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Event Category
Thu 9/27/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 9/27/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Pattra Chun-on

Paper: Predictors of Asthma/COPD Overlap in FDNY Firefighters With World Trade Center Dust Exposure

Authors:
Ankura Singh, MPH; Charles Liu, MD; Barbara Putman, MD; Rachel Zeig-Owens, DrPH, MPH; Charles B. Hall, PhD; Theresa Schwartz, MS; Mayris P. Webber, DrPH, MPH; Hillel W. Cohen, DrPH, MPH; Kenneth I. Berger, MD; Anna Nolan, MD; David J. Prezant, MD; and Michael D. Weiden, MD


Abstract:
BACKGROUND: Previously healthy firefighters with World Trade Center (WTC) dust exposure developed airway disease. Risk factors for irritant-associated asthma/COPD overlap are poorly defined.

METHODS: This study included 2,137 WTC-exposed firefighters who underwent a clinically indicated bronchodilator pulmonary function test (BD-PFT) between 9/11/2001 and 9/10/2017.Apost-BD FEV1 increase of>12% and 200 mL from baseline defined asthma, and a post-BD FEV1/FVC ratio < 0.7 identified COPD cases. Participants who met both criteria had asthma/COPD overlap. Eosinophil levels were measured on screening blood tests performed shortly after 9/11/2001 and prior to BD-PFT; a subgroup of participants also had serum IgE and 21 cytokines measured (n ¼215). Marginal Cox regression models formultiple events assessed the associations of eosinophil levels or serum biomarkers with subsequent diagnosis, with age, race, smoking,WTCexposure, first post-9/11 FEV1/FVC ratio, and BMI included as covariates.

RESULTS: BD-PFT diagnosed asthma/COPD overlap in 99 subjects (4.6%), isolated-asthma in 202 (9.5%), and isolated-COPD in 215 (10.1%). Eosinophil concentration $ 300 cells/mL was associated with increased risk of asthma/COPD overlap (hazard ratio [HR], 1.85; 95% CI,1.16-2.95) but not with isolated-asthma or isolated-COPD. Serum IL-4 also predicted asthma/COPD overlap (HR, 1.51 per doubling of cytokine concentration; 95% CI, 1.17-1.95). Greater IL-21 concentration was associated with both isolated-asthma and isolated-COPD (HRs of 1.73 [95% CI, 1.27-2.35] and 2.06 [95% CI, 1.31-3.23], respectively).

CONCLUSIONS: In WTC-exposed firefighters, elevated blood eosinophil and IL-4 levels are associated with subsequent asthma/COPD overlap. Disease-specific T-helper cell type 2 biomarkers present years before diagnosis suggest patient-intrinsic predisposition to irritantassociated asthma/COPD overlap.

KEY WORDS: asthma; airway obstruction; biomarkers; COPD; eosinophils

4140 Public Health, Young Seminar Room
EOH
Journal Club
Thu 10/4/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 10/4/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Omar Tahtamooni

Paper: Association of traffic air pollution and rhinitis quality of life in Peruvian children with asthma

Authors:
Bose S, Romero K, Psoter KJ, Curriero FC, Chen C, Johnson CM, Kaji D, Breysse PN, Williams DL, Ramanathan M, Checkley W, Hansel NN.


Abstract:
BACKGROUND:
Air pollution exposure may contribute to rhinoconjunctivitis morbidity in children with underlying airways disease. Prior studies have not assessed rhinoconjunctivitis-related quality of life (QOL) in children with asthma chronically exposed to air pollution.

METHODS:
Children ages 9-19 years with asthma from peri-urban Peru, self-reporting rhinoconjunctivitis symptoms (n = 484), were administered the Rhinoconjunctivitis QOL Questionnaire (RQLQ) at repeated intervals over one year, with scores dichotomized into bothered (>0) and not bothered (= 0). Individual weekly exposures to particulate matter<2.5μm (PM2.5) and its black carbon (BC) component were estimated by inverse distance weighted methods. Generalized estimating equations, adjusting for covariates, estimated associations of PM2.5 and BC with QOL.

RESULTS:
Participants were on average 13 years old, 55% female, and majority were atopic (77%). Mean (SD) PM2.5 and BC concentrations were 21(3.2) μg/m3 and 4.4(1.5) μg/m3, respectively. In adjusted multi-pollutant models, each 10μg/m3 increase in PM2.5 was associated with increased odds of worse rhinoconjunctivitis QOL (OR;[95% CI]: 1.83;[1.33,2.52]). A 10% increase in the BC proportion was associated with higher rhinitis burden (OR;[95% CI]: 1.80;[1.22,2.66]), while increases in the non-BC component of PM did not significantly impact rhinoconjunctivitis QOL. Associations were similar regardless of atopy.

CONCLUSION:
Higher PM2.5 and BC exposure is associated with worse rhinitis QOL among asthmatic children.

4140 Public Health, Young Seminar Room
EOH
Journal Club
Thu 10/11/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 10/11/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Shuo Cao

Paper: CCR10+ epithelial cells from idiopathic pulmonary fibrosis lungs drive remodeling.

Authors:
Habiel DM, Espindola MS, Jones IC, Coelho AL, Stripp B, Hogaboam CM.

Abstract:
Idiopathic pulmonary fibrosis (IPF) is a devastating fibrotic lung disease of unknown etiology and limited therapeutic options. In this report, we characterize what we believe is a novel CCR10+ epithelial cell population in IPF lungs. There was a significant increase in the percentage of CCR10+ epithelial cells in IPF relative to normal lung explants and their numbers significantly correlated to lung remodeling in humanized NSG mice. Cultured CCR10-enriched IPF epithelial cells promoted IPF lung fibroblast invasion and collagen 1 secretion. Single-cell RNA sequencing analysis showed distinct CCR10+ epithelial cell populations enriched for inflammatory and profibrotic transcripts. Consistently, cultured IPF but not normal epithelial cells induced lung remodeling in humanized NSG mice, where the number of CCR10+ IPF, but not normal, epithelial cells correlated with hydroxyproline concentration in the remodeled NSG lungs. A subset of IPF CCR10hi epithelial cells coexpress EphA3 and ephrin A signaling induces the expression of CCR10 by these cells. Finally, EphA3+CCR10hi epithelial cells induce more consistent lung remodeling in NSG mice relative to EphA3-CCR10lo epithelial cells. Our results suggest that targeting epithelial cells, highly expressing CCR10, may be beneficial in IPF.

KEYWORDS:
Cell Biology; Collagens; Fibrosis; Mouse models; Pulmonology

4140 Public Health, Young Seminar Room
EOH
Journal Club
Thu 10/18/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 10/18/2018 11:00AM - 12:00PM


Presenter: Heng Bai

Paper: The association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population

Authors: Xiao Chen, Zhongqiu Wang, Guoying Zhu, Gunnar F. Nordberg, Taiyi Jin & Xiaoqiang Ding


Abstract: 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, we evaluated the association between cumulative cadmium intake and osteoporosis and risk of fracture in a Chinese population. A total of 790 subjects (488 women and 302 men) living in a control area and two cadmium-polluted areas were included. The cumulative cadmium intake was estimated by a food survey. The bone mineral density was determined by using single-photon absorptiometry. The cumulative cadmium intakes were 0.48, 2.14, and 11.00 g for men, and 0.42, 2.11, and 11.12 g in women in control, and moderately and heavily polluted areas, respectively. In women, the odds ratios (ORs) of subjects with a cadmium intake between 2.21 and 10.63 g and >10.63 g were 1.30 (95% CI: 0.58–2.94) and 2.36 (95% CI: 1.14–5.16), compared with those with a cadmium intake < 0.58 g after adjusting to the confounders for osteoporosis. The ORs of subjects with a cadmium intake >10.63 g were 2.34 (95% CI: 1.23–4.38) for all of the women and 2.62 (95% CI: 1.02–5.58) in women ≥ 60 years old, compared with those with a cadmium intake <10.63 g after adjusting to the confounders for bone fractures. In men, similar trends were observed, but no statistical significance was found. In addition, those subjects with renal tubular dysfunction showed high risk of bone fracture. Our results indicate that a high level of cumulative cadmium intake is associated with an increased rate of osteoporosis and fractures among women.

EOH
Journal Club
Thu 10/25/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 10/25/2018 11:00AM - 12:00PM


Presenter: Amrita Sahu

Paper: Extracellular Vesicles Provide a Means for Tissue Crosstalk during Exercise

Authors: Martin Whitham, Benjamin L. Parker, Martin Friedrichsen, ..., David E. James, Jørgen F.P. Wojtaszewski, Mark A. Febbraio

Abstract: 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. Following a 1-hr bout of cycling exercise in healthy humans, we observed an increase in the circulation of over 300 proteins, with a notable enrichment of several classes of proteins that compose exosomes and small vesicles. Pulse-chase and intravital imaging experiments suggested EVs liberated by exercise have a propensity to localize in the liver and can transfer their protein cargo. Moreover, by employing arteriovenous balance studies across the contracting human limb, we identified several novel candidate myokines, released into circulation independently of classical secretion. These data identify a new paradigm by which tissue crosstalk during exercise can exert systemic biological effects.

EOH
Journal Club

Recent Events

Event Category
Fri 9/21/2018 1:00PM - 2:00PM
Synthetic Peptide Antibiotics to Overcome Multidrug Resistance - Berthony Deslouches EOH Seminar Series
Synthetic Peptide Antibiotics to Overcome Multidrug Resistance - Berthony Deslouches
Fri 9/21/2018 1:00PM - 2:00PM
A719 Public Health


EOH
Seminar Series
Thu 9/20/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 9/20/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Meghan Matlack

Paper: A Systems Vaccinology Approach Reveals Temporal Transcriptomic Changes of Immune Responses to the Yellow Fever 17D Vaccine.

Authors:
Jue Hou, Shuhui Wang, Manxue Jia, Dan Li, Ying Liu, Zhengpeng Li, Hong Zhu, Huifang Xu, Meiping Sun, Li Lu, Zhinan Zhou, Hong Peng, Qichen Zhang, Shihong Fu, Guodong Liang, Lena Yao, Xuesong Yu, Lindsay N. Carpp, Yunda Huang, Julie McElrath, Steve Self and Yiming Shao


Abstract: In this study, we used a systems vaccinology approach to identify temporal changes in immune response signatures to the yellow fever (YF)-17D vaccine, with the aim of comprehensively characterizing immune responses associated with protective immunity. We conducted a cohort study in which 21 healthy subjects in China were administered one dose of the YF-17D vaccine; PBMCs were collected at 0 h and then at 4 h and days 1, 2, 3, 5, 7, 14, 28, 84, and 168 postvaccination, and analyzed by transcriptional profiling and immunological assays. At 4 h postvaccination, genes associated with innate cell differentiation and cytokine pathways were dramatically downregulated, whereas receptor genes were upregulated, compared with their baseline levels at 0 h. Immune response pathways were primarily upregulated on days 5 and 7, accompanied by the upregulation of the transcriptional factors JUP, STAT1, and EIF2AK2. We also observed robust activation of innate immunity within 2 d postvaccination and a durable adaptive response, as assessed by transcriptional profiling. Coexpression network analysis indicated that lysosome activity and lymphocyte proliferation were associated with dendritic cell (DC) and CD4+ T cell responses; FGL2, NFAM1, CCR1, and TNFSF13B were involved in these associations. Moreover, individuals who were baseline-seropositive for Abs against another flavivirus exhibited significantly impaired DC, NK cell, and T cell function in response to YF-17D vaccination. Overall, our findings indicate that YF-17D vaccination induces a prompt innate immune response and DC activation, a robust Ag-specific T cell response, and a persistent B cell/memory B cell response

EOH
Journal Club
Thu 9/13/2018 11:00AM - 12:00PM
EOH Journal Club Seminar - Fall 2018 EOH Journal Club
EOH Journal Club Seminar - Fall 2018
Thu 9/13/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

Presenter: Cody Wolfe

Paper: High-Dimensional Single-Cell Mapping of Central Nervous System Immune Cells Reveals Distinct Myeloid Subsets in Health, Aging, and Disease

Authors: Dunja Mrdjen, Anto Pavlovic, Felix J. Hartmann, Doron Merkler, Melanie Greter, Burkhard Becher

Abstract: Individual reports suggest that the central nervous system (CNS) contains multiple immune cell types with diverse roles in tissue homeostasis, immune defense, and neurological diseases. It has been challenging to map leukocytes across the entire brain, and in particular in pathology, where phenotypic changes and influx of blood-derived cells prevent a clear distinction between reactive leukocyte populations. Here, we applied high-dimensional single-cell mass and fluorescence cytometry, in parallel with genetic fate mapping systems, to identify, locate, and characterize multiple distinct immune populations within the mammalian CNS. Using this approach, we revealed that microglia, several subsets of border-associated macrophages and dendritic cells coexist in the CNS at steady state and exhibit disease-specific transformations in the immune microenvironment during aging and in models of Alzheimer’s disease and multiple sclerosis. Together, these data and the described framework provide a resource for the study of disease mechanisms, potential biomarkers, and therapeutic targets in CNS disease.

