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Search Results: 1 - 10 of 200719 matches for " Geraghty P "
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Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process
Geraghty P, Wallace A, D'Armiento J
International Journal of Chronic Obstructive Pulmonary Disease , 2011, DOI: http://dx.doi.org/10.2147/COPD.S19599
Abstract: duction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process Original Research (3763) Total Article Views Authors: Geraghty P, Wallace A, D'Armiento J Published Date June 2011 Volume 2011:6 Pages 309 - 319 DOI: http://dx.doi.org/10.2147/COPD.S19599 Patrick Geraghty, Alison Wallace, Jeanine M D'Armiento Department of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USA Purpose: Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure. Methods: Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined. Results: Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression. Conclusion: A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.
Induction of the unfolded protein response by cigarette smoke is primarily an activating transcription factor 4-C/EBP homologous protein mediated process
Geraghty P,Wallace A,D'Armiento J
International Journal of COPD , 2011,
Abstract: Patrick Geraghty, Alison Wallace, Jeanine M D'ArmientoDepartment of Medicine, Divisions of Molecular and Pulmonary Medicine, Columbia University College of Physicians and Surgeons, New York, NY, USAPurpose: Cigarette smoke is the major risk factor associated with the development of chronic obstructive pulmonary disease (COPD). Recent studies propose a link between endoplasmic reticulum (ER) stress and emphysema, demonstrated by increased ER stress markers under smoking conditions. Here, we investigate whether cigarette smoke-induced ER stress is cell specific and correlates with acute and chronic cigarette smoke exposure.Methods: Gene and protein expression changes in human primary lung cell cultures following cigarette smoke extract (CSE) exposure were monitored by qPCR and Western blot analysis. Mice and guinea pigs were exposed to cigarette smoke and ER stress markers examined in whole lung homogenates. Inflammatory cells from the bronchoalveolar lavage fluid of 10 days smoke exposed mice were also examined.Results: Cigarette smoke induced a trend increase in the ER stress response through an activating transcription factor 4 (ATF4) mediated induction of C/EBP homologous protein (CHOP) in primary small airway epithelial cells. Bronchial epithelial cells and macrophages responded similarly to CSE. Wild-type mice and guinea pigs exposed to acute levels of cigarette smoke exhibited increased levels of CHOP but not at significant levels. However, after long-term chronic cigarette smoke exposure, CHOP expression was reduced. Interestingly, inflammatory cells from smoke exposed mice had a significant increase in CHOP/ATF4 expression.Conclusion: A trend increase in CHOP levels appear in multiple human lung cell types following acute cigarette smoke exposure in vitro. In vivo, inflammatory cells, predominately macrophages, demonstrate significant cigarette smoke-induced ER stress. Early induction of CHOP in cigarette smoke may play a pivotal role in early induction of lung disease, however in vivo long-term cigarette smoke exposure exhibited a reduction in the ER stress response.Keywords: COPD, ER stress, cigarette smoke, CHOP
The Lipid lowering and Onset of Renal Disease (LORD) Trial: A randomized double blind placebo controlled trial assessing the effect of atorvastatin on the progression of kidney disease
Robert G Fassett, Madeleine J Ball, Iain K Robertson, Dominic P Geraghty, Jeff S Coombes
BMC Nephrology , 2008, DOI: 10.1186/1471-2369-9-4
Abstract: The Lipid lowering and Onset of Renal Disease (LORD) trial is a three-year, single center, multi-site, double blind, randomized, placebo controlled trial. The primary outcome measure is kidney function measured by eGFR calculated by both Modification of Diet in Renal Disease (MDRD) and Cockcroft and Gault equations. Secondary outcome measures include kidney function measured by 24-hour urine creatinine clearance and also 24-hour urinary protein excretion, markers of oxidative stress, inflammation and drug safety and tolerability.The results of this study will help determine the effectiveness and safety of atorvastatin and establish its effects on oxidative stress and inflammation in patients with CKD.ANZCTRN012605000693628End stage kidney disease (ESKD) is a major health problem resulting in a considerable increase in morbidity and mortality, decreased quality of life, and substantial health care costs [1]. Clinical trials attempting to slow the progression of kidney disease should be a major focus of research. As treatments directed at primary kidney diseases are few, therapies have been directed towards slowing the progression of kidney disease by controlling hypertension, using angiotensin converting enzyme inhibitors (ACEI's) and angiotensin receptor blockers (ARB's) and lowering the protein intake in the diet [2-6]. Dyslipidemia has been identified as an independent risk factor for the progression of kidney disease [7]. The deleterious effect of hyperlipidemia on the progression of kidney disease is based on a number of lines of evidence.In a large number of different animal models hyperlipidemia has been clearly shown to accelerate the progression of kidney disease [8]. There is extensive evidence for the processes involved in lipid induced kidney damage, where multiple mechanisms appear to be involved but a common initiation by hyperlipidemia is present. In addition, intervention studies have assessed the effects of statins on limiting kidney damage, again, i
Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G.
Rajagopalan,Bryceson,Kuppusamy,Geraghty
PLOS Biology , 2005,
Abstract: Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4-containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.
