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Whole-Genome Sequencing And Disability In The Nicu: Exploring Practical And Ethical Challenges., Michael J. Deem

Manuscripts, Articles, Book Chapters and Other Papers

Clinical whole-genome sequencing (WGS) promises to deliver faster diagnoses and lead to better management of care in the NICU. However,several disability rights advocates have expressed concern that clinical use of genetic technologies may reinforce and perpetuate stigmatization of and discrimination against disabled persons in medical and social contexts. There is growing need, then, for clinicians and bioethicists to consider how the clinical use of WGS in the newborn period might exacerbate such harms to persons with disabilities. This article explores ways to extend these concerns to clinical WGS in neonatal care. By considering these perspectives during the early phases of …

Vector Competence Of American Mosquitoes For Three Strains Of Zika Virus, James Weger-Lucarelli, Claudia Rückert, Nunya Chotiwan, Chilinh Nguyen, Selene M. Garcia Luna, Joseph R. Fauver, Brian D. Foy, Rushika Perera, William C. Black, Rebekah C. Kading, Gregory D. Ebel

Journal Articles: Epidemiology

In 2015, Zika virus (ZIKV; Flaviviridae; Flavivirus) emerged in the Americas, causing millions of infections in dozens of countries. The rapid spread of the virus and the association with disease outcomes such as Guillain-Barré syndrome and microcephaly make understanding transmission dynamics essential. Currently, there are no reports of vector competence (VC) of American mosquitoes for ZIKV isolates from the Americas. Further, it is not clear whether ZIKV strains from other genetic lineages can be transmitted by American Aedes aegypti populations, and whether the scope of the current epidemic is in part facilitated by viral factors such as enhanced replicative fitness …

Early Identification And Prevention Of The Spread Of Ebola - United States, Chris A. Van Beneden, Harald Pietz, Robert D. Kirkcaldy, Lisa M. Koonin, Timothy M. Uyeki, Alexandra M. Oster, Deborah A. Levy, Maleeka Glover, Matthew J. Arduino, Toby L. Merlin, David T. Kuhar, Christine Kosmos, Beth P. Bell

Journal Articles: Epidemiology

In response to the 2014-2016 Ebola virus disease (Ebola) epidemic in West Africa, CDC prepared for the potential introduction of Ebola into the United States. The immediate goals were to rapidly identify and isolate any cases of Ebola, prevent transmission, and promote timely treatment of affected patients. CDC's technical expertise and the collaboration of multiple partners in state, local, and municipal public health departments; health care facilities; emergency medical services; and U.S. government agencies were essential to the domestic preparedness and response to the Ebola epidemic and relied on longstanding partnerships. CDC established a comprehensive response that included two new …

Biological Markers For Pulpal Inflammation: A Systematic Review., Dan-Krister Rechenberg, Johnah C. Galicia, Ove A. Peters

All Dugoni School of Dentistry Faculty Articles

BACKGROUND AND OBJECTIVE: Pulpitis is mainly caused by an opportunistic infection of the pulp space with commensal oral microorganisms. Depending on the state of inflammation, different treatment regimes are currently advocated. Predictable vital pulp therapy depends on accurate determination of the pulpal status that will allow repair to occur. The role of several players of the host response in pulpitis is well documented: cytokines, proteases, inflammatory mediators, growth factors, antimicrobial peptides and others contribute to pulpal defense mechanisms; these factors may serve as biomarkers that indicate the status of the pulp. Therefore, the aim of this systematic review was to …

Improving Patient Safety, Health Data Accuracy, And Remote Self-Management Of Health Through The Establishment Of A Biometric-Based Global Uhid, Guy Hembroff

Michigan Tech Publications, Part 1

Healthcare systems globally continue to face challenges surrounding patient identification. Consequences of misidentification include incomplete and inaccurate electronic patient health records potentially jeopardizing patients' safety, a significant amount of cases of medical fraud because of inadequate identification mechanisms, and difficulties affiliated with the value of remote health self-management application data being aggregated accurately into the user's Electronic Health Record (EHR). We introduce a new technique of user identification in healthcare capable of establishing a global identifier. Our research has developed algorithms capable of establishing a Unique Health Identifier (UHID) based on the user's fingerprint biometric, with the utilization of facial-recognition …