EOH
Journal Club
Wed 8/1/2018 1:00PM - 2:30PM
Hirunwut Praekunatham - Mechanisms of Azide and Cyanide Binding to Cobalt Complexes EOH Dissertation Defense
Hirunwut Praekunatham - Mechanisms of Azide and Cyanide Binding to Cobalt Complexes
Wed 8/1/2018 1:00PM - 2:30PM
A521 Public Health

EOH Departmental Dissertation Defense

Hirunwut Praekunatham, MD, MPH

"Mechanisms of Azide and Cyanide Binding to Cobalt Complexes Relevant to Antidotal Action"


EOH
Dissertation Defense
Fri 7/27/2018 11:00AM - 12:00PM
Gorazd B. Stokin - Axons, axonal pathology and Alzheimer's disease EOH Seminar Series
Gorazd B. Stokin - Axons, axonal pathology and Alzheimer's disease
Fri 7/27/2018 11:00AM - 12:00PM
1149 Public Health, Foster Conference Room

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


EOH
Seminar Series
Thu 7/12/2018 1:00PM - 5:00PM
Emilie Castranio - The Role of Apolipoprotein E in Traumatic Brain Injury EOH Dissertation Defense
Emilie Castranio - The Role of Apolipoprotein E in Traumatic Brain Injury
Thu 7/12/2018 1:00PM - 5:00PM
4140 Public Health, Young Seminar Room

EOH Departmental
Dissertation Defense

“The Role of Apolipoprotein E in Traumatic Brain Injury as determined by isoform and Abca1 Haplodeficiency”

Emilie Castranio

Department of Environmental And Occupational Health
Graduate School of Public Health

Thursday, July 12, 2018
1:00 pm

130 DeSoto Street
4th Floor Conference Room, #4140

http://www.eoh.pitt.edu


EOH
Dissertation Defense
Thu 4/12/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Shuo Cao EOH Journal Club
EOH Journal Club - Spring 2018 - Shuo Cao
Thu 4/12/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday April 12, 2018
Time: 11am - 12pm
Presenter: Shuo Cao

Paper: Inactivating mutations and hypermethylation of the NKX2-1/TTF-1 gene in non-terminal respiratory unit-type lung adenocarcinomas

Authors: Matsubara D, Soda M, Yoshimoto T, Amano Y, Sakuma Y, Yamato A, Ueno T, Kojima S, Shibano T, Hosono Y, Kawazu M, Yamashita Y, Endo S, Hagiwara K, Fukayama M, Takahashi T, Mano H, Niki T.

Abstract: The major driver mutations of lung cancer, EGFR mutations and EML4-ALK fusion, are mainly detected in terminal respiratory unit (TRU)-type lung adenocarcinomas, which typically show lepidic and/or papillary patterns, but are rarely associated with a solid or invasive mucinous morphology. In order to elucidate the key genetic events in non-TRU-type lung cancer, we carried out whole-exome sequencing on 43 non-TRU-type lung adenocarcinomas based on morphology (17 acinar, nine solid, and two enteric adenocarcinomas, and 15 adenocarcinomas with a mucinous morphology). Our analysis identified mutations in TP53 (16/43, 37.2%), KRAS (13/43, 30.2%), and NKX2-1/TTF-1 (7/43; 16.3%) as the top three significantly mutated genes, while the EGFR mutation was rare (1/43, 2.3%) in this cohort. Eight NKX2-1/TTF-1 mutations (five frameshift, two nonsense, and one missense) were identified, with one case harboring two distinct NKX2-1/TTF-1 mutations (one missense and one frameshift). Functional assays with the NK2 homeobox 1 (NKX2-1)/thyroid transcription factor 1 (TTF-1) mutants revealed that none of them retain the activity as a transcriptional factor. Histologically, invasive mucinous adenocarcinomas accounted for most of the NKX2-1/TTF-1 mutations (five cases), as well as one enteric and one acinar adenocarcinoma. Immunohistochemistry showed that the cohort was largely divided into TTF-1-postive/hepatocyte nuclear factor 4-α (HNF4-α)-negative and TTF-1-negative/HNF4-α-positive groups. NKX2-1/TTF-1 mutations were exclusively found in the latter, in which the gastrointestinal markers, mucin 5AC and cytokeratin 20, were frequently expressed. Bisulfite sequencing revealed that the NKX2-1/TTF-1 gene body was highly methylated in NKX2-1/TTF-1-negative cases, including those without the NKX2-1/TTF-1 mutations. The genetic or epigenetic inactivation of NKX2-1/TTF-1 may play an essential role in the development and aberrant differentiation of non-TRU-type lung adenocarcinomas.

EOH
Journal Club
Thu 4/5/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Travis Lear EOH Journal Club
EOH Journal Club - Spring 2018 - Travis Lear
Thu 4/5/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday April 5, 2018
Time: 11am - 12pm
Presenter: Travis Lear

Paper: TGFβ attenuates tumour response to PD-L1 blockade by contributing to exclusion of T cells

Authors: Sanjeev Mariathasan, Shannon J. Turley[…]Thomas Powles

Abstract: Therapeutic antibodies that block the programmed death-1 (PD-1)–programmed death-ligand 1 (PD-L1) pathway can induce robust and durable responses in patients with various cancers, including metastatic urothelial cancer1,2,3,4,5. However, these responses only occur in a subset of patients. Elucidating the determinants of response and resistance is key to improving outcomes and developing new treatment strategies. Here we examined tumours from a large cohort of patients with metastatic urothelial cancer who were treated with an anti-PD-L1 agent (atezolizumab) and identified major determinants of clinical outcome. Response to treatment was associated with CD8+ T-effector cell phenotype and, to an even greater extent, high neoantigen or tumour mutation burden. Lack of response was associated with a signature of transforming growth factor β (TGFβ) signalling in fibroblasts. This occurred particularly in patients with tumours, which showed exclusion of CD8+ T cells from the tumour parenchyma that were instead found in the fibroblast- and collagen-rich peritumoural stroma; a common phenotype among patients with metastatic urothelial cancer. Using a mouse model that recapitulates this immune-excluded phenotype, we found that therapeutic co-administration of TGFβ-blocking and anti-PD-L1 antibodies reduced TGFβ signalling in stromal cells, facilitated T-cell penetration into the centre of tumours, and provoked vigorous anti-tumour immunity and tumour regression. Integration of these three independent biological features provides the best basis for understanding patient outcome in this setting and suggests that TGFβ shapes the tumour microenvironment to restrain anti-tumour immunity by restricting T-cell infiltration.


EOH
Journal Club
Thu 3/29/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Meghan Matlack EOH Journal Club
EOH Journal Club - Spring 2018 - Meghan Matlack
Thu 3/29/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday March 29, 2018
Time: 11am - 12pm
Presenter: Meghan Matlack

Paper: Blockade of dengue virus infection and viral cytotoxicity in neuronal cells in vitro and in vivo by targeting endocytic pathway

Authors: Min-Ru Ho, Tsung-Ting Tsai, Chia-Ling Chen, Ming-Kai Jhan, Cheng-Chieh Tsai,  Yi-Chao Lee, Chun-Han Chen & Chiou-Feng Li

Abstract: Dengue virus (DENV) infection in neuronal cells was speculated to trigger neuropathy. Herein, we determined the blockade of DENV infection by targeting endocytic pathways in vitro and in vivo. In DENV-infected mouse brains, we previously showed that viral proteins are expressed in neuronal cells around the hippocampus with accompanying neurotoxicity. DENV caused infection, including entry, double-stranded (ds)RNA replication, protein expression, and virus release, followed by cytotoxicity in the mouse neuronal Neuro-2a cell line. Pharmacologically blocking clathrin-mediated endocytosis of the DENV retarded viral replication. Targeting vacuolar-type H+-ATPase (V-ATPase)-based endosomal acidification effectively blocked the DENV replication process, but had no direct effect on viral translation. Blockade of the clathrin- and V-ATPase-based endocytic pathways also attenuated DENVinduced neurotoxicity. Inhibiting endosomal acidification effectively retarded DENV infection, acute viral encephalitis, and mortality. These results demonstrate that clathrin mediated endocytosis of DENV followed by endosomal acidification-dependent viral replication in neuronal cells, which can lead to neurotoxicity.


EOH
Journal Club
Thu 3/22/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Emilie Castranio EOH Journal Club
EOH Journal Club - Spring 2018 - Emilie Castranio
Thu 3/22/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday March 22, 2018
Time: 11am - 12pm
Presenter: Emilie Castranio

Paper: ApoE4 markedly exacerbates tau-mediated neurodegeneration in a mouse model of tauopathy

Authors: Shi Y, Yamada K, Liddelow SA, Smith ST, Zhao L, Luo W, Tsai RM, Spina S, Grinberg LT, Rojas JC, Gallardo G, Wang K, Roh J, Robinson G, Finn MB, Jiang H, Sullivan PM, Baufeld C, Wood MW, Sutphen C, McCue L, Xiong C, Del-Aguila JL, Morris JC, Cruchaga C; Alzheimer’s Disease Neuroimaging Initiative, Fagan AM, Miller BL, Boxer AL, Seeley WW, Butovsky O, Barres BA, Paul SM, Holtzman DM.

Abstract: APOE4 is the strongest genetic risk factor for late-onset Alzheimer disease. ApoE4 increases brain amyloid-β pathology relative to other ApoE isoforms. However, whether APOE independently influences tau pathology, the other major proteinopathy of Alzheimer disease and other tauopathies, or tau-mediated neurodegeneration, is not clear. By generating P301S tau transgenic mice on either a human ApoE knock-in (KI) or ApoE knockout (KO) background, here we show that P301S/E4 mice have significantly higher tau levels in the brain and a greater extent of somatodendritic tau redistribution by three months of age compared with P301S/E2, P301S/E3, and P301S/EKO mice. By nine months of age, P301S mice with different ApoE genotypes display distinct phosphorylated tau protein (p-tau) staining patterns. P301S/E4 mice develop markedly more brain atrophy and neuroinflammation than P301S/E2 and P301S/E3 mice, whereas P301S/EKO mice are largely protected from these changes. In vitro, E4-expressing microglia exhibit higher innate immune reactivity after lipopolysaccharide treatment. Co-culturing P301S tau-expressing neurons with E4-expressing mixed glia results in a significantly higher level of tumour-necrosis factor-α (TNF-α) secretion and markedly reduced neuronal viability compared with neuron/E2 and neuron/E3 co-cultures. Neurons co-cultured with EKO glia showed the greatest viability with the lowest level of secreted TNF-α. Treatment of P301S neurons with recombinant ApoE (E2, E3, E4) also leads to some neuronal damage and death compared with the absence of ApoE, with ApoE4 exacerbating the effect. In individuals with a sporadic primary tauopathy, the presence of an ε4 allele is associated with more severe regional neurodegeneration. In individuals who are positive for amyloid-β pathology with symptomatic Alzheimer disease who usually have tau pathology, ε4-carriers demonstrate greater rates of disease progression. Our results demonstrate that ApoE affects tau pathogenesis, neuroinflammation, and tau-mediated neurodegeneration independently of amyloid-β pathology. ApoE4 exerts a 'toxic' gain of function whereas the absence of ApoE is protective.


