The Department of Environmental and Occupational Health presents:
"This beautiful, greasy and rusty life: why polyunsaturated lipids were selected?"
Valerian E. Kagan, PhD, DSc
Department of Environmental and Occupational Health
Graduate School of Public Health
University of Pittsburgh
Friday, January 24, 2020
1:00 pm – 2:00 pm
Conference Room 1155 - Public Health
Presenter: Fan Wu
Paper: Influence of Environment and Lifestyle on Incidence and Progress of Amyotrophic Lateral Sclerosis in A German ALS Population
Authors: Sonja Korner, Johanna Kammeyer, Antonia Zapf, Magdalena Kuzma-Kozakiewicz, Maria
Piotrkiewicz, Bożenna Kuraszkiewicz, Hanna Goszczynska, Marta Gromicho, Julian
Grosskreutz, Peter M. Andersen, Mamede de Carvalho, Susanne Petri
Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease mainly affecting upper and
lower motor neurons in the brain and spinal cord. Pathogenesis of ALS is still unclear, and a multifactorial etiology is presumed. The remarkable clinical heterogeneity between different phenotypes of ALS patients suggests that environmental and lifestyle factors could play a role in onset and progression of ALS. We analyzed a cohort of 117 ALS patients and 93 controls. ALS patients and controls were compared regarding physical activity, dietary habits, smoking, residential environment, potentially toxic environmental factors and profession before symptom onset and throughout the disease course. Data were collected by a personal interview. For statistical analysis descriptive statistics, statistical tests and analysis of variance were used. ALS patients and controls did not differ regarding smoking, diet and extent of physical training. No higher frequency of toxic influences could be detected in the ALS group. ALS patients lived in rural environment considerably more often than the control persons, but this was not associated with a higher percentage of occupation in agriculture. There was also a higher percentage of university graduates in the ALS group. Patients with bulbar onset were considerably more often born in an urban environment as compared to spinal onset. Apart from education and environment, ALS phenotypes did not differ in any investigated environmental or life-style factor. The rate of disease progression was not influenced by any of the investigated environmental and life-style factors. The present study could not identify any dietary habit, smoking, physical activity, occupational factor as well as toxic influences as risk factor or protective factor for onset or progression of ALS. Living in rural environment and higher education might be associated with higher incidence of ALS.
Presented by Beth L. Roman, associate professor of human genetics, member of the Heart, Lung, and Blood Vascular Medicine Institute, and basic research director, HHT Center.
Presenter: Jenna Kuhn
Paper: Organophosphorus pesticide chlorpyrifos intake promotes obesity and insulin resistance through impacting gut and gut microbiota
Authors: Yiran Liang, Jing Zhan, Donghui Liu, Mai Luo, Jiajun Han, Xueke Liu, Chang Liu, Zheng Cheng, Zhiqiang Zhou, and Peng Wang
Disruption of the gut microbiota homeostasis may induce low-grade inflammation leading to obesity-associated diseases. A major protective mechanism is to use the multi-layered mucus structures to keep a safe distance between gut epithelial cells and microbiota. To investigate whether pesticides would induce insulin resistance/obesity through interfering with mucus-bacterial interactions, we conducted a study to determine how long-term exposure to chlorpyrifos affected C57Bl/6 and CD-1 (ICR) mice fed high- or normal-fat diets. To further investigate the effects of chlorpyrifos-altered microbiota, antibiotic treatment and microbiota transplantation experiments were conducted.
The results showed that chlorpyrifos caused broken integrity of the gut barrier, leading to increased lipopolysaccharide entry into the body and finally low-grade inflammation, while genetic background and diet pattern have limited influence on the chlorpyrifos-induced results. Moreover, the mice given chlorpyrifos-altered microbiota had gained more fat and lower insulin sensitivity.
Our results suggest that widespread use of pesticides may contribute to the worldwide epidemic of inflammation-related diseases.
Presenter: Brandy Hill
Paper: Ambient black carbon particles reach the fetal side of human placenta
Authors: Hannelore Bové, Eva Bongaerts, Eli Slenders, Esmée M. Bijnens, Nelly D. Saenen, Wilfried Gyselaers, Peter Van Eyken, Michelle Plusquin, Maarten B.J. Roeffaers, Marcel Ameloot & Tim S. Nawrot
Particle transfer across the placenta has been suggested but to date, no direct evidence in real-life, human context exists. Here we report the presence of black carbon (BC) particles as part of combustion-derived particulate matter in human placentae using white-light generation under femtosecond pulsed illumination. BC is identified in all screened placentae, with an average (SD) particle count of 0.95 × 104 (0.66 × 104) and 2.09 × 104 (0.9 × 104) particles per mm3 for low and high exposed mothers, respectively. Furthermore, the placental BC load is positively associated with mothers’ residential BC exposure during pregnancy (0.63 2.42 μg per m3). Our finding that BC particles accumulate on the fetal side of the placenta suggests that ambient particulates could be transported towards the fetus and represents a potential mechanism explaining the detrimental health effects of pollution from early life
Presented by Raina Rippel, director of the SWPA Environmental Health Project and Sarah Rankin, SWPA Environmental Health Project.
Presenter: Kimberly Garrett
Paper: A Cobalt Schiff-base Complex as a Putative Therapeutic for Azide Poisoning
Authors: Hirunwut Praekunatham, Kimberly K Garrett, Yookyung Bae, Andrea A. Cronican, Kristin L. Frawley, Linda Lorraine Pearce, Jim Peterson
There is presently no antidote available to treat azide poisoning. Here, the Schiff-base compound Co(II)-2,12-dimethyl-3,7,11,17-tetraazabicyclo-[11.3.1]heptadeca-1(17)2,11,13,15-pentaenyl dibromide (Co(II)N4[11.3.1]) is investigated to determine if it has the capability to antagonize azide toxicity through a decorporation mechanism. The stopped-flow kinetics of azide binding to Co(II)N4[11.3.1] in the absence of oxygen exhibited three experimentally observable phases: I (fast); II (intermediate); and III (slow). The intermediate phase II accounted for ~70% of the overall absorbance changes, representing the major process observed, with second-order rate constants of 29 (±4) M-1s-1 at 25°C and 70 (±10) M-1s-1 at 37°C. The data demonstrated pH independence of the reaction around neutrality, suggesting the unprotonated azide anion to be the attacking species. The binding of azide to Co(II)N4[11.3.1] appears to have a complicated mechanism leading to less than ideal antidotal capability; but nonetheless, this cobalt complex does protect against azide intoxication. Administration of Co(II)N4[11.3.1] at 5 min post sodium azide injection (ip) to mice resulted in a substantial decrease of righting-recovery times, 12 (±4) min, compared to controls, 40 (±8) min. In addition, only 2 out of 7 mice “knocked down” when the antidote was administered compared to the controls given toxicant only (100% knockdown).
Presented by Bill Chen, associate professor of medicine, director, Small Molecule Therapeutic Center, co-director, Acute Lung Injury Center for Excellence, Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine.
