bluuebunny/crossref_metadata_2025_split huggingface dataset:
Rescue of Dysfunctional Autophagy Attenuates Hyperinflammatory Responses from Cystic Fibrosis Cells
Authors: Mayer Matthew L. , Blohmke Christoph J. , Falsafi Reza , Fjell Chris D. , Madera Laurence , Turvey Stuart E. , Hancock Robert E. W. 
Published: December 2012

AbstractA hallmark feature of cystic fibrosis (CF) is progressive pulmonary obstruction arising from exaggerated host proinflammatory responses to chronic bacterial airway colonization. The mechanisms for these heightened inflammatory responses have been only partially characterized, hampering development of effective anti-inflammatory therapies. The aim of this study was to identify and validate novel dysfunctional processes or pathways driving the hyperinflammatory phenotype of CF cells using systems biology and network analysis to examine transcriptional changes induced by innate defense regulator (IDR)-1018, an anti-inflammatory peptide. IDR-1018 selectively attenuated hyperinflammatory cytokine production from CF airway cells and PBMCs stimulated with multiple bacterial ligands, including flagellin (FliC). Network analysis of CF cell transcriptional responses to FliC and IDR-1018 identified dysfunctional autophagy as the target of the peptide via modulation of upstream adenosine monophosphate–activated protein kinase (AMPK)–Akt signaling. After treatment with FliC, CF cells were found to have elevated levels of the autophagosome marker LC3-II, and GFP-LC3–transfected CF airway cells showed abnormal perinuclear accumulation of GFP+ structures. In both instances, treatment of CF cells with IDR-1018 abolished the accumulation of LC3 induced by FliC. Furthermore, inhibition of autophagosome–lysosome fusion with bafilomycinA1 attenuated the anti-inflammatory and autophagosome-clearing effects of IDR-1018, as did a chemical inhibitor of Akt and an activator of AMPK. These findings were consistent with hypotheses generated in silico, demonstrating the utility of systems biology and network analysis approaches for providing pathway-level insights into CF-associated inflammation. Collectively, these data suggest that dysfunctional autophagosome clearance contributes to heightened inflammatory responses from CF transmembrane receptor mutant cells and highlight autophagy and AMPK–Akt signaling as novel anti-inflammatory targets in CF.
Inflammasome-Independent NLRP3 Augments TGF-β Signaling in Kidney Epithelium
Authors: Wang Wenjie , Wang Xiangyu , Chun Justin , Vilaysane Akosua , Clark Sharon , French Gabrielle , Bracey Nathan A. , Trpkov Kiril , Bonni Shirin , Duff Henry J. , Beck Paul L. , Muruve Daniel A. 
Published: December 2012

Abstract
Tubulointerstitial inflammation and fibrosis are strongly associated with the outcome of chronic kidney disease. We recently demonstrated that the NOD-like receptor, pyrin domain containing-3 (NLRP3) contributes to renal inflammation, injury, and fibrosis following unilateral ureteric obstruction in mice. NLRP3 expression in renal tubular epithelial cells (TECs) was found to be an important component of experimental disease pathogenesis, although the biology of NLRP3 in epithelial cells is unknown. In human and mouse primary renal TECs, NLRP3 expression was increased in response to TGF-β1 stimulation and associated with epithelial–mesenchymal transition (EMT) and the expression of α-smooth muscle actin (αSMA) and matrix metalloproteinase (MMP) 9. TGF-β1–induced EMT and the induction of MMP-9 and αSMA were significantly decreased in mouse Nlrp3−/− renal TECs, suggesting a role for Nlrp3 in TGF-β–dependent signaling. Although apoptosis-associated speck-like protein containing a CARD domain−/− TECs demonstrated a phenotype similar to that of Nlrp3−/− cells in response to TGF-β1, the effect of Nlrp3 on MMP-9 and αSMA expression was inflammasome independent, as IL-1β, IL-18, MyD88, and caspase-1 were dispensable. Smad2 and Smad3 phosphorylation in response to TGF-β1 was attenuated in Nlrp3−/− and apoptosis-associated speck-like protein containing a CARD domain−/− cells, accounting for the dampened EMT and TGF-β1 responsiveness in these cells. Consistent with these findings, overexpression of NLRP3 in 293T cells resulted in increased Smad3 phosphorylation and activity. Taken together, these data support a novel and direct role for NLRP3 in promoting TGF-β signaling and R-Smad activation in epithelial cells independent of the inflammasome.
Functional Characterization of T Cell Populations in a Mouse Model of Chronic Obstructive Pulmonary Disease
Authors: Eppert Bryan L. , Wortham Brian W. , Flury Jennifer L. , Borchers Michael T. 
Published: December 2012