EOH
Journal Club
Thu 3/15/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Antonella Marrocco EOH Journal Club
EOH Journal Club - Spring 2018 - Antonella Marrocco
Thu 3/15/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday March 15, 2018
Time: 11am - 12pm
Presenter: Antonella Marrocco

Paper: NF-κB Restricts Inflammasome Activation via Elimination of Damaged Mitochondria 

Authors: Zhong Z, Umemura A, Sanchez-Lopez E, Liang S, Shalapour S, Wong J, He F, Boassa D, Perkins G, Ali SR, McGeough MD, Ellisman MH, Seki E, Gustafsson AB, Hoffman HM, Diaz-Meco MT, Moscat J, Karin M.

Abstract: Nuclear factor κB (NF-κB), a key activator of inflammation, primes the NLRP3-inflammasome for activation by inducing pro-IL-1β and NLRP3 expression. NF-κB, however, also prevents excessive inflammation and restrains NLRP3-inflammasome activation through a poorly defined mechanism. We now show that NF-κB exerts its anti-inflammatory activity by inducing delayed accumulation of the autophagy receptor p62/SQSTM1. External NLRP3-activating stimuli trigger a form of mitochondrial (mt) damage that is caspase-1- and NLRP3-independent and causes release of direct NLRP3-inflammasome activators, including mtDNA and mtROS. Damaged mitochondria undergo Parkin-dependent ubiquitin conjugation and are specifically recognized by p62, which induces their mitophagic clearance. Macrophage-specific p62 ablation causes pronounced accumulation of damaged mitochondria and excessive IL-1β-dependent inflammation, enhancing macrophage death. Therefore, the "NF-κB-p62-mitophagy" pathway is a macrophage-intrinsic regulatory loop through which NF-κB restrains its own inflammation-promoting activity and orchestrates a self-limiting host response that maintains homeostasis and favors tissue repair.


EOH
Journal Club
Thu 3/1/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Heng Bai EOH Journal Club
EOH Journal Club - Spring 2018 - Heng Bai
Thu 3/1/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday March 1, 2018
Time: 11am - 12pm
Presenter: Heng Bai

Paper: Declining exposures to lead and cadmium contribute to explaining the reduction of cardiovascular mortality in the US population, 1988–2004

Authors: Adrian Ruiz-Hernandez, Ana Navas-Acien, Roberto Pastor-Barriuso, Ciprian M Crainiceanu, Josep Redon, Eliseo Guallar, Maria Tellez-Plaza

Abstract:

Background
Lead and cadmium exposures have markedly declined in the USA following the implementation of large-scale public health policies and could have contributed to the unexplained decline in cardiovascular mortality in US adults. We evaluated the potential contribution of lead and cadmium exposure reductions to explain decreasing cardiovascular mortality trends occurring in the USA from 1988–94 to 1999–2004.

Methods
Prospective study in 15 421 adults ≥40 years old who had participated in the National Health and Nutrition Examination Survey 1988–94 or 1999–2004. We estimated the amount of change in cardiovascular mortality over time that can be independently attributed to the intermediate pathway of changes in blood lead and urine cadmium concentrations.

Results
There was a 42.0% decrease in blood lead and a 31.0% decrease in urine cadmium concentrations. The cardiovascular mortality rate ratio [95% confidence intervals (CIs)] associated with a doubling of metal levels was 1.19 (1.07, 1.31) for blood lead and 1.20 (1.09, 1.32) for urine cadmium. The absolute reduction in cardiovascular deaths comparing 1999–2004 to 1988–94 was 230.7 deaths/100 000 person-years, in models adjusted for traditional cardiovascular risk factors. Among these avoided deaths, 52.0 (95% CI 8.4, 96.7) and 19.4 (4.3, 36.4) deaths/100 000 person-years were attributable to changes in lead and cadmium, respectively.

Conclusions
Environmental declines in lead and cadmium exposures were associated with reductions in cardiovascular mortality in US adults. Given the fact that lead and cadmium remain associated with cardiovascular disease at relatively low levels of exposure, prevention strategies that further minimize exposure to lead and cadmium may be needed.

EOH
Journal Club
Mon 2/26/2018 2:00PM - 3:00PM
Mitigating Climate Change by Transitioning to a Renewable Resource-Based Economy - Steven Cohen EOH Lecture
Mitigating Climate Change by Transitioning to a Renewable Resource-Based Economy - Steven Cohen
Mon 2/26/2018 2:00PM - 3:00PM
William Pitt Union - Assembly Room

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
Lecture
Thu 2/22/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Arron Chia-Hsin Liu EOH Journal Club
EOH Journal Club - Spring 2018 - Arron Chia-Hsin Liu
Thu 2/22/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday February 22, 2018
Time: 11am - 12pm
Presenter: Arron Chia-Hsin Liu

Paper: Gut microbiome influences efficacy of PD-1-based immunotherapy against epithelial tumors

Authors: Routy B, Le Chatelier E, et Al.

Abstract: Immune checkpoint inhibitors (ICIs) targeting the PD-1/PD-L1 axis induce sustained clinical responses in a sizable minority of cancer patients. We found that primary resistance to ICIs can be attributed to abnormal gut microbiome composition. Antibiotics inhibited the clinical benefit of ICIs in patients with advanced cancer. Fecal microbiota transplantation (FMT) from cancer patients who responded to ICIs into germ-free or antibiotic-treated mice ameliorated the antitumor effects of PD-1 blockade, whereas FMT from nonresponding patients failed to do so. Metagenomics of patient stool samples at diagnosis revealed correlations between clinical responses to ICIs and the relative abundance of Akkermansia muciniphila Oral supplementation with A. muciniphila after FMT with nonresponder feces restored the efficacy of PD-1 blockade in an interleukin-12-dependent manner by increasing the recruitment of CCR9+CXCR3+CD4+ T lymphocytes into mouse tumor beds.


EOH
Journal Club
Thu 2/15/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Brandy Hill EOH Journal Club
EOH Journal Club - Spring 2018 - Brandy Hill
Thu 2/15/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday February 15, 2018
Time: 11am - 12pm
Presenter: Brandy Hill

Paper:  Comparison of umbilical cord tissue and meconium for the confirmation of in utero drug exposure
Authors: Jennifer M.Colby

Abstract:
Objectives
Drug screening in neonates is traditionally performed using meconium, but cord tissue has been proposed as an alternative specimen. This study compares the detection of drugs in a large number of paired meconium and umbilical cord tissue samples from subjects at risk of in utero drug exposure.

Design and Methods
Physician-ordered toxicology results and clinical information were collected in a retrospective review of subject medical records. All toxicology testing was performed by a national reference laboratory using a combination of immunoassays and chromatography-mass spectrometry. The comparison was limited to drugs present in both cord and meconium panels.

Results
Overall agreement between cord and meconium ranged from 76% (cannabinoids) to 100% (barbiturates), but Cohen's kappa was < 65% for 5 of the 6 drug classes we studied. Considering meconium as the gold standard, cord was less sensitive for the detection of 5 of the 6 drug classes, and for the detection of all 5 individual opioids. For 3 of the 5 individual opioids, the concentration of drug measured in meconium did not correlate well with qualitative detection in cord.

Conclusions
This study reveals different sensitivities of drug detection in umbilical cord tissue and meconium. For the drugs studied here, meconium provides greater sensitivity, and is likely to remain the specimen of choice when sensitivity is of greatest importance. These results can help clinicians, laboratorians, and epidemiologists to (1) select the most appropriate test to confirm a suspected drug exposure and (2) interpret discordant results when testing is performed in multiple matrices.


EOH
Journal Club
Thu 2/8/2018 11:00AM - 12:00PM
Ambient air pollution and thrombosis - Omar Tahtamooni EOH Journal Club
Ambient air pollution and thrombosis - Omar Tahtamooni
Thu 2/8/2018 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2018
Date: Thursday February 8, 2018
Time: 11am - 12pm

Authors: Robertson S1, Miller MR

Abstract: Air pollution is a growing public health concern of global significance. Acute and chronic exposure is known to impair cardiovascular function, exacerbate disease and increase cardiovascular mortality. Several plausible biological mechanisms have been proposed for these associations, however, at present, the pathways are incomplete. A seminal review by the American Heart Association (2010) concluded that the thrombotic effects of particulate air pollution likely contributed to their effects on cardiovascular mortality and morbidity. The aim of the current review is to appraise the newly accumulated scientific evidence (2009-2016) on contribution of haemostasis and thrombosis towards cardiovascular disease induced by exposure to both particulate and gaseous pollutants.Seventy four publications were reviewed in-depth. The weight of evidence suggests that acute exposure to fine particulate matter (PM2.5) induces a shift in the haemostatic balance towards a pro-thrombotic/pro-coagulative state. Insufficient data was available to ascertain if a similar relationship exists for gaseous pollutants, and very few studies have addressed long-term exposure to ambient air pollution. Platelet activation, oxidative stress, interplay between interleukin-6 and tissue factor, all appear to be potentially important mechanisms in pollution-mediated thrombosis, together with an emerging role for circulating microvesicles and epigenetic changes.Overall, the recent literature supports, and arguably strengthens, the contention that air pollution contributes to cardiovascular morbidity by promoting haemostasis. The volume and diversity of the evidence highlights the complexity of the pathophysiologic mechanisms by which air pollution promotes thrombosis; multiple pathways are plausible and it is most likely they act in concert. Future research should address the role gaseous pollutants play in the cardiovascular effects of air pollution mixture and direct comparison of potentially susceptible groups to healthy individuals.


EOH
Journal Club
Thu 2/1/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Qiao Lin EOH Journal Club
EOH Journal Club - Spring 2018 - Qiao Lin
Thu 2/1/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

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 signalling; 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 signalling in cellular communities


EOH
Journal Club
Thu 1/25/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Hsiu-Chi Ting EOH Journal Club
EOH Journal Club - Spring 2018 - Hsiu-Chi Ting
Thu 1/25/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday January 25, 2018
Time: 11am - 12pm
Presenter: Hsiu-Chi Ting

Paper: Selenium Utilization by GPX4 Is Required to Prevent Hydroperoxide-Induced Ferroptosis

Authors: Ingold I, Berndt C, Schmitt S, et. Al.

