Digital Commons Network^™

Cis-Eqtl-Based Trans-Ethnic Meta-Analysis Reveals Novel Genes Associated With Breast Cancer Risk, Joshua Hoffman, Rebecca Graff, Nima Emami, Caroline Tai, Michael Passarelli

Dartmouth Scholarship

Breast cancer is the most common solid organ malignancy and the most frequent cause of cancer death among women worldwide. Previous research has yielded insights into its genetic etiology, but there remains a gap in the understanding of genetic factors that contribute to risk, and particularly in the biological mechanisms by which genetic variation modulates risk. The National Cancer Institute's "Up for a Challenge" (U4C) competition provided an opportunity to further elucidate the genetic basis of the disease. Our group leveraged the seven datasets made available by the U4C organizers and data from the publicly available UK Biobank cohort to …

The Potential Role Of Antiretroviral Efavirenz In Hiv Associated Neurocognitive Disorders, Lecia Ashanna Moya Brown

USF Tampa Graduate Theses and Dissertations

The prevalence of milder forms of HIV-associated neurocognitive disorders (HAND) is rising despite combination antiretroviral therapy (cART). Efavirenz (EFV) is among the most commonly used antiretroviral drugs globally, but causes neurological symptoms that may interfere with adherence and reduce tolerability, and may have central nervous system (CNS) effects that contribute in part to HAND in patients on cART. Thus we evaluated a commonly used EFV containing regimen: EFV/zidovudine (AZT)/lamivudine (3TC) in murine N2a cells transfected with the human “Swedish” mutant form of amyloid precursor protein (SweAPP N2a cells) to assess for promotion of amyloid-beta (Aβ) production (Chapter 3). Treatment with …

Glioma Stem Cells-Derived Exosomes Promote The Angiogenic Ability Of Endothelial Cells Through Mir-21/Vegf Signal, Xu Sun, Xiaotang Ma, Jinju Wang, Yuhui Zhao, Yue Wang, Ji C. Bihl, Yanfang Chen, Chuanlu Jiang

Pharmacology and Toxicology Faculty Publications

Glioma stem cells (GSCs) play an important role in glioblastoma prognosis. Exosomes (EXs) mediate cell communication by delivering microRNAs (miRs). Glioblastoma has a high level of miR-21 which could upregulate vascular endothelial growth factor (VEGF) expression. We hypothesized GSC-EXs can promote the angiogenic ability of endothelial cells (ECs) through miR-21/VEGF signal. GSCs were isolated from U-251 cells with stem cell marker CD133. GSCs transfected without or with scramble or miR-21 mimics were used to produce GSC-^EXscon, GSC-EXs^sc and GSC-EXs^miR-21. Human brain ECs were co-cultured with vehicle, GSC-EXs^con, GSC-EXs^sc or GSC-EXs^miR-21 plus …

Effects Of Storage Time On Glycolysis In Donated Human Blood Units, Zhen Qi, John D. Roback, Eberhard O. Voit

Toxicology and Cancer Biology Faculty Publications

Background: Donated blood is typically stored before transfusions. During storage, the metabolism of red blood cells changes, possibly causing storage lesions. The changes are storage time dependent and exhibit donor-specific variations. It is necessary to uncover and characterize the responsible molecular mechanisms accounting for such biochemical changes, qualitatively and quantitatively; Study Design and Methods: Based on the integration of metabolic time series data, kinetic models, and a stoichiometric model of the glycolytic pathway, a customized inference method was developed and used to quantify the dynamic changes in glycolytic fluxes during the storage of donated blood units. The method provides a …

Microscopic Examination Of Findings Encountered During Cadaver Dissection: Malignant, Benign Or Anatomic Variation?, Maria Cicioni, Vandi Ly, Guiyun Zhang, Bruce Fenderson

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Pathologic findings encountered during cadaver dissection provide an opportunity for integrating the preclinical basic sciences and encouraging critical thinking. The objective of this study was to determine whether it is possible to make a pathologic diagnosis of an unknown mass from an embalmed cadaver. Diagnoses would have to be based solely on gross and microscopic appearance of tissue, without clinical histories of the cadaveric donors. The tissue samples we removed from each mass were surprisingly well preserved and showed minimal autolysis. Indeed, some of the histological detail was as clear as may be found in any textbook. We were able …

