Neuropilin-2 (NRP2), a family member of NRPs, was shown to regulate autophagy and endocytic trafficking in cancer cells, a function distinctly different from its role as a co-receptor. WD Repeat and FYVE domain containing 1 (WDFY1)-protein acts downstream of NRP2 for this function. Our results indicated that NRP2 maintains an optimum concentration of WDFY1 by negatively regulating its expression. Since increased expression of WDFY1 reduces the endocytic activity, maintenance of WDFY1 level is crucial in metastatic cancer cells to sustain high endocytic activity, …

Hiv-1 Cellular And Tissue Replication Patterns In Infected Humanized Mice., Mariluz Araínga, Hang Su, Larisa Y Poluektova, Santhi Gorantla, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Cells were analyzed by flow cytometry …

Hiv-1 Cellular And Tissue Replication Patterns In Infected Humanized Mice., Mariluz Araínga, Hang Su, Larisa Y Poluektova, Santhi Gorantla, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

Humanized mice have emerged as a testing platform for HIV-1 pathobiology by reflecting natural human disease processes. Their use to study HIV-1 biology, virology, immunology, pathogenesis and therapeutic development has served as a robust alternative to more-well developed animal models for HIV/AIDS. A critical component in reflecting such human pathobiology rests in defining the tissue and cellular sites for HIV-1 infection. To this end, we examined the tissue sites for viral infection in bone marrow, blood, spleens, liver, gut, brain, kidney and lungs of human CD34+ hematopoietic stem cell engrafted virus-infected NOD.Cg-Prkdc(scid) Il2rg(tm1Wjl)/SzJ mice. Cells were analyzed by flow cytometry …

Ablation Of Matrix Metalloproteinase-9 Prevents Cardiomyocytes Contractile Dysfunction In Diabetics., Priyanka Prathipati, Naira Metreveli, Shyam Sundar Nandi, Suresh C. Tyagi, Paras K. Mishra

Journal Articles: Cellular & Integrative Physiology

Elevated expression and activity of matrix metalloproteinase-9 (MMP9) and decreased contractility of cardiomyocytes are documented in diabetic hearts. However, it is unclear whether MMP is involved in the regulation of contractility of cardiomyocytes in diabetic hearts. In the present study, we tested the hypothesis that MMP9 regulates contractility of cardiomyocytes in diabetic hearts, and ablation of MMP9 prevents impaired contractility of cardiomyocytes in diabetic hearts. To determine the specific role of MMP9 in cardiomyocyte contractility, we used 12-14 week male WT (normoglycemic sibling of Akita), Akita, and Ins(2+∕-)/MMP9(-∕-) (DKO) mice. DKO mice were generated by cross-breeding male Ins2(+∕-) Akita (T1D) …

Prevalence And Spectrum Of Brca Germline Variants In Mainland Chinese Familial Breast And Ovarian Cancer Patients., Yeong C. Kim, Linli Zhao, Hanwen Zhang, Ye Huang, Jian Cui, Fengxia Xiao, Bradley Downs, San Ming Wang

Journal Articles: Genetics, Cell Biology & Anatomy

Germline mutations in BRCA1 and BRCA2 are the most penetrating genetic predispositions for breast and ovarian cancer, and their presence is largely ethnic-specific. Comprehensive information about the prevalence and spectrum of BRCA mutations has been collected in European and North American populations. However, similar information is lacking in other populations, including the mainland Chinese population despite its large size of 1.4 billion accounting for one fifth of the world's population. Herein, we performed an extensive literature analysis to collect BRCA variants identified from mainland Chinese familial breast and ovarian cancer patients. We observed 137 distinct BRCA1 variants in 409 of …

Ceramide Induces Human Hepcidin Gene Transcription Through Jak/Stat3 Pathway., Sizhao Lu, Sathish Kumar Natarajan, Justin L. Mott, Kusum K. Kharbanda, Duygu Dee Harrison-Findik

Journal Articles: Biochemistry & Molecular Biology

Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked …

Ceramide Induces Human Hepcidin Gene Transcription Through Jak/Stat3 Pathway., Sizhao Lu, Sathish Kumar Natarajan, Justin L. Mott, Kusum K. Kharbanda, Duygu Dee Harrison-Findik

Journal Articles: Biochemistry & Molecular Biology

Changes in lipid metabolism and iron content are observed in the livers of patients with fatty liver disease. The expression of hepcidin, an iron-regulatory and acute phase protein synthesized by the liver, is also modulated. The potential interaction of lipid and iron metabolism is largely unknown. We investigated the role of lipid intermediate, ceramide in the regulation of human hepcidin gene, HAMP. Human hepatoma HepG2 cells were treated with cell-permeable ceramide analogs. Ceramide induced significant up-regulation of HAMP mRNA expression in HepG2 cells. The effect of ceramide on HAMP expression was mediated through transcriptional mechanisms because it was completely blocked …

Overexpression Of Pd2 Leads To Increased Tumorigenicity And Metastasis In Pancreatic Ductal Adenocarcinoma., Arokia Priyanka Vaz, Shonali Deb, Satyanarayana Rachagani, Parama Dey, Sakthivel Muniyan, Imayavaramban Lakshmanan, Saswati Karmakar, Lynette M. Smith, Sonny L. Johansson, Subodh M. Lele, M Ouellette, Moorthy P. Ponnusamy, Surinder K. Batra

Journal Articles: Biochemistry & Molecular Biology

Pancreatic differentiation 2 (PD2), an important subunit of the human PAF complex, was identified after differential screening analysis of 19q13 amplicon, and its overexpression induces oncogenic transformation of NIH3T3 cells, hence raising the possibility of a role for PD2 in tumorigenesis and metastasis. To test this hypothesis, we analyzed here the functional role and clinical significance of PD2 in pancreatic ductal adenocarcinoma (PDAC) and its pathogenesis. Using immunohistochemical analysis, we found that PD2 is detected in the acini but not in the ducts in the normal pancreas. In human PDAC specimens, PD2 was instead primarily detected in the ducts (12/48 …