Abstract: Selenoproteins are rare proteins among all kingdoms of life containing the 21st amino acid, selenocysteine. Selenocysteine resembles cysteine, differing only by the substitution of selenium for sulfur. Yet the actual advantage of selenolate- versus thiolate-based catalysis has remained enigmatic, as most of the known selenoproteins also exist as cysteine-containing homologs. Here, we demonstrate that selenolate-based catalysis of the essential mammalian selenoprotein GPX4 is unexpectedly dispensable for normal embryogenesis. Yet the survival of a specific type of interneurons emerges to exclusively depend on selenocysteine-containing GPX4, thereby preventing fatal epileptic seizures. Mechanistically, selenocysteine utilization by GPX4 confers exquisite resistance to irreversible overoxidation as cells expressing a cysteine variant are highly sensitive toward peroxide-induced ferroptosis. Remarkably, concomitant deletion of all selenoproteins in Gpx4cys/cys cells revealed that selenoproteins are dispensable for cell viability provided partial GPX4 activity is retained. Conclusively, 200 years after its discovery, a specific and indispensable role for selenium is provided


EOH
Journal Club
Thu 1/18/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Cody Wolfe EOH Journal Club
EOH Journal Club - Spring 2018 - Cody Wolfe
Thu 1/18/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday January 18, 2018
Time: 11am - 12pm
Presenter: Cody Wolfe

Paper:  Microglia-derived ASC specks crossseed amyloid-β in Alzheimer’s disease

Authors: Venegas C, Kumar S, Franklin BS, Dierkes T, Brinkschulte R, Tejera D, Vieira-Saecker A, Schwartz S, Santarelli F, Kummer MP, Griep A, Gelpi E, Beilharz M, Riedel D, Golenbock DT, Geyer M, Walter J, Latz E, Heneka MT

Abstract: The spreading of pathology within and between brain areas is a hallmark of neurodegenerative disorders. In patients with Alzheimer’s disease, deposition of amyloid-β is accompanied by activation of the innate immune system and involves inflammasome-dependent formation of ASC specks in microglia. ASC specks released by microglia bind rapidly to amyloid-β and increase the formation of amyloid-β oligomers and aggregates, acting as an inflammation-driven cross-seed for amyloid-β pathology. Here we show that intrahippocampal injection of ASC specks resulted in spreading of amyloid-β pathology in transgenic double-mutant APPSwePSEN1dE9 mice. By contrast, homogenates from brains of APPSwePSEN1dE9 mice failed to induce seeding and spreading of amyloid-β pathology in ASC-deficient APPSwePSEN1dE9 mice. Moreover, co-application of an anti-ASC antibody blocked the increase in amyloid-β pathology in APPSwePSEN1dE9 mice. These findings support the concept that inflammasome activation is connected to seeding and spreading of amyloid-β pathology in patients with Alzheimer’s disease.

EOH
Journal Club
Thu 1/11/2018 11:00AM - 12:00PM
EOH Journal Club - Spring 2018 - Amrita Sahu EOH Journal Club
EOH Journal Club - Spring 2018 - Amrita Sahu
Thu 1/11/2018 11:00AM - 12:00PM
4140 Public Health, Young Seminar Room

EOH Journal Club Seminar - Spring 2018
Date: Thursday January 11, 2018
Time: 11am - 12pm
Presenter: Amrita Sahu

Paper: Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss

Authors: Marco Quarta, Melinda Cromie, Robert Chacon, Justin Blonigan, Victor Garcia, Igor Akimenko, Mark Hamer, Patrick Paine, Merel Stok, Joseph B. Shrager & Thomas A. Rando

Abstract: Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with geneticallylabelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML.

EOH
Journal Club
Thu 12/14/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Amrita Sahu EOH Journal Club
EOH Journal Club - Fall 2017 - Amrita Sahu
Thu 12/14/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday December 14, 2017
Time: 11am - 12pm
Presenter: Amrita Sahu

Paper: Bioengineered constructs combined with exercise enhance stem cell-mediated treatment of volumetric muscle loss

Authors: Marco Quarta, Melinda Cromie, Robert Chacon, Justin Blonigan, Victor Garcia, Igor Akimenko, Mark Hamer, Patrick Paine, Merel Stok, Joseph B. Shrager & Thomas A. Rando

Abstract: Volumetric muscle loss (VML) is associated with loss of skeletal muscle function, and current treatments show limited efficacy. Here we show that bioconstructs suffused with genetically-labelled muscle stem cells (MuSCs) and other muscle resident cells (MRCs) are effective to treat VML injuries in mice. Imaging of bioconstructs implanted in damaged muscles indicates MuSCs survival and growth, and ex vivo analyses show force restoration of treated muscles. Histological analysis highlights myofibre formation, neovascularisation, but insufficient innervation. Both innervation and in vivo force production are enhanced when implantation of bioconstructs is followed by an exercise regimen. Significant improvements are also observed when bioconstructs are used to treat chronic VML injury models. Finally, we demonstrate that bioconstructs made with human MuSCs and MRCs can generate functional muscle tissue in our VML model. These data suggest that stem cell-based therapies aimed to engineer tissue in vivo may be effective to treat acute and chronic VML.

EOH
Journal Club
Thu 12/7/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Omar Tahtamooni EOH Journal Club
EOH Journal Club - Fall 2017 - Omar Tahtamooni
Thu 12/7/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday December 7, 2017
Time: 11am - 12pm
Presenter: Omar Tahtamooni

Paper:  Air Pollution and Mortality in the Medicare Population

Authors: Qian Di, M.S., Yan Wang, M.S., Antonella Zanobetti, Ph.D., Yun Wang, Ph.D., Petros Koutrakis, Ph.D., Christine Choirat, Ph.D., Francesca Dominici, Ph.D., and Joel D. Schwartz, Ph.D.

Abstract:

BACKGROUND
Studies have shown that long-term exposure to air pollution increases mortality. However, evidence is limited for air-pollution levels below the most recent National Ambient Air Quality Standards. Previous studies involved predominantly urban populations and did not have the statistical power to estimate the health effects in underrepresented groups.

METHODS
We constructed an open cohort of all Medicare beneficiaries (60,925,443 persons) in the continental United States from the years 2000 through 2012, with 460,310,521 person-years of follow-up. Annual averages of fine particulate matter (particles with a mass median aerodynamic diameter of less than 2.5 μm [PM2.5]) and ozone were estimated according to the ZIP Code of residence for each enrollee with the use of previously validated prediction models. We estimated the risk of death associated with exposure to increases of 10 μg per cubic meter for PM2.5 and 10 parts per billion (ppb) for ozone using a two-pollutant Cox proportionalhazards model that controlled for demographic characteristics, Medicaid eligibility, and area-level covariates.

RESULTS
Increases of 10 μg per cubic meter in PM2.5 and of 10 ppb in ozone were associated with increases in all-cause mortality of 7.3% (95% confidence interval [CI], 7.1 to 7.5) and 1.1% (95% CI, 1.0 to 1.2), respectively. When the analysis was restricted to person-years with exposure to PM2.5 of less than 12 μg per cubic meter and ozone of less than 50 ppb, the same increases in PM2.5 and ozone were associated
with increases in the risk of death of 13.6% (95% CI, 13.1 to 14.1) and
1.0% (95% CI, 0.9 to 1.1), respectively. For PM2.5, the risk of death among men, blacks, and people with Medicaid eligibility was higher than that in the rest of the population.

CONCLUSIONS
In the entire Medicare population, there was significant evidence of adverse effects related to exposure to PM2.5 and ozone at concentrations below current national standards. This effect was most pronounced among self-identified racial minorities and people with low income. (Supported by the Health Effects Institute and others.)

EOH
Journal Club
Thu 11/30/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Pattra Chunon EOH Journal Club
EOH Journal Club - Fall 2017 - Pattra Chunon
Thu 11/30/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday November 30, 2017
Time: 11am - 12pm
Presenter: Pattra Chunon

Paper:  Temporal Tracking of Microglia Activation in Neurodegeneration at Single-Cell Resolution

Authors: Hansruedi Mathys, Chinnakkaruppan Adaikkan, Fan Gao, Richard M. Ransohoff, Aviv Regev, Li-Huei Tsai

Abstract: Microglia, the tissue-resident macrophages in the brain, are damage sensors that react to nearly any perturbation, including neurodegenerative diseases such as Alzheimer’s disease (AD). Here, using single-cell RNA sequencing, we determined the transcriptome of more than 1,600 individual microglia cells isolated from the hippocampus of a mouse model of severe neurodegeneration with AD-like phenotypes and of control mice at multiple time points during progression of neurodegeneration. In this neurodegeneration model, we discovered two molecularly distinct reactive microglia phenotypes that are typified by modules of co-regulated type I and type II interferon response genes, respectively. Furthermore, our work identified previously unobserved heterogeneity in the response of microglia to neurodegeneration, discovered disease stagespecific microglia cell states, revealed the trajectory of cellular reprogramming of microglia in response to neurodegeneration, and uncovered the underlying transcriptional programs.


EOH
Journal Club
Thu 11/16/2017 12:30PM - 1:30PM
Analysis of quantitative High Throughput Screening (qHTS) assays. EOH Seminar Series
Analysis of quantitative High Throughput Screening (qHTS) assays.
Thu 11/16/2017 12:30PM - 1:30PM



EOH
Seminar Series
Thu 11/16/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Brandy Hill EOH Journal Club
EOH Journal Club - Fall 2017 - Brandy Hill
Thu 11/16/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday November 16, 2017
Time: 11am - 12pm
Presenter: Brandy Hill

Paper:  Traffic-Related Air Pollution and Telomere Length in Children and Adolescents Living in Fresno, CA: A Pilot Study

Authors: Eunice Y. Lee, MS, Jue Lin, PhD, Elizabeth M. Noth, PhD, S. Katharine Hammond, PhD, Kari C. Nadeau, MD, PhD, Ellen A. Eisen, ScD, and John R. Balmes, MD

Abstract:
Objective: The main objective of this pilot study was to gather preliminary information about how telomere length (TL) varies in relation to exposure to polycyclic aromatic hydrocarbons (PAHs) in children living in a highly
polluted city.

Methods: We conducted a cross-sectional study of children living in Fresno, California (n¼14). Subjects with and without asthma were selected based on their annual average PAH level in the 12-months prior to their blood draw. We measured relative telomere length from peripheral blood mononuclear cells (PBMC).

Results: We found an inverse linear relationship between average PAH level and TL (R2¼0.69), as well as between age and TL (R2¼0.21). Asthmatics had shorter mean telomere length than non-asthmatics (TLasthmatic¼1.13, TLnon-asthmatic¼1.29).

Conclusions: These preliminary findings suggest that exposure to ambient PAH may play a role in telomere shortening.

EOH
Journal Club
Thu 11/9/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Shuo Cao EOH Journal Club
EOH Journal Club - Fall 2017 - Shuo Cao
Thu 11/9/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday November 9, 2017
Time: 11am - 12pm
Presenter: Shuo Cao

Paper: TLR4 signaling induces TLR3 up-regulation in alveolar macrophages during acute lung injury

Authors: Ding X, Jin S, Tong Y, Jiang X, Chen Z, Mei S, Zhang L, Billiar TR, Li Q

Abstract: Acute lung injury is a life-threatening inflammatory response caused by severe infection. Toll-like receptors in alveolar macrophages (AMΦ) recognize the molecular constituents of pathogens and activate the host's innate immune responses. Numerous studies have documented the importance of TLR-TLR cross talk, but few studies have specifically addressed the relationship between TLR4 and TLR3. We explored a novel mechanism of TLR3 up-regulation that is induced by LPS-TLR4 signaling in a dose- and time-dependent manner in AMΦ from C57BL/6 mice, while the LPS-induced TLR3 expression was significantly reduced in TLR4-/- and Myd88-/- mice and following pretreatment with a NF-κB inhibitor. The enhanced TLR3 up-regulation in AMΦ augmented the expression of cytokines and chemokines in response to sequential challenges with LPS and Poly I:C, a TLR3 ligand, which was physiologically associated with amplified AMΦ-induced PMN migration into lung alveoli. Our study demonstrates that the synergistic effect between TLR4 and TLR3 in macrophages is an important determinant in acute lung injury and, more importantly, that TLR3 up-regulation is dependent on TLR4-MyD88-NF-κB signaling. These results raise the possibility that bacterial infections can induce sensitivity to viral infections, which may have important implications for the therapeutic manipulation of the innate immune system.



