Activation of nuclear factor-κB-dependent transcription by tumor necrosis factor-α is mediated through phosphorylation of RelA/p65 on serine 529

Nuclear factor-κB (NF-κB) is an essential transcription factor in the control of expression of genes involved in immune and inflammatory responses. In unstimulated cells, NF-κB complexes are sequestered in the cytoplasm through interactions with IκBα and other IκB proteins. Extracellular stimuli that activate NF-κB, such as tumor necrosis factor α (TNFα), cause rapid phosphorylation of IκBα at serines 32 and 36. The inducible phosphorylation of IκBα is followed by its ubiquitination and degradation, allowing NF-κB complexes to translocate into the nucleus and to activate gene expression. Previously, it has been shown that TNFα as well as other stimuli also lead to the phosphorylation of the RelA/p65 subunit of NF-κB. In this report, we demonstrate that the TNFα-induced phosphorylation of the RelA/p65 subunit occurs on serine 529, which is in the C-terminal (TA1) transactivation domain. Accordingly, the TNFα-induced phosphorylation of Rel/p65 increases NF-κB transcriptional activity but does not affect nuclear translocation or DNA binding affinity

Lopsided Galaxies, Weak Interactions and Boosting the Star Formation Rate

To investigate the link between weak tidal interactions in disk galaxies and the boosting of their recent star formation, we obtain images and spatially integrated spectra (3615A < lambda < 5315A) for 40 late-type spiral galaxies (Sab-Sbc) with varying degrees of lopsidedness (a dynamical indicator of weak interactions). We quantify lopsidedness as the amplitude of the m=1 Fourier component of the azimuthal surface brightness distribution, averaged over a range of radii. We compare the young stellar content, quantified by EW(H\delta_abs) and the strength of the 4000 Angstrom break (D_4000), with lopsidedness and find a 3-4 sigma correlation between the two. We also find a 3.2 sigma correlation between EW(H\beta_emission) and lopsidedness. Using the evolutionary population synthesis code of Bruzual & Charlot we model the spectra as an ``underlying population'' and a superimposed ``boost population'' with the aim of constraining the fractional boost in the SFR averaged over the past 0.5 Gyr (the characteristic lifetime of lopsidedness). From the difference in both EW(H\delta_abs) and D_4000 between the most and least symmetric thirds of our sample, we infer that ~ 1x10^9 M_solar of stars are formed over the duration of a lopsided event in addition to the ``underlying'' SFH (assuming a final galactic stellar mass of 10^10 M_solar). This corresponds to a factor of 8 increase in the SFR over the past 5x10^8 years. For the nuclear spectra, all of the above correlations except D_4000 vs. are weaker than for the disk, indicating that in lopsided galaxies, the SF boost is not dominated by the nucleus.Comment: 35 pages, including 10 figures, to appear in the Astrophysical Journal, abridged abstrac

Tumor Necrosis Factor α-induced Phosphorylation of RelA/p65 on Ser 529 Is Controlled by Casein Kinase II

Nuclear factor kappaB (NF-kappaB)/Rel transcription factors are key regulators of a variety of genes involved in immune and inflammatory responses, growth, differentiation, apoptosis, and development. In unstimulated cells, NF-kappaB/Rel proteins are sequestered in the cytoplasm by IkappaB inhibitor proteins. Many extracellular stimuli, such as tumor necrosis factor alpha (TNFalpha), cause rapid phosphorylation of IkappaB at N-terminal serine residues leading to ubiquitination and degradation of the inhibitor. Subsequently, NF-kappaB proteins translocate to the nucleus and activate gene expression through kappaB response elements. TNFalpha, as well as certain other stimuli, also induces the phosphorylation of the NF-kappaB proteins. Previously, we have shown that TNFalpha induces RelA/p65 phosphorylation at serine 529 and that this inducible phosphorylation increases NF-kappaB transcriptional activity on an exogenously supplied reporter (). In this report, we demonstrate that casein kinase II (CKII) interacts with p65 in vivo and can phosphorylate p65 at serine 529 in vitro. A CKII inhibitor (PD144795) inhibited TNFalpha-induced p65 phosphorylation in vivo. Furthermore, our results indicate that the association between IkappaBalpha and p65 inhibits p65 phosphorylation by CKII and that degradation of IkappaBalpha allows CKII to phosphorylate p65 to increase NF-kappaB transactivation potential. These data may explain the ability of CKII to modulate cell growth and demonstrate a mechanism whereby CKII can function in an inducible manner