Proteome Dynamics During Postnatal Mouse Corpus Callosum Development., Alexander I Son, Xiaoqin Fu, Fumikazu Suto, Judy S Liu, Kazue Hashimoto-Torii, Masaaki Torii

Pharmacology and Physiology Faculty Publications

Formation of cortical connections requires the precise coordination of numerous discrete phases. This is particularly significant with regard to the corpus callosum, whose development undergoes several dynamic stages including the crossing of axon projections, elimination of exuberant projections, and myelination of established tracts. To comprehensively characterize the molecular events in this dynamic process, we set to determine the distinct temporal expression of proteins regulating the formation of the corpus callosum and their respective developmental functions. Mass spectrometry-based proteomic profiling was performed on early postnatal mouse corpus callosi, for which limited evidence has been obtained previously, using stable isotope of labeled …

Th1 Differentiation Drives The Accumulation Of Intravascular, Non-Protective Cd4 T Cells During Tuberculosis, Michelle A. Sallin, Shunsuke Sakai, Keith D. Kauffman, Howard A. Young, Jinfang Zhu, Daniel L. Barber

United States Public Health Resources

Recent data indicate that the differentiation state of Th1 cells determines their protective capacity against tuberculosis. Therefore, we examined the role of Th1-polarizing factors in the generation of protective and non-protective subsets of Mtb-specific Th1 cells. We find that IL-12/23p40 promotes Th1 cell expansion and maturation beyond the CD73+CXCR3+T-betdim stage, and T-bet prevents deviation of Th1 cells into Th17 cells. Nevertheless, IL- 12/23p40 and T-bet are also essential for the production of a prominent subset of intravascular CX3CR1+KLRG1+ Th1 cells that persists poorly and can neither migrate into the lung parenchyma nor control Mtb growth. Furthermore, T-bet suppresses development of …

Whose Expertise Is It? Evidence For Autistic Adults As Critical Autism Experts, Kristen Gillespie-Lynch, Steven K. Kapp, Patricia J. Brooks, Jonathan Pickens, Ben Schwartzman

Publications and Research

Autistic and non-autistic adults’ agreement with scientific knowledge about autism, how they define autism, and their endorsement of stigmatizing conceptions of autism has not previously been examined. Using an online survey, we assessed autism knowledge and stigma among 636 adults with varied relationships to autism, including autistic people and nuclear family members. Autistic participants exhibited more scientifically based knowledge than others. They were more likely to describe autism experientially or as a neutral difference, and more often opposed the medical model. Autistic participants and family members reported lower stigma. Greater endorsement of the importance of normalizing autistic people was associated …

Week Of March 27, 2017, New York Medical College

InTouch

• Robert M. Califf, M.D., Will Deliver 158th Commencement Address
• Graduate Student Research Forum Showcases Impressive Scientific Work
• NYMC Hosts Women's Heart Health Discussion with Expert Panel
• Nicholas S. Janiga, J.D., Is Named Chief Counsel
• HSL Hosts Exhibit and Special Presentation on Violence Against Women
• Research Day Highlights Scientific Works of Residents

Mass-Spectrometry Based Proteomics Of Age-Related Changes In Murine Microglia, Antwoine Flowers

USF Tampa Graduate Theses and Dissertations

The last century has seen a steady increase in the extension of the average lifespan. This has concomitantly produced higher incidences of age-related chronic degenerative diseases like Alzheimer’s and Parkinson’s diseases. Age is the single greatest risk factor for the development of not just these degenerative conditions but cancer as well. The aged niche undergoes a number of maladaptive changes that allow underlying conditions to present and progress. Exactly which changes, contribute to the progression of which disease is currently an area of intense study. However, these answers often present therapeutic targets for disease prevention. Age is characterized by a …

A Novel Multi-Network Approach Reveals Tissue-Specific Cellular Modulators Of Fibrosis In Systemic Sclerosis, Jaclyn N. Taroni, Casey S. Greene, Viktor Martyanov, Tammara A. Wood

