3,489 research outputs found
Hypoxia activates IKK-NF-κB and the immune response in <em>Drosophila melanogaster</em>
Full text linkHypoxia, or low oxygen availability, is an important physiological and pathological stimulus for multicellular organisms. Molecularly, hypoxia activates a transcriptional programme directed at restoration of oxygen homoeostasis and cellular survival. In mammalian cells, hypoxia not only activates the HIF (hypoxia-inducible factor) family, but also additional transcription factors such as NF-?B (nuclear factor ?B). Here we show that hypoxia activates the IKK–NF-?B [I?B (inhibitor of nuclear factor ?B)–NF-?B] pathway and the immune response in Drosophila melanogaster. We show that NF-?B activation is required for organism survival in hypoxia. Finally, we identify a role for the tumour suppressor Cyld, as a negative regulator of NF-?B in response to hypoxia in Drosophila. The results indicate that hypoxia activation of the IKK–NF-?B pathway and the immune response is an important and evolutionary conserved response.</p
3.1 dB NF 20-29 GHz CMOS UWB LNA using a T-match input network
No full text[[abstract]]A 20-29 GHz CMOS ultra-wideband (UWB) low-noise amplifier (LNA) with excellent input return loss (S(11)), flat and high power gain (S(21)), and flat and low noise figure (NF) is demonstrated. Wideband input impedance matching was achieved by using the proposed T-match input network to generate two S(11) dips. Flat and high S(21) was achieved because the inductive-peaking second stage and the current-reused final two stages can compensate the gain degradation of the source-degenerative first stage at medium and high frequencies, respectively. Flat and low NF was achieved by adopting a slightly underdamped Q-factor for the second-order NF frequency response. The LNA consumed 22.07 mW and achieved S(11) of -15.5 to -26.8 dB, S(21) of 16.2 +/- 2.5 dB, minimum NF (NFmin) of 3.1 dB (at 20 GHz), and an average NF of 3.6 dB over the 20-29 GHz band of interest, one of the best reported average NF performances for a 24 GHz band CMOS LNA with bandwidth wider than 6 GHz in the literature.[[note]]SC
NF-κB translocation assay ImageJ macro
No full textThis is ImageJ macro used to determine the degree of NF-κB translocation in cells stained for NF-κB and nuclear signal. It is a part of publication entitled "Plasma extracellular vesicles signal spleen fibroblasts facilitating Plasmodium vivax adherence". Please see the publication for full author details.</p
Deletion of vitamin D receptor leads to premature emphysema/COPD by increased matrix metalloproteinases and lymphoid aggregates formation
Full text linkDeficiency of vitamin D is associated with accelerated decline in lung function. Vitamin D is a ligand for nuclear hormone vitamin D receptor (VDR), and upon binding it modulates various cellular functions. The level of VDR is reduced in lungs of patients with chronic obstructive pulmonary disease (COPD) which led us to hypothesize that deficiency of VDR leads to significant alterations in lung phenotype that are characteristics of COPD/emphysema associated with increased inflammatory response. We found that VDR knock-out (VDR(-/-)) mice had increased influx of inflammatory cells, phospho-acetylation of nuclear factor-kappaB (NF-κB) associated with increased proinflammatory mediators, and up-regulation of matrix metalloproteinases (MMPs) MMP-2, MMP-9, and MMP-12 in the lung. This was associated with emphysema and decline in lung function associated with lymphoid aggregates formation compared to WT mice. These findings suggest that deficiency of VDR in mouse lung can lead to an early onset of emphysema/COPD because of chronic inflammation, immune dysregulation, and lung destruction
An unexpected twist to the activation of IKKβ:TAK1 primes IKKβ for activation by autophosphorylation