Identification And Use Of Frailty Indicators From Text To Examine Associations With Clinical Outcomes Among Patients With Heart Failure., Yijun Shao, April F Mohanty, Ali Ahmed, Charlene R Weir, Bruce E Bray, Rashmee U Shah, Douglas Redd, Qing Zeng-Treitler

Clinical Research and Leadership Faculty Publications

Frailty is an important health outcomes indicator and valuable for guiding healthcare decisions in older adults, but is rarely collected in a quantitative, systematic fashion in routine healthcare. Using a cohort of 12,000 Veterans with heart failure, we investigated the feasibility of topic modeling to identify frailty topics in clinical notes. Topics were generated through unsupervised learning and then manually reviewed by an expert. A total of 53 frailty topics were identified from 100,000 notes. We further examined associations of frailty with age-, sex-, and Charlson Comorbidity Index-adjusted 1-year hospitalizations and mortality (composite outcome) using logistic regression. Frailty (≤ 4 …

Early Adverse Experiences And Health: The Transition To College, Kelly B. Filipkowski, Kristin E. Heron, Joshua M. Smyth

Psychology Faculty Publications

Objective: This study cross-sectionally and prospectively examined the impact of adversity experienced prior to college on the health and well-being of students adjusting to their first college semester. Methods: Two-hundred sixteen (216) first-year students completed measures of adverse life experiences, perceived stress, physical symptoms, and health-related behaviors during the first 2 weeks of college entry and again at the end of the first semester. Results: Reported adversity prior to college predicted greater perceived stress and physical symptoms at college entry and an increase in physical symptoms over the semester; perceived stress mediated the prospective changes. Early adversity …

Endothelial Cells Expressing Endothelial And Mesenchymal Cell Gene Products In Lung Tissue From Patients With Systemic Sclerosis-Associated Interstitial Lung Disease., Fabian A. Mendoza, Sonsoles Piera-Velazquez, John L. Farber, Carol Feghali-Bostwick, Sergio A. Jimenez

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: To examine whether lung endothelial cells (ECs) from patients with systemic sclerosis (SSc)-associated interstitial lung disease (ILD) express mesenchymal cell-specific proteins and gene transcripts, indicative of the occurrence of endothelial-to-mesenchymal phenotypic transition (EndoMT).

METHODS: Lung tissue from 6 patients with SSc-associated pulmonary fibrosis was examined by histopathology and immunohistochemistry. Confocal laser microscopy was utilized to assess the simultaneous expression of EC and myofibroblast molecular markers. CD31+CD102+ ECs were isolated from the lung tissue of 2 patients with SSc-associated ILD and 2 normal control subjects, and the expression of EC and mesenchymal cell markers and other relevant genes was analyzed …

Sofosbuvir And Velpatasvir For Hcv Genotype 2 And 3 Infection, Graham R. Foster, Nezam Afdhal, Stuart K. Roberts, Norbert Bräu, Edward J. Gane, Stephen Pianko, Eric Lawitz, Alex Thompson, Mitchell L. Shiffman, Curtis Cooper, William J. Towner, Brian Conway, Peter Ruane, Marc Bourlière, Tarik Asselah, Thomas Berg, Stefan Zeuzem, William Rosenberg, Kosh Agarwal, Catherine Am Stedman, Hongmei Mo, Hadas Dvory-Sobol, Lingling Han, Jing Wang, John Mcnally, Anu Osinusi, Diana M. Brainard, John G. Mchutchison, Francesco Mazzotta, Tram T. Tran, Stuart C. Gordon, Keyur Patel, Nancy Reau, Alessandra Mangia, Mark Sulkowski

Gastroenterology Articles

BACKGROUND: In phase 2 trials, treatment with the combination of the nucleotide polymerase inhibitor sofosbuvir and the NS5A inhibitor velpatasvir resulted in high rates of sustained virologic response in patients chronically infected with hepatitis C virus (HCV) genotype 2 or 3.