Abstract
Cigarette smoke (CS) exposure is the primary risk factor for the development of chronic obstructive pulmonary disease (COPD). COPD is characterized by chronic peribronchial, perivascular, and alveolar inflammation. The inflammatory cells consist primarily of macrophage, neutrophils, and lymphocytes. Although myeloid cells are well studied, the role of lymphocyte populations in pathogenesis of COPD remains unclear. Using a mouse model of CS-induced emphysema, our laboratory has previously demonstrated that CS exposure causes changes in the TCR repertoire suggestive of an Ag-specific response and triggers a pathogenic T cell response sufficient to cause alveolar destruction and inflammation. We extend these findings to demonstrate that T cells from CS-exposed mice of the BALB/cJ or C57B6 strain are sufficient to transfer pulmonary pathology to CS-naive, immunosufficient mice. CS exposure causes a proinflammatory phenotype among pulmonary T cells consistent with those from COPD patients. We provide evidence that donor T cells from CS-exposed mice depend on Ag recognition to transfer alveolar destruction using MHC class I–deficient recipient mice. Neither CD4+ nor CD8+ T cells from donor mice exposed to CS alone are sufficient to cause inflammation or pathology in recipient mice. We found no evidence of impaired suppression of T cell proliferation among regulatory T cells from CS-exposed mice. These results suggest that CS exposure initiates an Ag-specific response that leads to pulmonary destruction and inflammation that involves both CD8+ and CD4+ T cells. These results are direct evidence for an autoimmune response initiated by CS exposure.
Focal Adhesion Kinase Regulates the Localization and Retention of Pro-B Cells in Bone Marrow Microenvironments
Authors: Park Shin-Young , Wolfram Peter , Canty Kimberly , Harley Brendan , Nombela-Arrieta César , Pivarnik Gregory , Manis John , Beggs Hilary E. , Silberstein Leslie E. 
Published: December 2012

Abstract
Progenitor B cells reside in complex bone marrow (BM) microenvironments where they receive signals for growth and maturation. We reported previously that the CXCL12-focal adhesion kinase (FAK)-VLA4 pathway plays an important role in progenitor B cell adhesion and migration. In this study, we have conditionally targeted in B cells FAK, and found that the numbers of progenitor pro-B, pre-B, and immature B cells are reduced by 30–40% in B cell-specific FAK knockout mice. When cultured in methylcellulose with IL-7 ± CXCL12, Fak-deleted pro-B cells yield significantly fewer cells and colonies. Using in situ quantitative imaging cytometry, we establish that in longitudinal femoral BM sections, pro-B cells are preferentially localized in close proximity to the endosteum of the metaphyses and the diaphysis. Fak deletion disrupts the nonrandom distribution of pro-B cells and induces the mobilization of pro-B cells to the periphery in vivo. These effects of Fak deletion on pro-B cell mobilization and localization in BM are amplified under inflammatory stress, that is, after immunization with nitrophenol-conjugated chicken γ-globulin in alum. Collectively, these studies suggest the importance of FAK in regulating pro-B cell homeostasis and maintenance of their spatial distribution in BM niches.
Incidence and Time Trends of Herpes Zoster in Rheumatoid Arthritis: A Population‐Based Cohort Study
Authors: Veetil Bharath Manu Akkara , Myasoedova Elena , Matteson Eric L. , Gabriel Sherine E. , Green Abigail B. , Crowson Cynthia S. 
Published: December 2012