EOH
Journal Club
Thu 11/2/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Shawn Ting EOH Journal Club
EOH Journal Club - Fall 2017 - Shawn Ting
Thu 11/2/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017

Date: Thursday November 2, 2017

Time: 11am - 12pm

Presenter: Shawn/Hsiu-Chi Ting

Paper:  PEBP1 Wardens Ferroptosis by Enabling Lipoxygenase Generation of Lipid Death Signals

Authors: Sally E. Wenzel, Yulia Y. Tyurina, Jinming Zhao, ..., Ivet Bahar, Hulya Bayır, Valerian E. Kagan

Abstract: Ferroptosis is a form of programmed cell death that
is pathogenic to several acute and chronic diseases
and executed via oxygenation of polyunsaturated
phosphatidylethanolamines (PE) by 15-lipoxygenases
(15-LO) that normally use free polyunsaturated
fatty acids as substrates. Mechanisms
of the altered 15-LO substrate specificity are enigmatic.
We sought a common ferroptosis regulator
for 15LO. We discovered that PEBP1, a scaffold
protein inhibitor of protein kinase cascades,
complexes with two 15LO isoforms, 15LO1 and
15LO2, and changes their substrate competence
to generate hydroperoxy-PE. Inadequate reduction
of hydroperoxy-PE due to insufficiency or dysfunction
of a selenoperoxidase, GPX4, leads to
ferroptosis. We demonstrated the importance of
PEBP1-dependent regulatory mechanisms of ferroptotic
death in airway epithelial cells in asthma,
kidney epithelial cells in renal failure, and cortical
and hippocampal neurons in brain trauma. As master
regulators of ferroptotic cell death with profound
implications for human disease, PEBP1/15LO complexes
represent a new target for drug discovery.


EOH
Journal Club
Thu 10/26/2017 12:00PM - 1:00PM
Transitioning regulatory immune cell thereapy to the clinic in organ transplantation EOH Seminar Series
Transitioning regulatory immune cell thereapy to the clinic in organ transplantation
Thu 10/26/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 10/26/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Meghan Matlack EOH Journal Club
EOH Journal Club - Fall 2017 - Meghan Matlack
Thu 10/26/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday October 26, 2017
Time: 11am - 12pm
Presenter: Meghan Matlack

Paper:  Reduced biological effect of e-cigarette aerosol compared to cigarette smoke evaluated in vitro using normalized nicotine dose and RNA-seq-based toxicogenomics

Authors: Linsey E. Haswell, Andrew Baxter, Anisha Banerjee, Ivan Verrastro, Jessica Mushonganono, Jason Adamson, David Thorne, Marianna Gaça & Emmanuel Minet

Abstract: Electronic cigarettes (e-cigarettes) use has increased globally and could potentially offer a lower risk alternative to cigarette smoking. Here, we assessed the transcriptional response of a primary 3D airway model acutely exposed to e-cigarette aerosol and cigarette (3R4F) smoke. Aerosols were generated with standard intense smoking regimens with careful consideration for dose by normalizing the exposures to nicotine. Two e-cigarette aerosol dilutions were tested for equivalent and higher nicotine delivery compared to 3R4F. RNA was extracted at 24 hrs and 48 hrs post exposure for RNA-seq. 873 and 205 RNAs were differentially expressed for 3R4F smoke at 24 hrs and 48 hrs using a pFDR < 0.01 and a [fold change] > 2 threshold. 113 RNAs were differentially expressed at the highest dose of e-cigarette aerosol using a looser threshold of pFDR < 0.05, 3 RNAs exceeded a fold change of 2. Geneset enrichment analysis revealed a clear response from lung cancer, inflammation, and fibrosis associated genes after 3R4F smoke exposure. Metabolic/biosynthetic processes, extracellular membrane, apoptosis, and hypoxia were identified for e-cigarette exposures, albeit with a lower confidence score. Based on equivalent or higher nicotine delivery, an acute exposure to e-cigarette aerosol had a reduced impact on gene expression compared to 3R4F smoke exposure in vitro.

EOH
Journal Club
Thu 10/12/2017 12:00PM - 1:00PM
Mesenchymal Stem Cells shape Dendritic & T cell function by multiple mechanisms EOH Seminar Series
Mesenchymal Stem Cells shape Dendritic & T cell function by multiple mechanisms
Thu 10/12/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 10/12/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Qiao Lin EOH Journal Club
EOH Journal Club - Fall 2017 - Qiao Lin
Thu 10/12/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017

Date: Thursday October 12, 2017
Time: 11am - 12pm
Presenter: Qiao Lin
Paper:  Metabolic co-dependence gives rise to collective oscillations within biofilms
Authors: Liu J, Prindle A, Humphries J, Gabalda-Sagarra M, Asally M, Lee DY, Ly S, Garcia-Ojalvo J, Süel GM



Abstract: Cells that reside within a community can cooperate and also compete with each other for resources. It remains unclear how these opposing interactions are resolved at the population level. Here we investigate such an internal conflict within a microbial (Bacillus subtilis) biofilm community: cells in the biofilm periphery not only protect interior cells from external attack but also starve them through nutrient consumption. We discover that this conflict between protection and starvation is resolved through emergence of long-range metabolic co-dependence between peripheral and interior cells. As a result, biofilm growth halts periodically, increasing nutrient availability for the sheltered interior cells. We show that this collective oscillation in biofilm growth benefits the community in the event of a chemical attack. These findings indicate that oscillations support population-level conflict resolution by coordinating competing metabolic demands in space and time, suggesting new strategies to control biofilm growth.



EOH
Journal Club
Thu 10/5/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Arron Liu EOH Journal Club
EOH Journal Club - Fall 2017 - Arron Liu
Thu 10/5/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday October 5, 2017
Time: 11am - 12pm
Presenter: Arron Liu
Paper: Activation of tumor suppressor protein PP2A inhibits KRAS-driven tumor growth
Authors: Jaya Sangodkar, Abbey Perl, et Al.

Abstract: Targeted cancer therapies, which act on specific cancer-associated molecular targets, are predominantly inhibitors of oncogenic kinases. While these drugs have achieved some clinical success, the inactivation of kinase signaling via stimulation of endogenous phosphatases has received minimal attention as an alternative targeted approach. Here, we have demonstrated that activation of the tumor suppressor protein phosphatase 2A (PP2A), a negative regulator of multiple oncogenic signaling proteins, is a promising therapeutic approach for the treatment of cancers. Our group previously developed a series of orally bioavailable small molecule activators of PP2A, termed SMAPs. We now report that SMAP treatment inhibited the growth of KRAS-mutant lung cancers in mouse xenografts and transgenic models. Mechanistically, we found that SMAPs act by binding to the PP2A Aα scaffold subunit to drive conformational changes in PP2A. These results show that PP2A can be activated in cancer cells to inhibit proliferation. Our strategy of reactivating endogenous PP2A may be applicable to the treatment of other diseases and represents an advancement toward the development of small molecule activators of tumor suppressor proteins.

Click Here For Article

EOH
Journal Club
Thu 9/28/2017 12:00PM - 1:00PM
Engineering Vasculature for the Lung EOH Seminar Series
Engineering Vasculature for the Lung
Thu 9/28/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 9/28/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Antonella Marrocco EOH Journal Club
EOH Journal Club - Fall 2017 - Antonella Marrocco
Thu 9/28/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday September 28, 2017
Time: 11am - 12pm
Presenter: Antonella Marrocco
Paper: Succinate Dehydrogenase Supports Metabolic Repurposing of Mitochondria to Drive Inflammatory Macrophages
Authors: Evanna L. Mills, Beth Kelly, Angela Logan, Christian Frezza, Michael P. Murphy, Luke A. O’Neill
Abstract: Activated macrophages undergo metabolic reprogramming, which drives their pro-inflammatory phenotype, but the mechanistic basis for this remains obscure. Here, we demonstrate that upon lipopolysaccharide (LPS) stimulation, macrophages shift from producing ATP by oxidative phosphorylation to glycolysis while also increasing succinate levels. We show that increased mitochondrial oxidation of succinate via succinatedehydrogenase (SDH)andanelevation of mitochondrial membrane potential combine to drive mitochondrial reactive oxygen species (ROS) production. RNA sequencing reveals that this combination induces a pro-inflammatory gene expression profile, while an inhibitor of succinate oxidation, dimethyl malonate (DMM), promotes an anti-inflammatory outcome. Blocking ROS production with rotenone by uncoupling mitochondria or by expressing the alternative oxidase (AOX) inhibits this inflammatory phenotype, with AOX protecting mice from LPS lethality. The metabolic alterations that occur upon activation of macrophages therefore repurpose mitochondria from ATP synthesis to ROS production in order to promote a pro-inflammatory state.

EOH
Journal Club
Thu 9/21/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Travis Lear EOH Journal Club
EOH Journal Club - Fall 2017 - Travis Lear
Thu 9/21/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday September 21, 2017
Time: 11am - 12pm
Presenter: Travis Lear
Paper: Opposing effects of cancer-type-specific SPOP mutants on BET protein degradation and sensitivity to BET inhibitors
Authors: Hana Janouskova, Geniver El Tekle, Elisa Bellini, Namrata D Udeshi, Anna Rinaldi,
Anna Ulbricht, Tiziano Bernasocchi, Gianluca Civenni, Marco Losa, Tanya Svinkina,
Craig M Bielski, Gregory V Kryukov, Luciano Cascione, Sara Napoli, Radoslav I Enchev,
David G Mutch, Michael E Carney, Andrew Berchuck, Boris J N Winterhoff, Russell R Broaddus,
Peter Schram, Holger Moch, Francesco Bertoni, Carlo V Catapano, Matthias Peter, Steven A Carr,
Levi A Garraway, Peter J Wild & Jean-Philippe P Theurillat

Abstract: It is generally assumed that recurrent mutations within a given cancer driver gene elicit similar drug responses. Cancer genome studies have identified recurrent but divergent missense mutations affecting the substrate-recognition domain of the ubiquitin ligase adaptor SPOP in endometrial and prostate cancers. The therapeutic implications of these mutations remain incompletely understood. Here we analyzed changes in the ubiquitin landscape induced by endometrial cancer–associated SPOP mutations and identified BRD2, BRD3 and BRD4 proteins (BETs) as SPOP–CUL3 substrates that are preferentially degraded by endometrial cancer–associated SPOP mutants. The resulting reduction of BET protein levels sensitized cancer cells to BET inhibitors. Conversely, prostate cancer–specific SPOP mutations resulted in impaired degradation of BETs, promoting their resistance to pharmacologic inhibition. These results uncover an oncogenomics paradox, whereby mutations mapping to the same domain evoke opposing drug susceptibilities. Specifically, we provide a molecular rationale for the use of BET inhibitors to treat patients with endometrial but not prostate cancer who harbor SPOP mutations.

EOH
Journal Club
Thu 9/14/2017 12:00PM - 1:00PM
The role of micro-and macro-environmental factors on muscle stem cell function EOH Seminar Series
The role of micro-and macro-environmental factors on muscle stem cell function
Thu 9/14/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 9/14/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Heng Bai EOH Journal Club
EOH Journal Club - Fall 2017 - Heng Bai
Thu 9/14/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017
Date: Thursday September 14, 2017
Time: 11am - 12pm
Presenter: Heng Bai
Paper: Role of subcellular calcium redistribution in regulating apoptosis and autophagy in cadmium-exposed primary rat proximal tubular cells
Authors: Fei Liu, Zi-Fa Li, Zhen-Yong Wang, Lin Wang
Abstract: Ca2+ signaling plays a vital role in regulating apoptosis and autophagy.We previously proved that cytosolic Ca2+ overload is involved in cadmium(Cd)-induced apoptosis in rat proximal tubular (rPT) cells, but the source of elevated cytosolic Ca2+ concentration ([Ca2+]c) and the effect of potential subcellular Ca2+ redistribution on apoptosis and autophagy remain to be elucidated. Firstly, data showed that Cd-induced elevation of [Ca2+]c was primarily generated intracellularly. Moreover, elevations of [Ca2+]c and mitochondrial Ca2+ concentration ([Ca2+]mit) with depletion of endoplasmic reticulum (ER) Ca2+ levels ([Ca2+]ER) were revealed in Cd-treated rPT cells, but this subcellular Ca2+ redistributionwas significantly suppressed by 2-Aminoethoxydiphenyl borate (2-APB). Elevated inositol 1,4,5-trisphosphate (IP3) levels with up-regulated IP3 receptor (IP3R) protein levels were shown in Cd-exposed cells, confirming that IP3R-mediated ER Ca2+ release results in the elevation of [Ca2+]c. Up-regulated sequestosome 1 (p62) protein levels and autophagic flux assay demonstrated that Cd impaired autophagic degradation, while N-acetylcysteine (NAC) markedly attenuated Cd-induced p62 and microtubule- associated protein 1 light chain 3-II (LC3-II) accumulation, implying that the inhibition of autophagic flux was due to oxidative stress. Furthermore, pharmacological modulation of [Ca2+]c with 1,2-Bis (2- aminophenoxy) ethane-N,N,N′,N′-tetraacetic acid acetoxymethyl ester (BAPTA-AM) and 2-APB alleviated Cdmediated apoptosis, inhibition of autophagic degradation and subsequent cytotoxicity, while thapsigargin (TG) had the opposite regulatory effect on them. In summary, cytosolic calcium overload originated from IP3R-mediated ER Ca2+ release has a negative impact on Cd nephrotoxicity through its promotion of apoptosis and inhibition of autophagic flux.