Full text linkIKKß {IkB [inhibitor of NF-?B (nuclear factor ?B)] kinase ß} is required to activate the transcription factor NF-?B, but how IKKß itself is activated in vivo is still unclear. It was found to require phosphorylation by one or more 'upstream' protein kinases in some reports, but by autophosphorylation in others. In the present study, we resolve this contro-versy by demonstrating that the activation of IKKß induced by IL-1 (interleukin-1) or TNF (tumour necrosis factor) in embryonic fibroblasts, or by ligands that activate Toll-like receptors in macrophages, requires two distinct phosphorylation events: first, the TAK1 [TGFß (transforming growth factor ß)-activated kinase-1]-catalysed phosphorylation of Ser177 and, secondly, the IKKß-catalysed autophosphorylation of Ser181. The phosphorylation of Ser177 by TAK1 is a priming event required for the subsequent autophosphorylation of Ser181, which enables IKKß to phosphorylate exogenous substrates. We also provide genetic evidence which indicates that the IL-1-stimulated, LUBAC (linear ubiquitin chain assembly complex)-catalysed formation of linear ubiquitin chains and their interaction with the NEMO (NF-?B essential modulator) component of the canonical IKK complex permits the TAK1-catalysed priming phosphorylation of IKKß at Ser177 and IKKa at Ser176. These findings may be of general significance for the activation of other protein kinases.</p
Current concepts on oxidative/carbonyl stress, inflammation and epigenetics in pathogenesis of chronic obstructive pulmonary disease
Full text linkChronic obstructive pulmonary disease (COPD) is a global health problem. The current therapies for COPD are poorly effective and the mainstays of pharmacotherapy are bronchodilators. A better understanding of the pathobiology of COPD is critical for the development of novel therapies. In the present review, we have discussed the roles of oxidative/aldehyde stress, inflammation/immunity, and chromatin remodeling in the pathogenesis of COPD. An imbalance of oxidants/antioxidants caused by cigarette smoke and other pollutants/biomass fuels plays an important role in the pathogenesis of COPD by regulating redox-sensitive transcription factors (e.g., NF-κB), autophagy and unfolded protein response leading to chronic lung inflammatory response. Cigarette smoke also activates canonical/alternative NF-κB pathways and their upstream kinases leading to sustained inflammatory response in lungs. Recently, epigenetic regulation has been shown to be critical for the development of COPD because the expression/activity of enzymes that regulate these epigenetic modifications have been reported to be abnormal in airways of COPD patients. Hence, the significant advances made in understanding the pathophysiology of COPD as described herein will identify novel therapeutic targets for intervention in COPD
An 18.85 mW 20-29 GHz WIDEBaND CMOS LOW-NOISE AMPLIFIER WITH 3.85 +/- 0.25 dB NOISE FIGURE AND 18.1 +/- 1.9 dB GAIN
No full text[[abstract]]A 20-29 GHz wideband CMOS low-noise amplifier (LNA) with flat and low noise figure (NF), fiat and high-gain (S(21)), and excellent phase linearity property (group-delay-variation is only +/- 22.6 ps across the whole band) is demonstrated. To achieve flat and low NF, the size, layout, and bias of the input transistor were first optimized for minimum NF, and then the inductance of the input inductors was tuned to obtain a slightly under-damped (flat) NF frequency response. In addition, to achieve flat and high S(21) and small group-delay-variation, the inductive-peaking technique was adopted in the current-reused stage for bandwidth enhancement. The LNA consumed 18.85 tiff power and achieved flat and low NF of 3.85 +/- 0.25 dB, and flat and high S(21) of 18.1 +/- 1.9 dB over the 20-29 GHz band of interest. These are the best NF and S(21) performances ever reported for a 21.65-26.65 GHz or a 22-29 GHz wideband CMOS LNA. (C) 2010 Wiley Periodicals, Inc. Microwave Opt Technol Lett 52: 2017-2020, 2010; Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/mop.25380[[note]]SC
Pathogenetics mechanisms in celiac disease
No full textLa tesi di Dottorato, svolta presso il Dipartimento di Farmacologia Sperimentale, redatta in lingua inglese ed intitolata “PATHOGENETICS MECHANISMS IN CELIAC DISEASE” ha riguardato lo studio dei meccanismi molecolari coinvolti nella patogenesi della Celiachia.