Dartmouth Scholarship

Systemic sclerosis (SSc) is a multi-organ autoimmune disease characterized by skin fibrosis. Internal organ involvement is heterogeneous. It is unknown whether disease mechanisms are common across all involved affected tissues or if each manifestation has a distinct underlying pathology.We used consensus clustering to compare gene expression profiles of biopsies from four SSc-affected tissues (skin, lung, esophagus, and peripheral blood) from patients with SSc, and the related conditions pulmonary fibrosis (PF) and pulmonary arterial hypertension, and derived a consensus disease-associate signature across all tissues. We used this signature to query tissue-specific functional genomic networks. We performed novel network analyses to contrast …

Metabolic And Molecular Insights Into An Essential Role Of Nicotinamide Phosphoribosyltransferase., Li Q. Zhang, Leon Van Haandel, Min Xiong, Peixin Huang, Daniel P. Heruth, Chengpeng Bi, R Gaedigk, Xun Jiang, Ding-You Li, Gerald Wyckoff, Dmitry N. Grigoryev, Li Gao, Linheng Li, Min Wu, J Steven Leeder, Shui Qing Ye

Manuscripts, Articles, Book Chapters and Other Papers

Nicotinamide phosphoribosyltransferase (NAMPT) is a pleiotropic protein implicated in the pathogenesis of acute respiratory distress syndrome, aging, cancer, coronary heart diseases, diabetes, nonalcoholic fatty liver disease, obesity, rheumatoid arthritis, and sepsis. However, the underlying molecular mechanisms of NAMPT in these physiological and pathological processes are not fully understood. Here, we provide experimental evidence that a Nampt gene homozygous knockout (Nampt-/-) resulted in lethality at an early stage of mouse embryonic development and death within 5-10 days in adult mice accompanied by a 25.24±2.22% body weight loss, after the tamoxifen induction of NamptF/F × Cre mice. These results substantiate that Nampt …

Week Of March 20, 2017, New York Medical College

InTouch

• Class of 2017 Earns Choice Residencies at Match Day
• Medical Students Observe GHHS National Solidarity Week for Compassionate Patient Care
• Students Volunteer at 2017 Special Olympics New York State Winter Games
• TCDM Students Participate in ADEA's Hack-a-thon

Coccolithoviruses: A Review Of Cross-Kingdom Genomic Thievery And Metabolic Thuggery, Jozef I. Nissimov, António Pagarete, Fangrui Ma, Sean Cody, David D. Dunigan, Susan A. Kimmance, Michael J. Allen

Nebraska Center for Virology: Faculty Publications

Coccolithoviruses (Phycodnaviridae) infect and lyse the most ubiquitous and successful coccolithophorid in modern oceans, Emiliania huxleyi. So far, the genomes of 13 of these giant lytic viruses (i.e., Emiliania huxleyi viruses—EhVs) have been sequenced, assembled, and annotated. Here, we performed an in-depth comparison of their genomes to try and contextualize the ecological and evolutionary traits of these viruses. The genomes of these EhVs have from 444 to 548 coding sequences (CDSs). Presence/absence analysis of CDSs identified putative genes with particular ecological significance, namely sialidase, phosphate permease, and sphingolipid biosynthesis. The viruses clustered into distinct clades, based on their DNA polymerase …

Cigarette Smoking And Cardio-Renal Events In Patients With Atherosclerotic Renal Artery Stenosis, Christopher A. Drummond, Pamela S. Brewster, Wencan He, Kaili Ren, Yanmei Xie, Katherine R. Tuttle, Steven T. Haller, Kenneth Jamerson, Lance D. Dworkin, Donald E. Cutlip, Timothy P. Murphy, Ralph B. D'Agostino Sr., William L. Henrich, Jiang Tian, Joseph I. Shapiro Md, Christopher J. Cooper