EOH
Journal Club
Thu 9/7/2017 11:00AM - 12:00PM
EOH Journal Club - Fall 2017 - Cody Wolfe EOH Journal Club
EOH Journal Club - Fall 2017 - Cody Wolfe
Thu 9/7/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Fall 2017

Date: Thursday September 7, 2017
Time: 11am - 12pm
Presenter: Cody Wolfe
Paper: A Unique Microglia Type Associated with Restricting Development of Alzheimer's Disease

Abstract: Alzheimer's disease (AD) is a detrimental neurodegenerative disease with no effective treatments. Due to cellular heterogeneity, defining the roles of immune cell subsets in AD onset and progression has been challenging. Using transcriptional single-cell sorting, we comprehensively map all immune populations in wild-type and AD-transgenic (Tg-AD) mouse brains. We describe a novel microglia type associated with neurodegenerative diseases (DAM) and identify markers, spatial localization, and pathways associated with these cells. Immunohistochemical staining of mice and human brain slices shows DAM with intracellular/phagocytic Aβ particles. Single-cell analysis of DAM in Tg-AD and triggering receptor expressed on myeloid cells 2 (Trem2)-/- Tg-AD reveals that the DAM program is activated in a two-step process. Activation is initiated in a Trem2-independent manner that involves downregulation of microglia checkpoints, followed by activation of a Trem2-dependent program. This unique microglia-type has the potential to restrict neurodegeneration, which may have important implications for future treatment of AD and other neurodegenerative diseases

EOH
Journal Club
Thu 8/24/2017 12:00PM - 1:00PM
Mikhail Shchepinov - Stop lipid peroxidation without antioxidants: heavy handling of Neuro diseases EOH Seminar Series
Mikhail Shchepinov - Stop lipid peroxidation without antioxidants: heavy handling of Neuro diseases
Thu 8/24/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 6/15/2017 12:00PM - 1:00PM
Juan Celedon - Asthma in Hispanics EOH Seminar Series
Juan Celedon - Asthma in Hispanics
Thu 6/15/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 6/8/2017 12:00PM - 1:00PM
Sally Wenzel - Leveraging a Lifetime of Asthma Transl Res into a New Paradigm for Environ Med EOH Seminar Series
Sally Wenzel - Leveraging a Lifetime of Asthma Transl Res into a New Paradigm for Environ Med
Thu 6/8/2017 12:00PM - 1:00PM



EOH
Seminar Series
Mon 5/8/2017 12:00PM - 1:00PM
Marc Weisskopf, PhD, ScD - "Environmental Neuroepidemiology: From Neurons to Populations." EOH Seminar Series
Marc Weisskopf, PhD, ScD - "Environmental Neuroepidemiology: From Neurons to Populations."
Mon 5/8/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 5/4/2017 12:00PM - 1:00PM
Activity and asthma in the urban environ : Does air pollution offset the respir benefit of exercise? EOH Seminar Series
Activity and asthma in the urban environ : Does air pollution offset the respir benefit of exercise?
Thu 5/4/2017 12:00PM - 1:00PM



EOH
Seminar Series
Mon 5/1/2017 12:00PM - 1:00PM
Using Translational Science to Understand the Role of the Epigenome in Metals-Induced Toxicity EOH Seminar Series
Using Translational Science to Understand the Role of the Epigenome in Metals-Induced Toxicity
Mon 5/1/2017 12:00PM - 1:00PM



EOH
Seminar Series
Mon 4/17/2017 12:00PM - 1:00PM
Amin Cheikhi: Power Laws Govern Mitochondrial Optimization of Cellular Memory And Fate Decisions EOH Dissertation Defense
Amin Cheikhi: Power Laws Govern Mitochondrial Optimization of Cellular Memory And Fate Decisions
Mon 4/17/2017 12:00PM - 1:00PM


 
EOH Departmental Doctoral Defense

“Power Laws Govern Mitochondrial Optimization of Cellular Memory And Fate Decisions”
Amin Cheikhi, BSc
Graduate Student
Department of Environmental
And Occupational Health
Graduate School of Public Health

Monday, April 17, 2017
12:00 pm

Bridgeside Point, 100 Technology Drive
Fifth Floor Conference Room, #540
http://www.eoh.pitt.edu

EOH
Dissertation Defense
Fri 4/14/2017 11:00AM - 12:00PM
Sheila Tripahty -Hybrid land use regression modeling of fine particulate matter and metal component EOH Dissertation Defense
Sheila Tripahty -Hybrid land use regression modeling of fine particulate matter and metal component
Fri 4/14/2017 11:00AM - 12:00PM


 
EOH Departmental
Dissertation Defense

“Hybrid land use regression modeling
of fine particulate matter and metal components for application in two Pittsburgh cohorts”

Sheila Tripathy

Department of Environmental
And Occupational Health
Graduate School of Public Health
Friday, April 14, 2017
11:00 am
Bridgeside Point, 100 Technology Drive
Fifth Floor Conference Room, #540

http://www.eoh.pitt.edu

EOH
Dissertation Defense
Thu 4/6/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Teresa Anguiano EOH Journal Club
EOH Journal Club - Spring 2017 - Teresa Anguiano
Thu 4/6/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday April 6, 2017

Time: 11am - 12pm

Presenter: Teresa Anguiano

Paper: Inhibition of PDGFR signaling prevents muscular fatty infiltration after rotator cuff tear in mice

Authors: Hideyuki Shirasawa, Noboru Matsumura, Masayuki Shimoda, Satoshi Oki, Masaki Yoda, Takahide Tohmonda, Yae Kanai, Morio Matsumoto, Masaya Nakamura & Keisuke Horiuch

Abstract: Fatty infiltration in muscle is often observed in patients with sizable rotator cuff tear (RCT) and is thought to be an irreversible event that significantly compromises muscle plasticity and contraction strength. These changes in the mechanical properties of the affected muscle render surgical repair of RCT highly formidable. Therefore, it is important to learn more about the pathology of fatty infiltration to prevent this undesired condition. In the present study, we aimed to generate a mouse model that can reliably recapitulate some of the important characteristics of muscular fatty infiltration after RCT in humans. We found that fatty infiltration can be efficiently induced by a combination of the following procedures: denervation of the suprascapular nerve, transection of the rotator cuff tendon, and resection of the humeral head. Using this model, we found that platelet-derived growth factor receptor-α (PDGFRα)-positive mesenchymal stem cells are induced after this intervention and that inhibition of PDGFR signaling by imatinib treatment can significantly suppress fatty infiltration. Taken together, the present study presents a reliable fatty infiltration mouse model and suggests a key role for PDGFRα-positive mesenchymal stem cells in the process of fatty infiltration after RCT in humans.

EOH
Journal Club
Thu 3/30/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Shuo Cao EOH Journal Club
EOH Journal Club - Spring 2017 - Shuo Cao
Thu 3/30/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday March 30, 2017

Time: 11am - 12pm

Presenter: Shuo Cao

Paper: Structural and transcriptomic response to antenatal corticosteroids in an Erk3-null mouse model of respiratory distress

Authors: Pew BK, Harris RA, Sbrana E, Guaman MC, Shope C, Chen R, Meloche S, Aagaard K.

Abstract:
BACKGROUND:
Neonatal respiratory distress syndrome in preterm infants is a leading cause of neonatal death. Pulmonary insufficiency-related infant mortality rates have improved with antenatal glucocorticoid treatment and neonatal surfactant replacement. However, the mechanism of glucocorticoid-promoted fetal lung maturation is not understood fully, despite decades of clinical use. We previously have shown that genetic deletion of Erk3 in mice results in growth restriction, cyanosis, and early neonatal lethality because of pulmonary immaturity and respiratory distress. Recently, we demonstrated that the addition of postnatal surfactant administration to antenatal dexamethasone treatment resulted in enhanced survival of neonatal Erk3-null mice.

OBJECTIVE:
To better understand the molecular underpinnings of corticosteroid-mediated lung maturation, we used high-throughput transcriptomic and high-resolution morphologic analysis of the murine fetal lung. We sought to examine the alterations in fetal lung structure and function that are associated with neonatal respiratory distress and antenatal glucocorticoid treatment.

STUDY DESIGN:
Dexamethasone (0.4 mg/kg) or saline solution was administered to pregnant dams on embryonic days 16.5 and 17.5. Fetal lungs were collected and analyzed by microCT and RNA-seq for differential gene expression and pathway interactions with genotype and treatment. Results from transcriptomic analysis guided further investigation of candidate genes with the use of immunostaining in murine and human fetal lung tissue.

RESULTS:
Erk3(-/-) mice exhibited atelectasis with decreased overall porosity and saccular space relative to wild type, which was ameliorated by glucocorticoid treatment. Of 596 differentially expressed genes (q < 0.05) that were detected by RNA-seq, pathway analysis revealed 36 genes (q < 0.05) interacting with dexamethasone, several with roles in lung development, which included corticotropin-releasing hormone and surfactant protein B. Corticotropin-releasing hormone protein was detected in wild-type and Erk3(-/-) lungs at E14.5, with significantly temporally altered expression through embryonic day 18.5. Antenatal dexamethasone attenuated corticotropin-releasing hormone at embryonic day 18.5 in both wild-type and Erk3(-/-) lungs (0.56-fold and 0.67-fold; P < .001). Wild type mice responded to glucocorticoid administration with increased pulmonary surfactant protein B (P = .003). In contrast, dexamethasone treatment in Erk3(-/-) mice resulted in decreased surfactant protein B (P = .012). In human validation studies, we confirmed that corticotropin-releasing hormone protein is present in the fetal lung at 18 weeks of gestation and increases in expression with progression towards viability (22 weeks of gestation; P < .01).