Presenter: Rushikesh Deshpande
Paper: Protein Arginine Methyltransferase 4 (PRMT4) mediates lymphopenia in experimental sepsis
Authors: Yandong Lai, Xiuying Li, Tiao Li, Yan Chen, Chen Long, Toru Nyunoya, Kong Chen,Georgios D. Kitsios,Seyed Mehdi Nouraie,Yingze Zhang, Bryan J. McVerry, Janet S. Lee,Rama K. Mallampalli, and Chunbin Zou
Onehallmark of sepsis is a reduced number of lymphocytes, termed lymphopenia,that occurs from decreased lymphocyte proliferation or increased cell death contributing to immune suppression. Histone modification enzymes regulate immunity by epigenetically modulating chromatin architecture, however, the role of these enzymes in lymphopenia remains elusive. In this study, we identified that a chromatin modulator Protein Arginine N-methyltransferase 4/Coactivator-Associated Arginine Methyltransferase 1 (PRMT4/ CARM1) that is elevated systemically inseptic patients and experimental sepsis, and is crucialfor inducing T-lymphocyte apoptosis.An E3 ubiquitin ligase SCFFBXO9 docks on PRMT4 via a phosphodegron to ubiquitinate the protein at K228 for ubiquitin proteasomal degradation. High PRMT4 expression resulted from reduced levels of SCFFBXO9 that led to increased lymphocyte cell death after Escherichia coliorlipopolysaccharide(LPS) exposure. Ectopic expression of PRMT4 protein caused substantially mphocytedeathvia caspase 3 mediated cell death signaling, and knockout of PRMT4 abolished LPS mediated lymphocyte cell death. PRMT4 inhibition with a small molecule compound attenuated lymphocyte death in complementary models of sepsis. These findings demonstrate a previously uncharacterized role of a key chromatin modulator in lymphocytesurvival that may shed light on devising unique therapeutic modalities to lessen severity of septic immunosuppression.
Paper: Association of Environmental Toxins With Amyotrophic Lateral Sclerosis
Authors: Feng-Chiao Su,PhD; Stephen A. Goutman,MD; Sergey Chernyak,PhD; Bhramar Mukherjee,PhD; Brian C. Callaghan,MD; Stuart Batterman,PhD; Eva L. Feldman,MD,PhD
Persistent environmental pollutants may represent a modifiable risk factor involved in the gene-time-environment hypothesis in amyotrophic lateral sclerosis (ALS).
To evaluate the association of occupational exposures and environmental toxins on the odds of developing ALS in Michigan.
DESIGN, SETTING, AND PARTICIPANTS
Case-control study conducted between 2011 and 2014
at a tertiary referral center for ALS. Cases were patients diagnosed as having definitive,
probable, probable with laboratory support, or possible ALS by revised El Escorial criteria;
controls were excluded if they were diagnosed as having ALS or another neurodegenerative
condition or if they had a family history of ALS in a first- or second-degree blood relative.
Participants completed a survey assessing occupational and residential exposures. Blood
concentrations of 122 persistent environmental pollutants, including organochlorine
pesticides (OCPs), polychlorinated biphenyls (PCBs), and brominated flame retardants
(BFRs), were measured using gas chromatography–mass spectrometry. Multivariable models
with self-reported occupational exposures in various exposure time windows and
environmental toxin blood concentrations were separately fit by logistic regression models.
Concordance between the survey data and pollutant measurements was assessed using the
nonparametric Kendall τ correlation coefficient.
MAIN OUTCOMES AND MEASURES
Occupational and residential exposures to environmental toxins, and blood concentrations of 122 persistent environmental pollutants, including OCPs,
PCBs, and BFRs.
Participants included 156 cases (mean [SD] age, 60.5 [11.1] years; 61.5%male) and 128 controls (mean [SD] age, 60.4 [9.4] years; 57.8%male); among them, 101 cases and 110 controls had complete demographic and pollutant data. Survey data revealed that reported
pesticide exposure in the cumulative exposure windows was significantly associated with ALS
(odds ratio [OR] = 5.09; 95%CI, 1.85-13.99; P = .002). Military service was also associated
with ALS in 2 time windows (exposure ever happened in entire occupational history:
OR = 2.31; 95%CI, 1.02-5.25; P = .046; exposure ever happened 10-30 years ago: OR = 2.18;
95%CI, 1.01-4.73; P = .049). A multivariable model of measured persistent environmental
pollutants in the blood, representing cumulative occupational and residential exposure,
showed increased odds of ALS for 2 OCPs (pentachlorobenzene: OR = 2.57; 95%CI, 1.31-5.02;
P = .006; and cis-chlordane: OR = 6.51; 95%CI, 2.05-20.73; P = .002) and 1 PCB (PCB 151:
OR = 1.66; 95%CI, 1.03-2.67; P = .04. There was modest concordance between survey data
and the measurements of persistent environmental pollutants in blood; significant Kendall τ
correlation coefficients ranged from −0.18 (Dacthal and “use pesticides to treat home or
yard”) to 0.24 (trans-nonachlor and “store lawn care products in garage”).
CONCLUSIONS AND RELEVANCE
In this study, persistent environmental pollutants measured in blood were significantly associated with ALS and may represent modifiable ALS disease risk
Paper: Effects of Perfluorooctanoic Acid on Metabolic Profiles in Brain and Liver of Mouse Revealed by a Highthroughput Targeted Metabolomics Approach
Authors: Nanyang Yu, Si Wei, Meiying Li, Jingping Yang, Kan Li, Ling Jin, Yuwei Xie, John P. Giesy, Xiaowei Zhang & Hongxia Yu
Perfluorooctanoic acid (PFOA), a perfluoroalkyl acid, can result in hepatotoxicity and neurobehavioral effects in animals. The metabolome, which serves as a connection among transcriptome, proteome and toxic effects, provides pathway-based insights into effects of PFOA. Since understanding of changes in the metabolic profile during hepatotoxicity and neurotoxicity were still incomplete, a high-throughput targeted metabolomics approach (278 metabolites) was used to investigate effects of exposure to PFOA for 28 d on brain and liver of male Balb/c mice. Results of multivariate statistical analysis indicated that PFOA caused alterations in metabolic pathways in exposed individuals. Pathway analysis suggested that PFOA affected metabolism of amino acids, lipids, carbohydrates and energetics. Ten and 18 metabolites were identified as potential unique biomarkers of exposure to PFOA in brain and liver, respectively. In brain, PFOA affected concentrations of neurotransmitters, including serotonin, dopamine, norepinephrine, and glutamate in brain, which provides novel insights into mechanisms of PFOA-induced neurobehavioral effects. In liver, profiles of lipids revealed involvement of β-oxidation and biosynthesis of saturated and unsaturated fatty acids in PFOA-induced hepatotoxicity, while alterations in metabolism of arachidonic acid suggesting potential of PFOA to cause inflammation response in liver. These results provide insight into the mechanism and biomarkers for PFOA-induced effects.
Presenter: Yi Lu
Paper: TREM2 Acts Downstream of CD33 in Modulating Microglial Pathology in Alzheimer’s Disease
Authors: Ana Griciuc, Shaun Patel, Anthony N. Federico, ..., Joseph El Khoury, Marco Colonna, Rudolph E. Tanzi
Abstract: The microglial receptors CD33 and TREM2 have been associated with risk for Alzheimer’s disease (AD). Here, we investigated crosstalk between CD33 and TREM2. We showed that knockout of CD33 attenu-ated amyloid beta (Ab) pathology and improved cognition in 5xFAD mice, both of which were abro-gated by additional TREM2 knockout. Knocking out TREM2 in 5xFAD mice exacerbated Ab pathology and neurodegeneration but reduced Iba1+ cell numbers, all of which could not be rescued by addi-tional CD33 knockout. RNA-seq proﬁling of microglia revealed that genes related to phagocytosis and signaling (IL-6, IL-8, acute phase response) are upre-gulated in 5xFAD;CD33 and downregulated in 5xFAD;TREM2 mice. Differential gene expression in 5xFAD;CD33 microglia depended on the pres-ence of TREM2, suggesting TREM2 acts downstream of CD33. Crosstalk between CD33 and TREM2 in-cludes regulation of the IL-1b/IL-1RN axis and a gene set in the ‘‘receptor activity chemokine’’ cluster. Our results should facilitate AD therapeutics target-ing these receptors.