Biochemistry and Microbiology

Cigarette smoking causes cardiovascular disease and is associated with poor kidney function in individuals with diabetes mellitus and primary kidney diseases. However, the association of smoking on patients with atherosclerotic renal artery stenosis has not been studied. The current study utilized data from the Cardiovascular Outcomes in Renal Atherosclerotic Lesions (CORAL, NCT00081731) clinical trial to evaluate the effects of smoking on the risk of cardio-renal events and kidney function in this population. Baseline data showed that smokers (n = 277 out of 931) were significantly younger at enrollment than non-smokers (63.3±9.1 years vs 72.4±7.8 years; p<0.001). In addition, patients who smoke were also more likely to have bilateral renal artery stenoses and peripheral vascular disease (PVD). Longitudinal analysis showed that smokers experienced composite endpoint events (defined as first occurrence of: stroke; cardiovascular or renal death; myocardial infarction; hospitalization for congestive heart failure; permanent renal replacement; and progressive renal insufficiency defined as 30% reduction of GFR from baseline sustained for ≥ 60 days) at a substantially younger age compared to non-smokers (67.1±9.0 versus 76.1±7.9, p<0.001). Using linear regression and generalized linear modeling analysis controlled by age, sex, and ethnicity, smokers had significantly higher cystatin C levels (1.3±0.7 vs 1.2±0.9, p<0.01) whereas creatinine and estimated glomerular filtration rate (eGFR) were not different from non-smokers. From these data we conclude that smoking has a significant association with deleterious cardio-renal outcomes in patients with renovascular hypertension.

Role Of Cytokines And Chemokines In Alcohol-Induced Tumor Promotion, Danlei Chen, Fengyun Zhang, Haifeng Ren, Jia Luo, Siying Wang

Pharmacology and Nutritional Sciences Faculty Publications

Excessive chronic alcohol consumption has become a worldwide health problem. The oncogenic effect of chronic alcohol consumption is one of the leading concerns. The mechanisms of alcohol-induced tumorigenesis and tumor progression are largely unknown, although many factors have been implicated in the process. This review discusses the recent progress in this research area with concentration on alcohol-induced dysregulation of cytokines and chemokines. Based on the available evidence, we propose that alcohol promotes tumor progression by the dysregulation of the cytokine/chemokine system. In addition, we discuss specific transcription factors and signaling pathways that are involved in the action of these cytokines/chemokines …

Latexin Inactivation Enhances Survival And Long-Term Engraftment Of Hematopoietic Stem Cells And Expands The Entire Hematopoietic System In Mice, Yi Liu, Cuiping Zhang, Zhenyu Li, Chi Wang, Jianhang Jia, Tianyan Gao, Gerhard C. Hildebrandt, Daohong Zhou, Subbarao Bondada, Peng Ji, Daret K. St. Clair, Jinze Liu, Chang-Guo Zhan, Hartmut Geiger, Shuxia Wang, Ying Liang

Toxicology and Cancer Biology Faculty Publications

Natural genetic diversity offers an important yet largely untapped resource to decipher the molecular mechanisms regulating hematopoietic stem cell (HSC) function. Latexin (Lxn) is a negative stem cell regulatory gene identified on the basis of genetic diversity. By using an Lxn knockout mouse model, we found that Lxn inactivation in vivo led to the physiological expansion of the entire hematopoietic hierarchy. Loss of Lxn enhanced the competitive repopulation capacity and survival of HSCs in a cell-intrinsic manner. Gene profiling of Lxn-null HSCs showed altered expression of genes enriched in cell-matrix and cell-cell interactions. Thrombospondin 1 (Thbs1 …

A Role Of Central Nell2 In The Regulation Of Feeding Behavior In Rats., Jin Kwon Jeong, Jae Geun Kim, Han Rae Kim, Tae Hwan Lee, Jeong Woo Park, Byung Ju Lee

Pharmacology and Physiology Faculty Publications

A brain-enriched secreting signal peptide, NELL2, has been suggested to play multiple roles in the development, survival, and activity of neurons in mammal. We investigated here a possible involvement of central NELL2 in regulating feeding behavior and metabolism. In situ hybridization and an immunohistochemical approach were used to determine expression of NELL2 as well as its colocalization with proopiomelanocortin (POMC) and neuropeptide Y (NPY) in the rat hypothalamus. To investigate the effect of NELL2 on feeding behavior, 2 nmole of antisense NELL2 oligodeoxynucleotide was administered into the lateral ventricle of adult male rat brains for 6 consecutive days, and changes …