Every Seafarer Has a Primary Duty That May Provide the Basis of a Defense in a Personal Injury Action
J Patrick Geraghty
Journal of Law and Commerce , 2010, DOI: 10.5195/jlc.2010.17
Abstract: A seafarer injured while in the service of a merchant ocean vessel is accorded three causes of action against his or her employer: 1) Jones Act negligence, 2) the warranty of seaworthiness, and 3) maintenance and cure. The latter two causes of action arise under general maritime law, the first is statutory. This article deals with a defense to a seafarer’s claims for Jones Act negligence and unseaworthiness. This defense, commonly known as the “Primary Duty Rule,” has been restated in numerous variations since its inception. This article examines the history and evolution of the Rule and suggests a restatement of the Rule for continued application in the defense of seafarer personal injury cases.
Modularity Lifting beyond the Taylor-Wiles Method
Frank Calegari,David Geraghty
Mathematics , 2012,
Abstract: In this paper, we prove a new kind of modularity lifting theorem for p-adic Galois representations. Previous generalizations of the work of Wiles and Taylor--Wiles have (essentially) been restricted to circumstances where the automorphic forms in question have regular weight and arise from the middle degree cohomology of Shimura varieties. We show how one can overcome this restriction in certain cases. We give two applications. Firstly, we identify a certain unramified deformation ring R with a Hecke algebra T acting on a space of (Katz) weight one modular forms. In particular, the equality R = T holds even when T (equivalently, R) is not torsion free. Secondly, we prove an R = T theorem for ordinary two-dimensional regular representations over an imaginary quadratic field (of the type associated to elliptic curves), contingent on the existence of Galois representations associated to certain torsion classes. In the process of proving our main result, we also completely solved the problem (for p odd) of determining the multiplicity of an irreducible modular representation rhobar in the Jacobian J_1(N), where N is the minimal level such that rhobar arises in weight two.
Modularity Lifting Theorems beyond the Taylor-Wiles Method. II
Frank Calegari,David Geraghty
Mathematics , 2012,
Abstract: In a previous paper [CG], we showed how one could generalize Taylor-Wiles modularity lifting theorems [Wil95, TW95] to contexts beyond those in which the automorphic forms in question arose from the middle degree cohomology of Shimura varieties; in particular, to contexts in which the relevant automorphic forms contributed to cohomology in exactly two degrees. In this sequel, we extend our method to the general case in which Galois representations are expected to occur in cohomology, contingent on the (as yet unproven) existence of certain Galois representations with the expected properties. As an application, we prove the following result (conditional on the conjectures mentioned above): If E is an elliptic curve over an arbitrary number field, then E is potentially modular, and the Sato-Tate conjecture holds for E.
Companion forms for unitary and symplectic groups
Toby Gee,David Geraghty
Mathematics , 2010,
Abstract: We prove a companion forms theorem for ordinary n-dimensional automorphic Galois representations, by use of automorphy lifting theorems developed by the second author, and a technique for deducing companion forms theorems due to the first author. We deduce results about the possible Serre weights of mod l Galois representations corresponding to automorphic representations on unitary groups. We then use functoriality to prove similar results for automorphic representations of GSp4 over totally real fields.
The Breuil--Mezard conjecture for quaternion algebras
Toby Gee,David Geraghty
Mathematics , 2013,
Abstract: We formulate a version of the Breuil--Mezard conjecture for quaternion algebras, and show that it follows from the Breuil--Mezard conjecture for GL_2. In the course of the proof we establish a mod p analogue of the Jacquet--Langlands correspondence for representations of GL_2(k), k a finite field of characteristic p.
Activation of NK Cells by an Endocytosed Receptor for Soluble HLA-G
Sumati Rajagopalan,Yenan T. Bryceson,Shanmuga P. Kuppusamy,Daniel E. Geraghty,Arnold van der Meer,Irma Joosten,Eric O. Long
PLOS Biology , 2012, DOI: 10.1371/journal.pbio.0040009
Abstract: Signaling from endosomes is emerging as a mechanism by which selected receptors provide sustained signals distinct from those generated at the plasma membrane. The activity of natural killer (NK) cells, which are important effectors of innate immunity and regulators of adaptive immunity, is controlled primarily by receptors that are at the cell surface. Here we show that cytokine secretion by resting human NK cells is induced by soluble, but not solid-phase, antibodies to the killer cell immunoglobulin-like receptor (KIR) 2DL4, a receptor for human leukocyte antigen (HLA)-G. KIR2DL4 was constitutively internalized into Rab5-positive compartments via a dynamin-dependent process. Soluble HLA-G was endocytosed into KIR2DL4–containing compartments in NK cells and in 293T cells transfected with KIR2DL4. Chemokine secretion induced by KIR2DL4 transfection into 293T cells occurred only with recombinant forms of KIR2DL4 that trafficked to endosomes. The profile of genes up-regulated by KIR2DL4 engagement on resting NK cells revealed a proinflammatory/proangiogenic response. Soluble HLA-G induced secretion of a similar set of cytokines and chemokines. This unique stimulation of resting NK cells by soluble HLA-G, which is endocytosed by KIR2DL4, implies that NK cells may provide useful functions at sites of HLA-G expression, such as promotion of vascularization in maternal decidua during early pregnancy.
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