METHODS: We conducted two randomized, phase 3, open-label studies involving patients who had received previous treatment for HCV genotype 2 or 3 and those who had not received such treatment, including patients with compensated cirrhosis. In one trial, patients with HCV genotype 2 were randomly assigned in a 1:1 ratio to receive sofosbuvir-velpatasvir, in a once-daily, fixed-dose combination tablet …

Atp-Site Binding Inhibitor Effectively Targets Mtorc1 And Mtorc2 Complexes In Glioblastoma, Jayson Neil, Craig Shannon, Avinash Mohan, Dimitri Laurent, Raj Murali, Meena Jhanwar-Uniyal

NYMC Faculty Publications

The PI3K-AKT-mTOR signaling axis is central to the transformed phenotype of glioblastoma (GBM) cells, due to frequent loss of tumor suppressor PTEN (phosphatase and tensin homolog deleted on chromosome 10). The mechanistic target of rapamycin (mTOR) kinase is present in two cellular multi-protein complexes, mTORC1 and mTORC2, which have distinct subunit composition, substrates and mechanisms of action. Targeting the mTOR protein is a promising strategy for GBM therapy. However, neither of these complexes is fully inhibited by the allosteric inhibitor of mTOR, rapamycin or its analogs. Herein, we provide evidence that the combined inhibition of mTORC1/2, using the ATP-competitive binding …

Differential Impact Of Lpg-And Pg-Deficient Leishmania Major Mutants On The Immune Response Of Human Dendritic Cells, Michelle A. Favila, Nicholas S. Geraci, Asha Jayakumar, Suzanne Hickerson, Janet Mostrom, Salvatore J. Turco, Stephen M. Beverley, Mary Ann Mcdowell

Molecular and Cellular Biochemistry Faculty Publications

BACKGROUND: Leishmania major infection induces robust interleukin-12 (IL12) production in human dendritic cells (hDC), ultimately resulting in Th1-mediated immunity and clinical resolution. The surface of Leishmania parasites is covered in a dense glycocalyx consisting of primarily lipophosphoglycan (LPG) and other phosphoglycan-containing molecules (PGs), making these glycoconjugates the likely pathogen-associated molecular patterns (PAMPS) responsible for IL12 induction.

METHODOLOGY/PRINCIPAL FINDINGS: Here we explored the role of parasite glycoconjugates on the hDC IL12 response by generating L. major Friedlin V1 mutants defective in LPG alone, (FV1 lpg1-), or generally deficient for all PGs, (FV1 lpg2-). Infection with metacyclic, infective …

Genetic Factors Influencing B-Type Natriuretic Peptide-Mediated Production Of Cyclic Guanosine Monophosphate And Blood Pressure Effects In Heart Failure Patients, David E. Lanfear, Jia Li, Raza Abbas, Ruicong She, Badri Padhukasahasram, Ramesh C. Gupta, David Langholz, W Hw Tang, Keoki L. Williams, Hani N. Sabbah, Sheryl L. Chow

Cardiology Articles

Natriuretic peptides (NPs) represent a critical pathway in heart failure (HF). We explored genetic determinants of pharmacodynamic effects of B-type NP (BNP) and changes in plasma cyclic guanosine monophosphate (cGMP) and blood pressure (BP). HF patients (n = 135) received recombinant human BNP (nesiritide) at standard doses, and plasma cGMP levels were measured at baseline and during infusion. We tested the association of 119 single nucleotide polymorphisms (SNPs) in 4 candidate genes (NPR1, NPR2, NPR3, and membrane metallo-endopeptidase (MME)) with the change in cGMP and BP. Gene-based testing for association of genetic variation with endpoints was significant only for MME. …

Actin Filaments Target The Oligomeric Maturation Of The Dynamin Gtpase Drp1 To Mitochondrial Fission Sites, Wei-Ke Ji, Anna L. Hatch, Ronald A. Merrill, Stefan Strack, Henry N. Higgs

Dartmouth Scholarship

While the dynamin GTPase Drp1 plays a critical role during mitochondrial fission, mechanisms controlling its recruitment to fission sites are unclear. A current assumption is that cytosolic Drp1 is recruited directly to fission sites immediately prior to fission. Using live-cell microscopy, we find evidence for a different model, progressive maturation of Drp1 oligomers on mitochondria through incorporation of smaller mitochondrially-bound Drp1 units. Maturation of a stable Drp1 oligomer does not forcibly lead to fission. Drp1 oligomers also translocate directionally along mitochondria. Ionomycin, a calcium ionophore, causes rapid mitochondrial accumulation of actin filaments followed by Drp1 accumulation at the fission site, …