ObjectiveTo determine the incidence, time trends, risk factors, and severity of herpes zoster in a population‐based cohort of patients with newly diagnosed rheumatoid arthritis (RA) compared to a group of individuals without RA from the same population.MethodsAll residents of Olmsted County, Minnesota fulfilling for the first time the 1987 American College of Rheumatology criteria for RA between January 1, 1980 and December 31, 2007 and a cohort of similar residents without RA were assembled and followed by retrospective chart review until death, migration, or December 31, 2008.ResultsThere was no difference in the presence of herpes zoster prior to the RA incidence/index date between the cohorts (P = 0.85). During followup, 84 patients with RA (rate 12.1 cases per 1,000 person‐years) and 44 subjects without RA (rate 5.4 cases per 1,000 person‐years) developed herpes zoster. Patients with RA were more likely to develop herpes zoster than those without RA (hazard ratio [HR] 2.4 [95% confidence interval (95% CI) 1.7–3.5]). Herpes zoster occurred more frequently in patients diagnosed with RA more recently (HR 1.06 per year [95% CI 1.02–1.10]). Erosive disease, previous joint surgery, and use of hydroxychloroquine and corticosteroids were significantly associated with the development of herpes zoster in RA. There was no apparent association of herpes zoster with the use of methotrexate or biologic agents. Complications of herpes zoster occurred at a similar rate in both cohorts.ConclusionThe incidence of herpes zoster is increased in RA and has risen in recent years. There also has been an increasing incidence of herpes zoster in more recent years in the general population. RA disease severity is associated with the development of herpes zoster.
Competency‐Based Goals, Objectives, and Linked Evaluations for Rheumatology Training Programs: A Standardized Template of Learning Activities From the Carolinas Fellows Collaborative
Authors: Criscione‐Schreiber Lisa G. , Bolster Marcy B. , Jonas Beth L. , O'rourke Kenneth S. 
Published: December 2012

ObjectiveAmerican Council on Graduate Medical Education program requirements mandate that rheumatology training programs have written goals, objectives, and performance evaluations for each learning activity. Since learning activities are similar across rheumatology programs, we aimed to create competency‐based goals and objectives (CBGO) and evaluations that would be generalizable nationally.MethodsThrough an established collaboration of the 4 training programs' directors in North Carolina and South Carolina, we collaboratively composed CBGO and evaluations for each learning activity for rheumatology training programs. CBGO and linked evaluations were written using appropriate verbs based on Bloom's taxonomy. Draft documents were peer reviewed by faculty at the 4 institutions and by members of the American College of Rheumatology (ACR) Clinician Scholar Educator Group.ResultsWe completed templates of CBGO for core and elective rotations and conferences. Templates detail progressive fellow performance improvement appropriate to educational level. Specific CBGO are mirrored in learning activity evaluations. Templates are easily modified to fit individual program attributes, have been successfully implemented by our 4 programs, and have proven their value in 4 residency review committee reviews.ConclusionWe propose adoption of these template CBGO by the ACR, with access available to all rheumatology training programs. Evaluation forms that exactly reflect stated objectives ensure that trainees are assessed using standardized measures and that trainees are aware of the learning expectations. The objectives mirrored in the evaluations closely align with the proposed milestones for internal medicine training, and will therefore be a useful starting point for creating these milestones in rheumatology.
Cigarette smoke inhibits nasal airway epithelial cell growth and survival
Authors: Lee Hyun Sil , Kim Jean 
Published: December 2012