CONCLUSION:
Characterization of whole transcriptome gene expression revealed glucocorticoid-mediated regulation of corticotropin-releasing hormone and surfactant protein B via Erk3-independent and -dependent mechanisms, respectively. We demonstrated for the first time the expression and temporal regulation of corticotropin-releasing hormone protein in midtrimester human fetal lung. This unique model allows the effects of corticosteroids on fetal pulmonary morphologic condition to be distinguished from functional gene pathway regulation. These findings implicate Erk3 as a potentially important molecular mediator of antenatal glucocorticoid action in promoting surfactant protein production in the preterm neonatal lung and expanding our understanding of key mechanisms of clinical therapy to improve neonatal survival

Click Here For Article

EOH
Journal Club
Thu 3/23/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Heng Bai EOH Journal Club
EOH Journal Club - Spring 2017 - Heng Bai
Thu 3/23/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017
Date: Thursday March 23, 2017
Time: 11am - 12pm
Presenter: Heng Bai

Paper: 
In vivo activation of a T helper 2-driven innate immune response in
lung fibrosis induced by multi-walled carbon nanotubes

Authors: Dong J, Ma Q

Abstract:
Pulmonary exposure to certain forms of carbon nanotubes (CNT) induces
fibrosing lesions in the lungs that manifest an acute inflammation
followed by chronic interstitial fibrosis. The mechanism of CNT-induced
fibrogenesis is largely unknown. The biphasic development with
drastically distinct pathologic manifestations suggests a junction of
acute-to-chronic transition. Here we analyzed the molecular pathways and
regulators underlying the pathologic development of CNT-induced lung
fibrosis. Mice were exposed to multi-walled CNT (MWCNT; XNRI MWNT-7,
Mitsui; 40 μg) by pharyngeal aspiration for 7 days along with vehicle
and carbonaceous controls. Genome-wide microarray analyses of the lungs
identified a range of differentially expressed genes that potentially
function in the acute-to-chronic transition through pathways involving
immune and inflammatory regulation, responses to stress and
extracellular stimuli, and cell migration and adhesion. In particular, a
T helper 2 (Th2)-driven innate immune response was significantly
enriched. We then demonstrated that MWCNT induced the expression of Th2
cytokines interleukin (IL)-4 and IL-13, and a panel of signature
downstream genes, such as Il4i1, Chia, and Ccl11/Eotaxin, time
dependently. Induction of Th2 cytokines took place in CD4+ T lymphocytes
indicating activation of Th2 cells. Furthermore, induction involved
activation of a Th2 cell-specific signaling pathway through
phosphorylation of STAT6 and up-regulation of GATA-3 to mediate the
transcription of Th2 target genes. Our study uncovers activation of a
Th2-driven immune/inflammatory response during pulmonary fibrosis
development induced by MWCNT. The findings provide novel insights into
the molecular events that control the transition from an acute
inflammatory response to chronic fibrosis through Th2 functions in
CNT-exposed lungs

Click Here For Article

EOH
Journal Club
Thu 3/16/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Chai-Hsin/Aaron Liu EOH Journal Club
EOH Journal Club - Spring 2017 - Chai-Hsin/Aaron Liu
Thu 3/16/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday March 16, 2017

Time: 11am - 12pm

Presenter: Chai-Hsin/Aaron Liu

Paper: Combined inhibition of DDR1 and Notch signaling is a therapeutic strategy for KRAS-driven lung adenocarcinoma

Authors: Ambrogio C, Gómez-López G, Falcone M, Vidal A, Nadal E, Crosetto N, Blasco RB, Fernández-Marcos PJ, Sánchez-Céspedes M, Ren X, Wang Z, Ding K, Hidalgo M, Serrano M, Villanueva A, Santamaría D, Barbacid M.

Abstract:
Patients with advanced Kirsten rat sarcoma viral oncogene homolog (KRAS)-mutant lung adenocarcinoma are currently treated with standard chemotherapy because of a lack of efficacious targeted therapies. We reasoned that the identification of mediators of Kras signaling in early mouse lung hyperplasias might bypass the difficulties that are imposed by intratumor heterogeneity in advanced tumors, and that it might unveil relevant therapeutic targets. Transcriptional profiling of Kras(G12V)-driven mouse hyperplasias revealed intertumor diversity with a subset that exhibited an aggressive transcriptional profile analogous to that of advanced human adenocarcinomas. The top-scoring gene in this profile encodes the tyrosine kinase receptor DDR1. The genetic and pharmacological inhibition of DDR1 blocked tumor initiation and tumor progression, respectively. The concomitant inhibition of both DDR1 and Notch signaling induced the regression of KRAS;TP53-mutant patient-derived lung xenografts (PDX) with a therapeutic efficacy that was at least comparable to that of standard chemotherapy. Our data indicate that the combined inhibition of DDR1 and Notch signaling could be an effective targeted therapy for patients with KRAS-mutant lung adenocarcinoma.

Click Here For Article

EOH
Journal Club
Thu 3/2/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Qiao Lin EOH Journal Club
EOH Journal Club - Spring 2017 - Qiao Lin
Thu 3/2/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday March 2, 2017

Time: 11am - 12pm

Presenter: Qiao Lin

Paper: Combating multidrug-resistant Gram-negative bacteria with structurally nanoengineered antimicrobial peptide polymers

Authors: Lam SJ, O'Brien-Simpson NM, Pantarat N, Sulistio A, Wong EH, Chen YY, Lenzo JC, Holden JA, Blencowe A, Reynolds EC, Qiao GG.

Abstract: With the recent emergence of reports on resistant Gram-negative 'superbugs', infections caused by multidrug-resistant (MDR) Gram-negative bacteria have been named as one of the most urgent global health threats due to the lack of effective and biocompatible drugs. Here, we show that a class of antimicrobial agents, termed 'structurally nanoengineered antimicrobial peptide polymers' (SNAPPs) exhibit sub-μM activity against all Gram-negative bacteria tested, including ESKAPE and colistin-resistant and MDR (CMDR) pathogens, while demonstrating low toxicity. SNAPPs are highly effective in combating CMDR Acinetobacter baumannii infections in vivo, the first example of a synthetic antimicrobial polymer with CMDR Gram-negative pathogen efficacy. Furthermore, we did not observe any resistance acquisition by A. baumannii (including the CMDR strain) to SNAPPs. Comprehensive analyses using a range of microscopy and (bio)assay techniques revealed that the antimicrobial activity of SNAPPs proceeds via a multimodal mechanism of bacterial cell death by outer membrane destabilization, unregulated ion movement across the cytoplasmic membrane and induction of the apoptotic-like death pathway, possibly accounting for why we did not observe resistance to SNAPPs in CMDR bacteria. Overall, SNAPPs show great promise as low-cost and effective antimicrobial agents and may represent a weapon in combating the growing threat of MDR Gram-negative bacteria.

Click Here For Article

EOH
Journal Club
Thu 2/23/2017 12:00PM - 1:00PM
GPCR Dysfunction in Alzheimer's Disease EOH Seminar Series
GPCR Dysfunction in Alzheimer's Disease
Thu 2/23/2017 12:00PM - 1:00PM
Bridgeside Point


EOH
Seminar Series
Thu 2/23/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Hsiu-Chi/Shawn Ting EOH Journal Club
EOH Journal Club - Spring 2017 - Hsiu-Chi/Shawn Ting
Thu 2/23/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday February 23, 2017

Time: 11am - 12pm

Presenter: Hsiu-Chi/Shawn Ting

Paper: ACSL4 dictates ferroptosis sensitivity by shaping cellular lipid composition

Authors: Doll S, Proneth B, Tyurina YY, Panzilius E, Kobayashi S, Ingold I, Irmler M, Beckers J, Aichler M, Walch A, Prokisch H, Trümbach D, Mao G, Qu F, Bayir H, Füllekrug J, Scheel CH, Wurst W, Schick JA, Kagan VE, Angeli JP, Conrad M.

Abstract: Ferroptosis is a form of regulated necrotic cell death controlled by glutathione peroxidase 4 (GPX4). At present, mechanisms that could predict sensitivity and/or resistance and that may be exploited to modulate ferroptosis are needed. We applied two independent approaches-a genome-wide CRISPR-based genetic screen and microarray analysis of ferroptosis-resistant cell lines-to uncover acyl-CoA synthetase long-chain family member 4 (ACSL4) as an essential component for ferroptosis execution. Specifically, Gpx4-Acsl4 double-knockout cells showed marked resistance to ferroptosis. Mechanistically, ACSL4 enriched cellular membranes with long polyunsaturated ω6 fatty acids. Moreover, ACSL4 was preferentially expressed in a panel of basal-like breast cancer cell lines and predicted their sensitivity to ferroptosis. Pharmacological targeting of ACSL4 with thiazolidinediones, a class of antidiabetic compound, ameliorated tissue demise in a mouse model of ferroptosis, suggesting that ACSL4 inhibition is a viable therapeutic approach to preventing ferroptosis-related diseases.

Click Here For Article

EOH
Journal Club
Thu 2/16/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Antonella Marrocco EOH Journal Club
EOH Journal Club - Spring 2017 - Antonella Marrocco
Thu 2/16/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday February 16, 2017

Time: 11am - 12pm

Presenter: Antonella Marrocco

Paper: Mitochondrial respiratory-chain adaptations in macrophages contribute to antibacterial host defense

Authors:
Johan Garaude, Rebeca Acín-Pérez, Sarai Martínez-Cano, Michel
Enamorado, Matteo Ugolini, Estanislao Nistal-Villán, Sandra
Hervás-Stubbs, Pablo Pelegrín, Leif E Sander, José A Enríquez &
David Sancho  

Abstract: Macrophages tightly scale their core
metabolism after being activated, but the precise regulation of the
mitochondrial electron-transport chain (ETC) and its functional
implications are currently unknown. Here we found that recognition of
live bacteria by macrophages transiently decreased assembly of the ETC
complex I (CI) and CI-containing super-complexes and switched the
relative contributions of CI and CII to mitochondrial respiration. This
was mediated by phagosomal NADPH oxidase and the reactive oxygen species
(ROS)-dependent tyrosine kinase Fgr. It required Toll-like receptor
signaling and the NLRP3 inflammasome, which were both connected to
bacterial viability–specific immune responses. Inhibition of CII during
infection with Escherichia coli normalized serum concentrations of
interleukin 1β (IL-1β) and IL-10 to those in mice treated with dead
bacteria and impaired control of bacteria. We have thus identified ETC
adaptations as an early immunological-metabolic checkpoint that adjusts
innate immune responses to bacterial infection.

EOH
Journal Club
Thu 2/9/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Travis Lear EOH Journal Club
EOH Journal Club - Spring 2017 - Travis Lear
Thu 2/9/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

Date: Thursday February 9, 2017

Time: 11am - 12pm

Presenter: Travis Lear

Paper: Genome-wide in vivo screen identifies novel host regulators of metastatic colonization

Authors:
Louise van der Weyden, Mark J. Arends, Andrew D. Campbell, Tobias Bald,
Hannah Wardle-Jones, Nicola Griggs, Martin Del Castillo
Velasco-Herrera, Thomas Tüting, Owen J. Sansom, Natasha A. Karp, Simon
Clare, Diane Gleeson, Edward Ryder, Antonella Galli, Elizabeth Tuck,
Emma L. Cambridge, Thierry Voet, Iain C. Macaulay, Kim Wong, Sanger
Mouse Genetics Project, Sarah Spiegel, Anneliese O. Speak & David J.
Adams

Abstract: Metastasis is the leading cause of death for
cancer patients. This multi-stage process requires tumour cells to
survive in the circulation, extravasate at distant sites, then
proliferate; it involves contributions from both the tumour cell and
tumour microenvironment (‘host’, which includes stromal cells and the
immune system1). Studies suggest the early steps of the metastatic
process are relatively efficient, with the post-extravasation regulation
of tumour growth (‘colonization’) being critical in determining
metastatic outcome2. Here we show the results of screening 810 mutant
mouse lines using an in vivo assay to identify microenvironmental
regulators of metastatic colonization. We identify 23 genes that, when
disrupted in mouse, modify the ability of tumour cells to establish
metastatic foci, with 19 of these genes not previously demonstrated to
play a role in host control of metastasis. The largest reduction in
pulmonary metastasis was observed in sphingosine-1-phosphate (S1P)
transporter spinster homologue 2 (Spns2)-deficient mice. We demonstrate a
novel outcome of S1P-mediated regulation of lymphocyte trafficking,
whereby deletion of Spns2, either globally or in a lymphatic
endothelial-specific manner, creates a circulating lymphopenia and a
higher percentage of effector T cells and natural killer (NK) cells
present in the lung. This allows for potent tumour cell killing, and an
overall decreased metastatic burden.


EOH
Journal Club
Thu 2/2/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Rahel Birru EOH Journal Club
EOH Journal Club - Spring 2017 - Rahel Birru
Thu 2/2/2017 11:00AM - 12:00PM


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

Authors:
Richmond BW, Brucker RM, Han W, Du RH, Zhang Y, Cheng DS, Gleaves L,
Abdolrasulnia R, Polosukhina D, Clark PE, Bordenstein SR, Blackwell TS,
Polosukhin VV

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 remodelling 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 remodelling. 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 remodelling and emphysema.

