Involvement of double-stranded RNA-activated protein kinase in the synergistic activation of nuclear factor-κB by tumor necrosis factor-α and γ-interferon in preneuronal cells

Tumor necrosis factor-α (TNF-α) and γ-interferon (IFN-γ) cooperate during a variety of biological responses and ultimately synergistically enhance the expression of genes involved in immune and inflammatory responses. Recently, we demonstrated that IFN-γ can significantly potentiate TNF-α-induced nuclear factor (NF)-κB nuclear translocation in neuronal derived and endothelial cell lines. The mechanism by which these two cytokines exert their synergistic effect on NF-κB involves the de novo degradation of the NF-κB inhibitor, IκBβ. The double-stranded RNA- dependent kinase PKR is IFN-inducible and has been implicated in the activation of NF-κB; therefore, we examined the possibility that PKR may play a role in the synergistic activation of NF-κB during TNF-α/IFN-γ cotreatment. The PKR inhibitor 2-aminopurine (2-AP) inhibited TNF-α/IFN-γ- induced NF-κB nuclear translocation in neuronal derived cells but not in endothelial cells. The induced degradation of IκBβ, which is normally observed upon TNF-α/IFN-γ cotreatment, was blocked completely by 2-AP in neuronal derived cells. Also, 2-AP treatment or overexpression of a catalytically inactive PKR inhibited the TNF-α/IFN-γ-induced synergistic activation of κB-dependent gene expression. Our results suggest that the signal generated by IFN-γ, during TNF-α/IFN-γ cotreatment may require PKR to elicit enhanced NF-κB activity, and this signal may affect the stability of the IκBβ protein

Oncoprotein suppression of tumor necrosis factor-induced NFκB activation is independent of Raf-controlled pathways

Extensive data indicate that the transcription factor NFκB is activated by signals downstream of oncoproteins such as Ras or breakpoint cluster region (BCR)ABL. Consistent with this, evidence has been presented that NFκB activity is required for Ras and BCR-ABL to transform cells. However, it remains unclear whether these oncoproteins activate a full spectrum of NFκB-dependent gene expression or whether they may augment or interfere with other stimuli that activate NFκB. The data presented here indicate that BCR-ABL expression in 32D myeloid cells or oncogenic Ras expression in murine fibroblasts blocks the ability of tumor necrosis factor (TNF) to activate NFκB. This suppression of NFκB is manifested by an inhibition of TNF-induced inhibitor of NFκB (IKK) activity and NFκB DNA binding potential but not by blocking TNF-induced nuclear accumulation of NFκB/p65. The inhibition of NFκB is not observed in oncogenic Raf-expressing cells and is not fully restored by the suppression of PI3-kinase or MEK pathways. Oncogenic Ras suppresses the ability of TNF to activate the expression of NFκB-dependent genes, such as iNOS (inducible nitric oxide synthase) and RANTES (regulated on activation normal T-cell expressed and secreted). These studies suggest that the ability of Ras and BCRABL to activate NFκB involves an uncharacterized pathway that does not involve classic IKK activity and that suppresses the TNF-induced IKK pathway through a Raf/MEK/Erk-independent mechanism

Optical Spectra of SNR Candidates in NGC 300

We present moderate-resolution (<5A) long-slit optical spectra of 51 nebular objects in the nearby Sculptor Group galaxy NGC 300 obtained with the 2.3 meter Advanced Technology Telescope at Siding Spring Observatory, Australia. Adopting the criterion of [SII]/Ha>=0.4 to confirm supernova remnants (SNRs) from optical spectra, we find that of 28 objects previously proposed as SNRs from optical observations, 22 meet this criterion with six showing [SII]/Ha of less than 0.4. Of 27 objects suggested as SNRs from radio data, four are associated with the 28 previously proposed SNRs. Of these four, three (included in the 22 above) meet the criterion. In all, 22 of the 51 nebular objects meet the [SII]/Ha criterion as SNRs while the nature of the remaining 29 objects remains undetermined by these observations.Comment: Accepted for publication in Astrophysics & Space Scienc

Milk for a girl and bananas for a boy:recipes and reasons for sex-preference practices in a British Internet forum