Presenter: Emily Nicholls
Paper: Electronic cigarettes disrupt lung lipid homeostasis and innate immunity independent of nicotine
Authors: Matthew C. Madison, … , David B. Corry, Farrah Kheradmand
Abstract: Electronic nicotine delivery systems (ENDS) or e-cigarettes have emerged as a popular recreational tool among adolescents and adults. Although the use of ENDS is often promoted as a safer alternative to conventional cigarettes, few comprehensive studies have assessed the long-term effects of vaporized nicotine and its associated solvents, propylene glycol (PG) and vegetable glycerin (VG). Here, we show that compared with smoke exposure, mice receiving ENDS vapor for 4 months failed to develop pulmonary inflammation or emphysema. However, ENDS exposure, independent of nicotine, altered lung lipid homeostasis in alveolar macrophages and epithelial cells. Comprehensive lipidomic and structural analyses of the lungs revealed aberrant phospholipids in alveolar macrophages and increased surfactant-associated phospholipids in the airway. In addition to ENDS-induced lipid deposition, chronic ENDS vapor exposure downregulated innate immunity against viral pathogens in resident macrophages. Moreover, independent of nicotine, ENDS-exposed mice infected with influenza demonstrated enhanced lung inflammation and tissue damage. Together, our findings reveal that chronic e-cigarette vapor aberrantly alters the physiology of lung epithelial cells and resident immune cells and promotes poor response to infectious challenge. Notably, alterations in lipid homeostasis and immune impairment are independent of nicotine, thereby warranting more extensive investigations of the vehicle solvents used in e-cigarettes.
Presenter: Qi Wei
Paper: Maternal vitamin C regulates reprogramming of DNA methylation and germline development
Authors: Stephanie P. Ditroia, Michelle Percharde, Marie-Justine Guerquin, estelle Wall, evelyne Collignon, Kevin t. ebata, Kathryn Mesh, Swetha Mahesula, Michalis Agathocleous, Diana J. Laird, Gabriel Livera & Miguel Ramalho-Santos
Abstract: Development is often assumed to be hardwired in the genome, but several lines of evidence indicate that it is susceptible to environmental modulation with potential long-term consequences, including in mammals1,2. The embryonic germline is of particular interest because of the potential for intergenerational epigenetic effects. The mammalian germline undergoes extensive DNA demethylation3–7 that occurs in large part by passive dilution of methylation over successive cell divisions, accompanied by active DNA demethylation by TET enzymes3,8–10. TET activity has been shown to be modulated by nutrients and metabolites, such as vitamin C11–15. Here we show that maternal vitamin C is required for proper DNA demethylation and the development of female fetal germ cells in a mouse model. Maternal vitamin C deficiency does not affect overall embryonic development but leads to reduced numbers of germ cells, delayed meiosis and reduced fecundity in adult offspring. The transcriptome of germ cells from vitamin-C-deficient
embryos is remarkably similar to that of embryos carrying a null mutation in Tet1. Vitamin C deficiency leads to an aberrant DNA methylation profile that includes incomplete demethylation of key regulators of meiosis and transposable elements. These findings reveal that deficiency in vitamin C during gestation partially recapitulates loss of TET1, and provide a potential intergenerational mechanism for adjusting fecundity to environmental conditions
Presenter: Heng Bai
Paper: Muscle-generated BDNF is a sexually dimorphic myokine that controls metabolic flexibility
Authors: Xiuying Yang, Daniel Brobst, Wing Suen Chan, Margaret Chui Ling Tse, Oana Herlea-Pana, Palak Ahuja, Et. Al.
Abstract: The ability of skeletal muscle to switch between lipid and glucose oxidation for ATP production during metabolic stress is pivotal for maintaining systemic energy homeostasis, and dysregulation of this metabolic flexibility is a dominant cause of several metabolic disorders. However, the molecular mechanism that governs fuel selection in muscle is not well understood. Here, we report that brain-derived neurotrophic factor (BDNF) is a fasting-induced myokine that controls metabolic reprograming through the AMPK/CREB/PGC-1 pathway in female mice. Female mice with a muscle-specific deficiency in BDNF (MBKO mice) were unable to switch the predominant fuel source from carbohydrates to fatty acids during fasting, which reduced ATP production in muscle. Fasting-induced muscle atrophy was also compromised in female MBKO mice, likely a result of autophagy inhibition. These mutant mice displayed myofiber necrosis, weaker muscle strength, reduced locomotion, and muscle-specific insulin resistance. Together, our results show that muscle-derived BDNF facilitates metabolic adaption during nutrient scarcity in a gender-specific manner and that insufficient BDNF production in skeletal muscle promotes the development of metabolic myopathies and insulin resistance
Presenter: Meghan Matlack
Paper: The current and future global distribution and population at risk of dengue
Authors: Jane P. Messina, Oliver J. Brady, Nick Golding, Moritz U. G. Kraemer, G. R. William Wint, Sarah E. Ra, Et. Al.
Abstract: Dengue is a mosquito-borne viral infection that has spread throughout the tropical world over the past 60 years and now affects over half the world’s population. The geographical range of dengue is expected to further expand due to ongoing global phenomena including climate change and urbanization. We applied statistical mapping techniques to the most extensive database of case locations to date to predict global environmental suitability for the virus as of 2015. We then made use of climate, population and socioeconomic projections for the years 2020, 2050 and 2080 to project future changes in virus suitability and human population at risk. This study is the first to consider the spread of Aedes mosquito vectors to project dengue suitability. Our projections provide a key missing piece of evidence for the changing global threat of vector-borne disease and will help decision-makers worldwide to better prepare for and respond to future changes in dengue risk.
Presenter: Tengziyi Ge
Paper: Mutations in the nuclear bile acid receptor FXR cause progressive familial intrahepatic cholestasis
Authors: Natalia Gomez-Ospina, Carol J. Potter, Rui Xiao, Kandamurugu Manickam, Mi-Sun Kim, Kang Ho Kim, Benjamin L. Shneider, Et. Al.
Abstract: Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression. Our ﬁndings demonstrate a pivotal function for FXR in bile acid homeostasis and liver protection
Presenter: Shuangjia Xue
Paper: Environmental allergens induce allergic inflammation through proteolytic maturation of IL-33
Authors: Corinne Cayrol, Anais Duval, Pauline Schmitt, Stephane Roga, Mylène Camus, Alexandre Stella, Odile Burlet-Schiltz, Anne Gonzalez-de-Peredo and Jean-Philippe Girard
Abstract: Allergic inflammation has crucial roles in allergic diseases such as asthma. It is therefore important to understand why and how the immune system responds to allergens. Here we found that full-length interleukin 33 (IL-33FL), an alarmin cytokine with critical roles in type 2 immunity and asthma, functioned as a protease sensor that detected proteolytic activities associated with various environmental allergens across four kingdoms, including fungi, house dust mites, bacteria and pollens. When exposed to allergen proteases, IL-33FL was rapidly cleaved in its central ‘sensor’ domain, which led to activation of the production of type 2 cytokines in group 2 innate lymphoid cells. Preventing cleavage of IL-33FL reduced allergic airway inflammation. Our findings reveal a molecular mechanism for the rapid induction of allergic type 2 inflammation following allergen exposure, with important implications for allergic diseases.
Presenter: Brandy Hill
Paper: Particle Depletion Does Not Remediate Acute Effects of Traffic-related Air Pollution and Allergen. A Randomized, Double-Blind Crossover Study
Authors: Denise J. Wooding, Min Hyung Ryu, Anke Huls, Andrew D. Lee, David T. S. Lin, Christopher F. Rider, Agnes C. Y. Yuen, and Chris Carlsten
Rationale: Diesel exhaust (DE), an established model of trafficrelated
air pollution, contributes significantly to the global burden of
asthma and may augment the effects of allergen inhalation. Newer
diesel particulate-filtering technologies may increaseNO2 emissions,
raising questions regarding their effectiveness in reducing harm from
associated engine output.