Progressive Hearing Loss In Mice Carrying A Mutation In Usp53, Marcin Kazmierczak, Suzan L. Harris, Piotr Kazmierczak, Prahar Shah, Valentin Starovoytov, Kevin K. Ohlemiller, Martin Schwander

Open Access Publications

UNLABELLED: Disordered protein ubiquitination has been linked to neurodegenerative disease, yet its role in inner ear homeostasis and hearing loss is essentially unknown. Here we show that progressive hearing loss in the ethylnitrosourea-generated mambo mouse line is caused by a mutation in Usp53, a member of the deubiquitinating enzyme family. USP53 contains a catalytically inactive ubiquitin-specific protease domain and is expressed in cochlear hair cells and a subset of supporting cells. Although hair cell differentiation is unaffected in mambo mice, outer hair cells degenerate rapidly after the first postnatal week. USP53 colocalizes and interacts with the tight junction scaffolding proteins …

Cost Effectiveness Analysis Of Year 2 Of An Elementary School-Located Influenza Vaccination Program-Results From A Randomized Controlled Trial., Byung-Kwang Yoo, Sharon Humiston, Peter G. Szilagyi, Stanley J. Schaffer, Christine Long, Maureen Kolasa

Manuscripts, Articles, Book Chapters and Other Papers

BACKGROUND: School-located vaccination against influenza (SLV-I) has the potential to improve current suboptimal influenza immunization coverage for U.S. school-aged children. However, little is known about SLV-I's cost-effectiveness. The objective of this study is to establish the cost-effectiveness of SLV-I based on a two-year community-based randomized controlled trial (Year 1: 2009-2010 vaccination season, an unusual H1N1 pandemic influenza season, and Year 2: 2010-2011, a more typical influenza season).

METHODS: We performed a cost-effectiveness analysis on a two-year randomized controlled trial of a Western New York SLV-I program. SLV-I clinics were offered in 21 intervention elementary schools (Year 1 n = 9,027; …

Integrin Α6Β4 Promotes Autocrine Epidermal Growth Factor Receptor (Egfr) Signaling To Stimulate Migration And Invasion Toward Hepatocyte Growth Factor (Hgf), Brittany L. Carpenter, Min Chen, Teresa Knifley, Kelley A. Davis, Susan M.W. Harrison, Rachel L. Stewart, Kathleen O'Connor

Markey Cancer Center Faculty Publications

Integrin α6β4 is up-regulated in pancreatic adenocarcinomas where it contributes to carcinoma cell invasion by altering the transcriptome. In this study, we found that integrin α6β4 up-regulates several genes in the epidermal growth factor receptor (EGFR) pathway, including amphiregulin (AREG), epiregulin (EREG), and ectodomain cleavage protease MMP1, which is mediated by promoter demethylation and NFAT5. The correlation of these genes with integrin α6β4 was confirmed in The Cancer Genome Atlas Pancreatic Cancer Database. Based on previous observations that integrin α6β4 cooperates with c-Met in pancreatic cancers, we examined the impact of EGFR signaling on hepatocyte growth factor (HGF)-stimulated migration and …

Abcc9/Sur2 In The Brain: Implications For Hippocampal Sclerosis Of Aging And A Potential Therapeutic Target, Peter T. Nelson, Gregory A. Jicha, Wang-Xia Wang, Eseosa T. Ighodaro, Sergey C. Artiushin, Colin G. Nichols, David W. Fardo

Sanders-Brown Center on Aging Faculty Publications

The ABCC9 gene and its polypeptide product, SUR2, are increasingly implicated in human neurologic disease, including prevalent diseases of the aged brain. SUR2 proteins are a component of the ATP-sensitive potassium (“K _ATP ”) channel, a metabolic sensor for stress and/or hypoxia that has been shown to change in aging. The K _ATP channel also helps regulate the neurovascular unit. Most brain cell types express SUR2, including neurons, astrocytes, oligodendrocytes, microglia, vascular smooth muscle, pericytes, and endothelial cells. Thus it is not surprising that ABCC9 gene variants are associated with risk for human brain diseases. For example, Cantu syndrome is …