Dynamic Transcriptomes Identify Biogenic Amines And Insect-Like Hormonal Regulation For Mediating Reproduction In Schistosoma Japonicum., Jipeng Wang, Ying Yu, Haimo Shen, Tao Qing, Yuanting Zheng, Qing Li, Xiaojin Mo, Shuqi Wang, Nana Li, Riyi Chai, Bin Xu, Mu Liu, Paul J Brindley, Donald P Mcmanus, Zheng Feng, Leming Shi, Wei Hu

Microbiology, Immunology, and Tropical Medicine Faculty Publications

Eggs produced by the mature female parasite are responsible for the pathogenesis and transmission of schistosomiasis. Female schistosomes rely on a unique male-induced strategy to accomplish reproductive development, a process that is incompletely understood. Here we map detailed transcriptomic profiles of male and female Schistosoma japonicum across eight time points throughout the sexual developmental process from pairing to maturation. The dynamic gene expression pattern data reveal clear sex-related characteristics, indicative of an unambiguous functional division between males and females during their interplay. Cluster analysis, in situ hybridization and RNAi assays indicate that males likely use biogenic amine neurotransmitters through the …

Mammary Epithelial Polarity And Macrophage Infiltration, Ren Xu

Pharmacology and Nutritional Sciences Faculty Publications

Loss of epithelial cell polarity and inflammation are hallmarks of breast cancer development. Although the association between the disruption of tissue polarity and inflammation has been demonstrated, we know little about how these two events are coupled. Using the 3D co-culture model of mammary epithelial cells and monocytes, a recent study reveals a link between disruption of epithelial polarity and monocytes infiltration.

Week Of March 13, 2017, New York Medical College

InTouch

• School of Medicine Hosts Leadership Retreat
• The 21st Annual Medical Student Research Forum Boasts Broad Range of Student Scientific Investigations
• Department of Cell Biology and Anatomy Hosts Annual Research Forum
• Health Sciences Library Hosts Improving Women's Lives Display

P33. Design And Evaluation Of An Escherichia Coli Biomarker For Indication Of Ph, Kevin X. Zhou, Luana Langlois, Ashmita Singh, John Prince

Western Research Forum

Measuring pH is one of the most commonly used techniques in both the laboratory as well as the field due to its importance in a multitude of biochemical processes. Traditional methods of measuring pH may be highly developed in accuracy and precision but often involve disruption of the environment. Biological markers offer an alternative that allows for long-term pH monitoring. This innovative approach allows for vast applications such as in the manufacturing, food processing and research industries. Under moderate acidic conditions, the asr (acid shock RNA) gene is highly inducible and has been demonstrated to be crucial for growth at …

Pulmonary Surfactant Fortified With Cath-2 As A Novel Therapy For Bacterial Pneumonia, Brandon J. Baer

Western Research Forum

Background: Bacterial pneumonia is a leading cause of death worldwide, with high mortality rates persisting even after antibiotic treatment. Current treatments for pneumonia involve administration of antibiotics, however after the bacteria are killed they release toxic substances that induce inflammation and lung dysfunction. Host defense peptides represent a potential solution to this problem through their ability to down regulate inflammation. However, effective delivery to the lung is difficult because of the complex branching structure of the airways. My study addresses this delivery problem by using exogenous surfactant, a pulmonary delivery vehicle capable of improving spreading of these peptides throughout the …

The Effects Of Intrauterine Growth Restriction (Iugr) On The Pulmonary Surfactant And Lung Injury, Reza Khazaee

Western Research Forum

The Effects of Intrauterine Growth Restriction (IUGR) on the Pulmonary Surfactant and Lung Injury

Khazaee R¹, McCaig LA², Hardy D¹, Yamashita CM², Veldhuizen, RAW²

Department of Physiology and Pharmacology¹, Western University, London, ON, Canada. Lawson Health Research Institute², London, ON, Canada

Background: Acute respiratory distress syndrome (ARDS) is defined as severe lung dysfunction that occurs after an insult to the lung such as an infection. The lung dysfunction in ARDS is due to alterations to surfactant, a lipid-protein mixture coats the inside of the lung and …