I risultati della ricerca, condotta nel primo anno, ci hanno permesso di dimostrare che il fattore di trascrizione nuclear factor-B (NF-B) è attivato nella mucosa intestinale di pazienti celiaci indicando un ruolo per IB- nel regolare la persistente attivazione di NF-B in questa patologia. Le cellule epiteliali delle cripte e le cellule mononucleate della lamina propria di pazienti celiaci risultavano positive per p65 rispetto ai pazienti celiaci in remissione e di controllo. Inoltre, l'attivazione di NF-B era correlata con l'espressione della monossido d’azoto sintasi inducibile (iNOS) e della cicloossigenasi-2 (COX-2), enzimi che catalizzano la sintesi di monossido d’azoto (NO) e prostaglandine pro-infiammatorie.
Queste osservazioni potrebbero essere di una certa rilevanza clinica poichè una sostenuta attivazione di NF-B nella mucosa intestinale di pazienti celiaci conduce ad una prolungata induzione dell'espressione di geni pro-infiammatori perpetuando in tal modo il processo infiammatorio cronico.
I risultati della ricerca, condotta nel secondo e terzo anno, ci hanno permesso di approfondire alcuni meccanismi dell’interazione diretta della gliadina (un peptide del glutine) con i macrofagi murini RAW 264.7 stimolati con IFN-. In particolare, la gliadina in associazione con IFN- incrementava la produzione di NO, l’espressione della iNOS, l’attività di legame dei fattori di trascrizione NF-B, IRF-1 (interferon regulatory factor-1) e STAT-1 (signal transducer and activator of transcription-1 al DNA rispetto all’IFN- da solo. Questi effetti erano inibiti significativamente da pirrolidina ditiocarbammato, genisteina e tirfostina B42, rispettivamente, inibitori dell’attivazione di NF-B, IRF-1 e STAT-1. Approfondendo questi studi, è stato possibile accertare che la gliadina era in grado di aumentare i livelli di mRNA e l’attività del promotore del gene della iNOS nei macrofagi RAW 264.7 stimolati con IFN-per 1, 6 e 24 ore Questi effetti erano inibiti significativamente da genisteina e tirfostina B42 a 1 ora e da pirrolidina ditiocarbammato a 6 e 24 ore. E’ interessante osservare che le cinetiche di inibizione dell’espressione del gene della iNOS da parte di pirrolidina ditiocarbammato, genisteina e tirfostina B42 erano correlate con l’induzione dei livelli di mRNA dei fattori di trascrizione NF-B/p65, IRF-1 e STAT-1.
Questi risultati suggeriscono che la gliadina può modulare l’espressione del gene della iNOS come co-segnale con l’IFN- attraverso IRF-1 e STAT-1 nelle fasi precoci e NF-B nelle fasi tardive dell’induzione.
In conclusione, le nostre osservazioni possono contribuire ad una maggiore comprensione dei meccanismi molecolari della patogenesi della celiachia delineando nuove vie per il trattamento di questo disordine
Polyubiquitin binding to ABIN1 is required to prevent autoimmunity
Full text linkThe protein ABIN1 possesses a polyubiquitin-binding domain homologous to that present in nuclear factor kappa B (NF-kappa B) essential modulator (NEMO), a component of the inhibitor of NF-kappa B (I kappa B) kinase (IKK) complex. To address the physiological significance of polyubiquitin binding, we generated knockin mice expressing the ABIN1[D485N] mutant instead of the wild-type (WT) protein. These mice developed all the hallmarks of autoimmunity, including spontaneous formation of germinal centers, isotype switching, and production of autoreactive antibodies. Autoimmunity was suppressed by crossing to MyD88(-/-) mice, demonstrating that toll-like receptor (TLR)-MyD88 signaling pathways are needed for the phenotype to develop. The B cells and myeloid cells of the ABIN1[D485N] mice showed enhanced activation of the protein kinases TAK, IKK-alpha/beta, c-Jun N-terminal kinases, and p38 alpha mitogen-activated protein kinase and produced more IL-6 and IL-12 than WT. The mutant B cells also proliferated more rapidly in response to TLR ligands. Our results indicate that the interaction of ABIN1 with polyubiquitin is required to limit the activation of TLR-MyD88 pathways and prevent autoimmunity
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