Objectives: To assess the effects of DE and allergen coexposure on
lung function, airway responsiveness, and circulating leukocytes, and
determine whether DE particle depletion remediates these effects.
Methods: In this randomized, double-blind crossover study, 14
allergen-sensitized participants (9 with airway hyperresponsiveness)
underwent inhaled allergen challenge after 2-hour exposures to DE,
particle-depleted DE (PDDE), or filtered air. The control condition
was inhaled saline after filtered air. Blood sampling and spirometry
were performed before and up to 48 hours after exposures. Airway
responsiveness was evaluated at 24 hours.
Measurements and Main Results: PDDE plus allergen
coexposure impaired lung function more than DE plus allergen,
particularly in those genetically at risk. DE plus allergen and PDDE
plus allergen each increased airway responsiveness in normally
responsive participants.DEplus allergen increased blood neutrophils
and was associated with persistent eosinophilia at 48 hours. DE and
PDDE each increased total peripheral leukocyte counts in a manner
affected by participant genotypes. Changes in peripheral leukocytes
correlated with lung function decline.
Conclusions: Coexposure to DE and allergen impaired lung
function, which was worse after particle depletion (which increased
NO2). Thus, particulates are not necessarily the sole or main
culprit responsible for all harmful effects of DE. Policies and
technologies aimed at protecting public health should be scrutinized
in that regard.
Clinical trial registered with www.clinicaltrials.gov (NCT02017431).
Keywords: diesel exhaust; asthma; filter; genetic susceptibility
Paper: Antidotal Action of Some Gold(I) Complexes toward Phosphine Toxicity
Authors: Kimberly K. Garrett, Kristin L. Frawley, Samantha Carpenter Totoni, Yookyung Bae, Jim Peterson, and Linda L. Pearce
Abstract: Phosphine (PH3) poisoning continues to be a serious problem worldwide, for which there is no antidote currently available. An invertebrate model for examining potential toxicants and their putative antidotes has been used to determine if a strategy of using Au(I) complexes as phosphinescavenging compounds may be antidotally beneficial. When Galleria mellonella larvae (or wax worms) were subjected to phosphine exposures of 4300 (±700) ppm·min over a 20 min time span, they became immobile (paralyzed) for ∼35 min. The administration of Au(I) complexes auro-sodium bisthiosulfate (AuTS), aurothioglucose (AuTG), and sodium aurothiomalate (AuTM) 5 min prior to phosphine exposure resulted in a drastic reduction in the recovery time (0−4 min). When the putative antidotes were given 10 min after the phosphine exposure, all the antidotes were therapeutic, resulting in mean recovery times of 14, 17, and 19 min for AuTS, AuTG, and AuTM, respectively. Since AuTS proved to be the best therapeutic agent in the G. mellonella model, it was subsequently tested in mice using a behavioral assessment (pole-climbing test). Mice given AuTS (50 mg/kg) 5 min prior to a 3200 (±500) ppm·min phosphine exposure exhibited behavior comparable to mice not exposed to phosphine. However, when mice were given a therapeutic dose of AuTS
The 33rd Annual Meeting of the Allegheny-Erie Society of Toxicology Regional Chapter will focus on new approaches to hazard identification and risk assessment, as well as alternative models and modeling for toxicity testing and exposure assessment.
Murder, Suicide, Warfare, Old Myths And New Uncertainties In the Search For Improved Antidotes To Cyanide Poisoning
Presenter: Antonella Marrocco
Paper: Nuclear Receptor Nur77 Limits the Macrophage Inflammatory Response through Transcriptional Reprogramming of Mitochondrial Metabolism
Authors: Duco Steven Koenis, Lejla Medzikovic, Pieter Bas van Loenen, ... , Wilbert Zwart,
Eric Kalkhoven, Carlie Jacoba de Vries
Abstract: Koenis et al. show that nuclear receptor Nur77 regulates the reprogramming of mitochondrial metabolism in inflammatory macrophages. Nur77-deficient macrophages accumulate higher levels of succinate and produce more pro-inflammatory cytokines and nitric oxide in a succinate dehydrogenase-dependent manner. In vivo, bone marrow Nur77 deficiency exacerbates atherosclerosis and increases circulating succinate levels.
Presenter: Grace Tengziyi Ge
Paper: Marine n−3 Fatty Acids and Prevention of Cardiovascular Disease and Cancer
Authors: JoAnn E. Manson, M.D., Dr.P.H., Nancy R. Cook, Sc.D., I‑Min Lee, M.B., B.S., Sc.D., William Christen, Sc.D., Shari S. Bassuk, Sc.D., Samia Mora, M.D., M.H.S.,Heike Gibson, Ph.D., Christine M. Albert, M.D.,M.P.H., David Gordon, M.A.T.,Trisha Copeland, M.S., R.D., Denise D’Agostino, B.S., Georgina Friedenberg, M.P.H., Claire Ridge, M.P.H., Vadim Bubes, Ph.D., Edward L. Giovannucci, M.D., Sc.D., Walter C. Willet, M.D., Dr.P.H., and Julie E. Buring, Sc.D.,
Higher intake of marine n−3 (also called omega-3) fatty acids has been associated with reduced risks of cardiovascular disease and cancer in several observational studies. Whether supplementation with n−3 fatty acids has such effects in general populations at usual risk for these end points is unclear.
We conducted a randomized, placebo-controlled trial, with a two-by-two factorial design, of vitamin D3 (at a dose of 2000 IU per day) and marine n−3 fatty acids (at a dose of 1 g per day) in the primary prevention of cardiovascular disease and cancer among men 50 years of age or older and women 55 years of age or older in the United States. Primary end points were major cardiovascular events (a composite of myocardial infarction, stroke, or death from cardiovascular causes) and invasive cancer of any type. Secondary end points included individual components of the composite cardiovascular end point, the composite end point plus coronary revascularization (expanded composite of cardiovascular events), site-specific cancers, and death from cancer. Safety was also assessed. This article reports the results of the comparison of n−3 fatty acids with placebo.
A total of 25,871 participants, including 5106 black participants, underwent randomization. During a median follow-up of 5.3 years, a major cardiovascular event occurred in 386 participants in the n−3 group and in 419 in the placebo group (hazard ratio, 0.92; 95% confidence interval [CI], 0.80 to 1.06; P = 0.24). Invasive cancer was diagnosed in 820 participants in the n−3 group and in 797 in the placebo group (hazard ratio, 1.03; 95% CI, 0.93 to 1.13; P = 0.56). In the analyses of key secondary end points, the hazard ratios were as follows: for the expanded composite end point of cardiovascular events, 0.93 (95% CI, 0.82 to 1.04); for total myocardial infarction, 0.72 (95% CI, 0.59 to 0.90); for total stroke, 1.04 (95% CI, 0.83 to 1.31); for death from cardiovascular causes, 0.96 (95% CI, 0.76 to 1.21); and for death from cancer (341 deaths from cancer), 0.97 (95% CI, 0.79 to 1.20). In the analysis of death from any
cause (978 deaths overall), the hazard ratio was 1.02 (95% CI, 0.90 to 1.15). No excess risks of bleeding or other serious adverse events were observed.
Supplementation with n−3 fatty acids did not result in a lower incidence of major cardiovascular events or cancer than placebo. (Funded by the National Institutes of Health and others; VITAL ClinicalTrials.gov number, NCT01169259.)