Using postings from an internet forum, this paper explores the ways in which some women try to influence the sex of a future child. The extensive reproductive work involved give an indication of the women’s commitment to being able to choose a particular sex; in this case a preference for girls rather than boys. The findings revealed stereotypical views of masculinity and femininity at the heart of the preference. The presumption of fixed gendered identities helped to frame this desire as ‘natural,’ lessen the threat to maternal identities, and reinforce the logic of ‘choice,’ and support their reproductive work practices

Early phonological and sociocognitive skills as predictors of later language and social communication outcomes

Background:  Previous studies of outcome for children with early language delay have focused on measures of early language as predictors of language outcome. This study investigates whether very early processing skills (VEPS) known to underpin language development will be better predictors of specific language and social communication outcomes than measures of language itself. Method:  Participants were 163 children referred to clinical services with concerns about language at 2;6–3;6 years and followed up at 4–5 years. Novel assessments of phonological and sociocognitive processing were administered at Time 1 (T1), together with a standardised test of receptive and expressive language, and parental report of expressive vocabulary. The language test was re-administered at Time 2 (T2), together with assessments of morphosyntax and parental reports of social communication. Results:  Intercorrelations at and between T1 and T2 were high, and dissociations were rare. Ordinal regressions were run, entering predictors singly and simultaneously. With the exception of the phonological task, every early measure on its own was significantly predictive of most outcomes, and receptive language was the strongest all-round predictor. Results of simultaneous entry, controlling for the effect of other predictors, showed that early language was the strongest predictor of general language outcome, but early phonology was the strongest predictor of a measure of morphosyntax, and early sociocognition the strongest predictor of social communication. Conclusions:  Language measures which draw on a wide range of skills were the strongest overall predictors of general language outcomes. However, our VEPS measures were stronger predictors of specific outcomes. The clinical and theoretical implications of these findings are discussed

Supermassive Binaries and Extragalactic Jets

Some quasars show Doppler shifted broad emission line peaks. I give new statistics of the occurrence of these peaks and show that, while the most spectacular cases are in quasars with strong radio jets inclined to the line of sight, they are also almost as common in radio-quiet quasars. Theories of the origin of the peaks are reviewed and it is argued that the displaced peaks are most likely produced by the supermassive binary model. The separations of the peaks in the 3C 390.3-type objects are consistent with orientation-dependent "unified models" of quasar activity. If the supermassive binary model is correct, all members of "the jet set" (astrophysical objects showing jets) could be binaries.Comment: 31 pages, PostScript, missing figure is in ApJ 464, L105 (see http://www.aas.org/ApJ/v464n2/5736/5736.html

Determining the impact of an artificial intelligence tool on the management of pulmonary nodules detected incidentally on CT (DOLCE) study protocol: a prospective, non-interventional multicentre UK study.

Introduction In a small percentage of patients, pulmonary nodules found on CT scans are early lung cancers. Lung cancer detected at an early stage has a much better prognosis. The British Thoracic Society guideline on managing pulmonary nodules recommends using multivariable malignancy risk prediction models to assist in management. While these guidelines seem to be effective in clinical practice, recent data suggest that artificial intelligence (AI)-based malignant-nodule prediction solutions might outperform existing models. Methods and analysis This study is a prospective, observational multicentre study to assess the clinical utility of an AI-assisted CT-based lung cancer prediction tool (LCP) for managing incidental solid and part solid pulmonary nodule patients vs standard care. Two thousand patients will be recruited from 12 different UK hospitals. The primary outcome is the difference between standard care and LCP-guided care in terms of the rate of benign nodules and patients with cancer discharged straight after the assessment of the baseline CT scan. Secondary outcomes investigate adherence to clinical guidelines, other measures of changes to clinical management, patient outcomes and cost-effectiveness. Ethics and dissemination This study has been reviewed and given a favourable opinion by the South Central—Oxford C Research Ethics Committee in UK (REC reference number: 22/SC/0142). Study results will be available publicly following peer-reviewed publication in open-access journals. A patient and public involvement group workshop is planned before the study results are available to discuss best methods to disseminate the results. Study results will also be fed back to participating organisations to inform training and procurement activities. Trial registration number NCT05389774