Identification Of Regions Of Normal Grey Matter And White Matter From Pathologic Glioblastoma And Necrosis In Frozen Sections Using Raman Imaging, Rachel Kast, Gregory Auner, Sally Yurgelevic, Brandy Broadbent, Aditya Raghunathan, Laila M. Poisson, Tom Mikkelsen, Mark L. Rosenblum, Steven N. Kalkanis

Neurosurgery Articles

In neurosurgical applications, a tool capable of distinguishing grey matter, white matter, and areas of tumor and/or necrosis in near-real time could greatly aid in tumor resection decision making. Raman spectroscopy is a non-destructive spectroscopic technique which provides molecular information about the tissue under examination based on the vibrational properties of the constituent molecules. With careful measurement and data processing, a spatial step and repeat acquisition of Raman spectra can be used to create Raman images. Forty frozen brain tissue sections were imaged in their entirety using a 300-µm-square measurement grid, and two or more regions of interest within each …

Enos Transfection Of Adipose-Derived Stem Cells Yields Bioactive Nitric Oxide Production And Improved Results In Vascular Tissue Engineering., Stephen Mcilhenny, Ping Zhang, Thomas Tulenko, Jason Comeau, Sarah Fernandez, Aleksandra Policha, Matthew Ferroni, Elizabeth J Faul, Gabor Bagameri, Irving Shapiro, Paul J. Dimuzio

Department of Surgery Faculty Papers

This study evaluates the durability of a novel tissue engineered blood vessel (TEBV) created by seeding a natural vascular tissue scaffold (decellularized human saphenous vein allograft) with autologous adipose-derived stem cells (ASC) differentiated into endothelial-like cells. Previous work with this model revealed the graft to be thrombogenic, likely due to inadequate endothelial differentiation as evidenced by minimal production of nitric oxide (NO). To evaluate the importance of NO expression by the seeded cells, we created TEBV using autologous ASC transfected with the endothelial nitric oxide synthase (eNOS) gene to produce NO. We found that transfected ASC produced NO at levels …

Interdisciplinary Care Clinics In Chronic Kidney Disease, Tanya S. Johns, Jerry Yee, Terrian Smith-Jules, Ruth C. Campbell, Carolyn Bauer

Nephrology Articles

The burden of chronic kidney disease (CKD) is substantial, and is associated with high hospitalization rates, premature deaths, and considerable health care costs. These factors provide strong rationale for quality improvement initiatives in CKD care. The interdisciplinary care clinic (IDC) has emerged as one solution to improving CKD care. The IDC team may include other physicians, advanced practice providers, nurses, dietitians, pharmacists, and social workers--all working together to provide effective care to patients with chronic kidney disease. Studies suggest that IDCs may improve patient education and preparedness prior to kidney failure, both of which have been associated with improved health …

Optics Of Cone Photoreceptors In The Chicken (Gallus Gallus Domesticus), David Wilby, Matthew B Toomey, Peter Olsson, Rikard Frederiksen, M Carter Cornwall, Ruth Oulton, Almut Kelber, Joseph C Corbo, Nicholas W Roberts

2010-2019 OA Pubs

Vision is the primary sensory modality of birds, and its importance is evident in the sophistication of their visual systems. Coloured oil droplets in the cone photoreceptors represent an adaptation in the avian retina, acting as long-pass colour filters. However, we currently lack understanding of how the optical properties and morphology of component structures (e.g. oil droplet, mitochondrial ellipsoid and outer segment) of the cone photoreceptor influence the transmission of light into the outer segment and the ultimate effect they have on receptor sensitivity. In this study, we use data from microspectrophotometry, digital holographic microscopy and electron microscopy to inform …

The Nicotine Metabolite, Cotinine, Alters The Assembly And Trafficking Of A Subset Of Nicotinic Acetylcholine Receptors, Ashley M. Fox, Faruk H. Moonschi, Christopher I. Richards

Chemistry Faculty Publications

Exposure to nicotine alters the trafficking and assembly of nicotinic receptors (nAChRs), leading to their up-regulation on the plasma membrane. Although the mechanism is not fully understood, nicotine-induced up-regulation is believed to contribute to nicotine addiction. The effect of cotinine, the primary metabolite of nicotine, on nAChR trafficking and assembly has not been extensively investigated. We utilize a pH-sensitive variant of GFP, super ecliptic pHluorin, to differentiate between intracellular nAChRs and those expressed on the plasma membrane to quantify changes resulting from cotinine and nicotine exposure. Similar to nicotine, exposure to cotinine increases the number of α4β2 receptors on the …