Calculation of AGARD Wing 445.6 Flutter Using Navier-Stokes Aerodynamics

An unsteady, 3D, implicit upwind Euler/Navier-Stokes algorithm is here used to compute the flutter characteristics of Wing 445.6, the AGARD standard aeroelastic configuration for dynamic response, with a view to the discrepancy between Euler characteristics and experimental data. Attention is given to effects of fluid viscosity, structural damping, and number of structural model nodes. The flutter characteristics of the wing are determined using these unsteady generalized aerodynamic forces in a traditional V-g analysis. The V-g analysis indicates that fluid viscosity has a significant effect on the supersonic flutter boundary for this wing

Knowledge, attitudes and practice of healthcare ethics and law among doctors and nurses in Barbados

BACKGROUND: The aim of the study is to assess the knowledge, attitudes and practices among healthcare professionals in Barbados in relation to healthcare ethics and law in an attempt to assist in guiding their professional conduct and aid in curriculum development. METHODS: A self-administered structured questionnaire about knowledge of healthcare ethics, law and the role of an Ethics Committee in the healthcare system was devised, tested and distributed to all levels of staff at the Queen Elizabeth Hospital in Barbados (a tertiary care teaching hospital) during April and May 2003. RESULTS: The paper analyses 159 responses from doctors and nurses comprising junior doctors, consultants, staff nurses and sisters-in-charge. The frequency with which the respondents encountered ethical or legal problems varied widely from 'daily' to 'yearly'. 52% of senior medical staff and 20% of senior nursing staff knew little of the law pertinent to their work. 11% of the doctors did not know the contents of the Hippocratic Oath whilst a quarter of nurses did not know the Nurses Code. Nuremberg Code and Helsinki Code were known only to a few individuals. 29% of doctors and 37% of nurses had no knowledge of an existing hospital ethics committee. Physicians had a stronger opinion than nurses regarding practice of ethics such as adherence to patients' wishes, confidentiality, paternalism, consent for procedures and treating violent/non-compliant patients (p = 0.01) CONCLUSION: The study highlights the need to identify professionals in the workforce who appear to be indifferent to ethical and legal issues, to devise means to sensitize them to these issues and appropriately training them

A requirement for NF-κB activation in Bcr-Abl-mediated transformation

Bcr-Abl is a chimeric oncoprotein that is strongly implicated in acute lymphoblastic (ALL) and chronic myelogenous leukemias (CML). This deregulated tyrosine kinase selectively causes hematopoietic disorders resembling human leukemias in animal models and transforms fibroblasts and hematopoietic cells in culture. Bcr-Abl also protects cells from death induced on cytokine deprivation or exposure to DNA damaging agents. In addition, the antiapoptotic function of Bcr-Abl is thought to play a necessary role in hematopoietic transformation and potentially in leukemogenesis. The transcription factor NF-κB has been identified recently as an inhibitor of apoptosis and as a potential regulator of cellular transformation. This study shows that expression of Bcr-Abl leads to activation of NF-κB-dependent transcription by causing nuclear translocation of NF-κB as well as by increasing the transactivation function of the Re1A/p65 subunit of NF-κB. Importantly, this activation is dependent on the tyrosine kinase activity of Bcr-Abl and partially requires Ras. The ability of Bcr-Abl to protect cytokine-dependent 32D myeloid cells from death induced by cytokine deprivation or DNA damage does not, however, require functional NF-κB. However, using a super-repressor form of IκBα, we show that NF-κB is required for Bcr-Abl-mediated tumorigenicity in nude mice and for transformation of primary bone marrow cells. This study implicates NF-κB as an important component of Bcr-Abl signaling. NF-κB-regulated genes, therefore, likely play a role in transformation by Bcr-Abl and thus in Bcr- Abl-associated human leukemias