EOH
Journal Club
Thu 1/26/2017 12:00PM - 1:00PM
"Microglia and Astrocyte in Alzheimer's Disease: Partners in crime?" EOH Seminar Series
"Microglia and Astrocyte in Alzheimer's Disease: Partners in crime?"
Thu 1/26/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 1/26/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Amrita Sahu EOH Journal Club
EOH Journal Club - Spring 2017 - Amrita Sahu
Thu 1/26/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

 

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.


EOH
Journal Club
Thu 1/19/2017 12:00PM - 1:00PM
"Deciphering the risk architecture of multiple sclerosis" EOH Seminar Series
"Deciphering the risk architecture of multiple sclerosis"
Thu 1/19/2017 12:00PM - 1:00PM



EOH
Seminar Series
Thu 1/19/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Emilie Castranio EOH Journal Club
EOH Journal Club - Spring 2017 - Emilie Castranio
Thu 1/19/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017

 

Date: Thursday January 19, 2017 Time: 11am - 12pm

 

Presenter: Emilie Castranio

 

Paper:  Early changes in CSF sTREM2 in dominantly inherited Alzheimer’s disease occur after amyloid deposition and neuronal injury

 

Authors: Marc Suárez-Calvet, Miguel Ángel Araque Caballero, Gernot Kleinberger, Randall J. Bateman, Anne M. Fagan, John C. Morris, Johannes Levin, Adrian Danek, Michael Ewers, Christian Haass, for the Dominantly Inherited Alzheimer Network

EOH
Journal Club
Thu 1/12/2017 12:00PM - 1:00PM
Patricia Opresko Seminar - DNA Repair at telomeres and the implications for cancer and aging EOH Seminar Series
Patricia Opresko Seminar - DNA Repair at telomeres and the implications for cancer and aging
Thu 1/12/2017 12:00PM - 1:00PM
Starzl Biomedical Science Tower

Pharmacology and Chemical Biology Seminar Series
Thursday, January 12, 2017
Patricia Opresko, PhD
Associate Professor
Department of Environmental and Occupational Health
University of Pittsburgh Graduate School of Public Health
“DNA repair at telomeres and the implications for cancer and aging.”
12:00 PM
1395 Thomas E.Starzl Biomedical Science Tower
Hosted by: University of Pittsburgh Pharmacology and Chemical Biology

EOH
Seminar Series
Thu 1/12/2017 11:00AM - 12:00PM
EOH Journal Club - Spring 2017 - Cody Wolfe EOH Journal Club
EOH Journal Club - Spring 2017 - Cody Wolfe
Thu 1/12/2017 11:00AM - 12:00PM


EOH Journal Club Seminar - Spring 2017
Date: Thursday January 12, 2017
Time: 11am - 12pm
Presenter: Cody Wolfe

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


EOH
Journal Club
Mon 12/5/2016 1:00PM - 4:00PM
Alexis Carter: DISSERTATION DEFENSE EOH Dissertation Defense
Alexis Carter: DISSERTATION DEFENSE
Mon 12/5/2016 1:00PM - 4:00PM


Alexis Carter Dissertation Defense

 

Monday, December 5, 2016 from 1:00 - 4:00 PM


EOH
Dissertation Defense
Wed 10/26/2016 9:00AM - 10:00AM
Michelle A. Mendez - Environmental Contaminants in the Global Epidemic of Cardio-Metabolic Diseases: EOH Seminar Series
Michelle A. Mendez - Environmental Contaminants in the Global Epidemic of Cardio-Metabolic Diseases:
Wed 10/26/2016 9:00AM - 10:00AM
A425 Public Health

In a joint seminar by the departments of Epidemiology and Environmental & Occupational Health, Michelle A. Mendez of UNC-Chapel Hill presents "Environmental Contaminants in the global Epidemic of Cardio-Metabolic Diseases: Evidence for a Role of Low-To-Moderate Arsenic Exposure in Mexico and China."


EOH
Seminar Series
Wed 10/5/2016 12:00PM - 1:00PM
Lin Mantell, MD, PhD EOH Seminar Series
Lin Mantell, MD, PhD
Wed 10/5/2016 12:00PM - 1:00PM



EOH
Seminar Series
Fri 9/30/2016 2:00PM - 3:00PM
Samantha Malone Rubright - Cyanide and Hydrogen Sulfide: A Review of Two Blood Gases, Their Environm EOH Dissertation Defense
Samantha Malone Rubright - Cyanide and Hydrogen Sulfide: A Review of Two Blood Gases, Their Environm
Fri 9/30/2016 2:00PM - 3:00PM


EOH Department Dissertation Defense

Samantha Malone Rubright: Cyanide and Hydrogen Sulfide: A Review of Two Blood Gases, Their Environmental Sources, and Potential Risks


EOH
Dissertation Defense
Thu 6/9/2016 12:00PM - 1:00PM
Too close for comfort: health effects of diesel exhaust in chambers, cars, and communities" EOH Seminar Series
Too close for comfort: health effects of diesel exhaust in chambers, cars, and communities"
Thu 6/9/2016 12:00PM - 1:00PM


Health effects, diesel exhaust, chambers, cars, communities

EOH
Seminar Series
Thu 5/12/2016 12:00PM - 1:00PM
"Microglia as Sentinels and the Lung-Brain Axis" EOH Seminar Series
"Microglia as Sentinels and the Lung-Brain Axis"
Thu 5/12/2016 12:00PM - 1:00PM



EOH
Seminar Series
Fri 4/29/2016 12:00PM - 1:00PM
Department of Environmental and Occupational Health "Special" Seminar EOH Seminar Series
Department of Environmental and Occupational Health "Special" Seminar
Fri 4/29/2016 12:00PM - 1:00PM



EOH
Seminar Series
Thu 4/14/2016 12:00PM - 1:00PM
Keven M. Robinson - Influenza and bacterial super-infection: the role of IL-1 cytokines EOH Seminar Series
Keven M. Robinson - Influenza and bacterial super-infection: the role of IL-1 cytokines
Thu 4/14/2016 12:00PM - 1:00PM


Keven Mara Robinson, MD Assistant Professor of Medicine Division of Pulmonary, Allergy & Critical Care Medicine University of Pittsburgh School of Medicine "Influenza and bacterial super-infection: the role of IL-1 cytokines

EOH
Seminar Series
Thu 4/14/2016 11:00AM - 12:00PM
Amrita Sahu present on: ADVANCED IMAGING. Extended-resolution structured illumination ... EOH Journal Club
Amrita Sahu present on: ADVANCED IMAGING. Extended-resolution structured illumination ...
Thu 4/14/2016 11:00AM - 12:00PM


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
Mon 4/11/2016 2:00PM - 4:00PM
Lauren Chubb - Characterization of Silica Content in Gold Mine Dust with Respect to Particle Size EOH Dissertation Defense
Lauren Chubb - Characterization of Silica Content in Gold Mine Dust with Respect to Particle Size
Mon 4/11/2016 2:00PM - 4:00PM


DrPH defense
"Characterization of Silica Content in Gold Mine Dust with Respect to Particle Size"
Department of Environmental and Occupational Health, Graduate School of Public Health

EOH
Dissertation Defense
Thu 4/7/2016 12:00PM to Mon 4/11/2016 1:00PM
Evelyn O. Talbott EOH Seminar Series
Evelyn O. Talbott
Thu 4/7/2016 12:00PM to Mon 4/11/2016 1:00PM
Bridgeside Point

Evelyn O. Talbott, DrPH, MPH Professor Dept of Epidemiology GSPH University of Pgh "Environmental Risk Factors for Childhood Autism & other Childhood Developmental disorders"

EOH
Seminar Series
Thu 3/31/2016 12:00PM - 1:00PM
M. Ilyas Kamboh - Genetic Epidemiology of Alzheimer's Disease EOH Seminar Series
M. Ilyas Kamboh - Genetic Epidemiology of Alzheimer's Disease
Thu 3/31/2016 12:00PM - 1:00PM


M. Ilyas Kamboh, PhD, FAHA Professor of Human Genetics, Epidemiology and Psychiatry Department of Human Genetics Graduate School of Public Health Director, Neurogenetics Core, University of Pittsburgh Alzheimer's Disease Research Center University of Pittsburgh "Genetic Epidemiology of Alzheimer's Disease"

EOH
Seminar Series
Thu 3/31/2016 11:00AM - 12:00PM
Rahel Birru presents on: EGCG regulates the cross-talk between JWA and topoisomeras EOH Journal Club
Rahel Birru presents on: EGCG regulates the cross-talk between JWA and topoisomeras
Thu 3/31/2016 11:00AM - 12:00PM


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

 

 


EOH
Journal Club
Thu 3/24/2016 12:00PM - 1:00PM
Chunbin Zou - Does Epigenetics Matter in Acute Lung Injury? EOH Seminar Series
Chunbin Zou - Does Epigenetics Matter in Acute Lung Injury?
Thu 3/24/2016 12:00PM - 1:00PM


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?"


EOH
Seminar Series
Thu 3/24/2016 11:00AM - 12:00PM
Shuo Cao presents on: Proteasome function is not impaired in healthy aging of the lung EOH Journal Club
Shuo Cao presents on: Proteasome function is not impaired in healthy aging of the lung
Thu 3/24/2016 11:00AM - 12:00PM


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  

 


EOH
Journal Club
Thu 3/3/2016 11:00AM - 12:00PM
EOH Journal Club Seminar EOH Journal Club
EOH Journal Club Seminar
Thu 3/3/2016 11:00AM - 12:00PM


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
Thu 2/25/2016 11:00AM - 12:00PM
EOH Journal Club Seminar EOH Journal Club
EOH Journal Club Seminar
Thu 2/25/2016 11:00AM - 12:00PM


339 Bridgeside Point

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.


EOH
Journal Club
Thu 2/4/2016 12:00PM - 1:00PM
Environmental and Occupational Health Seminar EOH Seminar Series
Environmental and Occupational Health Seminar
Thu 2/4/2016 12:00PM - 1:00PM


540 Bridgeside Point

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"


EOH
Seminar Series
Thu 1/28/2016 12:00PM - 1:00PM
EOH Seminar EOH Seminar Series
EOH Seminar
Thu 1/28/2016 12:00PM - 1:00PM


540 Bridgeside Point

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"


EOH
Seminar Series
Thu 1/28/2016 11:00AM - 12:00PM
EOH Journal Club Seminar EOH Journal Club
EOH Journal Club Seminar
Thu 1/28/2016 11:00AM - 12:00PM


339 Bridgeside

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.


EOH
Journal Club
Tue 1/26/2016 1:00PM - 3:00PM
EOH Dissertation Defense EOH Dissertation Defense
EOH Dissertation Defense
Tue 1/26/2016 1:00PM - 3:00PM


5th Floor Conference Room, Bridgeside Point

Dushani Palliyaguru will present ""Characterizing Withaferin A as a novel Nrf2 inducer: implications for liver disease prevention."


EOH
Dissertation Defense
Thu 1/21/2016 11:00AM - 12:00PM
EOH Journal Club Seminar EOH Journal Club
EOH Journal Club Seminar
Thu 1/21/2016 11:00AM - 12:00PM


339 Bridgeside Point

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.


EOH
Journal Club
Thu 1/14/2016 11:00AM - 12:00PM
EOH Journal Club Seminar EOH Journal Club
EOH Journal Club Seminar
Thu 1/14/2016 11:00AM - 12:00PM


339 Bridgeside Point

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.


EOH
Journal Club
Thu 1/7/2016 12:00PM - 1:00PM
EOH Seminar EOH Seminar Series
EOH Seminar
Thu 1/7/2016 12:00PM - 1:00PM


540 Bridgeside Point

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"


EOH
Seminar Series
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