BackgroundCigarette smoke (CS) exposure has been shown to be associated with chronic rhinosinusitis (CRS). We hypothesized that that CS exposure results in impairment nasal epithelial cell growth and survival necessary for normal cell function. Furthermore, we hypothesized that normal nasal epithelial cell growth is dependent on vascular endothelial growth factor (VEGF) and that CS inhibits normal nasal epithelial cell growth and survival through VEGF‐dependent mechanisms.MethodsTo examine whether nasal epithelial cell growth is dependent upon VEGF, we exposed in vitro cultures of human primary nasal epithelial cells (PNECs) from normal subjects to blocking antibodies against the VEGF co‐receptor, neuropilin‐1 (NP1), and measured cell growth using a proliferation assay. To study whether CS inhibits cell growth, we exposed PNECs to cigarette smoke extract (CSE). We also examined the ability of CSE exposure of PNECs to induce apoptosis.ResultsExposure of PNECs from normal subjects to VEGF receptor anti‐NP1 antibody resulted in inhibition of constitutive cell growth. CSE exposure resulted in dose‐dependent inhibition of constitutive cell growth. Addition of anti‐NP1 antibody to CSE‐exposed cells resulted in no further inhibition of cell growth. CSE exposure also resulted in induction of apoptosis in a dose‐dependent manner, comparable to that seen with VEGF blockade using anti‐NP1 antibody.ConclusionPNECs from normal healthy control subjects display VEGF‐dependent constitutive cell growth. CSE impairs cell growth and promotes apoptosis of normal healthy nasal epithelial cells. The effect of CSE may occur in part through VEGF‐dependent mechanisms.
Expression of dual oxidases and secreted cytokines in chronic rhinosinusitis
Authors: Cho Do‐Yeon , Nayak Jayakar V. , Bravo Dawn T. , Le Wei , Nguyen Alan , Edward Justin A. , Hwang Peter H. , Illek Beate , Fischer Horst 
Published: December 2012

BackgroundThe airway epithelium generates reactive oxygen species (ROS) as a first line of defense. Dual oxidases (DUOX1 and DUOX2) are the H2O2‐producing isoforms of the nicotinamide adenine dinucleotide phosphate (NADPH) oxidase family in the airway epithelium. The purpose of this study was to explore the molecular expression, function, and regulation of DUOXs in chronic rhinosinusitis (CRS).MethodsHuman nasal tissue samples and nasal secretions were collected from 3 groups of patients undergoing sinus surgery (normal, n = 7; CRS with polyposis [CRSwP], n = 6; CRS without polyposis [CRSsP], n = 6). Nasal secretions were studied for cytokine and H2O2 content. Tissue samples were used to determine DUOX mRNA and protein expression.ResultsDUOX1 mRNA level (80.7 ± 60.5) was significantly increased in CRSwP compared to normal (2.7 ± 1.2) and CRSsP (2.3 ± 0.5, p = 0.042). DUOX2 mRNA levels were increased in both CRSwP (18.6 ± 9.9) and CRSsP (4.0 ± 1.3) compared to normal (1.1 ± 0.3; p = 0.008). DUOX protein was found in the apical portion of the nasal epithelium and protein expression was increased in CRSwP and CRSsP. H2O2 production was significantly higher in CRSwP (160.9 ± 59.4 nM) and CRSsP (81.7 ± 5.6 nM) compared to normal (53.5 ± 11.5 nM, p = 0.032). H2O2 content of nasal secretions correlated tightly with DUOX expression (p < 0.001). Cytokines (eotaxin, monokine‐induced by interferon γ [MIG], tumor necrosis factor [TNF]‐α, interleukin [IL]‐8) showed significantly higher levels in nasal secretions from CRSwP compared to normal (p < 0.05). Levels of eotaxin, MIG, and TNF‐α correlated closely with DUOX expression.ConclusionDUOX1 and DUOX2 were identified as factors upregulated in CRS. Close correlations between DUOX expression and H2O2 release, and correlation between key inflammatory cytokines and DUOX expression, indicate DUOX in the inflammatory response in CRS.
Synthesis and in vitro release of guest drugs‐loaded copolymer nanospheres MMA/HEMA via differential microemulsion polymerization
Authors: Moustafa A. B. , Sobh R. A. , Rabie A. M. , Nasr H. E. , Ayoub M. M. H. 
Published: December 2012