Presenter: Nicole Shuangjia Xue
Paper: Maternal phthalate exposure promotes allergic airway inflammation over 2 generations through epigenetic modifications
Authors: Susanne Jahreis, PhD, Saskia Trump, PhD, Mario Bauer, MD, Tobias Bauer, PhD,c Loreen Th€urmann, MSc, Ralph Feltens, PhD, Qi Wang, PhD, Lei Gu, PhD, Konrad Gr€utzmann, PhD, Stefan R€oder, PhD, Marco Averbeck, MD, Dieter Weichenhan, PhD, Christoph Plass, PhD, Ulrich Sack, MD, Michael Borte, MD, Virginie Dubourg, MSc, Gerrit Sch€u€urmann, PhD, Jan C. Simon, MD, Martin von Bergen, PhD, J€org Hackerm€uller, PhD,h Roland Eils, PhD, Irina Lehmann, PhD, and Tobias Polte, PhD
Background: Prenatal and early postnatal exposures to environmental factors are considered responsible for the increasing prevalence of allergic diseases. Although there is some evidence for allergy-promoting effects in children because of exposure to plasticizers, such as phthalates, findings of previous studies are inconsistent and lack mechaistic information.
Objective: We investigated the effect of maternal phthalate exposure on asthma development in subsequent generations and their underlying mechanisms, including epigenetic alterations.
Methods: Phthalate metabolites were measured within the prospective mother-child cohort Lifestyle and Environmental Factors and Their Influence on Newborns Allergy Risk (LINA) and correlated with asthma development in the children. A murine transgenerational asthma model was used to identify involved pathways.
Results: In LINA maternal urinary concentrations of mono-nbutyl phthalate, a metabolite of butyl benzyl phthalate (BBP), were associated with an increased asthma risk in the children. Using a murine transgenerational asthma model, we demonstrate a direct effect of BBP on asthma severity in the offspring with a persistently increased airway inflammation up to the F2 generation. This disease-promoting effect was mediated by BBP-induced global DNA hypermethylation in CD41 T cells of the offspring because treatment with a DNA-demethylating agent alleviated exacerbation of allergic
airway inflammation. Thirteen transcriptionally downregulated genes linked to promoter or enhancer hypermethylation were identified. Among these, the GATA-3 repressor zinc finger protein 1 (Zfpm1) emerged as a potential mediator of the enhanced susceptibility for TH2-driven allergic asthma.
Conclusion: These data provide strong evidence that maternal BBP exposure increases the risk for allergic airway inflammation in the offspring by modulating the expression of genes involved in TH2 differentiation through epigenetic alterations. (J Allergy Clin Immunol 2018;141:741-53.)
Presenter: Pattra Chun-On
Paper: Dysfunctional CD8 T Cells Form a Proliferative, Dynamically Regulated Compartment within Human Melanoma
Authors: Hanjie Li, Anne M. van der Leun, Ido Yofe, Yaniv Lubling, ..., Ton N. Schumacher, Amos Tanay, Ido Amit
Single-cell analysis of melanoma tumor immune infiltrates reveals a separation between bystander cytotoxic T cells and a population that displays a continuous progression from a transitional toward a dysfunctional state that is associated with active proliferation and tumor reactivity.
Paper: Inhibition of Mevalonate Pathway Prevents Adipocyte Browning in Mice and Men by Affecting Protein Prenylation
Authors: Miroslav Balaz, Anton S. Becker, Lucia Balazova, ..., Matthias Johannes Betz, Irene A. Burger, Christian Wolfrum
Through genetic and pharmacological in vivo and in vitro approaches, Balaz et al. show that the mevalonate pathway is important for adipocyte browning. The importance of this pathway is supported by a retrospective clinical study and a small volunteer trial with fluvastatin. The authors identify geranylgeranyl pyrophosphate as the key mevalonate intermediate driving adipocyte browning.
Presenter: Emma Yi Lu
Paper: Exposure to Secondhand Smoke and Arrhythmogenic Cardiac Alternans in a Mouse Model
Authors: Zhen Wang, Lianguo Wang, Srinivas Tapa, Kent E. Pinkerton, Chao-Yin Chen, and Crystal M. Ripplinger
BACKGROUND: Epidemiological evidence suggests that a majority of deaths attributed to secondhand smoke (SHS) exposure are cardiovascular related. However, to our knowledge, the impact of SHS on cardiac electrophysiology, Ca2þ handling, and arrhythmia risk has not been studied.
OBJECTIVES: The purpose of this study was to investigate the impact of an environmentally relevant concentration of SHS on cardiac electrophysiology and indicators of arrhythmia.
METHODS: Male C57BL/6 mice were exposed to SHS . Hearts were excised and Langendorﬀ perfused for dual optical mapping with voltage- and Ca2þ-sensitive dyes.
RESULTS:At slow pacing rates, SHS exposure did not alter baseline electrophysiological parameters. With increasing pacing frequency, action potential duration (APD), and intracellular Ca2þ alternans magnitude progressively increased in all groups. At 4 and 8 wk, there were no statistical diﬀerences in APD or Ca2þ alternans magnitude between SHS and FA groups. At 12 wk, both APD and Ca2þ alternans magnitude were signiﬁcantly increased in the SHS compared to FA group (p<0 :05). SHS exposure did not impact the time constant of Ca2þ transient decay (s) at any exposure time point. At 12 wk exposure, the recovery of Ca2þ transient amplitude with premature stimuli was slightly (but nonsigniﬁcantly) delayed in SHS compared to FA hearts, suggesting that Ca2þ release via ryanodine receptors may be impaired.
CONCLUSIONS: In male mice, chronic exposure to SHS at levels relevant to social situations in humans increased their susceptibility to cardiac alternans, a known precursor to ventricular arrhythmia
Catch Dr. Rachel Miller of Columbia University's Irving Medical Center address what you (and your grandchildren) need to know about air pollution, epigenetic regulation, and asthma. Venue: 1195 Biomedical Sciences Tower
Presented by Bernard D. Goldstein, dean emeritus and professor emeritus of environmental and occupational health.
Paper: Role of NS1 antibodies in the pathogenesis of acute secondary dengue infection
Authors: Deshni Jayathilaka, Laksiri Gomes, Chandima Jeewandara, Geethal.S.Bandara Jayarathna, et. Al
The role of NS1-speciﬁc antibodies in the pathogenesis of dengue virus infection is poorly understood. Here we investigate the immunoglobulin responses of patients with dengue fever (DF) and dengue hemorrhagic fever (DHF) to NS1. Antibody responses to recombinant-NS1 are assessed in serum samples throughout illness of patients with acute secondary DENV1 and DENV2 infection by ELISA. NS1 antibody titres are signiﬁcantly higher in patients with DHF compared to those with DF for both serotypes, during the critical phase of illness. Furthermore, during both acute secondary DENV1 and DENV2 infection, the antibody repertoire of DF and DHF patients is directed towards distinct regions of the NS1 protein. In addition, healthy individuals, with past non-severe dengue infection have a similar antibody repertoire as those with mild acute infection (DF). Therefore, antibodies that target speciﬁc NS1 epitopes could predict disease severity and be of potential beneﬁt in aiding vaccine and treatment design.
Fan Wu presented a paper on the association of dairy intake with cardiovascular disease and mortality in 21 countries from five continents (PURE): a prospective cohort study which found that dairy consumption was associated with lower risk of mortality and major cardiovascular disease events in a diverse multinational cohort.