A New Genotype Of Bovine Leukemia Virus In South America Identified By Ngs-Based Whole Genome Sequencing And Molecular Evolutionary Genetic Analysis., Meripet Polat, Shin-Nosuke Takeshima, Kazuyoshi Hosomichi, Jiyun Kim, Taku Miyasaka, Kazunori Yamada, Mariluz Araínga, Tomoyuki Murakami, Yuki Matsumoto, Veronica De La Barra Diaz, Carlos Javier Panei, Ester Teresa González, Misao Kanemaki, Misao Onuma, Guillermo Giovambattista, Yoko Aida

Journal Articles: Pharmacology & Experimental Neuroscience

BACKGROUND: Bovine leukemia virus (BLV) is a member of retroviridae family, together with human T cell leukemia virus types 1 and 2 (HTLV-1 and -2) belonging to the genes deltaretrovirus, and infects cattle worldwide. Previous studies have classified the env sequences of BLV provirus from different geographic locations into eight genetic groups. To investigate the genetic variability of BLV in South America, we performed phylogenetic analyses of whole genome and partial env gp51 sequences of BLV strains isolated from Peru, Paraguay and Bolivia, for which no the molecular characteristics of BLV have previously been published, and discovered a novel BLV …

The Mixed Lineage Kinase-3 Inhibitor Urmc-099 Improves Therapeutic Outcomes For Long-Acting Antiretroviral Therapy., Gang Zhang, Dongwei Guo, Prasanta Dash, Mariluz Araínga, Jayme Wiederin, Nicole A. Haverland, Jaclyn Knibbe-Hollinger, Andrea Martinez-Skinner, Pawel Ciborowski, Val S. Goodfellow, Tadeusz A. Wysocki, Beata J. Wysocki, Larisa Y. Poluektova, Xin-Ming Liu, Joellyn Mcmillan, Santhi Gorantla, Harris A. Gelbard, Howard Gendelman

Journal Articles: Pharmacology & Experimental Neuroscience

During studies to extend the half-life of crystalline nanoformulated antiretroviral therapy (nanoART) the mixed lineage kinase-3 inhibitor URMC-099, developed as an adjunctive neuroprotective agent was shown to facilitate antiviral responses. Long-acting ritonavir-boosted atazanavir (nanoATV/r) nanoformulations co-administered with URMC-099 reduced viral load and the numbers of HIV-1 infected CD4+ T-cells in lymphoid tissues more than either drug alone in infected humanized NOD/SCID/IL2Rγc-/- mice. The drug effects were associated with sustained ART depots. Proteomics analyses demonstrated that the antiretroviral responses were linked to affected phagolysosomal storage pathways leading to sequestration of nanoATV/r in Rab-associated recycling and late endosomes; sites associated with viral …

Exome Screening To Identify Loss-Of-Function Mutations In The Rhesus Macaque For Development Of Preclinical Models Of Human Disease, Adam Cornish, Robert M. Gibbs, Robert B. Norgren

Journal Articles: Genetics, Cell Biology & Anatomy

BACKGROUND: Exome sequencing has been utilized to identify genetic variants associated with disease in humans. Identification of loss-of-function mutations with exome sequencing in rhesus macaques (Macaca mulatta) could lead to valuable animal models of genetic disease. Attempts have been made to identify variants in rhesus macaques by aligning exome data against the rheMac2 draft genome. However, such efforts have been impaired due to the incompleteness and annotation errors associated with rheMac2. We wished to determine whether aligning exome reads against our new, improved rhesus genome, MacaM, could be used to identify high impact, loss-of-function mutations in rhesus macaques that would …

Low-Dose Aronia Melanocarpa Concentrate Attenuates Paraquat-Induced Neurotoxicity., Adam J. Case, D Agraz, Iman M. Ahmad, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Herbicides containing paraquat may contribute to the pathogenesis of neurodegenerative disorders such as Parkinson's disease. Paraquat induces reactive oxygen species-mediated apoptosis in neurons, which is a primary mechanism behind its toxicity. We sought to test the effectiveness of a commercially available polyphenol-rich Aronia melanocarpa (aronia berry) concentrate in the amelioration of paraquat-induced neurotoxicity. Considering the abundance of antioxidants in aronia berries, we hypothesized that aronia berry concentrate attenuates the paraquat-induced increase in reactive oxygen species and protects against paraquat-mediated neuronal cell death. Using a neuronal cell culture model, we observed that low doses of aronia berry concentrate protected against paraquat-mediated …

Angiotensin Ii-Induced Hypertension Is Attenuated By Overexpressing Copper/Zinc Superoxide Dismutase In The Brain Organum Vasculosum Of The Lamina Terminalis., John P. Collister, Heather Taylor-Smith, Donna Drebes, David Nahey, Jun Tian, Matthew C. Zimmerman

Journal Articles: Cellular & Integrative Physiology

Angiotensin II (AngII) can access the brain via circumventricular organs (CVOs), including the subfornical organ (SFO) and organum vasculosum of the lamina terminalis (OVLT), to modulate blood pressure. Previous studies have demonstrated a role for both the SFO and OVLT in the hypertensive response to chronic AngII, yet it is unclear which intracellular signaling pathways are involved in this response. Overexpression of copper/zinc superoxide dismutase (CuZnSOD) in the SFO has been shown to attenuate the chronic hypertensive effects of AngII. Presently, we tested the hypothesis that elevated levels of superoxide (O2 (∙-)) in the OVLT contribute to the hypertensive effects …