AbstractThe synthesis and characterization of different series of methyl methacrylate/hydroxyethyl methacrylate (MMA/HEMA) copolymeric nanoparticles with different monomer feed compositions and utilization of them in entrapment and controlling the release of hydrophilic drug (sodium warfarin) and hydrophobic drugs (ibuprofen and praziquantel) were investigated. The polymeric nanoparticles and their entrapment with drugs were prepared using oil‐in‐water (O/W) differential microemulsion polymerization technique in the presence of polyvinyl pyrrolidone and polyethylene glycol as biocompatible emulsifiers as well as ammonium persulfate as an initiator. The effect of HEMA content in the monomer feed composition on the colloidal properties was studied, and it is found that the particle size Dv, turbidity, and the negative charge increase with increasing of HEMA content but the surface tension decrease. Moreover, the entrapment efficiency (EE) is affected by the content of HEMA in the monomer feed composition, the drug hydrophobicity, and the monomer to drug ratio. It is concluded that, EE into MMA/HEMA in monomer feed composition as 90/10, 70/30, and 50/50 is found to be (95.3–98)%, (84–96.9)%, and (69.5–94.6)% for sodium warfarin (with high hydrophilicity) as well as, ibuprofen and praziquantel (with high hydrophobicity), respectively. The entrapment of drugs in polymeric nanoparticles is confirmed by IR‐spectroscopy and transmission electronic microscopy. In vitro drug release experiments show that controlled release of drugs from copolymeric nanoparticles depend on HEMA content, the monomer to drug ratio, and the physiological pH. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Fluorene‐based conjugated polymer with tethered thymines: click postpolymerization synthesis and optical response to mercury(II)
Authors: Lei Yanli , Ma Fudong , Tian Yong , Niu Qiaoli , Mi Hongyu , Nurulla Ismayil , Shi Wei 
Published: December 2012

AbstractA kind of fluorene‐based conjugated polymer with tethered thymine (T) groups {poly[(9,9‐dioctyl)‐2,7‐fluorene‐{9,9‐dioctyl‐4–1,2,3‐triazol‐[5‐(hydroxymethyl)tetrahydrofuran‐2‐yl]‐5‐methylpyrimidine‐2,4(1H,3H)‐dione}‐2,7‐fluorene]‐co‐[(9,9‐dioctyl)‐2,7‐fluorene‐4,7‐bis(5‐thiophen‐2‐yl)benzo‐2,1,3‐thiadiazole] (P‐3)} was successfully synthesized by a Cu(I)‐catalyzed click reaction between the acetylene‐substituted polymer precursor {poly[(9,9‐dioctyl)‐2,7‐fluorene‐(9,9‐dioctyl‐4‐phenylacetylene fluorene)]‐co‐[(9,9‐dioctyl)‐2,7‐fluorene‐4,7‐bis(5‐thiophen‐2‐yl)benzo‐2,1,3‐thiadiazole]} and 3′‐azido‐3′‐deoxythymidine. The chemical structures of the intermediates and target polymer were verified by Fourier transform infrared spectroscopy and 1H‐NMR analyses. The specific binding with Hg2+ of P‐3 was corroborated by ultraviolet–visible spectroscopy and photoluminescence analyses against other metal ions. The results show that P‐3 possessed selectivity and sensitivity toward Hg2+. Around 77% of photoluminescence intensity of P‐3 was quenched when the concentration of Hg2+ reached 7.7 × 10−4
M and with a detection limit in the range of about 4.8 μM. A comparison experiment suggested that a synergic effect of the tethered T and S atoms interrelated with Hg2+ existed in P‐3. Most of the fluorescence intensity of P‐3 was recovered upon the addition of iodide anions to the P‐3/Hg2+ complex; this suggested that P‐3 could be used as a potential reversible optical Hg2+ probe. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Pattern formation and morphology in the course of drying a droplet of a ternary polymer solution
Authors: Sun Xiaoli , Li Huihui , Yan Shouke , Lieberwirth Ingo 
Published: December 2012