Evidence That The Dna Mismatch Repair System Removes 1-Nucleotide Okazaki Fragment Flaps., Lyudmila Y Kadyrova, Basanta K Dahal, Farid A Kadyrov

Articles

The DNA mismatch repair (MMR) system plays a major role in promoting genome stability and suppressing carcinogenesis. In this work, we investigated whether the MMR system is involved in Okazaki fragment maturation. We found that in the yeast Saccharomyces cerevisiae, the MMR system and the flap endonuclease Rad27 act in overlapping pathways that protect the nuclear genome from 1-bp insertions. In addition, we determined that purified yeast and human MutSα proteins recognize 1-nucleotide DNA and RNA flaps. In reconstituted human systems, MutSα, proliferating cell nuclear antigen, and replication factor C activate MutLα endonuclease to remove the flaps. ATPase and endonuclease …

Social Media In The Dental School Environment, Part B: Curricular Considerations, Heiko Spallek, Sharon P. Turner, Evelyn Donate-Bartfield, David Chambers, Maureen Mcandrew, Pamela Zarkowski, Nadeem Karimbux

Oral Health Practice Faculty Publications

The goal of this article is to describe the broad curricular constructs surrounding teaching and learning about social media in dental education. This analysis takes into account timing, development, and assessment of the knowledge, skills, attitudes, and behaviors needed to effectively use social media tools as a contemporary dentist. Three developmental stages in a student's path to becoming a competent professional are described: from undergraduate to dental student, from the classroom and preclinical simulation laboratory to the clinical setting, and from dental student to licensed practitioner. Considerations for developing the dental curriculum and suggestions for effective instruction at each stage …

Dissemination Of An Electronic Manual To Build Capacity For Implementing Farmers’ Markets With Community Health Centers, M Aaron Guest, Darcy Freedman, Kassandra A. Alia, Heather M. Brandt, Daniela B. Friedman

Faculty Publications

Community-university partnerships can lend themselves to the development of tools that encourage and promote future community health development. The electronic manual, "Building Farmacies," describes an approach for developing capacity and sustaining a community health center-based farmers' market that emerged through a community-university partnership. Manual development was guided by the Knowledge to Action Framework and experiences developing a multivendor, produce-only farmers' market at a community health center in rural South Carolina. The manual was created to illustrate an innovative solution for community health development. The manual was disseminated electronically through 25 listservs and interested individuals voluntarily completed a Web-based survey to …

Social Media In The Dental School Environment, Part A: Benefits, Challenges, And Recommendations For Use, Heiko Spallek, Sharon P. Turner, Evelyn Donate-Bartfield, David Chambers, Maureen Mcandrew, Pamela Zarkowski, Nadeem Karimbux

Oral Health Practice Faculty Publications

Social media consist of powerful tools that impact not only communication but relationships among people, thus posing an inherent challenge to the traditional standards of who we are as dental educators and what we can expect of each other. This article examines how the world of social media has changed dental education. Its goal is to outline the complex issues that social media use presents for academic dental institutions and to examine these issues from personal, professional, and legal perspectives. After providing an update on social media, the article considers the advantages and risks associated with the use of social …

The Niehs Superfund Research Program: 25 Years Of Translational Research For Public Health, Philip J Landrigan, Robert O. Wright, Jose F. Cordero, David L. Eaton, Bernard D. Goldstein, Bernhard Hennig, Raina M. Maier, David M. Ozonoff, Martyn T. Smith, Robert H. Tukey

Animal and Food Sciences Faculty Publications

BACKGROUND: The Superfund Research Program (SRP) is an academically based, multidisciplinary, translational research program that for 25 years has sought scientific solutions to health and environmental problems associated with hazardous waste sites. SRP is coordinated by the National Institute of Environmental Health Sciences (NIEHS). It supports multi-project grants, undergraduate and postdoctoral training programs, individual research grants, and Small Business Innovation Research (SBIR) and Technology Transfer Research (STTR) grants.