Paper: Toll-like Receptor 4 Pathway Polymorphisms Interact with Pollution to Influence Asthma Diagnosis and Severity
Authors: Shepherd H. Schurman, Mercedes A. Bravo, Cynthia L. Innes, W. Braxton Jackson, II, John A. McGrath, Marie Lynn Miranda, and Stavros Garantziotis
Asthma is a common chronic lung disease, the incidence and severity of which may be influenced by gene-environment interactions. Our objective was to examine associations between single nucleotide polymorphisms (SNPs) and combinations of SNPs in the toll-like receptor 4 (TLR4) pathway, residential distance to roadway as a proxy for traffic-related air pollution exposure, and asthma diagnosis and exacerbations. We obtained individual-level data on genotype, residential address, and asthma diagnosis and exacerbations from the Environmental Polymorphisms Registry. Subjects (n = 2,704) were divided into three groups (hyper-responders, hypo-responders, and neither) based on SNP combinations in genes along the TLR4 pathway. We geocoded subjects and calculated distance, classified as <250 m or ≥250 m, between residence and nearest major road. Relationships between genotype, distance to road, and odds of asthma diagnosis and exacerbations were examined using logistic regression. Odds of an asthma diagnosis among hyper-responders <250 m from a major road was 2.37(0.97, 6.01) compared to the reference group (p < 0.10). Hypo-responders ≥250 m from the nearest road had lower odds of activity limitations (0.46 [0.21, 0.95]) and sleeplessness (0.36 [0.12, 0.91]) compared to neither-responders (p < 0.05). Specific genotype combinations when combined with an individual’s proximity to roadways, possibly due to traffic-related air pollution exposure, may affect the likelihood of asthma diagnosis and exacerbations.
Presented by Sarah Haig, assistant professor of civil and environmental engineering at Pitt.
Presenter: Omar Tahtamooni
Paper: All-cause mortality risk associated with long-term exposure to ambient PM2.5 in China: a cohort study
Authors: Tiantian Li, Yi Zhang, Jiaonan Wang, Dandan Xu, Zhaoxue Yin, Huashuai Chen, Yuebin Lv, Jiesi Luo, Yi Zeng, Yang Liu, Patrick L Kinney, Xiaoming S
Background Evidence from cohort studies in North America and Europe indicates that long-term exposure to fine particulate matter (PM₂·₅) is associated with an increased mortality risk. However, this association has rarely been quantified at higher ambient concentrations. We estimated the hazard ratio (HR) for all-cause mortality from longterm exposure to PM₂·₅ in a well established Chinese cohort of older adults.
Methods The Chinese Longitudinal Healthy Longevity Survey (CLHLS) is a prospective cohort study of men and women aged 65 years and older enrolled in 2008 and followed up through 2014 for mortality events. We studied individuals for whom residential locations were available in 2008 for linkage to 1 km grids of PM₂·₅ concentrations, derived from satellite remote sensing. Cox proportional hazards models were used to estimate the effect of long-term exposure to PM₂·₅ on all-cause mortality, controlling for age, sex, smoking status, drinking status, physical activity, body-mass index, household income, marital status, and education. We then used our results to estimate premature mortality related to PM₂·₅ exposure in the population aged 65 years and older in China in 2010.
Findings 13 344 individuals in the CLHLS cohort had data for all timepoints, yielding follow-up data for 49 440 person-years. In a 3-year window, these individuals were exposed to a median PM₂·₅ concentration of 50∙7 μg/m³ (range 6∙7–113∙3). The overall HR for a 10 μg/m³ increase in this value was 1∙08 (95% CI 1∙06–1∙09). In stratified analyses, HRs were higher in rural than in urban locations, in southern versus northern regions, and with exposure to lower versus higher PM₂·₅ concentrations. Based on the overall HR, we estimated that 1 765 820 people aged 65 years and older in China in 2010 had premature mortality related to PM₂·₅ exposure.
Interpretation Long-term exposure to PM₂·₅ is associated with an increased risk of all-cause mortality among adults aged 65 years and older in China, but the magnitude of the risk declines as the concentration of PM₂·₅ increases
James Fabisiak presents: A Risk-Based Model to Assess Environmental Justice and Coronary Heart Disease Burden from Air Pollution in Allegheny County. How Many Angels Can Dance on a PM2.5?
Paper: Metal Concentrations in e-Cigarette Liquid and Aerosol Samples: The Contribution of Metallic Coils
Authors: Pablo Olmedo, Walter Goessler, Stefan Tanda, Maria Grau-Perez, Stephanie Jarmul, Angela Aherrera, Rui Chen, Markus Hilpert, Joanna E. Cohen, Ana Navas-Acien, and Ana M. Rul
BACKGROUND: Electronic cigarettes (e-cigarettes) generate an aerosol by heating a solution (e-liquid) with a metallic coil. Whether metals are transferred from the coil to the aerosol is unknown.
OBJECTIVE:Our goal was to investigate the transfer of metals from the heating coil to the e-liquid in the e-cigarette tank and the generated aerosol.
METHODS: We sampled 56 e-cigarette devices from daily e-cigarette users and obtained samples from the reﬁlling dispenser, aerosol, and remaining e-liquid in the tank. Aerosol liquid was collected via deposition of aerosol droplets in a series of conical pipette tips. Metals were reported as mass fractions (lg=kg) in liquids and converted to mass concentrations (mg=m3) for aerosols.
RESULTS: Median metal concentrations (lg=kg) were higher in samples from the aerosol and tank vs. the dispenser (all p<0 :001): 16.3 and 31.2 vs. 10.9 for Al; 8.38 and 55.4 vs. <0:5 for Cr; 68.4 and 233 vs. 2.03 for Ni; 14.8 and 40.2 vs. 0.476 for Pb; and 515 and 426 vs. 13.1 for Zn. Mn, Fe, Cu, Sb, and Sn were detectable in most samples. Cd was detected in 0.0, 30.4, and 55.1% of the dispenser, aerosol, and tank samples respectively. Arsenic was detected in 10.7% of dispenser samples (median 26:7 lg=kg) and these concentrations were similar in aerosol and tank samples. Aerosol mass concentrations (mg=m3) for the detected metals spanned several orders of magnitude and exceeded current health-based limits in close to 50% or more of the samples for Cr, Mn, Ni, and Pb.
CONCLUSIONS: Our ﬁndings indicate that e-cigarettes are a potential source of exposure to toxic metals (Cr, Ni, and Pb), and to metals that are toxic when inhaled (Mn and Zn). Markedly higher concentrations in the aerosol and tank samples versus the dispenser demonstrate that coil contact induced e-liquid contamination
Presenter: Amrita Sahu
Paper: Age-related declines in α-Klotho drive progenitor cell mitochondrial dysfunction and impaired muscle regeneration
Authors: A. Sahu, H. Mamiya, S.N. Shinde, A. Cheikhi,...
Abstract: While young muscle is capable of restoring the original architecture of damaged myoﬁbers, aged muscle displays a markedly reduced regeneration. We show that expression of the “anti-aging” protein, α-Klotho, is up-regulated within young injured muscle as a result of transient Klotho promoter demethylation. However, epigenetic control of the Klotho promoter is lost with aging. Genetic inhibition of α-Klotho in vivo disrupted muscle progenitor cell (MPC) lineage progression and impaired myoﬁber regeneration, revealing a critical role for αKlotho in the regenerative cascade. Genetic silencing of Klotho in young MPCs drove mitochondrial DNA (mtDNA) damage and decreased cellular bioenergetics. Conversely, supplementation with α-Klotho restored mtDNA integrity and bioenergetics of aged MPCs to youthful levels in vitro and enhanced functional regeneration of aged muscle in vivo in a temporally-dependent manner. These studies identify a role for α-Klotho in the regulation of MPC mitochondrial function and implicate α-Klotho declines as a driver of impaired muscle regeneration with age.
Title of the dissertation: "How organisms lacking oxidizable lipids utilize lipid peroxidation for signaling: lipidomics approach."
Advisor: Valerian E. Kagan, PhD, DSc, Professor, Department of Environmental and Occupational Health
Committee members and departments:
Bruce R. Pitt, PhD, Professor, Department of Environmental and Occupational Health
Hülya Bayır, MD, Professor, Departments of Critical Care Medicine and Environmental and Occupational Health
Joel S. Greenberger, MD, FACRO, FACR, Professor and Chairman, Department of Radiation Oncology
Exercise stimulates the release of molecules into the circulation, supporting the concept that inter-tissue signaling proteins are important mediators of adaptations to exercise. Recognizing that many circulating proteins are packaged in extracellular vesicles (EVs), we employed quantitative proteomic techniques to characterize the exercise-induced secretion of EV-contained proteins.