Capillaries, Old Age And Alzheimer’S Disease, Charles T. Ambrose

Microbiology, Immunology, and Molecular Genetics Faculty Publications

Many of the minor complaints of old age may have a common etiology and are grouped together here under the term ‘the lesser ailments of aging’ (LAA). This essay proposes that they are due in large part to an age-linked reduced microcirculation. Capillary density (CD) in the tissues is determined by levels of angiogenic growth factors (AGFs). Over 47 studies have reported a reduced CD and/or waning AGFs throughout the bodies of aging animals and people. More convincing than such a generalization are the 80 sets of data comparing these two parameters in adult vs. the aged. These data have …

Amidated Dopamine Neuron Stimulating Peptides For Cns Dopaminergic Upregulation, Luke H. Bradley, Don M. Gash, Greg A. Gerhardt

Neuroscience Faculty Patents

The present invention relates to novel proteins, referred to herein as amidated glial cell line-derived neurotrophic factor (GDNF) peptides (or "Amidated Dopamine Neuron Stimulating peptides (ADNS peptides)"), that are useful for treating brain diseases and injuries that result in dopaminergic deficiencies.

Tissue-Specific Mitochondrial Decoding Of Cytoplasmic Ca(2+) Signals Is Controlled By The Stoichiometry Of Micu1/2 And Mcu., Melanie Paillard, György Csordás, Gergö Szanda, Tünde Golenár, Valentina Debattisti, Adam Bartok, Nadan Wang, Cynthia Moffat, Erin L. Seifert, András Spät, György Hajnóczky

Department of Pathology, Anatomy, and Cell Biology Faculty Papers

Mitochondrial Ca(2+) uptake through the Ca(2+) uniporter supports cell functions, including oxidative metabolism, while meeting tissue-specific calcium signaling patterns and energy needs. The molecular mechanisms underlying tissue-specific control of the uniporter are unknown. Here, we investigated a possible role for tissue-specific stoichiometry between the Ca(2+)-sensing regulators (MICUs) and pore unit (MCU) of the uniporter. Low MICU1:MCU protein ratio lowered the [Ca(2+)] threshold for Ca(2+) uptake and activation of oxidative metabolism but decreased the cooperativity of uniporter activation in heart and skeletal muscle compared to liver. In MICU1-overexpressing cells, MICU1 was pulled down by MCU proportionally to MICU1 overexpression, suggesting that …

The Effect Of Object-Centered Instructions In Cartesian And Polar Coordinates On Saccade Vector, Jay A. Edelman, Alexa M. Mieses, Kira Konnova, David Shiu

Publications and Research

Express saccades (ES) are the most reflexive saccadic eye movements, with very short reaction times of 70– 110 ms. It is likely that ES have the shortest saccade reaction times (SRTs) possible given the known physiological and anatomical delays present in sensory and motor systems. Nevertheless, it has been demonstrated that a vector displacement of ES to spatially extended stimuli can be influenced by spatial cognition. Edelman, Kristjansson, and Nakayama (2007) found that when two horizontally separated visual stimuli appear at a random location, the spatial vector, but not the reaction time, of human ES is strongly influenced by an …

Week Of March 6, 2017, New York Medical College

InTouch

• Lasker Award-Winning Virologist Set to Address the 29th Annual Graduate Student Research Forum
• Black History Month Event at Metropolitan Honors NYMC Alumna Myra Adele Logan, M.D. '33
• Officials Talk Shop at BioInc@NYMC

Cool-Associated Tyrosine-Phosphorylated Protein 1 Is Required For The Anchorage-Independent Growth Of Cervical Carcinoma Cells By Binding Paxillin And Promoting Akt Activation., Sungsoo M. Yoo, Arash Latifkar, Richard A. Cerione, Marc A. Antonyak

Department of Biochemistry and Molecular Biology Faculty Papers

Cool-associated tyrosine-phosphorylated protein 1 (Cat-1) is a signaling scaffold as well as an ADP-ribosylation factor-GTPase-activating protein. Although best known for its role in cell migration, we recently showed that the ability of Cat-1 to bind paxillin, a major constituent of focal complexes, is also essential for the anchorage-independent growth of HeLa cervical carcinoma cells. Here we set out to learn more about the underlying mechanism by which Cat-paxillin interactions mediate this effect. We show that knocking down paxillin expression in HeLa cells promotes their ability to form colonies in soft agar, whereas ectopically expressing paxillin in these cells inhibits this …