RESULTS: SRP has had many successes: discovery of arsenic's toxicity to the developing human central nervous system; documentation of benzene toxicity to hematologic progenitor cells in human bone marrow; development …

Janus Kinase 2/Signal Transducer And Activator Of Transcription 3 Inhibitors Attenuate The Effect Of Cardiotrophin-Like Cytokine Factor 1 And Human Focal Segmental Glomerulosclerosis Serum On Glomerular Filtration Barrier., Mukut Sharma, Jianping Zhou, Jean-François Gauchat, Ram Sharma, Ellen T. Mccarthy, Tarak Srivastava, Virginia J. Savin

Manuscripts, Articles, Book Chapters and Other Papers

Recurrence of idiopathic focal segmental glomerulosclerosis (FSGS) after renal transplantation is believed to be caused by a circulating factor(s). We detected cardiotrophin-like cytokine factor 1 (CLCF1), a member of the interleukin 6 family, in the plasma from patients with recurrent FSGS. We hypothesized that CLCF1 contributes to the effect of FSGS serum on the glomerular filtration barrier in vitro. Presently, we studied the effect of CLCF1 on isolated rat glomeruli using an in vitro assay of albumin permeability (P(alb)). CLCF1 (0.05-100 ng/mL) increased P(alb) and caused maximal effect at 5-10 ng/mL (P < 0.001). The increase in Palb was analogous to the effect of FSGS serum. Anti-CLCF1 monoclonal antibody blocked the CLCF1-induced increase in P(alb) and significantly attenuated the effect of FSGS serum (P < 0.001). The heterodimer composed of CLCF1 and cosecreted molecule cytokine receptor-like factor 1 (CRLF1) attenuated the increase in P(alb) caused by CLCF1 or FSGS serum. Western blot analysis showed that CLCF1 upregulated phosphorylation of signal transducer and activator of transcription 3 (STAT3) (Tyr705) in glomeruli. This effect was diminished by the heterodimer CLCF1-CRLF1. Janus kinase 2 (JAK2) inhibitor BMS-1119543 or STAT3 inhibitor Stattic significantly blocked the effect of CLCF1 or FSGS serum on P(alb) (P < 0.001). These novel findings suggest that when monomeric CLCF1 increases P(alb), the heterodimer CLCF1-CRLF1 may protect the glomerular filtration barrier. We speculate that albuminuria in FSGS is related to qualitative or quantitative changes in the CLCF1-CRLF1 complex, and that JAK2 or STAT3 inhibitors may be novel therapeutic agents to treat FSGS.

Increased Expression Of Napdh Oxidase 4 In Systemic Sclerosis Dermal Fibroblasts: Regulation By Transforming Growth Factor Β., Sonsoles Piera-Velazquez, Alma Makul, Sergio A. Jimenez

Department of Dermatology and Cutaneous Biology Faculty Papers

OBJECTIVE: Systemic sclerosis (SSc) is characterized by severe and often progressive fibrosis of the skin and multiple internal organs. The mechanisms responsible for these alterations remain obscure, although excessive reactive oxygen species (ROS)-mediated oxidative stress has been implicated. NOX-4 is 1 of 7 isoforms of NADPH oxidase responsible for the generation of ROS. The purpose of this study was to examine NOX-4 expression in skin and cultured dermal fibroblasts from SSc patients and to examine its regulation by transforming growth factor β1 (TGFβ1).

METHODS: NOX-4 was assessed in normal and SSc skin by immunohistologic analysis and in normal and SSc …

Parasite Manipulation Of The Invariant Chain And The Peptide Editor H2-Dm Affects Major Histocompatibility Complex Class Ii Antigen Presentation During Toxoplasma Gondii Infection, Louis-Philippe Leroux, Manami Nishi, Sandy El-Hage, Barbara A. Fox, David I Bzik, Florence Dzierszinsk

Dartmouth Scholarship

Toxoplasma gondii is an obligate intracellular protozoan parasite. This apicomplexan is the causative agent of toxoplasmosis, a leading cause of central nervous system disease in AIDS. It has long been known that T. gondii interferes with major histocompatibility complex class II (MHC-II) antigen presentation to attenuate CD4(+) T cell responses and establish persisting infections. Transcriptional downregulation of MHC-II genes by T. gondii was previously established, but the precise mechanisms inhibiting MHC-II function are currently unknown. Here, we show that, in addition to transcriptional regulation of MHC-II, the parasite modulates the expression of key components of the MHC-II antigen presentation pathway, …