AbstractA micro‐structured polymer film was prepared by drying a droplet of a ternary polymer solution of polystyrene (PS), poly(vinyl pyrrolidone) (PVP), and chloroform. Within a certain weight ratio of PS to PVP an ordered pattern of cylindrical PVP domains was formed on the film surface. The diameter of the individual PVP domains was in the order of 2–3 μm. The effect of polymer weight ratios on the surface morphology was investigated by atomic force microscopy. Additionally, scanning electron microscopy of cross‐sections of the polymer composite film yielded supplementary information on the bulk morphology and revealed an unexpected complex structure underneath the surface pattern. The reasons for this formation mechanism possibly included aspects of phase separation, convective transport in a drying droplet, and the continuous increase of viscosity during solvent evaporation. At a certain solvent concentration in the evaporation path, it will lead to a vitrification of any structure. The “evolution time”, the time between the onset of phase separation and this “point of vitrification”, will determine the resulting film morphology. © 2012 Wiley Periodicals, Inc. J. Appl. Polym. Sci., 2013
Interaction with activated monocytes enhances cytokine expression and suppressive activity of human CD4+CD45ro+CD25+CD127low regulatory T cells
Authors: Walter Gina J. , Evans Hayley G. , Menon Bina , Gullick Nicola J. , Kirkham Bruce W. , Cope Andrew P. , Geissmann Frédéric , Taams Leonie S. 
Published: December 2012

AbstractObjectiveDespite the high frequency of CD4+ T cells with a regulatory phenotype (CD25+CD127low FoxP3+) in the joints of patients with rheumatoid arthritis (RA), inflammation persists. One possible explanation is that human Treg cells are converted into proinflammatory interleukin‐17 (IL‐17)–producing cells by inflammatory mediators and thereby lose their suppressive function. The aim of this study was to investigate whether activated monocytes, which are potent producers of inflammatory cytokines and are abundantly present in the rheumatic joint, induce proinflammatory cytokine expression in human Treg cells and impair their regulatory function.MethodsThe presence and phenotype of CD4+CD45RO+CD25+CD127low T cells (memory Treg cells) and CD14+ monocytes in the peripheral blood (PB) and synovial fluid (SF) of patients with RA were investigated by flow cytometry. Memory Treg cells obtained from healthy control subjects underwent fluorescence‐activated cell sorting and then were cocultured with autologous activated monocytes and stimulated with anti‐CD3 monoclonal antibodies. Intracellular cytokine expression, phenotype, and function of cells were determined by flow cytometry, enzyme‐linked immunosorbent assay, and proliferation assays.ResultsIn patients with RA, the frequencies of CD4+CD45RO+CD25+CD127low Treg cells and activated CD14+ monocytes were higher in SF compared with PB. In vitro–activated monocytes induced an increase in the percentage of IL‐17–positive, interferon‐γ (IFNγ)–positive, and tumor necrosis factor α (TNFα)–positive Treg cells as well as IL‐10–positive Treg cells. The observed increase in IL‐17–positive and IFNγ‐positive Treg cells was driven by monocyte‐derived IL‐1β, IL‐6, and TNFα and was mediated by both CD14+CD16− and CD14+CD16+ monocyte subsets. Despite enhanced cytokine expression, cells maintained their CD25+FoxP3+CD39+ Treg cell phenotype and showed an enhanced capacity to suppress T cell proliferation and IL‐17 production.ConclusionTreg cells exposed to a proinflammatory environment show increased cytokine expression as well as enhanced suppressive activity.