Heng Bai will present The association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population by Xiao Chen, Zhongqiu Wang, Guoying Zhu, Gunnar F. Nordberg, Taiyi Jin & Xiaoqiang Ding.
Bone is one of the target organs for cadmium toxicity. However, few studies have shown the association between cumulative cadmium intake and prevalence of osteoporosis and bone fracture. In the present study, the authors evaluated the association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population.
Hirunwut Praekunatham, MD, MPH
Chair - International Clinical Research Centre
Principle Investigator - Translational Ageing and Neuroscience Program,
Centre for Translational Medicine
International Clinical Research Centre, St. Anne's University Hospital
Brno, Czech Republic
Dr. Steven Cohen of the Earth Institute at Columbia University will discuss how to address the global climate crisis by taking on political, organizational, and financial challenges as we transition economies from fossil fuels to renewable resources. Reserve a seat online for this free lecture in the Pitt Honors College Climate Change Series.
EOH Journal Club Seminar - Spring 2018
Date: Thursday February 1, 2018
Time: 11am - 12pm
Presenter: Qiao Lin
Paper: Ion channels enable electrical communication in bacterial communities
Authors: Prindle A, Liu J, Asally M, Ly S, Garcia-Ojalvo J, Süel GM
Abstract: The study of bacterial ion channels has provided fundamental insights into the structural basis of neuronal signaling; however, the native role of ion channels in bacteria has remained elusive. Here we show that ion channels conduct long-range electrical signals within bacterial biofilm communities through spatially propagating waves of potassium. These waves result from a positive feedback loop, in which a metabolic trigger induces release of intracellular potassium, which in turn depolarizes neighbouring cells. Propagating through the biofilm, this wave of depolarization coordinates metabolic states among cells in the interior and periphery of the biofilm. Deletion of the potassium channel abolishes this response. As predicted by a mathematical model, we further show that spatial propagation can be hindered by specific genetic perturbations to potassium channel gating. Together, these results demonstrate a function for ion channels in bacterial biofilms, and provide a prokaryotic paradigm for active, long-range electrical signaling in cellular communities
EOH Journal Club Seminar - Spring 2017
Date: Thursday February 2, 2017
Time: 11am - 12pm
Presenter: Rahel Birru
Paper: Airway bacteria drive a progressive COPD-like phenotype in mice with polymeric immunoglobulin receptor deficiency
Richmond BW, Brucker RM, Han W, Du RH, Zhang Y, Cheng DS, Gleaves L,
Abdolrasulnia R, Polosukhina D, Clark PE, Bordenstein SR, Blackwell TS,
Abstract: Mechanisms driving persistent airway
inflammation in chronic obstructive pulmonary disease (COPD) are
incompletely understood. As secretory immunoglobulin A (SIgA) deficiency
in small airways has been reported in COPD patients, we hypothesized
that immunobarrier dysfunction resulting from reduced SIgA contributes
to chronic airway inflammation and disease progression. Here we show
that polymeric immunoglobulin receptor-deficient (pIgR(-/-)) mice, which
lack SIgA, spontaneously develop COPD-like pathology as they age.
Progressive airway wall remodeling and emphysema in pIgR(-/-) mice are
associated with an altered lung microbiome, bacterial invasion of the
airway epithelium, NF-κB activation, leukocyte infiltration and
increased expression of matrix metalloproteinase-12 and neutrophil
elastase. Re-derivation of pIgR(-/-) mice in germ-free conditions or
treatment with the anti-inflammatory phosphodiesterase-4 inhibitor
roflumilast prevents COPD-like lung inflammation and remodeling. These
findings show that pIgR/SIgA deficiency in the airways leads to
persistent activation of innate immune responses to resident lung
microbiota, driving progressive small airway remodeling and emphysema.
Date: Thursday January 26, 2017
Time: 11am - 12pm Presenter: Amrita Sahu
Paper: A single heterochronic blood exchange reveals rapid inhibition of multiple tissues by old bloodAuthors: Justin Rebo, Melod Mehdipour, Ranveer Gathwala, Keith Causey, Yan Liu, Michael J. Conboy & Irina M. Conboy
Abstract: Heterochronic parabiosis rejuvenates the performance of old tissue stem cells at some expense to the young, but whether this is through shared circulation or shared organs is unclear. Here we show that heterochronic blood exchange between young and old mice without sharing other organs, affects tissues within a few days, and leads to different outcomes than heterochronic parabiosis. Investigating muscle, liver and brain hippocampus, in the presence or absence of muscle injury, we find that, in many cases, the inhibitory effects of old blood are more pronounced than the benefits of young, and that peripheral tissue injury compounds the negative effects. We also explore mechanistic explanations, including the role of B2M and TGF-beta. We conclude that, compared with heterochronic parabiosis, heterochronic blood exchange in small animals is less invasive and enables better-controlled studies with more immediate translation to therapies for humans.
Paper: Neurodegenerative disease mutations in TREM2 reveal a functional surface and distinct loss-of-function mechanisms
Authors:Daniel L Kober, Jennifer M Alexander-Brett, Celeste M Karch, Carlos Cruchaga, Marco Colonna, Michael J Holtzman, Thomas J Brett
Monday, December 5, 2016 from 1:00 - 4:00 PM
EOH Department Dissertation Defense
Samantha Malone Rubright: Cyanide and Hydrogen Sulfide: A Review of Two Blood Gases, Their Environmental Sources, and Potential Risks
Presenter: Amrita Sahu
Paper: ADVANCED IMAGING. Extended-resolution structured illumination imaging of endocytic and cytoskeletal dynamics
Authors: Li D, Shao L, Chen BC, Zhang X, Zhang M, Moses B, Milkie DE, Beach JR, Hammer JA 3rd, Pasham M, Kirchhausen T, Baird MA, Davidson MW, Xu P, Betzig E
EOH Journal Club
Rahel Birru will present on the article: EGCG regulates the cross-talk between JWA and topoisomerase IIα in non-small-cell lung cancer (NSCLC) cells
100 Technology Drive, 3rd Floor Conference Room, 339
540 Bridgeside Point
Chunbin Zou, MD, PhD Associate Professor of Medicine Acute Lung Injury Center of Excellence Department of Medicine Division of Pulmonary, Allergy and Critical Care Medicine University of Pittsburgh, School of Medicine "Does Epigenetics Matter in Acute Lung Injury?"
Presenter: Shuo Cao
Paper: Proteasome function is not impaired in healthy aging of the lung
Authors: Anne Caniard, Korbinian Ballweg, Christina Lukas, Ali Ö. Yildirim, Oliver Eickelberg, and Silke Meiners
EOH Journal Club Seminar - Spring 2016 Date: Thursday March 24, 2016 Time: 11am - 12pm
339 Bridgeside Point
EOH Journal Club Seminar - Spring 2016 Date: Thursday March 3, 2016 Time: 11am - 12pm Presenter: Chia-Hsin/Aaron Lui Paper: Targeting LUNX inhibits non-small cell lung cancer growth and metastasis Authors: Zheng X, Cheng M, Fu B, Fan X, Wang Q, Yu X, Sun R, Tian Z, Wei H Abstract: There remains a great need for effective therapies for lung cancer, the majority of which are non-small cell lung cancers (NSCLC). Here, we report the identification of a novel candidate therapeutic target, LUNX, as a molecule overexpressed in primary NSCLC and lymph node metastases that is associated with reduced postoperative survival. Functional studies demonstrated that LUNX overexpression promoted lung cancer cell migration and proliferation by interactions with the chaperone protein 14-3-3. Conversely, LUNX silencing disrupted primary tumor growth, local invasion, and metastatic colonization. The finding that LUNX was expressed on cell membranes prompted us to generate and characterize LUNX antibodies as a candidate therapeutic. Anti-LUNX could downregulate LUNX and reduce lung cancer cell proliferation and migration in vitro. Administered in vivo to mice bearing lung cancer xenografts, anti-LUNX could slow tumor growth and metastasis and improve mouse survival. Together, our work provides a preclinical proof of concept for LUNX as a novel candidate target for immunotherapy in lung cancer
EOH Journal Club Seminar - Spring 2016 Date: Thursday February 25, 2016 Time: 11am - 12pm Presenter: Cody Wolfe Paper: TREM2 sustains microglial expansion during aging and response to demyelination Authors: Poliani PL, Wang Y, Fontana E, Robinette ML, Yamanishi Y, Gilfillan S, Colonna M. Abstract: Microglia contribute to development, homeostasis, and immunity of the CNS. Like other tissue-resident macrophage populations, microglia express the surface receptor triggering receptor expressed on myeloid cells 2 (TREM2), which binds polyanions, such as dextran sulphate and bacterial LPS, and activates downstream signaling cascades through the adapter DAP12. Individuals homozygous for inactivating mutations in TREM2 exhibit demyelination of subcortical white matter and a lethal early onset dementia known as Nasu-Hakola disease. How TREM2 deficiency mediates demyelination and disease is unknown. Here, we addressed the basis for this genetic association using Trem2(-/-) mice. In WT mice, microglia expanded in the corpus callosum with age, whereas aged Trem2(-/-) mice had fewer microglia with an abnormal morphology. In the cuprizone model of oligodendrocyte degeneration and demyelination, Trem2(-/-) microglia failed to amplify transcripts indicative of activation, phagocytosis, and lipid catabolism in response to myelin damage. As a result, Trem2(-/-) mice exhibited impaired myelin debris clearance, axonal dystrophy, oligodendrocyte reduction, and persistent demyelination after prolonged cuprizone treatment. Moreover, myelin-associated lipids robustly triggered TREM2 signaling in vitro, suggesting that TREM2 may directly sense lipid components exposed during myelin damage. We conclude that TREM2 is required for promoting microglial expansion during aging and microglial response to insults of the white matter.
Yves Alarie, PhD Professor Emeritus Dept of Environmental & Occupational Health Graduate School of Public Health Univ of Pgh "QSAR for the Fiftieth Anniversary of the RD50"
Beth L. Roman, PhD Visiting Assoc Professor Dept of Human Genetics Graduate School of Public Health Univ of Pittsburgh "Etiology of HHT-associated arteriovenous malformations"
Antonella Marrocco will present on the paper: "Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction"
EOH Journal Club Seminar - Spring 2016 Date: Thursday January 28, 2016 Time: 11am - 12pm Presenter: Antonella Marrocco Paper: Mice with Pulmonary Fibrosis Driven by Telomere Dysfunction Authors: Povedano JM, Martinez P, Flores JM, Mulero F, Blasco MA Abstract: Idiopathic pulmonary fibrosis (IPF) is a degenerative disease of the lungs with an average survival post-diagnosis of 2-3 years. New therapeutic targets and treatments are necessary. Mutations in components of the telomere-maintenance enzyme telomerase or in proteins important for telomere protection are found in both familial and sporadic IPF cases. However, the lack of mouse models that faithfully recapitulate the human disease has hampered new advances. Here, we generate two independent mouse models that develop IPF owing to either critically short telomeres (telomerase-deficient mice) or severe telomere dysfunction in the absence of telomere shortening (mice with Trf1 deletion in type II alveolar cells). We show that both mouse models develop pulmonary fibrosis through induction of telomere damage, thus providing proof of principle of the causal role of DNA damage stemming from dysfunctional telomeres in IPF development and identifying telomeres as promising targets for new treatments.
5th Floor Conference Room, Bridgeside Point
Dushani Palliyaguru will present ""Characterizing Withaferin A as a novel Nrf2 inducer: implications for liver disease prevention."
Emilie Castranio will present on the article - "TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model"
EOH Journal Club Seminar - Spring 2016 Date: Thursday January 21, 2016 Time: 11am - 12pm Presenter: Emilie Castranio Paper: TREM2 Lipid Sensing Sustains the Microglial Response in an Alzheimer’s Disease Model Authors: Wang Y, Cella M, Mallinson K, Ulrich JD, Young KL, Robinette ML, Gilfillan S, Krishnan GM, Sudhakar S, Zinselmeyer BH, Holtzman DM, Cirrito JR, Colonna M Abstract: Triggering receptor expressed on myeloid cells 2 (TREM2) is a microglial surface receptor that triggers intracellular protein tyrosine phosphorylation. Recent genome-wide association studies have shown that a rare R47H mutation of TREM2 correlates with a substantial increase in the risk of developing Alzheimer's disease (AD). To address the basis for this genetic association, we studied TREM2 deficiency in the 5XFAD mouse model of AD. We found that TREM2 deficiency and haploinsufficiency augment β-amyloid (Aβ) accumulation due to a dysfunctional response of microglia, which fail to cluster around Aβ plaques and become apoptotic. We further demonstrate that TREM2 senses a broad array of anionic and zwitterionic lipids known to associate with fibrillar Aβ in lipid membranes and to be exposed on the surface of damaged neurons. Remarkably, the R47H mutation impairs TREM2 detection of lipid ligands. Thus, TREM2 detects damage-associated lipid patterns associated with neurodegeneration, sustaining the microglial response to Aβ accumulation.
Teresa Anguiano will present on the article - "Intravital Imaging Reveals Ghost Fibers as Architectural Units Guiding Myogenic Progenitors during Regeneration"
EOH Journal Club Seminar - Spring 2016 Date: Thursday January 14, 2016 Time: 11am - 12pm Presenter: Teresa Anguiano Paper: Intravital Imaging Reveals Ghost Fibers as Architectural Units Guiding Myogenic Progenitors during Regeneration Authors: Micah T. Webster, Uri Manor, Jennifer Lippincott-Schwartz, Chen-Ming Fan Abstract: How resident stem cells and their immediate progenitors rebuild tissues of pre-injury organization and size for proportional regeneration is not well understood. Using 3D, time-lapse intravital imaging for direct visualization of the muscle regeneration process in live mice, we report that extracellular matrix remnants from injured skeletal muscle fibers, ‘‘ghost fibers,’’ govern muscle stem/progenitor cell behaviors during proportional regeneration. Stem cells were immobile and quiescent without injury whereas their activated progenitors migrated and divided after injury. Unexpectedly, divisions and migration were primarily bi-directionally oriented along the ghost fiber longitudinal axis, allowing for spreading of progenitors throughout ghost fibers. Re-orienting ghost fibers impacted myogenic progenitors’ migratory paths and division planes, causing disorganization of regenerated muscle fibers. We conclude that ghost fibers are autonomous, architectural units necessary for proportional regeneration after tissue injury. This finding reinforces the need to fabricate bioengineered matrices that mimic living tissue matrices for tissue regeneration therapy.
Paul Henneberger, MPH, ScD Sr Scientist Resp Health Div NIOSH Ctrs for Disease Control & Prev Morgantown, WV "An Eval of non-response and bias in a study of healthcare workers"
Paul K. Henneberger, MPH, ScD Senior Scientist Respiratory Health Division National Institute for Occupational Safety and Health Centers for Disease Control & Prevention Morgantown, West Virginia "An Evaluation of non-response and bias in a study of healthcare workers"
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